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838 Cards in this Set
- Front
- Back
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Bone marrow and all blood corpuscles
Liver Spleen Lymph Nodes Thymus |
Tissues of the Hematopoietic System
These tissues are embryologically related Hematologic disorders often affect all of these tissues (lymphoma, leukemia, hemochromatosis, myelofibrosis). |
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Hollow space of bones filled with all blood cell precursors
Infant: Activity in all bones from skull to feet. Cellularity is 100%. Cellularity decreases by 10% with each decade of life until age 70-80, when cellularity remains at 20-30% |
Bone Marrow
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Normal myeloid to erythroid ratio is 3:1
Controlled growth with increase in activity based upon demand Infection Low tissue oxygenation Activity is decreased when demand is met Mediated by growth factors Increase in production results in greater numbers of mature cells and some young cells, but no immature cells are released. |
Bone Marrow: Normal Production
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Bone Marrow - What is normal production?
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2.4 billion white blood cells
10 billion red blood cells 175 billion platelets |
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Stromal cells
Fibroblasts Fat cells Endothelial cells Adhesion molecules Growth factors |
Stromal Matrix
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Sites of Embryonic Hematopoiesis
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First 6 weeks --Yolk sac
6-18 weeks -- Liver 18-30 weeks -- Liver and spleen 30 weeks to birth to 8 week old infant -- Liver, spleen, and bone marrow >10 weeks -- Bone marrow only |
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Cell size
-Decreases with maturation Nuclei -Always round -Chromatin condenses with maturation -N:C ratio decreases with maturation Cytoplasm -Basophilia: immaturity -Magenta: as maturation occurs and hemoglobin accumulates -No granules |
Erythropoiesis
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No nucleus
No cytoplasmic organelles No protein or lipid synthesis No oxidative phosphorylation Picks up oxygen from the lungs Delivers oxygen to the tissues Picks up CO2 from the tissues Delivers CO2 to the lungs |
Red Cells: Function
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Biconcave disk shape large surface area good for gas exchange
Highly deformable; allows changes in size -8 microns in a large vein to 2 microns in a capillary Red cell function is essential for the function of the rest of the body |
Red Cell: Shape
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Polys
PMN (Polymorphonuclear neutrophil) Seg (segmented neutrophil) 3 lobes separated by a thread |
Neutrophil
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Myeloblast
Promyelocyte Myelocyte Metamyelocyte Band Neutrophil |
Stages of Neutrophil maturation
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Granules contain enzymes involved in oxidative and non-oxidative killing of bacteria and fungi
-Particularly bacteria Circulate in the blood and tumble along endothelium, loosely adhering -Circulating pool -Marginating pool |
Neutrophil - function
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Bi-lobed nucleus
Eosinophilic granules Parasitic infections Allergic reactions Vasculitis Some hematologic malignancies |
Eosinophils
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(Mast cell)
Basophilic granules Release histamine IgE Increased in myeloproliferative disorders |
Basophils
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Circulate in the bloodstream for only 24 hours
Then go into tissues to become macrophages Ingest fungi, mycobacteria, and play a role in battling pyogenic bacteria |
Monocyts
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No morphologically distinct stages of maturation
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Lymphoblast
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Intricate acquisition and loss of surface antigens takes place as cells mature and differentiate in to B, T, and NK cells
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Lymphocyte
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Produced in the bone marrow
Migrate to other sites of the body to mature and acquire specific properties T cells (thymus): helper and suppressor cells B cells (bursa of Fabricius in birds): produce antibodies against foreign antigens (plasma cells) NK (natural killer) cells: large granular lymphocytes |
Lymphocyte: Development
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Very little cytoplasm
Nucleus is about the same size as a red blood cell Life span is years Peripheral blood: 70% T cells 25% B cells < 5% NK cells no plasma cells |
Lymphocyte
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CD10
CD19 CD20 CD79a sIg kappa/lambda |
B-Cell Antigens
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CD16
CD56 |
NK-cell antigens
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CD3
CD4 CD5 CD7 CD8 |
T-cell antigens
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Megakaryocytes are multinucleated
Largest cells in the body Do not circulate Filtered out by lung microvasculature No intermediate maturation stages |
Platelets brak off from megakaryocytes
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Filters blood
Examines blood cells and destroys injured erythrocytes and cells that have been sensitized by IgG and complement Activates complement Extremely important in helping clear encapsulated organisms from the blood -Streptococcus pneumoniae -Haemophilus influenzae -Neisseria meningitidis |
Spleen - function
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During periods of extensive red cell damage and splenic activity, blood may enter the spleen but be unable to exit (sequestration)
~10% of the population will have an accessory spleen |
Spleen - function
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Spleen:
Lymphocytes around arterioles |
White pulp
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Spleen:
splenic sinusoids |
Red pulp
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2 alpha chains (pink)
2 beta chains (yellow) Aka: non-alpha chains 4 heme molecules (blue balls) |
The hemoglobin molecule
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A ring structure called protoporphyrin IX
Has an atom of divalent/ferrous iron (Fe+2) attached One group per chain Each combines reversibly with one molecule of oxygen What makes blood red |
Heme
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2 pairs of polypeptide chains (4 total)
Each chain has ~140 amino acids Alterations in the amino acid sequences results in different globin chains |
Globin chains
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Chromosome 16
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The alpha globin genes
Humans have two copies of the a and g genes per chromatid for a total of 4 genes per person |
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Chromosome 11
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The beta, delta, gamma glogin genes
Humans have two copies of the a and g genes per chromatid for a total of 4 genes per person |
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Genes get transcribed to mRNA
mRNA gets translated to a globin polypeptide chain and then released into the cytoplasm from the ribosomes Each globin chain binds with a heme molecule Heterodimers are formed between an alpha chain and a non-alpha chain Two heterodimers combine to form tetramers hemoglobin |
Hemoglobin formation
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2 alpha chains and 2 beta chains
The main form of hemoglobin after birth |
Hemoglobin A
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2 alpha chains and 2 delta chains
Delta chains are not expressed efficiently Normally only a small amount after birth |
Hemoglobin A2
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2 alpha chains and 2 gamma chains
In adults, this is only in a few RBCs, called F cells |
Hemoglobin F
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Have different mobilities in electrophoresis
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Hemoglobin
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Can also undergo post-translational modification
Reactions can occur with various sugars and the amino groups of the globin chains -Results in glycated hemoglobin -Monitor this to monitor diabetic patients |
Hemoglobin A
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Bind oxygen in the lungs
Transport it to tissues Unload oxygen in the tissues |
Hemoglobin Function
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affinity for oxygen depends on the partial pressure of oxygen (pO2)
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Hemoglobin
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Sigmoid shaped
At low oxygen tension, Hb has a low affinity for oxygen At high oxygen tension, Hb has a high affinity for oxygen As each heme group binds oxygen, the avidity increases |
Hemoglobin - obtaining oxygen
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2,3-bisphosphoglycerate (2,3-BPG)
Normally found in RBCs With high 2,3-BPG, Hb molecule goes from relaxed and oxygenated to tense and deoxygenated Need a higher pO2 to saturate the same amount of Hb |
Shifts curve to right
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Bohr effect: a shift of the curve as a result of pH
Low pH (acidic environment) |
Shifts curve to right
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Has increased oxygen affinity compared to Hb A
Extracts oxygen from maternal circulation Doesn’t release oxygen as easily as Hb A; so fetus needs more Hb to adequately oxygenate tissues |
Hemoglobin F
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Oxygen delivery process does not require energy consumption
Mature erythrocyte does not have a nucleus, mitochondria, and other organelles Can’t synthesize proteins or lipids Can’t undergo oxidative phosphorylation (which forms ATP, which generates energy) |
RBC Metabolism
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So how does the RBC generate energy for the metabolic pathways that it needs for survival?
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Embden-Meyerhof pathway
Anaerobic glycolytic pathway Glucose enters RBC through facilitated membrane transport system Glucose gets metabolized to lactic acid Requires 2 molecules of ATP per glucose molecule Generates up to 4 molecules of ATP per glucose molecule |
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Hexose monophosphate shunt (aerobic glycolysis)
Without (enzyme), no NADPH is formed Without NADPH, glutathione metabolism doesn’t occur – H2O2 doesn’t get converted to water Results in oxidative damage (and RBCs carry large amounts of oxygen) |
G6PD deficiency is the most common enzyme deficiency in the world
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Obtaining blood samples
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Venipuncture, port, PICC (peripherally inserted central catheter)
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Blood collections
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Different tubes have different additives
Some allow blood to clot, others don’t, etc |
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Automated
Results in minutes Quantity of each major cell type Differential: -Percentage of different types of white cells “Flags” abnormal values |
Complete Blood Count (CBC)
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Red cells are highest
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At birth (RBC, Hb, Hct)
-30% are Hb F Number of red cells remains stable until puberty, then male values exceed female Number of red cells does not decrease as part of aging |
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Value is measured in grams per deciliter
Tells you how much hemoglobin (in grams) is in one deciliter of blood |
Hemoglobin
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Value is a percentage
Tells you the volume of packed red blood cells in a given volume of whole blood |
Hematocrit
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tells average weight of hemoglobin per cell
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MCH - Mean corpuscular hemoglobin
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Tells average concentration of hemoglobin per cell
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MCHC - Mean corpuscular hemoglobin concentration
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Tells us the size of the red blood cell
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MCV - Mean corpuscular volume
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Tells us the how varied the sizes of the red cells are
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RDW - Red cell distribution width
If RDW is normal, all cells are similar size (whether they’re all big or all small) If RDW is increased, cell size is NOT known |
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Larger than mature RBC; with less central pallor
Not part of CBC; need to order separately |
Reticulocyte count
Measures the percentage of reticulocytes circulating in the blood Methylene blue stain identifies precipitated RNA in young cells |
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Order of percentage of all white cells
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Neutrophils (segs and bands)
Lymphs Monos Eos Basos Others |
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Too few platelets
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Thrombocytopenia
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Too many platelets
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Thrombocytosis
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Low MCH
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Hypochromia
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Iron deficiency anemia
Hemoglobinopathies (sickle cell, thalassemias, etc) Anemia of chronic disease Copper deficiency Lead poisoning (decreased heme synthesis) |
Low MCV - microcytic anemia
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Punctate basophilic precipitation of undegraded RNA
-A sign of ineffective hematopoiesis -Seen in lead toxicity |
Basophilic stippling
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Result of redundant red cell membrane/ decreased cell volume
Hemoglobinopathies/thalassemias Iron deficiency anemia Drug-induced hemolytic anemia Liver disease |
Target cells - also called sombrero or Mexican hat cells
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disseminated intravascular coagulation, TTP
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Schistocyte (helmet cell)
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Liver disease, artifact
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acanthocyte
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French for “rolls” as in rolls or stacks of coins
RBCs abnormally adhere to each other due to increased immunoglobulin production -Multiple myeloma, plasma cell leukemia, infection -Artifact |
Rouleaux formation
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Remnants of nuclear chromatin normally removed by the spleen
Seen in surgically or functionally asplenic patients and patients on dialysis |
Howell Jolly Bodies
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No central pallor
Seen in hereditary spherocytosis |
Spherocytes
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Bone marrow biopsy and aspirate - where?
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Posterior, superior iliac crest (pelvis) or breastbone
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Needle/liquid withdrawal
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Aspirate
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Pulled out like soil sample
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Core biopsy
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Aspirate sampling
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Flow cytometry
FISH Cytogenetics Microscope |
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Core sampling
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Look at under microscope
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Sodium
Potassium Chloride CO2 BUN Creatinine Glucose Calcium |
Basic metabolic panel
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Sodium
Potassium Chloride CO2 BUN Creatinine Glucose Calcium Total Protein Albumin AST ALT Alkaline Phosphatase Total Bilirubin |
Comprehensive metabolic panel
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Use to separate and quantitate serum protein including hemoglobin
Separates different proteins based upon their physical and chemical properties Mobility of protein depends on molecular weight and charge |
Electrophoresis
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Serum Proteins:
Albumin (main component) Microglobulins: -Alpha 1 (alpha 1 antitrypsin), Alpha 2 -Beta 1, Beta 2 (predicts change in immunoglobulin production; used to assess disease activity of multiple myeloma) -mmunoglobulins: IgG, M, A, >>>E, D |
Electrophoresis - SPEP
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Red cells are lysed, Hb is separated and applied to a gel. A current is applied.
Different hemoglobins migrate at different speeds across the gel |
Electrophoresis - Hemoglobin
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RBC mixed with reducing agent and observed under microscope for characteristic change in shape.
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Sickle cell "screen)
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takes place within macrophages outside vascular stream
-Physiological conditions -Low-grade chronic hemolytic states |
Extravascular hemolysis
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major red cell lysis occurs within the circulation
-15% of Hb catabolism follows this pathway -Transfusion reactions |
Intravascular hemolysis
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Primary site of RBC destruction
In patients without organ macrophages of other organs assume this function -Liver -Bone marrow |
Spleen
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Cells may be retained if:
Shape is less adaptable (spherocytes) Membrane is less flexible (older cells) There are inclusions or particles stuck to the membrane -Heinz bodies (denatured Hb) -Howell-Jolly bodies (nuclear remnants) |
Spleen
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Hemoglobin (Hb) binding glycoprotein made in the liver
It is an acute phase reactant Absent in the newborn |
Haptoglobin (Hp)
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Low or absent plasma Hp is an indicator of
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recent or ongoing intravascular hemolysis
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Rapid saturation of Hp and rapid clerance of HB/Hp complex during
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Massive intravascular hemolysis
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degraded into a.a for recycling
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Globin and Hp
The Hp/Hb complex is internalized by the hepatocyte |
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Catabolized to bilirubin and iron
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Heme
The Hp/Hb complex is internalized by the hepatocyte |
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Free excess of heme is bound to (2 things) and taken by hepatic receptors for catabolism
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Hemopexin and methemalbumin
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Hb appears in the urine (haemoglobinuria)
-Can precipitate and cause ARF |
Massive intravascular hemolysis
Some free Hb is reabsorbed into cells of the proximal tubules |
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ferritin accumulates in the tubular cells
-Hemosiderin via Prussian blue staining |
Low chronic intravascular hemolysis
Some free Hb is reabsorbed into cells of the proximal tubules |
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Shorter life-span of erythrocytes
Compensatory increase in erythrocyte production (reticulocytosis) |
Hemolytic anemia
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Intrinsic red cell abnormalities
Extrinsic causes of hemolysis Immune mediated hemolysis Non-immune mediated hemolysis |
Hemolytic anemia
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-Red Cell Membrane Disorders
Hereditary Spherocytosis Hereditary Elliptocytosis -Red Cell Enzyme Disorders G6PD Deficiency Pyruvate Kinase Deficiency -Hemoglobin Disorders Unstable Hemoglobins Methemoglobinemia Thalassemia Sickle Cell Disease |
Intrinsic red cell abnormalities
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-Immune mediated hemolysis
Warm Reactive Autoimmune Hemolytic Anemia (AIHA) Cold Agglutinin Disease Paroxysmal Cold Hemoglobinuria (PCH) -Schistocytic hemolytic anemia: Mechanical destruction of RBC as they travel Hemangiomas (Kasabach-Merritt syndrome) Prosthetic heart valves Microangiopathic hemolytic anemia (MAHA) --TTP --HUS |
Extrinsic Causes of Hemolysis
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Pallor
Icterus, jaundice Fatigue Splenomegaly Gallstones Cholecystitis Dark urine May present with parvovirus associated aplasia Family history |
Clinical Presentation of Hemolytic Anemia
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Increased Nutritional Requirements of Chronic Hemolysis
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Greatest requirement is for folic acid and lowest body stores (10 day storage)
Amino acid to make globin chains (normal nutritional status) B12 (10 years storage) No increase Fe requirement since it is “recycled” and stored in bone marrow |
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Purpose: to identify the presence of immunoglobulins or complement on the surface of the red cells.
Sample from the patient is mixed with reagent that has antibodies against human immunoglobulins and complement. If agglutination forms, the test is +. |
Direct Coombs (Direct Antiglobulin Test)
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If the test is positive, further tests are done.
Three main patterns: IgG only on surface of RBC IgG and C3complement C3 only on surface cells, antibody on cells may be IgM |
Direct Coombs Test
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Testing patient’s serum for antibodies
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Indirect Coombs
Normal to have antibody to major blood groups but not to minor blood groups unless prior transfusion (or through exposure due to baby’s blood during pregnancy or delivery) |
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IgG mediated
Extravascular clearance primarily via the reticuloendothelial system (spleen) May be idiopathic or associated with SLE, lymphoid malignancies, immunodeficiency |
Warm Reactive Autoimmune Hemolytic Anemia (AIHA)
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IgM mediated
Can be associated with Mycoplasma, EBV Intravascular lysis |
Cold Agglutinin Disease
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Acute illness, often after viral URI
-Inciting infections include measles, mumps, varicella, syphilis, Mycoplasma Caused by cold reactive IgG (Donath Landsteiner Antibody) Intravascular hemolytic anemia |
Paroxysmal Cold Hemoglobinuria (PCH)
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Management of hemolytic anemia
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Observe growth, development
Determine baseline hemoglobin Follow for splenomegaly Educate family regarding risks for gallstones, parvovirus B19 aplastic crisis Folate supplementation Erythrocyte transfusions, intermittent vs chronic Splenectomy Cholecystectomy if symptomatic gallstones |
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Whole Blood Phlebotomy
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Packed Red Blood Cells
Platelets Plasma |
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Apheresis
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Same as phlebotomy (except we can collect more)
White Blood Cells -Granulocytes, Monocytes, T Cells, Stem Cells |
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Donation of 1 unit of whole blood (WB) yields:
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1 unit of packed red blood cells (PRBC)
1 unit of plasma 1 unit of random donor platelets |
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Transfuse (1 or 2 units) to treat anemia
Hemoglobin (Hb) usually < 8 g/dL Stored in the refrigerator |
PRBC
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Dose
-1 unit will increase the Hb by 1 g/dL -Increase Hematocrit (Hct) by 3% Pediatric -10 mL/kg will increase Hb by 2 g/dL -Increase Hct by 6% |
PRBC
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replacement of 1 total blood volume (usually 10 units of PRBC) in less than 24 hours
May be complicated by dilutional coagulopathy, hypocalcemia, hyperkalemia, arrhythmia |
Massive transfusion
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PRBC can be frozen
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For ten years
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Thrombocytopenia requiring platelet tranfusion
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<20,000/microliter
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Plasma frozen within 8 hours of phlebotomy
Will have normal levels of Factor VIII Factor VIII levels degrade over several days Factor VIII levels are 50-80% normal by 5 days |
Fresh Frozen Plasma (FFP)
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Plasma frozen within 24 hours of phlebotomy
Used for all plasma orders at Wake Forest Now used interchangeably with FFP |
24 hour plasma
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Transfuse (2 units) to treat clotting factor deficiencies
Prolonged Prothrombin time (PT) and activated partial thromboplastin time (PTT) Frozen – takes about 30 min to thaw |
Plasma
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Transfused (5 or 10 units) usually to replace fibrinogen
and provides a more concentrated form of: -Fibrinogen -Factor VIII -von Willebrand Factor -Factor XIII -Fibronectin Used to treat bleeding from deficiency of these factors. -Safer, purified, virus inactivated or recombinant concentrates are now available for Hemophilia A and von Willebrand’s Disease -It is NOT concentrated FFP |
Cryoprecipitated AHF
(Anti-Hemophilic Factor) (Cryo) |
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present on all human red blood cells. Think of as the “O” antigen.
Is the precursor of the A & B antigens |
RED BLOOD CELLS (“H” Antigen) Group O
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Red blood cells "A" antigen
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Galnac (added on top of the "H" antigen)
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Red blood cell "B" antigen
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Gal (added on top of the "H" antigen)
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Anti-B antibodies
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Group A person
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Anti-A antibodies
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Group B person
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No ABO antibodies
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Group AB person
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Anti-A and Anti-B antibodies
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Group O (H antigen) person
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A person needs an exposure to foreign, non-self red blood cells to have an antibody response
-Pregnancy -Blood transfusion -?? Sharing needles ?? |
The D antigen
Antibodies to D antigen are NOT “naturally” occurring |
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test the PATIENT’S red cells for A or B antigen
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forward type
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test the PATIENT’S serum for the expected antibody
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Reverse type
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test the red cells for the D antigen
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Rh type
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check the PATIENT’S serum for other antibodies against red cell antigens
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Other than ABO – such as Kell, Duffy, Kidd
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Mix the PATIENT’S serum with a sample of DONOR red cells from the exact unit that we wish to transfuse
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Crossmatch
If the red cells and serum mixture clumps, then the unit is INCOMPATIBLE The endpoint of most blood bank tests is AGGLUTINATION... “clumping” |
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Used to evaluate hemolytic transfusion reactions or autoimmune hemolytic anemia
IgG or C3d |
The Direct Antiglobulin Test (DAT) or Direct Coombs Test
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Mother = Rh neg
Fetus = Rh pos Fetal red cells enter maternal circulation Mother synthesizes Anti-D Anti-D crosses placenta and hemolyzes fetal red cells |
Hemolytic Disease of the Newborn (HDN)
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Anemia with possible organ failure, edema (Hydrops), jaundice
Cardiac failure and Liver failure +DAT Mother: High titer of Anti-D Other antibodies to red cells can cause hemolytic disease of the newborn Bilirubin & Bile Pigments in the amniotic fluid Peripheral smear of baby -Spherocytes -Nucleated red cells |
Hemolytic Disease of the Newborn (HDN)
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Which is more common for bacterial/septic transfusion reactions - platelets or RBCs?
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Platelets b/c not refrigerated
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Acute hemolytic
Transfusion-related acute lung injury (TRALI) Septic (Bacterial contamination of the product) Anaphylaxis |
Life Threatening - Rare transfusion reactions
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Febrile non-hemolytic
Urticarial (mild allergic) Circulatory overload |
More common - benign transfusion reactions
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Most common RBC reaction
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Hemolytic
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Most common platelet reaction
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Septic
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Most common plasma reaction
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Transfusion-related acute lung injury (TRALI)
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-Signs and Symptoms
Fever and chills – Most common Renal failure DIC Back pain -Laboratory + DAT Hemoglobinemia Hemoglobinuria INCREASED: LDH ; Bilirubin DECREASED: Hemoglobin / Hematocrit ; Haptoglobin Peripheral Smear Schistocytes or Spherocytes |
Hemolytic transfusion reactions
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Trying to reverse effects of hemolytic transfusion reaction
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Early recognition & stopping the transfusion.
Fluid & blood pressure support if needed. Prevent renal failure / maintain urine output Intravenous fluids, diuretics, and renal dose dopamine if necessary |
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What is blood tested for?
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HIV
HCV Bacteria in platelets West Nile Virus HBV HTLV Syphilis Chagas Disease |
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Now a regulatory requirement
Why does the patient need a transfusion? There is no other alternative therapy Risks of transfusion Infectious diseases HIV, Hepatitis, West Nile virus, many more... Transfusion reactions Administrative errors Rare fatal reactions |
Informed consent
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Occurs after extrusion of nucleus from orthochromic normoblast
Remains in marrow for approx 3 days Released into circulation – remodeled with loss of water and membrane Normal are macrocytic |
Reticulocytes
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Reticulocyte shift with anemia
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Normal (45% hematocrit) - 3.5 days in bone marrow and 1.0 days in blood
When hematocrit drops, reticulocytes stay in bone marrow for a shorter period of time and spend more time in blood |
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Mechanism unknown
Acetaldehyde -can induce membrane changes -Interferes with cellular division |
Alcohol as a cause of macrocytic anemia
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May be caused by increased lipid deposition on red cell membranes
Target Cells |
Liver disease and macrocytosis
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Autoimmune thyroiditis associated with antiparietal (think about HCl production in the stomach and the ability to convert protein to absorbable material) cell antibodies
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Thyroid disease and macrocytosis
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Artifacts that can occur to normal sized RBCs
Clumps of RBCs counted as single cells by automated cell counters |
Spurious macrocytosis
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National Cancer Institute definition: A group of diseases in which the bone marrow does not make enough healthy blood cells. Also called preleukemia and smoldering leukemia.
Hypolobulated or hypogranular neutrophils Large and/or abnormally granulated platelets Monocytosis Occasional blast forms |
Myelodysplastic Syndromes
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Pronounced reduction in the number of erythrocytes, all types of leukocytes, and the blood platelets in the circulating blood.
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Pancytopenia
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Anemia, often pancytopenia, with macrocytic red blood cells and hypersegmented neutrophils due to an impairment in DNA synthesis
Inadequate conversion of deoxyuridylate to thymidylate Slows DNA synthesis Delayed nuclear maturation Nuclear/cytoplasmic dyssynchrony (ie, immature nucleus/mature cytoplasm) |
Megaloblastic anemia
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Folate deficiency
Cobalamin deficiency Drugs -Inhibit absorption of B12 or folate -Inhibit enzymes required for DNA synthesis |
Interference with DNA synthesis
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Characterized by defect in DNA synthesis resulting in unbalanced cell growth and impaired division
Immature-appearing nucleus, but mature cytoplasm, and large cells Most common causes are B12 and folate deficiency |
Megalobalstic Anemias
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Sources of B12
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Fish, eggs, poultry
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Sources of folate
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Fortified cereals, beef liver, cowpeas, spinach
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Cobalamin absorption defect in stomach
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Pernicious anemia (lack of IF)
Defect in IF Partial or total gastrectomy Gastric bypass Atrophic gastritis Acid-blocking drugs |
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Cobalamin absorption defect in jejunum
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Bacterial overgrowth
Parasites Sprue |
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Cobalamin absorption defect in ileum
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Ileal resection
Crohn's disease Imerslund-Grasbeck disease Cbl-F disease |
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Cobalamin absorption defect in blood vessel
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TCII deficiency
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Cobalamin absorption defect due to pancreas
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Chronic pancreatitis
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Intake of cobalamin strictly through food
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Strict vegetarianism w/o supplementation
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B12 deficiency and MMA and homocysteine levels
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MMA high
Homocysteine high |
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Folate deficiency and MMA and homocysteine
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MMA - no
Homocysteine - high |
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A stage of cellular necrosis in which the fragments of the nucleus fragments and its chromatin are distributed irregularly throughout the cytoplasm.
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Nuclear-cytoplasmic dyssynchrony
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-Peripheral blood
Hypersegmented neutrophils Oval macrocytosis with or without anemia Thrombocytopenia and/or leukopenia with immature forms Basophilic stippling, leukoerythroblastic changes -Bone marrow Hypercellular Giant bands and metamyelocytes Nuclear-cytoplasmic dyssynchrony Open and immature nuclear chromatin pattern Karyorrhexis Blood chemistry -increased indirect bilirubin -increased lactate dehydrogenase |
Hematologic abnormalities in Cobalamin or Folate deficiency
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Karyorrhexis
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Fragmentation of the nucleus whereby its chromatin is distributed irregularly throughout the cytoplasm; a stage of necrosis usually followed by karyolysis.
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Considerable variation in the size of cells that are normally uniform, especially with reference to red blood cells.
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Anisocytosis
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Characteristic hematologic abnormalities seen in megaloblastic anemia
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A, Macro-ovalocytes and marked anisocytosis are seen under low and high power. B, A hypersegmented neutrophil with at least six lobes. C, Megaloblastic pronormoblast (left) and megaloblastic polychromatophilic normoblast (right). D, Megaloblastic “giant” metamyelocyte (left) and band (right).
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All proliferating cells exhibit (phrase), including epithelial cells lining the gastrointestinal tract (buccal mucosa, tongue, small intestine), cervix, vagina, and uterus.
However, such changes are most striking in the blood and bone marrow. |
Megaloblastosis
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Other clinical manifestations:
Glossitis Secondary malabsorption caused by megaloblastic GI changes Weight loss or growth failure Infertility Thrombosis Hyperpigmentation Immune deficiency |
Cobalamin and Folate Deficiency
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causes neuropsychiatric manifestations:
Peripheral neuropathies Dorsal column involvement (loss of position and vibratory sense, ataxia) Subacute combined degeneration of spinal cord Psychiatric symptoms (dementia, psychosis) |
B12 deficiency
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Treatment of B12 deficiency
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Parenteral 1000 micrograms/day for 1 week and and then 1000 micrograms/wk for 1 month; then 1000 micrograms/month for life for PA
Oral - 1000 micrograms/day for 1 month and then 125-500 micrograms/day for intake deficiency or 1000 micrograms/day for Pa |
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may normalize MCV and Hgb but allow neurologic manifestions to persist
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Folate repletion without B12 repletion
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Part 1: Give radioactive cobalamin by mouth. After 1 hour, give injection of unlabelled cobalamin by injection (“flushing dose”) to saturate plasma B12 binders so that labeled cobalamin will not bind but be excreted via the kidney
An individual with pernicious anemia would absorb little or none of the oral B12 since these patients lack intrinsic factor. The amount of radiolabeled B12 recovered in the urine would be less than normal. Part 2: Give exogenous intrinsic factor with the radiolabeled cobalamin. In a patient with pernicious anemia, this should correct the absorption and increase the urinary excretion into the normal range. If still abnormal, then the small intestine can’t absorb the B12-IF complex |
Schilling Test – measures cobalamin absorption
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Schilling Test Results for B12
1. Prolonged inadequate intake of B12 2. Absent IF (PA) 3. Small-bowel disease interfering with absorption 4. Bacterial competition for B12 |
With IF Without IF
1. Normal Normal 2. Abnormal Normal 3. Abnormal Abnormal 4. Abnormal Abnormal |
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Anti-parietal cell antibodies
Anti-intrinsic factor antibodies Low serum pepsinogen I High serum gastrin Schilling test, stage 1 and 2 Pentagastrin-resistant achlorhydria Endoscopy with biopsy |
Diagnostic tests for Pernicious Anemia
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Diet lacking fruits and vegetables
Alcoholism Sprue, Crohn's disease and others Hemodialysis Increased cellular proliferation (pregnancy, skin diseae, hemolysis, malignancies) Drugs (antifolates and anticonvulsants) |
Cause of folate deficiency
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A reduction in oxygen carryng capacity resulting in decreased tissue oxygenation
Measured as a decrease in RBC, Hgb or Hct |
Anemia
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Fatigue
Dyspnea Palpitations Headache Dizziness Decreased Exercise or Work tolerance Decreased Concentration |
Symptoms of Anemia (impaired tissue oxygenation)
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Bleeding site(s)
Stools + blood |
Blood loss anemia
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Jaundice
Splenomegaly Maxillary hyperplasia |
Hemolysis or dyserythropoiesis
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Excessive milk intake
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Iron deficiency
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Pagophagia
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Iron deficiency
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Pica
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Iron deficiency
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Neonatal jaundice
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Hemolysis
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Splenectomy/Cholecystectomy
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Hemolysis
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Abdominal Surgery (ileal resection)
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Vitamin B12 deficiency
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Jaundice
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Hemolysis
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Splenomegaly
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Hemolysis
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Maxillary hyperplasia/frontal "bossing"
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Hemolysis
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Koilonychia (spooning of nails)
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Iron deficiency
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Hepato-splenomegaly
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infltrative disorders
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Lab tests used to diagnose and evaluate anemia
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CBC, reticulocyte count, peripheral blood smear
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CBC includes:
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Hgb
RBC MCV RDW HCT MCH MCHC |
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A reduction in the size of red cells (erythrocytes)
Measured as a decrease in the mean cell volume (MCV) of red cells. |
Microcytosis
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associated with defects in DNA synthesis
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Macrocytes
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associated with defects in Hgb synthesis
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Microcytes
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What Can Cause a Microcytic Anemia?
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Decreased Iron Availability
Disordered Heme Synthesis Disordered Globin Synthesis |
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Iron deficiency anemia in infancy in adults
Disorders of iron metabolism congenital / acquired Sideroblastic anemias congenital / acquired Thalassemias Hemoglobinopathies (Hb E) |
Causes of Microcytic Anemias
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LOW Hb
LOW Hct LOW MCV LOWMCH &MCHC HIGH RDW |
CBC IN IRON DEFICIENCY
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-IRON PROFILE:
Serum Iron TIBC / Transferrin % Iron Saturation of TIBC Serum Ferritin -Soluble Transferrin Receptor -Free Erythrocyte Protoporphyrin |
Lab tests in iron deficiency
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TIBC
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Total iron-binding capacity - an indirect method of determining the transferrin level in serum. Transferrin is saturated by the addition of iron to a serum specimen. Excess iron is removed, and the specimen is analyzed for iron content. The result is the total amount of iron that can be bound by transferrin. This result is helpful in differentiating anemias: high TIBC is associated with iron deficiency, low TIBC is associated with excess iron.
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Causes: BLOOD LOSS BLOOD LOSS BLOOD LOSS BLOOD LOSS
usually from large bowel especially males and post-menopausal females |
Iron deficiency in adults; other causes include:
Increased requirements (pregnancy and lactation) Decreased absorption (decreased gastic acidity, small bowel disease) |
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Low birthweight
Perinatal bleeding Low hemoglobin at birth High growth rate Early cow’s milk and solid food intake Frequent tea intake |
Infants at risk for iron deficiency
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CONGENITAL:
X-linked or autosomal recessive MITOCHONDRIAL DISEASE ACQUIRED: DRUGS (isoniazid) TOXINS (lead) NEOPLASTIC (MDS) |
Sideroblastic anemia
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Disorders of globin chain imbalance
Any of the globin chains can be affected Alpha Beta Gamma Delta The globin chains are structurally normal |
Thalassemias
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decreased synthesis of alpha globin chain “new” hemoglobins:
“Barts”-Gamma chain tetramer “H”- Beta chain tetramer Varied clinical features- determined by the number of alpha genes deleted |
Alpha Thalassemias
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Types of alpha thalassemia based on gene deletion
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One gene deleted: Silent Carrier
Two genes deleted: “thalassemia minor” Three genes deleted: hemoglobin “H” disease Four genes deleted: Hydrops fetalis |
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MICROCYTIC HYPOCHROMIC RED CELLS
“TARGET” CELLS PRESENT DECREASED MCV NORMAL RDW MILD ANEMIA |
AlphaThalassemia Trait (thalassemia minor 2 alpha genes deleted)
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MODERATELY SEVERE HEMOLYSIS
ELEVATED RETICULOCYTES RED CELL INCLUSIONS ON SUPRAVITAL STAINING |
HEMOGLOBIN H DISEASE (3 alpha genes deleted)
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Incompatible with life thalassemia
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HYDROPS FETALIS (4 alpha genes deleted)
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DECREASED SYNTHESIS OF BETA CHAINS (usually due to mutations not deletions)
HETEROZYGOTE- (condition) minor (condition trait) HOMOZYGOTE (or compound heterozygote) (condition) major (Cooley’s anemia) |
Beta thalassemia
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MILD MICROCYTIC HYPOCHROMIC ANEMIA.
ELEVATED Hb. A2 AUTOSOMAL DOMINANT Low MCV Normal RDW |
B-THALASSEMIA MINOR
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VERY LOW HEMOGLOBIN
TRANSFUSION DEPENDENT AUTOSOMAL RECESSIVE BONE MARROW TRANSPLANT CAN BE CURATIVE |
B-THALASSEMIA MAJOR
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Maxillary hyperplasia
Hepatomegaly Splenomegaly Marrow hyperplasia "Hair on End" on X-ray |
B-THALASSEMIA MAJOR
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B-CHAIN MUTATION (B26lys..glu)
PREVALENT IN S.E. ASIA MICROCYTIC HYPOCHROMIC INTERACTS WITH B-THALASSEMIA |
Hemoglobin E
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COMPOUND HETEROZYGOTES FOR HEMOGLOBIN E AND BETA THALASSEMIA
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MODERATELY SEVERE ANEMIA
SPLENOMEGALY GROWTH DELAY TRANSFUSION REQUIREMENT |
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Rule of threes
RBC x 3 = Hb x 3 = |
Hb
Hct |
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LOW MCV & NORMAL RDW
LOW MCV & HIGH/NORMAL RBC |
Think thalassemia
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LOW MCV& HIGH RDW
LOW MCV & LOW RBC |
Think iron deficiency
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Mentzer index - MCV/RBC
>13.5 = <11.5 = |
Iron deficiency
Thalassemia trait |
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Decreased Hb/Hct
Other cell lines decreased? Yes |
Consider bone marrow exam
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Decrased Hb/Hct
Other cell lines decreased? No |
Evaluate RBC indices -
microcytic normocytic macrocytic |
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Iron Deficiency Anemia (IDA)
Anemia of Chronic Disease (ACD) Iron excess/sideroblastic states -Hemosiderosis -Hemochromatosis -Sideroblastic anemias -Lead poisoning (Plumbism) Porphyrias - heme synthesis disorders |
Heme synthesis: iron metabolism disorders
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Thalassemias
Hemoglobinopathies: HbC, HbE |
Globin synthesis disorders
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Iron Deficiency
Anemia of chronic disease Thalassemias Sideroblastic anemia |
Microcytic anemias
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Macrocytic Anemia
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Defective DNA synthesis
Asynchrony between nuclear and cytoplasmic maturation Gigantic cells with immature chromatin: megaloblasts Macrocytic-normochromic red cells (macro-ovalocytes) Granulocytes are hypersegmented Megakaryocytes are abnormal resulting in thrombocytopenia |
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Vitamin B12 Deficiency
Folate Deficiency Inherited Megaloblastic Anemias Drug-Induced (dilantin, sulfa, AZT, methotrexate) Other (Alcoholism, Hypothyroidism, Liver Disease, MDS, Reticulocytosis) |
Macrocytic anemias
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Acute hemorrhage
RBC enzyme defects, e.g. G6PD deficiency RBC membrane defects, e.g. Hereditary spherocytosis Bone marrow disorders (aplastic anemia, leukemia) Hemoglobinopathies: HbS Autoimmune hemolytic anemia Anemia of chronic disease |
Normocytic anemias
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MCV formula =
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Hct/RBC
Mean volume of all erythrocytes |
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MCV<80 fL
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Microcytic
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MCV > 100 fL
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Macrocytic
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MCH formula =
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Hb/RBC
Amount of hemoglobin in an average RBC Normal range: 26 - 33 pg |
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MCH > 34
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this is considered to be too high because of macrocytic anemia (thus fitting more hemoglobin)
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MCH < 26
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this is considered too low. The MCH level can be too low because of blood loss over time, too little iron in the body, or microcytic anemia.
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MCHC formula
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Hb/Hct
Normal range: 32-36 g/dL |
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MCHC > 36 g/dL
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Hyperchromic
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MCHC < 32 g/dL
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Hypochromic
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RDW formula =
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Standard deviation RBC volume x10/mean MCV
Measure of anisocytosis – variation/range in cell volume Normal range: 12-16% The MCV can be normal while individual RBCs vary in volume Useful in early nutritional deficiency anemias, e.g. IDA Increased/bimodal distributions: agglutination, fragmentation, transfusions, recently treated nutritional deficiency, reticulocytosis |
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Reticulocytosis
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normally ↑ % in response to anemia
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Reticulocytopenia
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abnormal ↓ % in response to anemia
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soluble protein-iron complex (apoferritin and Fe+3-phosphate core)
Synthesis stimulated by the presence of iron |
Ferritin
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insoluble protein-iron complex
Formed by lysosomal digestion of ferritin |
Hemosiderin
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-Present in food as ferric hydroxide and ferric-protein complexes
Meat and liver is good source of dietary iron Average western diet contains 10-15 mg Daily requirement 1-2 mg per day -5-10% is absorbed in duodenum and jejunum Facilitated by acid and reducing agents (citrates, ascorbate) in Fe+2 form Inhibited by tannins, phytates Increased absorption with demand (pregnancy, growth) and excessive loss due to acute or chronic hemorrhage |
Iron in diet
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Synthesized in liver, serum half-life of 8-10 days
Each molecule binds two iron atoms Normally only about 30% saturated Erythroblasts have transferrin receptors, CD71 |
Transferrin
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-Primary cause of defective heme synthesis
Most common cause of anemia worldwide About 20% of women, 50% of pregnant women; and 3% of men -Etiology is age-related Infants/children – dietary insufficiency Adults – chronic blood loss, malabsorption, menstruation, blood donation, hemoglobinuria, etc. -Clinical Features 1. Insidious, slowly progressive 2. Fatigue, irritability, dizziness, headache, breathlessness 3. Pica – craving/ingestion of unusual substance 4. Impaired neuromuscular activity 5. Brittle, pitted nails 6. Atrophy of lingual papillae, burning/sore mouth 7. Dysphagia, gastritis |
Iron deficiency anemia
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Hematologic Findings:
Hb usually < 8 g/dL Reduced indices (MCV, MCH, MCHC) RDW elevated 3. Reticulocytosis - mild 4. Thrombocytosis – may be twice normal (reactive) 5. BM – erythroid hyperplasia mild/moderate Diagnostic Labs (Fe Studies): 1. Serum Ferritin decreased 2. TIBC increased 3. Saturation transferrin reduced <16% supply to marrow below minimal requirement for heme production 4. Serum transferrin receptors increased 5. BM Fe stores depleted |
iron deficiency anemia: diagnostic approach
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Green leafy vegetables, beans, legumes, whole grains, oranges (heat labile)
Serum normal levels >3.7 ng/mL Liver stores 20 – 70 mg Sufficient for only 3 – 5 months Polyglutamate deconjugated in GI/bile for absorption in jejunum Circulates unbound (5-methyl THF) Requires Vitamin B12 for entry Essential for: Purine/pyrimidine synthesis Methionine synthesis Methylation transfer reactions |
Folate
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Dietary insufficiency
Common in alcoholic, drug addicts Low SE status Chronic liver/kidney disease Increased requirement Pregnancy - supplemented prior to and during pregnancy Cause neural tube defects in utero Infancy Hematologic diseases w/ rapid cellular proliferation, e.g. sickle cell anemia, leukemias Defective absorption, e.g. Tropical/celiac sprue malabsorption Drugs Methotrexate (chemotherapy drug that is a folate antagonist) Alcohol Oral contraceptives Others drug-induced folate deficiency (dilantin, sulfasalazine), |
Mechanisms of Folate deficiency
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synthesized by bacteria, found in meat, fish, dairy (heat stabile)
Normal levels 10-1000pg/mL; Liver stores 3000 – 5000 mg Sufficient for 2-5 years Released by gastric acid Binds to R-binder which is subsequently degraded by pancreatic enzymes Binds to IF Complex adheres to brush border of ileum (pH and Ca dependent) TCI/III delivered to liver TCII delivers to liver, BM Essential for synthesis of: Methionine Succinate |
Vitamin B12
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Dietary lack (vegetarians)
Increased requirement Defective absorption Pernicious Anemia Most common syndrome Gastric parietal cell atrophy: ↓ IF F>>M; disease of late adulthood Severe atrophic gastritis Neurologic problems Gastrectomy Blind loop syndrome: intestinal bacterial overgrowth Fish tapeworm (competes for B12) Other: Crohn’s disease, Zollinger-Ellison, Tropical/celiac sprue, Imerslund Syndrome (familial selective B12 malabsorption), hemodialysis, HIV Rare causes: defective transport, disorders of metabolism |
Vitamin B12 deficiency
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Insidious onset
Moderate to severe fatigue, malaise Lemon-yellow skin Mucosal atrophy: tongue, vagina, GI with pain, malabsorption Neurologic deficits/peripheral neuropathy (methionine loss) Posterior and lateral columns of spinal cord Paresthesias, numbness, tingling, ↓ vibration sense, ataxia, symmetric paralysis CNS deficits Megaloblastic madness (paranoia, depression) |
Macrocytic anemia
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-Moderate to severe anemia
MCV range from 100 – 150 fL MVC > 120fL generally diagnostic, except for drug sulfasalazine MCHC normal Circulating macrocytes, minute RBC fragments, basophilic stippling, Howell-Jolly bodies RDW usually markedly elevated Reticulocytopenia -Hypersegmentation of neutrophils Early sign ≥ 6 nuclear lobes (or significant % with > 5) |
Megaloblastic anemia diagnostic approach
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Bone Marrow:
Hypercellular, with erythroid and myeloid hyperplasia Increased mitoses, apoptosis Large cells, immature nuclei with mature cytoplasm, multinuclearity Giant myelocytes, bizarrely nucleated metamyelocytes WARNING: May be mis-diagnosed as leukemia |
Meagaloblastic anemia diagnostic approach
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Defective DNA synthesis
Asynchrony between nuclear and cytoplasmic maturation Gigantic cells with immature chromatin: Macrocytic-normochromic red cells (macro-ovalocytes) Granulocytes are hypersegmented Megakaryocytes are abnormal resulting in thrombocytopenia |
Morphologic Classification: Macrocytic Anemias
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Vitamin B12 Deficiency
Folate Deficiency Inherited Megaloblastic Anemias Drug-Induced (dilantin, sulfa, AZT, methotrexate) Other (Alcoholism, Hypothyroidism, Liver Disease, MDS, Reticulocytosis) |
Macrocytic Anemias
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Vinca alkaloids
Taxanes interfere with what part of the cell cycle? |
Mitosis
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Anti-metabolites
Epipodophyllotoxins Camptothecins interfere with what part of the cell cycle? |
DNA synthesis
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Alkylating Agents
Anthracyclines interfere with what part of the cell cycle? |
Cycle nonspecific
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More Common:
Cyclophosphamide* (CTX, Cytoxan®) Ifosfamide Platinums -Cisplatin (CDDP) -Carboplatin -Oxaliplatin Nitrosureas -Lomustine* (CCNU) -Carmustine (BCNU) Less Common: Mechlorethamine Melphalan* (Alkeran®) Chlorambucil* (Leukeran®) Busulfan* (Myleran®) Thiotepa Procarbazine* Dacarbazine (DTIC) Temozolamide* |
Alkylating agents - cycle non-specific
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Alkylating agents also work on:
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Mucosa, GI, hair
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Template being replicated is misread or mispaired during DNA synthesis
Cross-linking prevents DNA strands from unwinding Single or double-strand breaks in DNA occur |
Potential outcomes of alkylating agents
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Parent drug is converted by hepatic microsomal enzymes to 4-hydroxycyclophosphamide (4-HCP); liver impairment will affect dosing of the patient
4-HCP is converted to acrolein and phosphoramide mustard Phosphoramide mustard alkylates DNA Acrolein is responsible for causing hemorrhagic cystitis |
Mechanism of Action Cyclophosphamide
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Parent drug is converted to acrolein and ifosforamic mustard
There is more acrolein formed with (drug); more hepatic cystitis Acrolein is responsible for causing hemorrhagic cystitis |
Mechanism of Action Ifosfamide - Prodrug
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Clinical uses of (drug):
leukemia, lymphomas, solid tumors bone marrow transplant treat graft-versus-host-disease Rheumatic disorders & autoimmune nephritis |
Cyclophosphamide
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Clinical uses of (drug):
Solid tumors |
Ifosfamide
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Cyclophosphamide side effects
|
Myelosuppression (dose-limiting)
Hemorrhagic cystitis Nausea & vomiting Alopecia Syndrome of inappropriate anti-diuretic hormone (SIADH) – get low sodium; increases risk for seizure and vomiting |
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Ifosfamide side effects
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Hemorrhagic cystitis (dose-limiting)
Myelosuppression CNS toxicity (can be increased when administered with other cyp450 drugs) Nausea & vomiting Alopecia Pulmonary & cardiac toxicity |
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Caused by accumulation of acrolein
-Binds to thiol in bladder wall Hematuria, urinary frequency & irritation Prevent with vigorous hydration (≥2 L/day) & MESNA Treat with bladder irrigation, alum irrigation, and other therapies Heme test urine while on therapy |
Hemorrhagic cystitis
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Uroprotectant containing sulfhydryl group
-Binds to acrolein in the bladder to form a nontoxic compound Not systemically absorbed so does not interfere with cytotoxic activity – goes straight to the bladder Use with cyclophosphamide >2 g/m2/dose, ifosfamide ALWAYS Effective in prevention only |
MESNA
(mercaptoethane sodium) |
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-Cisplatin
Filtered by glomerulus & concentrated in renal tubules; incompletely cleared Nephrotoxicity – ↓ GFR, electrolyte losses (Mg, K), and renal failure Prevent with aggressive hydration (NaCl) -Carboplatin Not concentrated in the renal tubules; more efficiently cleared Dosing based on area under the curve (AUC) Dose = AUC ( GFR + 25 ) Option for those with problems with renal function -Oxaliplatin |
Platinum chemotherapeutic drugs
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Clinical uses of (drug):
-Testicular, ovarian, metastatic bladder, lung and other solid tumors Cisplatin – most active single agent in cervical cancer Oxaliplatin – colorectal cancer -Non-Hodgkin’s lymphoma |
Clinical uses of platinum
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Cisplatin toxicities
|
Vomiting – need antiemetic*
Nephrotoxicity* Peripheral neuropathy Neurotoxicity Ototoxicity |
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Carboplatin toxicities
|
Myelosuppression*
Neurotoxicity Vomiting |
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Oxaliplatin toxicities
|
Peripheral neuropathy (can’t drink cold drinks for almost 2 weeks)*
Myelosuppression |
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chemoprotectant agent that is metabolized to an active free thiol which binds to cisplatin and prevents damage to normal tissue
free radical scavenger side effects include hypotension and nausea and vomiting also used to prevent radiation-associated xerostomia |
Amifostine (Ethyol) – administered with cisplatin to reduce some cytotoxic effects
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-Chlorambucil (Leukeran)
Used for the treatment of chronic lymphocytic leukemia -Busulfan (Myleran) Used for treatment of leukemia and transplant Also available IV form (used more for transplant) toxicity is decreasing seizure threshold (require seizure prophylaxis) -**Melphalan (Alkeran) Used for the treatment of multiple myeloma 8 mg/m2 PO daily day 1-4 repeat every 28 days All three of these medications come as 2 mg tablets (watch dispensing by brand name) -Temozolomide (Temodar) Used for treatment of brain tumors 150 mg/m2 PO daily days 1-5 a cycle repeat cycle every 28 days |
Oral alkylating agents
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Doxorubicin (Adriamycin®, hydroxy-daunorubicin)
Daunorubicin Idarubicin Epirubicin Mitoxantrone |
Anthracyclines
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Mechanism of action (drug):
Inhibition of topoisomerase II Intercalation between DNA base pairs, interfering with DNA synthesis Formation of free radicals that damage DNA and cell membranes |
Anthracyclines
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Clinical use of (drug)
Breast cancer -Most active agent Sarcomas GI tumors Lymphoma |
Doxorubicin and Epirubicin
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Clinical use of (drug):
-acute leukemia treatment |
Daunorubicin
Idarubicin Mitoxantrone |
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Anthracyline Toxicities
|
Myelosuppression*
Cardiotoxicity* Extravasation injury – leaks out of vein into surrounding tissue* -Treat with Wydase and cold Nausea and vomiting Mucositis red/orange urine discoloration |
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|
Acute:
Arrhythmias (free radicals causing damage to cardio tissue) within 24 hours of administration Related more to peak concentrations Chronic: cardiomyopathy secondary to free radical formation cumulative doses > 550 mg/m2 |
Anthracycline cardiotoxicity
|
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|
Chronic cardiotoxicity with anthracycline is function of:
|
Total dose
Probability of CHF – probably should not administer to those with a poor ejection fraction (EJ) |
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|
-Dexrazoxane (Zinecard®)
Disrupts iron-anthracycline complex Prevents free radical formation without interfering with cytotoxic activity Used in leukemia with patients who have underlying (x) dysfunction -Liposomal doxorubicin (Doxil®) Liposomal delivery system not as readily taken up by tissue Used in breast, ovarian cancer |
How to mitigate the cardiotoxicty of anthracycline
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|
Similar ring structure to anthracyclines
Similar mechanism of action, with decreased tendency for free radical formation Decreased cardiotoxicity and extravasation Decreased nausea and vomiting Blue-green urine discoloration |
Mitoxantrone
|
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Anthracycline for:
Used in testicular cancer, Hodgkin’s Disease Test dose needed only for Hodgkin’s disease Watch for pulmonary toxicity and N/V |
Bleomycin
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Anthracycline for:
used in gastrointestinal tumors used intravesicularly in bladder cancer Sent to OR for shake and bake (placed directly in GI during operation – drug warmed and a med student rocks the patient back and forth to get the drug into small spaces) |
Mitomycin C
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Antifolates
Purine analogs Plyrimidine antagonist |
Antimetabolites
|
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Taken up intracellularly by cancer & healthy cells
Inhibits dihydrofolate reductase decreases tetrahydrofolate decreases purine & thymidylate Lack of purines & thymidylate prevents DNA synthesis Leucovorin rescue Reduced folate that bypass (drug) inhibition of tetrahydrofolate synthesis Uptake healthy cells > cancer cells |
Methotrexate
|
|
|
Clinical uses of (drug):
Hematological and solid malignancies ALL, non-Hodgkin’s lymphoma Breast and bladder CA Osteosarcoma (high-dose) Non-oncologic uses |
Methotrexate
|
|
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Toxicities of Methotrexate:
|
Myelosuppression and mucositis*
Nephrotoxicity (crystallization of MTX)* -Avoid nephrotoxic meds (NSAIDs, sulfa) Neurotoxicity (with intrathecal therapy) Photosensitivity, eye discomfort Pneumonitis Hepatotoxicity |
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How to reduce toxicities of methotrexate
|
prevent renal damage by alkalinizing the urine with sodium bicarbonate solutions
avoid drugs that can interfere with excretion of methotrexate: Bactrim, NSAIDS, etc. leucovorin rescue with high doses (yellow card) can accumulate in fluid and leach out over time causing serious toxicity – ensure patient has no fluid collections (ascitis, pleural effusions, etc.) Make sure CXR is obtained prior to dose |
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needed when administering high-doses of methotrexate > 100-500 mg/m2
directly converted into tetrahydrofolate without the need for dihydrofolate reductase begin 24 hours after methotrexate given should be given until methotrexate level is < 0.05 micromolar (5 x 10-8M) Refer to yellow card May give carboxypeptidase (from NCI) Needs IRB approval prior to dose |
Leucovorin rescue
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inhibits multiple enzymes involved in folate metabolism and DNA synthesis
used for malignant pleural mesothelioma, non-small cell lung cancer cutaneous reactions – prevent with dexamethasone 4 mg bid day -1, 0, +1 (folate is very important for skin growth) give folic acid 350-1000 mcg daily and vitamin B12 1000 mcg IM q 9 weeks starting week before initiation and for 21 days after therapy to prevent hematologic and gastrointestinal toxicity |
Pemetrexed (Alimta)
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Standard of care in acute leukemias
Arabinose analog of cytosine Phosphorylated to active component within cancer cells Inhibits DNA polymerase |
Cytarabine (Ara-C)
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Clinical uses of drug:
Acute leukemias Non-Hodgkin's lymphoma No significant activity against solid tumors |
Cytarabine (Ara-C)
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Cytarabine (Ara-C) toxicities
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Myelosuppression (100 mg/M2/day)
Alopecia Gastrointestinal Rash—plantar-palmer syndrome High dose toxicities (3 g/M2 q12h) -nausea -CNS toxicity -chemical conjunctivitis, acral erythema |
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MOA & structure similar to cytarabine
Intermittent dosing more effective than continuous dosing Effective for solid tumors Pancreatic cancer NSCLC Achieves intracellular concentrations 20x greater than cytarabine |
Gemcitabine (Gemzar)
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Gemcitabine toxicities
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Myelosuppression
Generalized rashes Fever and flu-like symptoms Peripheral edema Nausea and vomiting-mild NOT Neurotoxic |
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Clofarabine (Clolar)
Relapsed pediatric ALL Peds 52 mg/m2 IV daily x 5 days ($36,000) Adults 30-40 mg/m2 IV daily x 5 days AE-skin toxicity-rash to desquamation Nelarabine (Arranon) Tcell ALL or Tcell lymphoblastic lymphoma Peds 650 mg/m2 IV daily for 5 days Adults 1500 mg/m2 IV Day 1,3,5 AE-neurotoxicity |
Other pyrimidine antagonists
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prodrug that is metabolized to FdUMP in order to be active
FdUMP binds to thymidylate synthase (TS) prevents conversion of uracil (RNA) to thymidine (DNA) stabilizes TS & FdUMP in the presence of leucovorin (given with leucovorin to treat colon cancer) |
Mechanism of action of Fluorouracil
-fluorinated analog of uracil |
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Clinical uses of (drug):
Treatment of solid tumors including breast, colorectal and other GI tumors Non-oncologic uses: actinic keratoses and noninvasive skin cancers |
Fluorouracil
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Leukovorin enhances the efficacy of this drug by locking it onto thymidylate synthase
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Fluorouracil
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Myelosuppression (bolus)*
Bloody diarrhea (CI)* Mucositis (CI)* Dermatologic (rings on your fingernails – like tree trunks) Ocular Nausea and vomiting (mild) Cardiotoxicity (rare) |
Toxicity of fluorouracil
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Oral prodrug of fluorouracil
Metabolized to active component in tumor tissue Use in metastatic colorectal & breast cancer Take BID with food (↓ N/V) Diarrhea, palmar-plantar rash |
Capecitabine (Xeloda)
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-Mercaptopurine (6-MP)
Metabolized by xanthine oxidase (same as allopurinol) ↓ dose x 75% if used with allopurinol -Thioguanine (6-TG) No dose reduction required with allopurinol -Fludarabine & cladribine Immunosuppressive → risk of opportunistic infections |
Purine analogs
Inhibit de novo purine synthesis |
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-Vinca alkaloids
Vincristine (Oncovin®) Vinblastine (Velban®) Vinorelbine (Navelbine®) -Taxanes Paclitaxel (Taxol®) Docetaxel (Taxotere®) |
Mitotic inhibitors
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“Spindle poisons” which bind to tubulin
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MOA of mitotic inhibitors
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Inhibit microtubule assembly
Interfere with formation of mitotic spindle Cells accumulate in mitosis |
Vinca alkaloids (plate spaghetti)
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Promote microtubule assembly
Interfere with microtubule disassembly |
Taxanes (hard spaghetti)
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Neurotoxicity
Constipation Vesicant Extravasation SIADH Do not give Intrathecally Should never be greater than 2 mg – can’t reverse |
Vincristine toxicities
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Myelosuppression
Vesicant Extravasation |
Vinblastine/vinorelbine
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semi-synthetic vinca alkaloid
used for lung, breast, ovarian, lymphoma toxicities: myelosuppression neuropathy nausea and vomiting extravasation alopecia |
Vinorelbine (Navelbine)
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Myelosuppression
Mucositis Peripheral neuropathy (cumulative) – tends to occur 18 months after therapy Alopecia Hypersensitivity reactions* (due to the mixing of this compound with oil) Nausea and vomiting (rare) |
Toxicities of Taxanes
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Myalgia
Bradycardia Cremaphor EL (oily solution) |
Paclitaxel toxicity
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Fluid retention
Palmar-plantar rash Polysorbate-80 (oily solution) |
Docetaxel toxicity
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Semi-synthetic analog of epothilone B
Binds directly to ß-tubulin on microtubules, leading to suppression of microtubule dynamics Some binding sites overlap with paclitaxel -accounts for its activity in taxane resistant patients |
Ixabepilone (ix-a-BEP-i-lone)Ixempra® (ix-EM-pra)
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Treatment of patients with metastatic or locally advanced breast cancer:
In combination with capecitabine in patients resistant to treatment with an anthracycline and a taxane Monotherapy in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine |
Ixabepilone: Indication
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Neurotoxicity about 65% overall in studies
Neutropenia incidence 65% but febrile neutropenia incidence only 3-4% Premeds: H1 blocker – diphenhydramine 50 mg H2 blocker – ranitidine 50 mg IV |
Ixabepilone: Adverse effects
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Etoposide (VP-16) & teniposide (VM-26)
Inhibit topoisomerase II Toxicities: -Myelosuppression* -Mucositis (BMT) -Hypotension (alcohol-based diluent) Clinical uses -VP16 – AML, NHL, BMT, solid tumors (IV or oral) -VM26 – ALL, SCLC |
Epipodophyllotoxins
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Irinotecan & topotecan
Inhibit topoisomerase I Clinical uses: Ovarian cancer Lung cancer CML, MDS Cervical, ovarian cancer Colorectal cancer |
Camptothecins
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Topotecan toxicity
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myelosuppression
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Irinotecan toxicities
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Severe diarrhea (20%)
Acute (≤ 24 hours) Facial flushing, abdominal cramping Treat with scopolamine or atropine Prevent with 5HT-antagonist & antihistamines Chronic (~11 days) Secretory → life threatening dehydration Treat with high-dose loperamide |
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Degrades asparagine found in the serum
In lymphoid malignancies the lymphocytes are unable to produce asparagine due to a lack of or low levels of asparagine synthetase and rely on serum asparagine for its needs. Without the serum asparagine the cells are unable to grow and reproduce Used for ALL Adverse Events pancreatitis (check amylase) *decreased fibrinogen < 100mg% (clotting problems) if low give cryoprecipitate *hypersensitivity reactions |
L-asparaginase
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Used for CML
Causes myelosuppression Doses 50 mg/kg/d (aprx 500 mg PO BID & titrate to WBC effect) |
Hydroxurea
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Selective, reversible inhibitor of the proteasome -
Proteasome: multi-enzyme complex in all cells; degrades proteins and regulates cell-cycle progression Adverse events: peripheral neuropathy, fatigue, malaise, weakness, GI effects, thrombocytopenia Used for Multiple Myeloma, NHL, ? leukemias |
Bortezomib (Velcade)
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Used with APL
Matures promyelocytes blasts inducing a CR May cause (drug) syndrome that needs to be treated with dexamethasone Dose: 45 mg/m2/d (round to nearest 10 mg) PO divided BID with food up to 90 days Give with cytarabine and daunorubicin (Drug) syndrome (maturation syndrome – cytokine release)- -fever, dyspnea, pleural effusion, peripheral edema, hypotension -treat-dexamethasone 10 mg IV BID x 3 days |
All-trans retinoic acid (Vesinoid)
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arsenic trioxide (Trisenox) – used for APL
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retinoic acid syndrome (differentiation syndrome)
QTC prolongation |
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thalidomide – for multiple myeloma
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increase risk for thromboembolism
drowsiness peripheral neuropathies pts / prescribers / dispensers must enroll in STEPS Very teratogenic |
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Lenalidomide (Revlimid)-for MDS (myelodysplastic syndrome) and MM
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Myelosuppression
Dose for MDS: 10 mg po day (patients are already myelosuppressed) Dose for MM: 25 mg po day |
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Cells need methyl groups to grow
Removes methyl groups leading to cancer cell death Well tolerated drugs |
Hypomethylating agents
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Used for MDS
Given 75-150 mg/m2 SQ or IV daily x 7 days SQ route has local reaction |
Azacitadine (Vidaza)
Hypmethylating agent |
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Used for MDS
15 mg/m2 IV every 8 hours x 9 doses every 6 weeks 20 mg/m2 IV daily x 5 days every 4 weeks |
Decitabine (Dacogen)
Hypomethylating agent |
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Cancer cells can have too much (x) which allows the cell to grow unregulated (unable to die)
If inhibit (x), then allows the cell to develop normally and complete cell life Ultimate goal is cell death through normal cell regulation |
Histone Deacetylators (HDACs)
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Histone: “spools” around which DNA wind
Histones contain lysine-rich amino-terminal tails that are responsible for conformational change by DNA Remove acetyl group to lysine tail, restores charge, increases attraction between histones and DNA → condensation of chromatin → represses transcription |
Histone Deacetylators (HDACs)
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Some tumor cells produce excess amounts of histone deacetylase (HDAC), leading to a closed chromatin structure and prevention of DNA transcription
HDAC inhibitors have also been shown to: Cause cell cycle arrest Induce apoptosis Inhibit angiogenesis Clinical Use Cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies No dosing recommendations for hepatic or renal impairment Patients should drink at least 2 liters/day of fluid to prevent dehydration |
Vorinostat (Zolinza)
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-Hematologic abnormalities
Anemia Thrombocytopenia -Gastrointestinal symptoms Diarrhea, nausea Taste disorders -May prolong QTc interval -Serious but rare Pulmonary embolism Squamous cell carcinoma Anemia -Laboratory abnormalities Increased serum creatinine Hyperglycemia Proteinuria |
Vorinostat (Zolinza) toxicities
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MOA: Inhibition of mTOR blocks translation of mRNA and halts progression from G1 to S phase
Treatment of advanced renal cell carcinoma (came about approx. 3 years ago) Dose 25 mg IV over 30-60 minutes once a week Premedicate with antihistamine (i.e. diphenhydramine) Hold for ANC < 1,000/mm3, platelet < 75,000/mm3, grade 3 AE’s Restart when toxicities resolve to grade 2 Reduce dose by 5 mg/week (minimum dose 15 mg) |
mTOR inhibitor:
Temsirolimus (Torisel) |
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Hypersensitivity reactions (9%)
Hyperglycemia / Hyperlipidemia -plays role in glucose and lipid metabolism Immunosuppression -Infections and impaired wound healing Bowel Perforation -Fatal in 1 patient Renal Failure Interstitial lung disease (2%) |
Temsirolimus: adverse effects
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Destroys tumor cells through a number of possible mechanisms, including activation of complement and antibody-dependent cell-mediated cytotoxicity
Useful as means of targeting cytotoxic radioisotopes, toxins, or drugs to tumors, enhancing their delivery to tumors while minimizing systemic exposure Animal (murine/equine), human or chimeric (from two species) derived |
Monoclonal Antibodies (-mab) MOA
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Monoclonal Ab naming:
momab: zumab: ximab: |
radiolabeled
human chimeric with murine and human |
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Infusion-related toxicity (65-80%): SOB, temp, chills, nausea, asthenia, and HA
-premedications—acetaminophen, diphenhydramine, hydrocortisone Hypotension (10%)-recommend holding anti-hypertensives |
MAB toxicities
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-Rituximab (Rituxan) – called Vitamin R by patients; #5 drug used with all cancer patients at WFUBMC
Anti-CD-20 antigen found on B lymphocytes Used for B-cell non-Hodgkin’s lymphoma -Gemtuzumab ozogamicin (Mylotarg) Anti-CD-33 antigen linked to ozogamicin Used for Acute melogenous leukemia (AML) Profound bone marrow suppression -Alemtuzumab (Campath) – “liquid AIDS” Anti-CD-52 antigen found on B and T lymphocytes Used for B-cell chronic lymphocytic leukemia Profound immunosuppression |
1st generation MAB
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-ibritumomab (Zevalin)
directed against CD-20 given with rituximab used in follicular non-Hodgkin’s lymphoma -tositumomab (Bexxar) - $20,000 directed against CD-20 used in follicular non-Hodgkin's lymphoma |
Radiolabelled MAB
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Regulates cellular proliferation, differentiation, function, & survival
Receptor & non-receptor enzymess FLT3, VEGF, ABL, c-KIT, etc. Activity tightly controlled in normal cells |
Tyrosine Kinase (TK)
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-Small molecule inhibition
Blocks ATP binding to (enzyme) domain Stops intracellular signaling pathways Cellular apoptosis -Monoclonal antibodies Target receptor (enzymes) or the ligand Interrupt (enzyme) signaling Antibody-mediated cytotoxicity |
TK inhibitors
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Imatinib (Gleevec®)
Gefitinib (Iressa®) Erlotinib (Tarceva®) Sunitinib (Sutent®) Sorafenib (Nexavar®) |
Small molecule TK inhibitors
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Cetuximab (Erbitux®)
Trastuzumab (Herceptin®) Bevacizumab (Avastin®) |
Monoclonal antibodies TK inhibitors
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binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER-2) found on some breast cancers
used for metastatic breast cancer whose tumors overexpress the HER-2/neu protein can cause congestive heart failure (therefore used as maintenance therapy after chemo) |
trastuzumab (Herceptin)
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antibody against vascular endothelial growth factor (VEGF)
used for metastatic colorectal cancer inhibits blood vessel formation (do not give within a month of surgery) causes hypertension |
bevacizumab (Avastin)
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antibody against epidermal growth factor receptor (EGFR)
used for metastatic colorectal cancer causes acneform rash |
cetuximab (Erbitux)
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Patients with EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following one or more regimens containing:
Fluoropyrimidine, Oxaliplatin, or Irinotecan 6 mg/kg IV every other week Premedications are necessary Toxicities: Pulmonary fibrosis dermatologic toxicity infusion reactions Hypomagnesemia N/V/constipation |
Panitumumab (Vectibix)
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inhibits epidermal growth factor receptor (EGFR) tyrosine kinase
used as salvage treatment of non-small cell lung cancer causes acneiform rash (can be a marker of actually having clinical effect), diarrhea, interstitial lung disease |
erlotinib (Tarceva)
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inhibits epidermal growth factor receptor (EGFR) tyrosine kinase
used for non-small cell lung cancer in patients who are benefiting or have benefited from gefitinib skin rash, ocular symptoms, pulmonary symptoms Off-market b/c so few patients respond to this |
gefitinib (Iressa)
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Skin rash (72%)
Diarrhea (35%) Nausea/vomiting Myelosuppression Pulmonary symptoms (SOB, cough, fever) with acute onset or worsening |
TK inhibitor toxicities
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inhibits Bcr-Abl (enzyme)
-Bcr-Abl is the abnormal gene product that is caused by the Philadelphia chromosome in chronic myeloid leukemia (CML) -also inhibits (enzyme) for platelet derived growth factor (PDGF), stem cell factor (SCF) and c-kit |
Tyrosine Kinase Inhibitors: CML
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Musculoskeletal pain
Fluid retention QT prolongation Myelosuppression GI Bleeding Dyspnea Cardiac failure Diarrhea Headache Dizziness Constipation Pyrexia Fatigue Skin Rash Nausea/Vomiting Cough Anorexia Pain Neuropathy |
CML TK inhibitor
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used to treat Philadelphia chromosome + CML and Kit-positive gastrointestinal stromal tumors (GIST)
Dose: 400 to 800 mg daily There are a lot of mutations that may be overcome except T315I – have to have transplant if you have this mutation |
Imatinib (Gleevec)
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Adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy including imatinib
Don’t take antacid 2 hrs prior to or after dose Major drug interactions: With CYP3A4 inhibitor, decrease dose to 20-40 mg daily Consider increase in dose if given with CYP3A4 inducer |
Dasatinib (Sprycel) or
Nilotinib (Tasigna) |
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Tyrosine Kinase Inhibitors: renal cell cancer
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Sorafenib (Nexavar)
Advanced renal cell carcinoma in adults Sunitinib (Sutent) Gastrointestinal stromal tumors (GIST) after disease progression or intolerance to imatinib Advanced renal cell carcinoma in adults |
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DECREASED OXYGEN CARRYING CAPACITY (RBC,Hb,Hct)
FUNCTIONAL DEFINITION DECREASED CAPACITY FOR OXYGEN DELIVERY |
Anemia
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What does statistical anemia imply?
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People might normally lie outside 2 SD - they might not really have problems
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MACROCYTIC
(x) HEMOGLOBIN ALTERED ENZYME ACTIVITIES SOME WILL HAVE TARGET APPEARANCE ALTERED MEMBRANE ANTIGEN EXPRESSION |
Fetal erythrocytes
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NEONATAL PERIOD Birth – 1 month
Erythropoiesis |
MARKED ERYTHROPOIETIC ACTIVITY AT BIRTH
INCREASED RETICULOCYTES PREDOMINANCE OF FETAL ERYTHROCYTES INCREASED ERYTHROCYTE MCV (mean cell volume) |
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EARLY INFANCY 2 – 6 months Erythropoiesis
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“PHYSIOLOGIC” (adaptational) ANEMIA
HEMOGLOBIN NADIR @ 8-10 WEEKS OF AGE HEMATOPOIETIC RECOVERY WITH INCREASED RETICULOCYTES AT END OF “PHYSIOLOGIC” ANEMIA. |
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PHYSIOLOGIC ANEMIA DEVELOPS EARLIER AND HAS A LOWER NADIR.
INCREASED RISK FOR IRON DEFICIENCY ANEMIA – LESS IRON STORES |
Erythropoietic effects of prematurity
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LATE INFANCY 6 – 24 months erythropoiesis
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RAPID SOMATIC GROWTH, INCREASED IRON REQUIREMENTS.
NUTRITIONAL IRON DEFICIENCY ANEMIA PREVALENT “ADULT-TYPE” ERYTROCYTES PREDOMINATE |
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CHILDHOOD erythropoiesis
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“ADULT-TYPE” ERYTHROCYTES PREDOMINANT.
WBC DIFFERENTIAL SHOWS INCREASING NEUTROPHILS AND DECREASING LYMPHOCYTES. |
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Adolescence erythropoiesis
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RAPID SOMATIC GROWTH.
INCREASED NUTRITIONAL IRON REQUIREMENT. GENDER DIFFERENCES APPEAR IN HEMOGLOBIN LEVELS (androgenic effect). |
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HEMORRHAGE
Feto-Maternal Bleeding (look at mother’s blood for the presence of fetal cells) Feto-Fetal Bleeding HEMOLYSIS: Inherited Red Cell Disorders Alloimmune |
Common Neonatal Anemias
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IgG (IgM too big) CAN CROSS PLACENTA AND HEMOLYZE FETAL ERYTHROCYTES IF MOTHER IS IMMUNIZED TO A RED CELL ANTIGEN INHERITED FROM THE FATHER
Positive coombs' test (DAT) Spherocytes |
ALLOIMMUNE HEMOLYTIC ANEMIA of the NEWBORN
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Hemolysis
Red Cell Disorders |
MEMBRANE: HEREDITARY SPHEROCYTOSIS HEREDITARY ELLIPTOCYTOSIS
ENZYME HEMOGLOBIN |
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MOST COMMON HEMOLYTIC ANEMIA DUE TO A MEMBRANE DEFECT.
THE DEFECTS ARE MUTATIONS IN PROTEINS THAT LINK VERTICALLY WITH THE LIPID BILAYER. |
Hereditary Spherocytosis
SPLENOMEGALY NEONATAL JAUNDICE HEMOLYTIC ANEMIA CHOLELITHIASIS AUTOSOMAL DOMINANT (75%) RESPONSE TO SPLENECTOMY INCREASED MCHC – can be diagnostic |
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INCREASED OSMOTIC FRAGILITY
MEMBRANE INSTABILITY ANKYRIN SPECTRIN BAND 3 BAND 4.2 |
Hereditary Spherocytosis
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COMPLICATIONS OF HERDITARY SPHEROCYTOSIS
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“APLASTIC CRISES” (parvovirus B19) – fifth disease
FOLIC ACID DEFICIENCY INCREASED HEMOLYSIS CHOLELITHIASIS LEG ULCERS – because of decreased oxygen delivery |
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AUTOSOMAL DOMINANT
PROTEIN 4.1 SPECTRIN DEFECTS MANY VARIANTS CAN BE ASYMPTOMATIC |
Elliptocytosis
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Membranopathies
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Spherocytosis
Elliptocytosis Pyropoikilocytosis Stomatocytosis |
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Most common glycolytic pathway enzymopathy
Autosomal Recessive Neonatal Jaundice Chronic Severe-Moderate Hemolysis Transfusion dependant Variable response to splenectomy Very high reticulocyte count |
Pyruvate Kinase Deficiency
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Most common enzyme deficiency
X-Linked inheritance Neonatal Jaundice Infection induced hemolysis Drug induced hemolysis Fava bean hemolysis Heinz body hemolytic anemia "Blister" cells |
G6PD Deficiency
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MULTIPLE ENZYME VARIANTS
Congenital Nonspherocytic Hemolytic Anemia Chronic Hemolysis B- variant (Mediterranean) unstable enzyme Fava bean hemolysis A- (African) paroxysmal oxidant hemolysis. Hb down and reticulocyte up with drugs like primaquine due to lower oxygen levels. |
G6PD Deficiency
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CONGENITAL PURE RED CELL APLASIA (DIAMOND-BLACKFAN ANEMIA)
HEMOLYSIS Inherited Red Cell Disorders |
Early Infancy anemias
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CONGENITAL PURE RED CELL APLASIA
TYPICAL “FACIES” THUMB ANOMALIES FETAL RED CELLS (high MCV – low Hb, low reticulocyte, low RBC, low hct) RPS 19 mutation (25%) ELEVATED RBC ADENOSINE DEAMINASE |
DIAMOND-BLACKFAN ANEMIA
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HEREDITARY OROTIC ACIDURIA
PEARSON SYNDROME TRANSCOBALAMIN II DEFICIENCY (leads to intracellular vitamin B12 deficiency) |
PEDIATRIC ANEMIAS (UNCOMMON)
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NUTRITIONAL IRON DEFICIENCY ANEMIA.
TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD (T.E.C.) |
Late infancy anemias
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NORMOCYTIC NORMOCHROMIC (normal MCV)
LOW RETICULOCYTES VERY LOW HEMOGLOBIN SPONTANEOUS RESOLUTION |
TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD
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SECONDARY TO OTHER DISEASE (anemia)
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Childhood anemias
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PANCYTOPENIA WITH CONGENITAL ANOMALIES
BONE MARROW HYPOPLASIA RADIAL/THUMB ANOMALIES ALTERED SKIN PIGMENT (HYPER OR HYPO PIGMENTED) INCREASED RISK FOR MALIGNANCIES |
Fanconi's Anemia
Fanconi’s Anemia is the most common type of inherited aplastic anemia. It is inherited as an autosomal recessive and has a carrier frequency of about 1:300. |
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Associated physical abnormalities include:
Skin hyperpigmentation and/or heterochromia (62%) Short stature (59%) Skeletal anomalies, esp. of the thumb (48%) Hypogonadism in males (42%) Renal anomalies- “horseshoe kidney” (24%) Microcephaly or micrognathia (26%) Mental retardation (13%) Ear anomalies +/- deafness (10%) |
Fanconi's Anemia
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IRON DEFICIENCY ANEMIA
SECONDARY TO OTHER DISEASE SPORTS ANEMIA |
Adolescence anemias
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IgG (warm) OR IgM (cold) MEDIATED
Paroxysmal Cold Hemoglobinuria (PCH)….IgG that behaves like IgM |
Autoimmune hemolytic anemia
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FIBRIN DEPOSITION IN CAPILLARY BEDS CAUSES FRAGMENTATION OF RED CELLS AND PLATELET TRAPPING
HEMOLYTIC UREMIC SYNDROME (HUS) THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) DISSEMINATED INTRAVASCULAR COAGULATION (DIC) |
MICROANGIOPATHIC HEMOLYTIC ANEMIA
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Hb. S is most common in U.S., followed by C and E.
Hb. S and E are most common world wide. |
HEMOGLOBINOPATHIES
Electrophoresis or chromatography identifies variants with charge change. |
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Hb. S/S
Hb. S/C Hb. S/B-thal. (+/0) HEMOLYSIS VASO-OCCLUSION |
SICKLE CELL DISEASE
Splenic sequestration Avascular necrosis Stroke Dactylitis Acute chest syndrome |
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EARLY DIAGNOSIS (NEONATAL SCREENING)
HYPOSPLENIC FUNCTION PNEUMOCOCCAL VACCINE PROPHYLACTIC PENICILLIN DACTYLITIS (HAND FOOT SYNDROME) SPLENIC SEQUESTRATION STROKE PREVENTION (HTN meds?) |
SICKLE CELL DISEASE IN CHILDREN
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UNSTABLE HEMOGLOBINS
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MUTATIONS AFFECT HEME BINDING OR CONTACT POINTS.
NOT RECOGNIZED BY ELECTROPHORESIS. OFTEN NEW MUTATIONS. HEINZ-BODIES (DENATURED HEMOGLOBIN) FORMED. |
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EXCESSIVE MILK INTAKE
PICA -A perverted appetite for substances not fit as food or of no nutritional value; e.g., clay, dried paint, starch, ice. |
Iron deficiency
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NEONATAL JAUNDICE
FAMILY HISTORY OF SPLENECTOMY OR CHOLECYSTECTOMY |
Hemolysis (congenital)
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SHORT STATURE
THUMB & RADIAL ANOMALIES HORSESHOE KIDNEY MICRO-OPHTHALMIA |
Fanconi's anemia
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THUMBS
FACIES |
DIAMOND-BLACKFAN ANEMIA
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LACTIC ACIDOSIS
FAILURE TO THRIVE |
Pearson syndrome
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LOW MCV & NORMAL RDW
LOW MCV & HIGH/NORMAL RBC |
Think thalassemia
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LOW MCV& HIGH RDW
LOW MCV & LOW RBC |
Think iron deficiency
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High MCHC
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Spherocytes
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High MCV
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? Marrow disease
?Reticulocytosis |
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High RDW
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Check blood smear
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Disc shaped, 2-4um, anuclear
Blue gray on Wright's stain with reddish-purple granules Normal counts 150-450K Circulate for 7-9 days 2/3rds in blood, 1/3 in spleen |
Platelets
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What drives platelet production?
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Thrompoietin
The level of free eTPO in the blood drives platelet production Platelet levels, in turn, regulate eTPO levels via binding and clearance by TPO-Rs on the platelets Normal platelet levels allow more eTPO to be bound, leaving less eTPO available to bind to hematopoietic cells With less eTPO binding to hematopoietic cells, fewer platelets are created by megakaryocytes Normal platelet counts are maintained In general thrombocytopenia, platelet levels are low Low platelet levels result in less eTPO bound by TPO-Rs Serum levels of unbound eTPO are increased More eTPO is available to bind to progenitor cells and megakaryocytes; platelet production increases More platelets are released into circulation, allowing platelet levels to return to normal levels The width of the blue arrow represents the serum level of TPO, with wider arrows representing higher concentrations |
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a glycoprotein that binds to its receptor on platelets and megakaryocytes
produced at a constant rate by the liver inverse relationship between serum levels and platelet mass concentration regulated by the total mass of PLTs/megakaryocytes available to bind and degrade the protein |
Thrombopoietin (TPO)
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What is involved in all phases of differnentiation and maturation of platelets
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Thrombopoietin
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Beta-thromboglobulin
Factor V Factor XI Protein S Fibrinogen vWF Platelet factor 4 Platelet-derived growth factor |
Alpha granules of Platelets
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ADP (activate neighbors)
ATP Calcium Serotonin (vasoconstrictor) |
Dense bodies in platelet granules
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Main function – formation of mechanical plugs during the normal haemostatic response to vascular injury
-If absent, spontaneous leakage of blood through small vessels may occur Local release of vasoconstrictors (serotonin) to decrease blood flow to the injured area Catalysis of reactions of the soluble coagulation cascade leading to fibrin clot formation Initiation of the tissue repair process Regulation of local inflammation |
Platelet function
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small blood cells produced by megakaryocytes. In the event of blood vessel injury, these tiny blood cells are rapidly recruited to the area of damage, where they effectively seal off the injured site to prevent blood loss. This is achieved through the execution of a series of functional events beginning with adhesion, followed by spreading and aggregation, leading to thrombus (clot) formation.
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Platelets
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Platelets roll and cling to non-platelet surfaces
Reversible, seals endothelial gaps, requires vWF in arterioles |
Platelet adhesion
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platelets cling to each other
Irreversible, platelet plugs form, secretion of all platelet contents, requires fibrinogen |
Platelet aggregation
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discharge the contents of their granules
Irreversible, occurs during aggregation, essential to coagulation |
Platelet secretion
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Following blood vessel injury, platelets adhere to the exposed subendothelial connective tissues.
Under the influence of shear stress, platelets move along the surface of vessels until the platelet engages collagen. Following adhesion, platelets extrude long pseudopods which enhance interaction between adjacent platelets. Platelet activation is then achieved by glycoprotein IIb/IIIa binding fibrinogen to produce platelet aggregation. |
Events of primary hemostasis
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Defects in GPIb result in:
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Bernard-Soulier disease
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Defects in GPIIbIIIa result in:
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Glanzmann Thromboasthenia
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Thombin
TXA2 ADP Collagen PAF |
Inducer of aggregation
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Consists of a series of reactions (coagulation cascade) that are triggered at the same time as platelet plug formation, resulting in the generation of cross-linked fibrin that encases and interlaces the platelet plug. Once endothelial injury has healed, the physiologic thrombus is no longer required. The endogenous fibrinolytic system results in the production of plasmin that degrades the cross-linked fibrin into cross-linked fibrin degradation products. The degraded thrombus is washed
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Secondary hemostasis
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Defined as platelet count <150,000/ul
Consequences Bleeding following surgery or trauma with PLT counts < 50K Spontaneous hemorrhage with PLT counts < 10K Transfusion threshold |
Thrombocytopenia
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Cutaneous (petechiae, purpura, ecchymosis, venipuncture sites)
Mucosal (epistaxis, menorrhagia, hemorrhagic bullae in mouth - blood blisters, gastrointestinal bleeding) Central nervous system (intracranial bleeding is most feared) An “ooze” rather than a “gush” |
Sites of bleeding with platelet disorders
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Often see petechiae, ecchymoses, subconjunctival hemmorhage in what platelet disorder
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Immune-mediated thrombocytopenic purpura
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Cutaneous hemorrhage and pupura in what platelet disorder
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drug-induced thrombocytopenia
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Failure of platelet production
Increased consumption of platelets Abnormal distribution of platelets Dilutional Loss |
Causes of Thrombocytopenia
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Selective megakaryocyte depression
Rare congenital defects Drugs, chemicals, viral infections Part of general bone marrow failure Cytotoxic drugs Radiation Marrow infiltration HIV infection |
Failure of Platelet Production
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Absent radii syndrome
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Associated with thrombocytopenia
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Lack of dense granules in platelets
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Gray platelet syndrome
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Increased consumption of platelets
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Immune
Autoimmune/idiopathic (ITP) Infections: HIV, malaria Drug-induced Heparin (HIT) Post-transfusional purpura Disseminated intravascular coagulation (DIC) Thrombotic thrombocytopenic purpura (TTP) |
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Immune Thrombocytopenic Purpura
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Acute
Abrupt onset of bruising, petechiae, mucosal bleeding in a previously healthy person May follow an infection, usually a nonspecific URI or GI virus Majority recover without treatment Chronic Less responsive to therapy |
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Found in: Increased platelet turnover Myeloproliferative disorders Myelodysplastic disorders
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Giant platelet
Morphology:Platelet larger than a normal red cell. |
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A Disease of Accelerated Platelet Destruction and Suboptimal Platelet Production
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ITP pathophysiology
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Treatment of ITP
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Target the Immune System
Steroids Splenectomy Immune Globulin (gives the macrophage something else to chew on) Increase Platelet Production Thrombopoietin Receptor Agonists stimulate megakaryocytes |
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IgG Abs directed against heparin-platelet factor 4 complex
Suspect if platelet count falls to <100,000/ul or <50% of baseline value 5 to 15 days after heparin therapy is started Venous, arterial, and microvascular thrombosis threatens life and limb |
Heparin Induced Thrombocytopenia
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Devastating disorder; fatal if untreated
Clinical pentad (FatRN): Fever Anemia Thrombocytopenia Renal dysfunction Neurologic deficits Blood film: schistocytes + few platelets |
TTP-Thrombotic Thrombocytopenic Purpura
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The absence or impairment of ADAMTS13 (vWF cleaving enzyme) allows for the persistence of the ultralarge “sticky” forms of vWF, which trap platelets and cause thrombi in vessels, thus leading to end-organ damage, and the appearance of the pentad of clinical features.
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Pathophysiology of TTP - thrombotic throbocytopenic purpura
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Thrombocytopenia Due to Dilution
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Thrombocytopenia occurs in patients receiving massive transfusions (10-20 units) of PRBCs over a brief time frame due to the absence of viable platelets in stored PRBCs
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Fibrin strands/clots
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Give falsely low platelet counts
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Normally, what percentage of platelets are circulating and what percentage are in the spleen?
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70% circulating/30% spleen
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Defined as a PLT count > 500K
Mechanisms reactive : Cytokine driven (>80% of cases) autonomous/clonal/neoplastic (Essential Thromboctyosis or thrombocythemia – these are “stupid” platelets) Complications Thrombosis in 15-20%, Bleeding in 3-5% Neither typical in patients with reactive thrombocytosis |
Thrombocytosis-Too Many Platelets
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Obligate intracellular organisms
Utilize host cell machinery to replicate Tropism for specific cell type(s) Therapeutic window typically small Latency/chronic infection frequently part of the natural history of infection |
General Principles of Viral Infection
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Occurred only once in a lifetime
Could be life threatening, profound anemia Transfusions life saving and patients spontaneously recovered Often preceded by a nonspecific ‘viral’ illness Appeared to be outbreaks and even transmission to ‘roommates’ in the hospital |
Aplastic Crises in Patients with Chronic Hemolytic Anemia Historical Context
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-DNA virus, discovered in 1974, but only associated with disease in the early 1980’s
-Now clearly shown to be the causative agent of: hydrops fetalis erythema infectiosum (fifth disease) aplastic crises in hemolytic subjects seronegative RA syndrome chronic anemia in immunocompromised hosts |
Parvovirus B-19
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about half of all adults are antibody positive
-prevalence rises rapidly during school years 20-60% of children in an outbreak situation will be symptomatic virus shed in respiratory secretions -patients with aplastic crisis and virtually no transmission once symptomatic (Erythema infectiosum) |
Parvovirus B-19 Epidemiology
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-Infects erythroid progenitor cells
thus marked anemia out of proportion to reductions in other cell lines w/infection -Acute infection causes mild illness in most immunocompetent children (Erythema infectiosum) onset of rash about the time of seroconversion fever, myalgias, HA precede rash by a few days No/little anemia due to RBC life span of 120 days |
Parvovirus B-19 Pathogenesis
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Arthropathy - mimics acute onset of RA, but seronegative; occurs with acute infection in ~60% of adults, but only 10% of children, women > > men (many think RA is infectious b/c this looks so similar)
Aplastic crisis: due to high reticulocyte counts in chronic hemolytic anemias Chronic anemia due to inadequate immune response (Dx requires PCR, no Ab detectable); primarily seen in advanced HIV |
Parvovirus B-19
Additional Clinical Syndromes |
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18 yo college freshman comes in on Monday after attending his first big rush party that weekend. Doesn’t remember much, but he’s been feeling poorly for several weeks which he related to being away from home for the first time, 8 o’clock classes, rush,etc. Major complaints now are sore throat, chills, fatigue. Noticed some swelling in his neck and difficulty swallowing
Atypical monocytes on smear 1st sexual encounter just a few weeks before |
Epstein Barr virus/mono
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-Cytomegalovirus
particularly in allogeneic BMT patients -Varicella Zoster or Herpes simplex usually as part of dissemination -Community acquired Respiratory Syncytial Virus (RSV) Influenza Parainfluenza |
Viral Causes of Pneumonia in Immunocompromised Hosts
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Idiopathic pneumonia
ARDS Alveolar Hemorrhage Leukemic Infiltration Lymphoma Pulmonary Emboli Aspiration Drug Induced Lung Injury: bleomycin cyclophosphamide busulfan ifosfamide methotrexate BCNU doxorubicin |
Non-infectious Causes of Fever and Pulmonary Infiltrates in Immunocompromised Hosts
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Seropositive status (donor or recipient)
older age conditioning regimens with agents other than cyclophosphamide GvHD!!!!!!! Idiopathic is unlikely infectious b/c of lack of variation in severity with level of immuno compromise |
Risk Factors of CMV in BMT Recipients
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Diagnosis is usually clinical, but BAL cytology and culture helpful
Very often found in presence of another pathogen -(condition) immunosuppressive in and of itself -fungi (including PCP) and Pseudomonas most common |
CMV pneumonia
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IV GCV (ganciclovir) 5 mg/kg q 12h (dose adjusted for renal failure) is cornerstone
-duration unclear; personal style - - -> bid x 14 d, then qd x7d, then off -Can substitute valganciclovir 900 mg po bid as equivalent if tolerating/absorbing po meds Foscarnet for salvage/intolerance unclear if (virus) Ig has any role in SOT, perhaps in unresponsive disease, but Either (virus) Ig or IVIg is absolutely necessary for treatment in HSCT recipients |
Therapy of CMV disease
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-Prophylaxis
anti-(viral) therapy when either donor or recipient is (virus) seropositive easier to write into a protocol no need for surveillance may expose many to risks of drug for benefit of a few -Preemptive Therapy more targeted therapy for brief periods given with: ‘induction’ therapy ALA (anti-lymphocyte antibody) therapy defined lab evidence of infection fewer patients exposed may improve reconstitution of immunity requires sensitive and predictive lab tests |
Two Major Strategies to Reduce the Risk of CMV Disease
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-Anemia
DRUGS neoplasia (Kaposi Sarcoma, lymphoma) Folate/B12 deficiency Infection: MAC MTb CMV Chronic Parvovirus B19 Fungi (histo, cocci) -Thrombocytopenia ITP: most common responds to therapy for HIV can Rx with steroids, IVIG, etc, but short-term help TTP: also may be initial manifestation of HIV DIC |
Hematologic Manifestations of HIV
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68 yo man (diagnosed late 50s) with CLL treated with Chlorambucil/prednisone followed by fludarabine intermittently, but reasonably well controlled
admitted to the CCU with gradual onset of left sided chest pain became very severe, no associated symptoms exam demonstrated marked left sided chest tenderness Ruled out for MI by enzymes/EKGs on rounds, medical student notices a rash under his left arm vesicular, erythematous base by the time the attending gets there two hours later it has spread to the left chest, but does not cross the midline |
Herpes Zoster
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Frequent in patients with lymphoma, lymphoid leukemias and after bone marrow or PBSC transplantation (up to 50% in some series)
increased risk of dissemination, but still rare Probability of (virus) increased with graft vs. host disease Vaccine NOT indicated (yet) in immunocompromised treatment options not compared in RCTs: IV acyclovir 10mg/kg q 8h PO Acyclovir 800 mg 5x/day PO Valacyclovir 1000 mg tid PO famciclovir 500 mg tid |
Herpes Zoster
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Do peripheral blood counts decrease with age?
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Not significantly
Marrow can sustain normal peripheral blood counts throughout the human lifespan, but… Diminished reserve capacity in times of stress |
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Common causes of anemia in the elderly
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Iron deficiency 20%
Anemia of chronic disease (ACD) or anemia of inflammation 20-25% Chronic kidney disease B12 or folate deficiency |
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Relationship between hemoglobin and mortality
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<12 g/dL increased risk of mortality (HR >1)
12-16 g/dl have (HR <1) |
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Increased mortality
Increased cardiac disease (CHF, MI)Decreasedmuscle mass/ strength Increaseddisability Increased falls and fractures Associated with cognitive impairment |
Clinical associations of anemia in elderly
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May be the first sign of underlying serious illness (ie. Colon cancer)
May be an independent cause of morbidity and mortality |
Iron Deficiency Anemia
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Longer duration of carcinogen exposure
Decreased DNA repair ability Increased genomic instability Decreased tumor suppressor activity Decreased immune surveillance |
Theories of Carcinogenesis in Aging
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Do elderly patients benefit from aggressive chemotherapy?
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Selected elderly patients can benefit from aggressive treatments
Study compares aggressive tx versus supportive care for older adults with AML |
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Population statistics consistently demonstrate decreased survival in adults >65
Patients >65 are 16 times more likely to die of disease1 Older adults experience increased toxicity related to treatment |
As a group, older adults experience inferior outcomes
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Outcome disparity for older cancer patients is multi-factorial
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Treatment disparity:
-research bias and under-treatment Tumor characteristics: -tumor biology Host characteristics: -physiologic changes -impairment in physical function -comorbidities |
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Research bias
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Only 1/3 of patients on NCI sponsored trials were >65 years of age1
Very few adults >75 years of age are enrolled on clinical trials2 Poor generalizability due to selection bias |
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Up front “dose attenuation” results in inferior outcomes when treating for cure in:
Aggressive NHL1 Small cell lung cancer2 Breast cancer3 |
Dose reduction may not be doing older adults any favors
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Why are older adults treated differently?
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Concern for increased toxicity
Question effectiveness of treatment Lack of referral Social marginalization Patient preference? Lack of clinical trial data |
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Age related physiology
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Older adults tend to have decreased reserve capacity in times of stress
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Decreased intestinal absorption
Decline in renal excretion Changes in volume of distribution Altered metabolism by cytochrome P450 |
? Bioavailability
Increased toxicity? Increased toxicity due to increased free drug Impaired activation or elimination? |
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What outcomes are most meaningful to your patients?
Survival? Avoidance of Disability? Maintenance of functional independence? “Quality of life”? |
Treatment Decisions in Elderly Cancer Patients
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Myelosuppression: Use prophylactic colony stimulating factors in patients >65 years old receiving myelosuppressive combination therapy
Renal : Consider adjustment of renally excreted drugs based on GFR Mucositis: Nutritional support, early hospitalization if dysphagia/diarrhea develops Neurotoxicity: monitor neurotoxic regimens closely (ex. hearing loss, neuropathy, cerebellar toxicity)- consider alternatives if possible Cardiac: careful pretreatment assessment, avoid cardiotoxic regimens if possible |
Emerging Guidelines to Minimize Toxicity in Elderly Patients
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Aging is not a disease but does decrease physiologic reserve
Blood counts do not decrease with normal aging Anemia is common and should be evaluated Malignancy is more common in the elderly Considerations of treatment of malignancies in older adults should be individualized on the basis of multiple factors including functional status, comorbidities, and goals of treatment |
Take home points about aging and cancer treatment
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% of all people with cancer will receive radiation at some point during their cancer treatment.
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50-60%
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The “mother of Radiation Oncology”
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Marie Curie. The Curie’s were the first to use ionizing radiation as a potential therapy. The Curie’s received the Nobel Prize early in the 20th century for their work.
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Attacks reproducing cells, it does not distinguish between cancer cells and normal tissues.
The damage to normal cells can result in side effects. Therapy involves a balance between destroying the cancer cells (in order to cure or control the disease) and sparing the normal cells (to minimize undesirable side effects). |
Radiation oncology principles
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is thought to work by damaging the DNA in cells.
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Radiation
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TYPES OF RADIATION USED TO TREAT CANCER
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Electromagnetic radiation, (x-rays and gamma rays). Particulate radiation (electrons, protons, neutrons, alpha particles, and beta particles) are all forms of ionizing radiation
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uses high-energy photons from radioactive sources such as cobalt, cesium or a machine called a linear accelerator.
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The most common type of radiation therapy
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GOALS OF RADIATION THERAPY
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Radiation is considered a local treatment because only cells in the area being treated are affected.
Radiation may be used in early stage cancers in an attempt to cure or control the disease. Radiation may be used before surgery to shrink the tumor or following surgery to prevent the cancer from coming back. It may be used in combination with surgery and/or chemotherapy. |
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is the first part of treatment planning.
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Simulation (sometimes referred to as a marking session)
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At simulation, the size or volume of the tumor is determined. Potential route of spread and normal tissues in the treatment area are assessed. Also consider dosing lymph nodes due to likelihood.
The radiation dose will be decided based on a number of factors and by the ability of the normal tissue to tolerate the radiation; dose is normally based on dose to normal tissue – side effects. |
Treatment planning for radiation oncology
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One Gray is equal to
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100 rads and one cGray (cGy) = one rad.
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the radiation is focused from a source outside the body onto the area affected by the cancer. It is much like getting a x-ray, but for a longer time. This type of radiation may be given by machines called linear accelerators.
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External beam radiation
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is also known as brachytherapy. Brachytherapy means short-distance therapy. The two main types of brachytherapy are interstitial radiation and intracavitary radiation.
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Internal radiation therapy
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several techniques used to deliver a large precise radiation dose to a small tumor volume. The term surgery may be confusing since no incision is actually made. The most common site being treated with this technique is the brain. (Gamma Knife)
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Sterotactic surgery or sterotactic radiation therapy
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A genetic alteration occurs in an immature hematopoietic cell
Resulting in clonality, and excess growth ie: neoplastic transformation ie: cancer Usually occurs with myeloid or lymphoid cells but can involve other cells, including cells in the erythroid or megakaryocytic lineage |
Leukemia pathogenesis
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“Acute” Leukemias
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Describes which cell is in excess
Describes when people present Describes rate of growth Describes type of treatment |
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Acute Myelogenous Leukemia
Acute Nonlymphocytic Leukemia |
Synonyms for Acute Myeloid Leukemia
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AML: What do these blasts do?
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Grow uncontrollably
Signal to grow is always on Signal to stop growing or die gets turned off Maturation (differentiation) is halted Inhibit growth of normal cells in the marrow Quickly becomes a life-threatening disease |
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Prior chemotherapy
Alkylating agents and epipodophyllotoxins Prior ionizing radiation Particularly prenatal (less relevant now) Exposure to benzenes Abnormal genetics: Down syndrome Neurofibromatosis Schwachman syndrome Bloom syndrome Familial monosomy 7 Kostmann syndrome Fanconi anemia |
AML: Risk Factors
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How do we diagnose AML?
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Bone marrow biopsy
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There must be >=?% of blasts to have diagnosis of AML
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20%
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What is definitive for being a myeloid cell?
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Auer rods
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What do we do with the aspirate?
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Flow Cytometry
-This helps us determine lineage -This is how we tell an AML from an ALL –always do this for confirmation Cytogenetics Fish |
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What do we do with the core?
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Look at the cellularity
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AML with t(8;21)(q22;q22), (AML1/ETO)
AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13;q22), (CBFb /MYH11) Acute promyelocytic leukemia with t(15;17)(q22;q12), PML/RAR-alpha and variants AML with 11q23 (MLL) abnormalities |
AML with recurrent genetic abnormalities
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Following MDS or MDS/MPD
Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50 percent of cells in two or more myeloid lineages |
AML with multilineage dysplasia
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Alkylating agent/radiation-related type
Topoisomerase II inhibitor-related type Other |
AML and myelodysplastic syndromes, therapy related
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AML, minimally differentiated
AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic/acute monocytic leukemia Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia variants) Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma |
AML, not otherwise categorized
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AML: Treatment
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Don’t use surgery
Don’t use radiation Use chemotherapy – circulates in the blood like the leukemia cells do Chemotherapy is nonspecific: Kills the good cells as well as the bad cells |
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First treatment patients get
Called so because we are trying to induce a remission (this is our goal) Standard of care: Cytarabine (or ara-C) 100-200 mg/m2/d IV CI on days 1-7 Daunorubicin 45-90 mg/m2/d IV on days 1-3 (and sometimes we add…) Etoposide 100 mg/m2/d IV on days 1-3 “7+3+3” |
AML: Treatment: Induction chemotherapy
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So if the chemo only takes 7 days to give why do we make patients stay in the hospital for 4 to 6 weeks?
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Supportive care (during time of pancytopenia)
Need RBCs Need platelets Preventing and treating tumor lysis syndrome (uric acid, phosphorous, calcium goes to kidneys, potassium – these are chemicals released from the lysed cells) Monitoring for and treating side effects of the medications: Nausea, vomiting, diarrhea, mucositis Cardiotoxicity (daunorubicin), hepatic toxicity, renal dysfunction/failure, etc. |
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AML - How do we know our chemo is working?
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Repeat a marrow on day 14 (nadir marrow)
If no leukemia is visible, await count recovery – takes about another two weeks If leukemia still present, need additional chemo – either “5+2+2” or different chemo regimen This resets the clock and extends hospital stay |
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Recovery marrow taken before patient leaves after induction therapy
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To make sure that the only cells that came back were the good ones.
If we can’t see any leukemia cells, the patient is in remission, and we have achieved our first goal |
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Sludging” symptoms:
Chest pain, shortness of breath, headaches, blurry vision Usually occurs when patients have WBCs >75K with majority of those cells being blasts Need emergent leukopheresis Central line is placed and blasts are filtered out of blood by a pheresis machine (give hydroxyurea to impair cell cycle) WBC can drop from 300K to 150K, for example, in a matter of hours |
Leukostasis associated with AML induction chemotherapy
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Involves three rounds “booster treatments”
Round: high dose ara-C: 3 grams/m2 IV q12 hrs on days 1, 3, and 5 Patients go home after chemo has finished running in (six day hospitalization) – but they still need supportive care Discharge patients on antibiotic pills Arrange for outpatient transfusions as needed ~50% of patients will have to return to the hospital because of fevers while neutropenic, to get IV antibiotics |
AML Treatment: Consolidation
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Increased age
(In)Ability to tolerate chemotherapy Higher incidence of MDR (multi-drug resistant) abnormalities Higher incidence of antecedent hematologic disorders (MDS, etc.) Secondary AML (toxin-induced) Certain genetic abnormalities -5, -7, 11q23 (MLLgene) <10% CR rate Not obtaining a remission after induction chemotherapy |
AML: Bad Prognostic Factors
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APL: acute promyelocytic leukemia t(15:17)
AML FAB M3 >80% CR at 5 years Inv(16) or t(16;16) Some AML FAB M4 ~60% CR at 5 years t(8;21) Some AML FAB M2 >40% CR at 5 years |
AML: Good Prognostic Factors
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Normal cytogenetics and AML?
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Considered to be an intermediate risk factor.
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1st CR if pt has poor cytogenetics
At the time of relapse – but need to get them into CR again |
AML and transplant
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Comprises ~10% of AMLs
In > 90% of cases involves t(15;17) – is diagnostic Patients are younger at the time of diagnosis Associated with risk of DIC High incidence of early fatal hemorrhage (10-20%) 7% of patients will die of intracranial hemorrhage |
AML M3: Acute Promyelocytic Leukemia
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Treatment is different than AML
ie: we don’t use 7+3+3 Instead, we use 7+4+ATRA “7”: 7 days of cytarabine, as before “4”: 4 days of daunorubicin, instead of 3 ATRA: all-trans retinoic acid |
APL: Treatment
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t(15;17)
Chromosome 15 has PML gene (promyelocytic leukemia) Chromosome 17 has RARalpha gene (retinoic acid receptor alpha) – normal promoters don’t work with the translocation Retinoic acid promotes normal promyelocyte differentiation When the translocation occurs, supra-physiological doses of retinoic acid are needed to promote differentiation of the promyelocytes |
ATRA all-trans retinoic acid (Vitamin A)
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Helps decrease bleeding complications associated with APL and DIC
Improves CR rate Works by a different mechanism, we skip the day 14 marrow and just do a recovery marrow |
APL: Treatment: ATRA
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-Hyperleukocytosis
Why cytotoxic chemo follows (drug) by 2 days -(Drug) syndrome AKA: differentiation syndrome Fever, pulmonary infiltrates, hypotension, dyspnea Thought to be due to cytokines from granules Treat with 2 to 3 day course of decadron |
APL: Treatment: ATRA
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CALGB 9710:
Arsenic trioxide improved overall survival and event-free survival Overall treatment is for 2 years, much longer than other AML regimens |
APL: Treatment
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What is the least common type of leukemia in children?
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CLL
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What is relative incidence of leukemia as a cancer in children?
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30%
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What is the most common leukemia in children?
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ALL
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predominance of very immature WBC precursors; these cells proliferate, and lack differentiation.
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Acute leukemia
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Proliferation of relatively mature WBC’s; often indolent; more commonly seen in adults than children
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Chronic leukemia
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peak incidence at age 2-5 years
whites > blacks males > females |
ALL epidemiology
80% of all childhood leukemias are ALL |
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fatigue
pallor bruising, bleeding fever lymphadenopathy hepatosplenomegaly mediastinal mass pain (musculoskeletal) |
Clinical manifestations of ALL
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leukocytosis or leukopenia (high or low white blood cell count, respectively); may see “blasts” on the blood smear
anemia (low hemoglobin/hematocrit) thrombocytopenia (low platelets) may see chemical abnormalities consistent with “tumor lysis” (increased uric acid, phosphorus, potassium, creatinine) |
Blood findings of ALL
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Infection (especially EBV, other viruses)
Immune thrombocytopenic purpura (ITP) juvenile rheumatoid arthritis aplastic anemia other malignancies (e.g. neuroblastoma) |
ALL differential diagnosis
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>25% lymphoblasts in bone marrow (usually upwards of 80%)
lumbar puncture also required for evaluation of CNS disease (loves to go to the brain) |
Diagnosis of ALL
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Diagnosis/classification of ALL
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Morphology
Cytochemical stains Immunophenotyping |
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Hyperdiploidy (>50 chromosomes per leukemia cell)
t(12;21) translocation (TEL-AML1 fusion gene, aka ETV6-RUNX1) Trisomies of chromosomes 4, 10, and 17 |
Cytogenetic findings associated with favorable ALL prognosis
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Hypodiploidy (<44 chromosomes per leukemia cell)
t(4;11) translocation (MLL-AF4 fusion) t(9;22) translocation (BCR-ABL fusion or Philadelphia chromosome) |
Cytogenetic findings associated with an unfavorable ALL prognosis
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Classification of ALL
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-Acute lymphoblastic leukemia (L1/L2 morphology)
Precursor B cell (B-lineage, pre-B, early pre-B) Precursor T cell (T cell) -Acute lymphoblastic leukemia, B-cell (L3 morphology) (mature B-cell, Burkitt cell leukemia) -Acute leukemia, biphenotypic |
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associated with:
Males > Females older age (5-12 years) high WBC count bulky adenopathy, mediastinal mass, hepatosplenomegaly CNS disease |
Precursor T cell (T cell) ALL
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ALL emergencies
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Sepsis (infection)
Bleeding (from thrombocytopenia) Tumor lysis syndrome Hyperleukocytosis (very high WBC count) Tracheal compression/SVC syndrome |
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ALL - treatment
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Combination chemotherapy
4 components of therapy: 1. Remission induction (~1 month) 2. Intensification (consolidation) (~6 months) 3. CNS treatment (throughout all phases) 4. Continuation (“maintenance”) (2-3 years) |
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Commonly used drugs for ALL
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Steroids (prednisone, dexamethasone) – don’t give unless you know what you are treating (can mask “real” problems) – only for lymphoblastic
Vincristine Asparaginase Doxorubicin/daunorubicin (antharcycline) Methotrexate Mercaptopurine Cytarabine Cyclophosphamide |
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Imatinib for ALL
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BCR-ABL (Philadelphia t (9;22))positive
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Nelarabine for ALL
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T-cell
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Rituximab for ALL
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CD20-positive
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Clofarabine for ALL
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All subtypes
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ALL - CNS treatment
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Intrathecal chemotherapy (delivered by lumbar puncture (LP)) – start on first day of therapy and continue throughout treatment duration (18-20 LPs over ~3 years)
radiation therapy (e.g. CNS positive at diagnosis or relapse, T-ALL) Only 5-20% patients currently get CNS radiation Can it be omitted for all patients? high dose IV methotrexate - penetrates CNS |
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ALL - treatment timeframe
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Treatment generally lasts 2.5 - 3 years (exception is B-cell (Burkitt’s) ALL, which is treated intensively for only about 5 months)
stem cell/bone marrow transplants generally reserved for refractory disease or very high risk patients |
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Pediatric ALL - Prognosis
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Depends on multiple factors (age, WBC at diagnosis, etc. – see next slide) but prognosis is generally GOOD, with ~80% overall event-free survival (Unlike adult ALL, where prognosis is relatively poor - only 30-50% of adults are cured)
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ALL - risk assessment
|
Best done by combining the following data for each patient:
presenting clinical features (age, WBC count) blast cell immunophenotype (T-cell vs. B-cell) and genotype (cytogenetics, other DNA tests) early responsiveness to treatment Patients are currently classified as low, standard, high, or very high risk |
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Late effects of ALL therapy (and primary culprits)
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Neurocognitive delay (CNS therapy)
Endocrinopathies (CNS therapy and steroids) Gonadal failure/sterility (alkylating agents) Cardiac dysfunction (antharcyclines) Musculoskeletal disease (steroids) Second malignancies (chemotherapy and radiation therapy) |
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Relapsed ALL
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Longer first remissions are better than shorter first remissions
In general, prognosis for relapsed ALL is 30-50% if long first remission - chemotherapy alone if short first remission - stem cell transplant CNS, testicles (“sanctuaries”) are a relatively common sites of extramedullary (outside bone marrow) relapse |
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– there are some mature cells
Cancer of the white blood cells Malignant cell is relatively immature stem cell Result is excess production of mature cells of multiple lineages and bands RBCs are not elevated – could be anemic |
CML
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How do we diagnose CML?
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Find the Philadelphia chromosome
t(9;22) Chromosome 9: abl gene (Abelson leukemia virus) Chromosome 22: bcr gene (breakpoint cluster region) |
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How does the t(9;22) work in CML?
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The abl protein is a tyrosine kinase, which is an enzyme involved in signal transduction
When the t(9;22) is present, the tyrosine kinase is always phosphorylated (ie always “on”) This provides a constant signal to certain pathways that results in cell growth that exceeds apoptosis |
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Chromosome 22 can break in different regions within the bcr gene, resulting in different sizes of bcr-abl protein products
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p190 (190 kDa protein): seen in ALL
p210 (210 kDa protein): seen in CML |
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Chronic phase of CML
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<5% blasts in the marrow
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Accelerated phase of CML
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Many different criteria
5-20% blasts in the marrow |
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Blast crisis in CML
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>20% blasts in the marrow
Just like any other acute leukemia Can be myeloid or lymphoid (flow cytometry) Treat like a new AML crisis |
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How do you treat CML?
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Gleevec (imatinib mesylate)
TKI (tyrosine kinase inhibitor) – remember that the ABL is always phosphorolated and TK always on STI (signal transduction inhibitor) Small molecule inhibitor Pill taken once a day Side effects: Mild nausea and vomiting Periorbital edema Pleural effusions Well-tolerated |
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Binds to c-kit
On GISTs (GI stromal tumors) Binds to PDGFR-alpha Seen in hypereosinophilic syndrome |
Gleevec
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Gleevec resistance
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Some via T315I mutations
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Dasatinib
Nilotinib Neither are effective against the T315I mutation – go back to caveman tx of CML |
2nd generation tyrosine kinase inhibitors
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Acclerated phase of CML can be treated with
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Higher doses of Gleevec
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Blast crisis in CML is treated like:
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acute leukemia:
Myeloid blast crisis: “7+3” cytarabine x 7 days with daunorubicin x 3 days Lymphoid blast crisis: Complex multi-agent chemotherapy regimen; exactly what we would use for de novo ALL |
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Cancer of the white blood cells
Malignant cell is more differentiated than CML Results in excess numbers of mature-appearing lymphocytes Continuum with SLL (small lymphocytic lymphoma – cancer of lymphocyte – type of NHL) that has no circulating neoplastic cells and resides in lymph nodes |
Chronic lymphocytic leukemia
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What will the CLL CBC look like?
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Elevated total white cell count
Differential is primarily lymphocytic Hemoglobin and platelets are normal Except in advanced stages of disease when Hb and platelets can be low |
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How do we diagnose CLL?
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Peripheral blood sample for flow cytometry
Do not need a bone marrow for diagnosis (+) CD5 (normal t-cell), CD19, CD23 (normal b-cell) (+/-) CD20 (weak expression) (+) surface immunoglobulin Light chain restriction Only kappa or lambda, not both Send chromosomal studies to get information on prognosis |
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When do you start treatment of CLL?
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Need to have symptoms:
Symptomatic lymphadenopathy Symptomatic splenomegaly “Symtomatic” counts Anemia or thrombocytopenia as a result of progression of CLL in the marrow Stage III or stage IV disease Note that the absolute white cell count is NOT listed as an indication to treat |
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Immune dysregulation (do not say functionally neutropenic)
Insufficient immune system: Difficult to fight infection Often need prolonged courses of antibiotics Hypogammaglobulinemic Quantitative immunoglobulins often reveal patients to be pan-hypoglobulinemic If patients have persistent infections or infections severe enough to require hospitalization, will treat with IVIG |
Seen in CLL
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Overactive immune system
Inappropriate destruction of “self” cells Immune thrombocytopenic purpura Labs are the same as with any other: Elevated LDH, bilirubin Low Hb, haptoglobin Can be Coombs positive (a test for antibodies, the so-called anti–human globulin test using either the direct or indirect) Generally treat with steroids Don’t need a bone marrow to make this diagnosis |
AIHA in CLL
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How can we tell if a CLL patient’s thrombocytopenia is from ITP or stage IV disease?
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Do a bone marrow - if it is stage IV, there will be no room in the bone marrow for megakaryocytes to make the plateletes
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Development of diffuse large B cell lymphoma arising from one CLL clone
May have B symptoms, one area of lymphadenopathy out of proportion to others PET scan will show transformed sites CLL is not PET avid (slow growing) DLBCL is very PET avid (fast growing – diffuse large B-cell lymphoma) Must document with biopsy to prove transformed disease Treat with DLBCL regimen such as R-CHOP CLL chemo is ineffective Pts are still left with underlying CLL after treatment complete |
Richter's transformation in CLL
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CLL Treatment
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-Chemotherapy - purine analog based
Fludarabine based Pentostatin based -Patients are at significant risk for tumor lysis syndrome with the first cycle of treatment -Hydration and frequent lab monitoring is important |
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Comprises 2% of all leukemias
Very slow-growing B cell malignancy (CD19, 20, 22) Has aberrant expression of T cell marker CD103 TRAP-positive (tartrate-resistant acid phosphatase), a stain – diagnostic for HCL, only present on HCL Clinically, notable for very large spleens, and dry taps on bone marrows (lot of fibrosis/scaring of bone marrow) |
Hairy Cell Leukemia
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In the bone marrow, cells look like fried eggs
Marrow also has lots of fibrosis Treatment is also with purine analogs: Cladribine – might only need one treatment in a lifetime because this is so slow-growing |
Hairy Cell Leukemia
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-Rolling, tight adhesion, spreading, diapedesis, chemotaxis
-phagocytosis -degranulation -release of antimicrobial products (O2 dependent and O2 independent) |
Neutrophil functions
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Definition: absolute increase in number of leukocytes in peripheral blood
Without reference to cell type or level of maturity In adults, greater than 10,000-11,000/mm3 Majority of cases of leukocytosis are due to an increase in neutrophils |
Leukocytosis
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Leukocytosis caused by:
Infection Inflammation Stress Drugs Trauma Hemolytic anemia |
Normally responding bone marrow
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Leukocytosis caused by:
Acute leukemias Chronic leukemias Myeloproliferative disorders |
Abnormal bone marrow
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An excessive white blood cell response (i.e. 50,000 white blood cells per cm3) associated with a cause outside the bone marrow
May be neutrophilic, eosinophilic, lymphocytic, monocytic Usually caused by relatively benign processes (i.e., infection or inflammation) An underlying malignancy is the most serious but least common cause. Down syndrome babies can have – resolve spontaneously |
Leukemoid reaction
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Decrease emigration of neutrophils from blood into the tissues
Increase release of mature neutrophils from the bone marrow (release of storage pool) Decrease margination of neutrophils inside vasculature |
Corticosteroids
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Defined as absolute neutrophil count of 8,000/mm3 or higher
Mechanisms of: -Increased production by bone marrow Infection Inflammatory stimulus Hemolysis and chronic blood loss Exogenously administered hematopoietic growth factors (G-CSF and GM-CSF) -Increased mobilization from storage pool or marginated pools (pseudo(term)) - White cell count not over 15,000/mm3 Vigorous exercise Epinephrine Labor and pregnancy -Failure to exit the circulation Anatomic or functional asplenia Adhesion deficiency syndromes (decreased endothelial adhesion and migration) – LAD (leukocyte adhesion deficiency) |
Neutrophilia
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Partial or total deficiency of CD11/CD18
Number of circulating neutrophils is increased Associated with severe and fatal bacterial infections Delayed detachment or prolonged healing of umbilical stump |
Leukocyte adhesion deficiency
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Absolute lymphocytosis:
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>9,000/mm3 in infants and small children (2-3 yrs)
7,200/mm3 in older children >4,000/mm3 in adults |
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seen in children due to rapid tissue growth and development of the immune system
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Physiologic lymphocytosis
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Causes of absolute lymphocytosis
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Acute infections: CMV, EBV, pertussis, hepatitis, toxoplasmosis
Chronic infections: TB, brucellosis Lymphoid malignancies: CLL |
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Causes of relative lymphocytosis
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Normal in young children
During viral infections Splenomegaly |
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Benign Reactive Lymphocytosis
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Pronounced :
Pertussis Acute Infectious Lymphocytosis (Coxsackie) Infectious Mononucleosis (EB) |
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Allergic events
Parsitic infections Dermatologic conditions Scarlet fever, cholera, leprosy, GI infections Immunologic disorders: RA, SLE, eosinophilia-myalgia syndrome Malignancies: NHL, Hodgkin's disease MPD Adrenal insufficiency Sarcoidosis Pleural and pulmonary conditions |
Etiology of eosinophilia
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Infections: varicella, chronic sinusitis
Inflammatory conditions: IBS, chronic airway inflammation MPD Endocrinologic: hypothyroid, ovulation, estrogens Alteration of marrow and RE compartments |
Basophilia
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Decrease in the absolute neutrophil count (ANC) below accepted norms for age
Ethnic and racial groups < 900 Benign ethnic neutropenia (some African and Asian) Altitude (lower ANC above 5,000 ft) |
Neutropenia
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Age related “lower limits of normal” for neutrophils
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Term newborn (up to 1 week) < 3,000
Infant (1 week – 2 years) < 1,100 Child, adolescent, adult < 1,500 |
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immune neutropenias, hypersplenism, infection
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Normal marrow reserve
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congenital neutropenias, marrow failure syndromes, chemotherapy, etc
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Decreased marrow reserve
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Low normal neutrophil count
No history of infections Most due to increased neutrophil margination along blood vessel wall Entry into circulation and exit from vascular pool are normal Rapid mobilization of neutrophils from marginal pool with exercise, epinephrine |
Pseudoneutropenia
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Common during viral infections, usually transient
Proctated can be seen with mononucleosis, hep B and HIV Mechanisms: Increased use Up regulation of adhesion and migration due to complement and cytokines Marrow suppression |
Infection induced neutropenia
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More than 100 drugs implicated
Immune mediated or direct destruction of granulocyte precursors |
Drug induced neutropenia
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Antibodies directed to neutrophils or their precursors
Can be associated with other immune cytopenias (hemolytic anemia and immune thrombocytopenia) or autoimmune disorders Chronic benign neutropenia: occur in children and adults. Infections are infrequent despite low ANC (how do you diagnose? – challenge test?). Majority resolve spontaneosly within few yrs from diagnosis |
Immune neutropenia
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-Cyclic neutropenia:
Autosomal disorder Marked neutropenia every 21 days, nadir last 3-7days Patients are subject to recurrent severe infections -Kostmann syndrome Present at birth ANC < 200/ul Predispose to leukemia and preleukemic conditions |
Congenital neutropenia
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Absolute lymphocyte count (ALC) of <1,000/mm3 in adults or <1,500/mm3 in children
ALC of less than 1000/mm3 in an infant is highly abnormal Decreased Production Immunodeficiency Diseases: SCID (severe combined immunodeficiency) or AIDS, aplastic anemia Increased destruction: acute stress (steroid administration), irradiation, immunosuppressive agents, chemotherapeutic agents Increased loss: congenital lymphatic abnormalities |
Lymphopenia
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Stimulation of chemoreceptor trigger zone (CTZ) (outside BBB – then transmits inside BBB to vomiting center)
Peripheral mechanisms - Damage of gastrointestinal (GI) mucosa - Stimulation of GI neurotransmitter receptors Cortical mechanisms - Direct cerebral activation - Indirect (psychogenic) mechanisms Vestibular mechanisms |
Potential mechanisms of chemotherapy induced nausea/vomiting
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Central Mechanism
Chemotherapeutic agent activates the CTZ located in the area postrema in the brainstem Activated CTZ invokes release of various neurotransmitters, which activates brainstem vomiting center Peripheral mechanism Chemotherapeutic agent causes GI irritation and damage to GI mucosa, resulting in release of neurotransmitters Activated receptors mediated by vagal afferents send signals to brainstem vomiting center Neurotransmitters may act independently or in combination to induce vomiting |
Proposed pathophysiology of chemotherapy induced n/v
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Acute phase of CINV
|
Most common
Begins 1 to 2 hours, peaks 4 to 10 hours, resolves within 12 to 24 hours Usually associated with high frequency and severity Serotonin antagonists are most effective Neurokinin antagonists are also effective |
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Delayed phase of CINV
|
Begins 1 to 5 days after chemotherapy, peaks 48 to 72 hours
Less severe than acute N/V, longer duration Associated with high-dose cyclophosphamide, mitomycin-C, cisplatin, doxorubicin, and ifosfamide Neurokinin-1 antagonists are most effective |
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Anticipatory phase of CINV
|
Not associated with a time frame
Conditioned response Usually prior history of severe N/V Stimulated from environment Occurs in up to 25% of patients Often refractory to therapy |
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Blocks serotonin both centrally and peripherally
Effective for acute N/V but not any more effective for delayed N/V than other therapies Most effective when given 30 minutes prior to administration of chemotherapy Increase efficacy when given with corticosteroids (90% effective with corticosteroid/60% w/o) |
Serotonin (5HT3) Receptor Antagonists
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5HT3 Receptor Antagonists Adverse Events
|
Headache (migraine patients don’t have enough serotonin)
Constipation Diarrhea EKG changes – concern only with underlying arrhythmias |
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Ondansetron (Zofran®) (5 cents)
8-32 mg po/iv daily (either daily or divided) 8 mg oral dissolving tablets (ODT) available Granisetron (Kytril®) 1-2 mg po daily 10 mcg/kg IV daily Granisetron (Sancuso) ($250/patch – lasts 7 days) Dolasetron (Anzemet®) 50-100 mg po/iv daily Palonosetron (Aloxi®) 0.25 mg IV x 1 – may last 3-5 days Only indicated for highly emetogenic chemotherapy as oral agent – starting to be used more generally due to availability of generics |
5HT3 Receptor Antagonists
-setron are serotonin receptor antagonists |
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Inhibits Substance P
Indicated for the prevention of acute and delayed CINV in combination with serotonin antagonists and corticosteroids Part of combination regimen with a 5HT3-receptor antagonist plus dexamethasone: Day 1 125 mg PO 1 hour prior to chemotherapy Days 2-3 80 mg PO in morning |
Neurokinin-1(NK-1) Receptor Antagonists Aprepitant (Emend)
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Aprepitant (Emend) Adverse Events
|
Asthenia/fatigue (18%)
Nausea (13%) Hiccups (11%) Diarrhea (10%) Somnolence |
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|
Steroids should be decreased by 50% when given IV or 25% when given PO
Should be used in caution when administering agents that are metabolized by CYP3A4 Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of the following agents: Etoposide* - Irinotecan Ifosfamide (increase in CNS toxicity) - Paclitaxel* Vinorelbine* - Docetaxel* Vinblastine - Vincristine Imatinib - Warfarin *The company has provided data to say that these agents can be administered safely together. |
Drug interactions with Aprepitant (Emend)
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Phenothiazines
prochlorperazine (Compazine®), promethazine (Phenergan®) – you sleep with these Butyrophenones droperidol (Inapsine®) Substituted benzamide metoclopramide (Reglan®) |
Dopamine Receptor Antagonists (use with other antiemetics)
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|
|
Effective for delayed nausea/vomiting
Adverse events Akathisia (shifting in seat; restlessness) – lorazepam can help Dystonia (tremor) – diphenhydramine or benztropine can help sedation – more common with promethazine (will become tolerant to this) |
Phenothiazines
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Prochlorperazine (Compazine®)
5-10 mg PO/IV/PR q 4-6 hours promethazine(Phenergan®) 12.5-50 mg PO/IV/PR q 4-6 hours Prochlorperazine is a more potent antiemetic in cancer patients but has a higher incidence of akathisia and dystonia |
Phenothiazines
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|
Blocks dopamine in the CTZ and peripherally
increases esophageal sphincter tone improves gastric emptying increases transit through small bowel Also blocking serotonin at high dosing – that’s why you low dose dopamine and high dose serotonin Adverse events: EPS, restlessness, sedation, fatigue, nausea and diarrhea (dexamethasone may decrease diarrhea) |
Substituted benzamides
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Metoclopramide (Reglan)
|
10 mg PO q6h (useful for mild nausea)
0.5 mg/kg IV q6h (blocks serotonin) |
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|
Possesses amnesic (retrograde), anxiolytic and sedative properties
Used for anticipatory nausea Not effective for preventing emesis and is usually given with other antiemetics Lorazepam (Ativan) 1-2 mg IV q4h prn |
Benzodiazepines
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|
Increases appetite, improve mood and sense of well being
Immunosuppression May increase the differentiation of WBC and therefore is not given in acute myelogenous leukemia (AML) - demargenation Most information with dexamethasone 10-20 mg po/iv daily Adverse events: mood changes, anxiety, euphoria, headache, metallic taste, abdominal discomfort |
Corticosteroids
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|
|
Less effective than metoclopramide but more effective than phenothiazines
Not effective with highly emetogenicity Adverse events: mood changes, dysphoria, memory loss, hallucinations, blurred vision, hypotension, tachycardia Beneficial with younger patients Dose is 2.5-5 mg po TID Can increase appetite |
Cannabinoids Dronabinol (Marinol)
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|
|
Beneficial for nausea associated with movement (works through vestibular system)
Scopolamine 1.5 mg patch changed every 3 days (transderm patch for seasickness) |
Anticholinergics
Can't see or spit, urinary retention and constipation |
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Regulate hematopoiesis
Proliferation Differentiation Maturation Effects of CSFs on mature cells Increase chemotaxis Enhance phagocytosis Increase cytotoxic killing Improve responsiveness to antigens Enhance eosinophil function |
Growth factors
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|
Granulocyte colony-stimulating factor (G-CSF)
|
Filgastim (Neupogen)
Pegylated filgastim (Neulasta) |
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Granulocyte-macrophage colony stimulating factor (GM-CSF)
|
sargramostim (Leukine)
|
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Erythropoietin (EPO)
|
Procrit or Epogen
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Megakaryocyte CSF
|
Oprelvekin (IL-11) (Neumega)
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|
Supports proliferation of neutrophils
Stimulates neutrophil function No effect on mature eosinophils and macrophages Cancer patients receiving: Myelosuppressive chemotherapy Bone marrow/stem cell transplantation Peripheral blood stem cell collection Severe chronic neutropenia |
Activity of G-CSF Filgrastim (Neupogen)
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Filgrastim (Neupogen®) Adverse Events
|
Bone Pain
Occurs in the lumbar, sternal and pelvic areas Common during initiation of therapy and times of rapid growth May reflect increased bone marrow activity Pain responsive to acetaminophen or NSAIDs (be careful of these b/c they will suppress any fever should it occur) Only attributable adverse event of G-CSF |
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Pegylated (peg means big) Filgrastim (Neulasta)
|
This larger chemical structure makes clearance slower and therefore allows administration once after chemotherapy
Cleared by neutrophils so as the white blood cells recover then they are able to clear the drug (patient dependent) |
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|
Stimulates CFU-GM and CFU-GEMM to increase neutrophils, macrophages, monocytes, eosinophils
No clinically significant activity on other cell lines Autologous bone marrow transplant Treat of BMT failure or engraftment delay (auto or allo BMT) Neutrophil recovery following chemotherapy for AML Mobilization of PBPC Peripheral stem cell transplantation May increase response to antifungal therapy because of macrophage involvement |
Activity of GM-CSF Sargramostim (Leukine®)
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Sargramostim (Leukine®) Adverse Events
|
Constitutional Symptoms
Fever, headache, myalgias, arthralgias Fever responds well to antipyretics May have less fever with SQ administration Bone pain Skin reactions Pleural and pericardial effusions First-dose effect |
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|
Enhances RBC production (inc HCT)
Decreases need for RBC transfusions (so these have gone up so that patients can feel better and not receive blackbox drug) Patients should have Hgb < 10 g/dL or HCT < 30% Monitor iron stores (need the iron for binding!) Requires 2-6 weeks to see response This unfortunately increased the risk of death – only use in non-curable patients End stage renal disease AIDS patients treated with zidovudine Anemia associated with cancer chemo Anemia of prematurity Myelodysplastic syndrome Bone marrow/stem cell transplant Preoperative blood collection |
Activity of EPO Erythropoietin (Procrit/Epogen) and ESAs (Erythropoietin stimulating agents)
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Adverse Events of EPO
|
Hypertension (24%)
Headache (16%) tendency to clot vascular access (more RBCs to clot) Iron deficiency anemia Seizures Achiness and cold sensation in long bones Pyrexia (fever) (38% of AZT-treated patients) |
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|
Larger molecule with more carbohydrate groups to allow for slower elimination
Dose: indicated 2.5 mcg/kg SQ weekly or 500 mcg SQ every 3 weeks (this is given less frequently) Should be used in patients receiving chemotherapy with no intent for cure New FDA guidelines state that all patients should receive medication guide prior to therapy |
Darbopoietin (AraNesp)
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|
|
Activity
Promotes megakaryocyte production Prevents severe thrombocytopenia – this has only prevented a minimal number of platelet transfusions Dosage 50 mcg/kg SQ daily Continue until plt > 50,000 Clinical use has not been shown to prevent transfusions of platelets because transfusion of platelets does not occur until count < 10,000 |
Activity and Dosage of IL-11 Oprelvekin (Neumega)
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|
Adverse Events of IL-11 (no reason to give this dinosaur)
|
Tachycardia (19-30%)
Atrial arrhythmias (60-75%) Peripheral edema (60-75%) Headache (41%) Dizziness (38%) Insomnia (33%) Fatigue (30%) Fever (35%) Rash (25%) Dyspnea (48%) |
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Diseases treatable by HSCT (human stem cell transplant)
|
Leukemias and lymphomas
AML, ALL, CML, CLL Hodgkin's lymphoma Non-Hodgkin's lymphoma Multiple myeloma and other plasma cell disorders Myelodysplastic/ myeloproliferative disorders Myelodysplastic syndrome Chronic myelomonocytic leukemia Agnogenic myeloid metaplasia/myelofibrosis Other malignancies Testicular lymphoma Renal cell Bone marrow failure syndromes: Severe aplastic anemia Fanconi anemia Paroxysmal nocturnal hemoglobinuria (PNH) Pure red cell aplasia Amegakaryocytic thrombocytopenia Immunodeficiency states: Severe combined immunodeficiency (SCID) Wiskott-Aldrich syndrome Hemoglobinopathies: Beta thalassemia major Sickle cell disease Inborn metabolic disorders: Hurler's syndrome (MPS-IH) Adrenoleukodystrophy Metachromatic leukodystrophy |
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collected from and infused into the same person
|
Autologous
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|
collected from an identical twin
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Syngenic
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collected from another member of the same species
Related - member of same family, usually a sibling Unrelated - general population (NMDP) |
Allogeneic
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|
The most important cells are the cells earliest in development, that can then differentiate into WBC, RBC, platelets. The hematopoetic stem cells!
It is now more common to utilize peripherally collected HSC’s. After GCSF priming (+/- preceding chemotherapy) the peripheral blood WBC is monitored. After it increases an outpatient procedure called apheresis is performed |
Peripheral HSCT collection
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|
|
nothing more than glorified high dose chemotherapy, or chemotherapy with a cellular rescue.
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Autologous HSCT
|
|
|
Tumors for which we would consider (treatment) as a therapy have steep dose response curves to chemotherapy.
Increasing the doses of chemotherapy continues to increase the numbers of cancer cells killed. The dose limiting toxicity to even more effective doses of chemotherapy is myelosuppression Is a mechanism to get around the dose limiting toxicity |
Autologous HSCT
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|
To be successful, you need to have a chemosensitive disease
You need to be able to harvest a healthy graft Ex- not contaminated by active tumor Ex- can not use in bone marrow failure states such as aplastic anemia, myelofibrosis, etc |
Autologous HSCT
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|
Common indications for autoHSCT
|
Multiple myeloma
Large cell lymphoma in first relapse Hodgkins disease in relapse AML with high risk cytogenetics in first CR if not a candidate for allogeneic HSCT due to lack of donor or underlying patient status High risk peripheral T cell lymphomas in first CR |
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Guarantee of a clean graft
Can be used in marrow failure states Largest difference is this is an immunologic intervention, hoping to harness a graft versus tumor (leukemia in the past) effect Much of our immunity is based on our blood cells (we think of this in infection). Cellular immunity also is involved in cancer surveillance Donor lymphocytes in absence of chemotherapy can induce regression of leukemias Higher rate of relapse in syngeneic than allogeneic HSCT in AML 52 vs 16% at three yrs |
Benefits: Allogeneic vs AutoHSCT
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Need to find an HLA matched donor, most often a sibling.
Graft versus host disease- essentially grafted cells recognizing patient as “non-self” and attacking. Primarily a T cell mediated process Acute vs chronic. Need to give additional immunosuppressive drugs to prevent this, which further increases risk of infection Largely due to GVHD and increased infections, TRM is much higher- 10-20% by day 100. |
Negatives Allo vs AutoHSCT
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Who is a compatible donor? Immunology and HLA typing
|
Histocompatibility typing - “tissue typing”
HLA: human leukocyte antigens= MHC (Major histocompatibility complex) in humans Chromosome 6 has the genes that determine the compatibility antigens ( Class I and Class II) Gene Loci are designated as: A, B, C (Class I) D (Class II) C appears to have little role in “compatibility” 6 main antigens expressed ( 2 copies of each A, B, D) one from each chromosome 6 |
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Immediate access to stored stem cells after search
Are relatively immune incompetent in mounting normal allogeneic response Has been shown to have less GVHD Donors are less allo-immunized Can tolerate wider HLA disparity Less likely to be CMV+, hence less CMV infections Eurocord reported 0.3% positive for CMV by PCR, compared to > 40% positive in adult BM 20% are collected from ethnic minorities ethnic minorities are underrepresented in most marrow donor registries |
Umbilical Cord Blood
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Risk factors for acute GVHD – can happen any time post transplant
Occurs in 10-50% of all allogeneic stem cell transplant pts |
Increasing age of host
Prior exposure of donor to other blood groups (including pregnancy) Donor and recipient gender disparity – relatively minor CMV status of donor and host Intensity of the transplant conditioning regimen Peripheral blood stem cell versus bone marrow transplantation Acute GVHD prophylactic regimen used |
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Most common site is skin, often manifesting as an erythematous maculopapular rash at the time of engraftment
Can also be involved in chronic (condition) leading to sclerodermatous changes |
GVHD - Skin
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Liver is second most common site
Often first increased serum levels of conjugated bilirubin and alkaline phosphatase . This reflects the pathology associated with liver (condition): damage to the bile canaliculi, leading to cholestasis DDx includes, VOD (veno-occlusive disease), viral hepatitis, drug toxicities Diagnosis best made by biopsy, which is technically difficult due thrombocytopenia. Often done via transjugular biopsy to minimize blood loss. |
Acute GVHD- Liver
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GI tract involvement is also very common
Most commonly manifests as diarrhea and abdominal cramping. Often very severe and can cause over 10L stool output per day DDx: includes reaction to preparative regimen, antibiotics, infection –c.diff Generally requires endoscopy and biopsy |
GVHD - GI
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Note apoptotic bodies in the crypts and “popcorn lesions”
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GVHD Colon
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Use the best matched donor
T cell depletion: ATG, alemtuzumab; but increased risk of tumor recurring Chemotherapy ex- Methotrexate, immunosuppressants :Steroids, cyclosporine, mycophenylate. Planned gradual reduction of immunosuppression Reduced intensity allografting with gradually increased cellular dose of transplanted cells |
Prevention - Treatment of GVHD
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Additional immunosuppression
First step is pulsed steroids Increased immune suppression Cyclosporine, tactolimus, mycophenylate ATG Other experimental measures |
GVHD: Treatment
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Obviously this represents a very aggressive therapy, and patients have to be fairly healthy
Remember for most patients this is not the first step, but the final step Preserved cardiac, pulmonary, liver function Chemosensitive disease at a minimum, preferably disease in remission No substantial ongoing infections |
HSCT Host factors
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Evaluation of the Patient with Possible Infection The 3 Preliminary Questions to Always Ask
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What type of host is being evaluated? Is the patient immunocompetent or is he/she immunocompromised (or immunoincompetent or immunodeficient)?
If the patient is immunocompromised, what is the nature of the major defect in host defenses? Can the major defect be identified or predicted? If more than 1 defect is likely present, is 1 dominant? How long has the defect been present (i.e., Is a discrete time of onset identifiable?)? |
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An ICH has impaired resistance to infection that is secondary to:
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Combination of underlying disease and treatment
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Impaired resistance to infection is a consequence of disease or Rx-induced alterations in one or more of the basic host defenses:
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-Neutropenia (ANC <500)
-decreased antibody production -decreased CMI (CD4 <200 cells/cu mm) -disrupted barriers -hypgammaglubinemia (IgG level <800 mg/dl) |
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Since the treatment of established infection in the ICH still is associated with suboptimal outcomes, the primary goal of management should be:
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The prevention of infection
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Effective prevention of infection in the ICH is predicated upon a knowledge of the
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Origin of infecting pathogens (exogenously acquired vs endogenously present)
For those organisms that are exogenously acquired, it is imperative that the route of transmission to humans be known (ie, direct contact, airborne, etc) so attempts can be made to disrupt transmission or minimize risk of exposure |
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Organisms native to host & present on admission (e.g. - resident flora of GI tract including Candida species)
Account for ~50% of infections Suppressive measures Frequent washing of skin surfaces Administration of prophylactic antimicrobials |
EPIDEMIOLOGY OF INFECTION IN THE ICH Endogenous Organisms
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Organisms not part of the host’s resident microbial flora on admission (e.g. - Aspergillus)
Account for ~50% of infections Sources of acquisition would include hands of personnel, air, food, fomites, and medical devices Measures to reduce acquisition Strict handwashing Protective isolation Special air handling systems (ie, HEPA filtration) Special diets |
EPIDEMIOLOGY OF INFECTION IN THE ICH Exogenously Acquired Organisms
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less sensitive markers for infection in the overtly neutropenic.
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Rubor, Calor, Tumor and Dolor
However, Fever is a reliable marker! |
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The most frequently occurring and reliable sign of infection in the neutropenic host
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FEVER! FEVER! FEVER!
Infection may begin and progress in the absence of fever and Fever is not specific for infection (30% to 45% of febrile episodes may be noninfectious in etiology) |
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NONINFECTIOUS CAUSES OF FEVER IN ICHs Special Considerations
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Underlying Diseases
Malignant neoplasms Rheumatic disorders including vasculitis Hypersensitivity Drug, blood products, diagnostic agents, prostheses Metabolic Gout, hyperthyroidism, adrenal insufficiency Cardiac and Vascular Thrombophlebitis, myocardial infarction, pericarditis, arteritis Pulmonary Emboli, atelectasis, infarcts Central Nervous System Infarct, hemorrhage, post-neurosurgical inflammation |
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FEVER IN THE ICH
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Single temperature > 38.3°C (101°F)
or Temperature > 38°C (100.4°F) for > 1 hr or Temperature > 38°C (100.4°F) on 2 or more occasions within 24 hrs |
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Skin GI tract
Cutaneous lesions Esophagitis HEENT Perianal infections Eye disease CNS Oral lesions Meningitis/encephalitis Sinusitis Blood Lungs Septicemia (? catheters) Pneumonitis FUO (fever of unknown origin) |
COMMON “CLINICAL SYNDROMES” IN THE IMMUNOCOMPROMISED HOST
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FEVER, RESPIRATORY SYMPTOMS, and ABNORMAL CXR IN THE ICH
% infectious vs. % noninfectious causes |
75% vs. 25%
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Geman helmets
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Seen on pneumocystis smear
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ICH patients
---Fever + cough = Pneumonia ---Fever + headache = CNS infection |
When you are evaluating an ICH with fever, try to identify the clinical syndrome that the patient is manifesting as that offers important insight into potentially causative organisms. The patient has fever + ……….
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Pneumonia in GRANULOCYTOPENIC PATIENTS WITH ACUTE LEUKEMIA RECEIVING REMISSION INDUCTION THERAPY
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Pseudomonas aeruginosa
Klebsiella pneumoniae Staphylococcus aureus Aspergillus fumigatus and flavus Agents of mucormycosis |
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Anorectal lesions in GRANULOCYTOPENIC PATIENTS WITH ACUTE LEUKEMIA RECEIVING REMISSION INDUCTION THERAPY
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Pseudomonas aeruginosa
Escherichia coli |
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Pharyngitis in GRANULOCYTOPENIC PATIENTS WITH ACUTE LEUKEMIA RECEIVING REMISSION INDUCTION THERAPY
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Mixed flora
Normal oral flora Gram-negative bacilli Candida sp. Staphylococcus aureus |
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Esophagitis in GRANULOCYTOPENIC PATIENTS WITH ACUTE LEUKEMIA RECEIVING REMISSION INDUCTION THERAPY
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Candida sp.
Cytomegalovirus Herpes simplex Gram-negative bacilli |
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Skin lesions in GRANULOCYTOPENIC PATIENTS WITH ACUTE LEUKEMIA RECEIVING REMISSION INDUCTION THERAPY
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Gram-negative bacilli
Staphylococcus aureus Normal skin flora Corynebacterium sp. Staphylococcus epidermidis |
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UTI IN GRANULOCYTOPENIC PATIENTS WITH ACUTE LEUKEMIA RECEIVING REMISSION INDUCTION THERAPY
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Stool flora
E. coli |
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Pathogens in the ICH
Extracellular pathogens Pyogenic bacteria (S. aureus, GNRs) Filamentous fungi (Aspergillus, Zygomycetes) Candida sp. |
Phagocyte cell deficiency
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Pathogens in the ICH
Intracellular pathogens Viruses (HSV, VZV, CMV) Parasites (Toxoplasma, Pneumocystis) Mycobacteria Fungi (Candida, Cryptococcus) Selected bacteria (Legionella, Nocardia) |
CMI deficiency
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Pathogens in the ICH
Encapsulated bacteria S. pneumoniae H. influenzae |
Antibody deficiency
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Heterogeneous group of disorders
Many (over 40) Due to multiple stages of normal lymphocyte development Genetic abnormalities result in uncontrolled proliferation of neoplastic lymphocytes at a particular developmental stage |
Lymphomas
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Primary Lymphoid Tissues
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Bone marrow
Thymus |
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Secondary Lymphoid Tissues
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Lymph nodes
Spleen Tonsils Clusters of lymphoid tissue in the GI and pulmonary tracts |
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Mature in the bone marrow
Enter the peripheral blood circulation and migrate to secondary lymphoid tissues |
Normal B Cell Development
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is made up of spherical clusters of B-lymphocytes called follicles
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Cortex of lymph node
If the "virgin" B-cells are unexposed to antigen, they compose homogeneous primary follicles. If the B-cells have been stimulated by antigen and are in the process of proliferating and transforming themselves, they form a pale-staining germinal center surrounded by a mantle zone of smaller, darker B-lymphocytes. The whole assembly is called a secondary follicle |
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Lymph node area:
T cells Antigen presenting dendritic cells High endothelial venules |
Paracortex
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Lymph node region:
Plasma cells Medullary sinuses |
Medulla
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Lymph node region:
Macrophages, histiocytes that capture antigen and process it |
Sinuses
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Naive B cells are located here
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Primary follicle of lymph node
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B cells that are proliferating after encountering an antigen
Naïve B cells get pushed to periphery and form the mantle zone Have germinal centers Dark zone: centroblasts (grow and divide) Light zone: centrocytes (more mature and differentiating) Tingible body macrophages: destroy B cells with “wrong” antibodies |
Secondary follicles in lymph node
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Normal T Cell Development
|
Lymphoid stem cells migrate to thymus (still a lot not known) via the peripheral blood circulation
Occurs even after puberty |
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Normal T Cell Development in lymph node
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Cortex
Thymic epithelial cells interact with lymphocytes to help them differentiate Physical and chemical interactions Rapid proliferation (look like lymphoblasts) and move in toward medulla Medulla Final development occurs here Look like resting lymphocytes Only 5% of the cells in the cortex make it this far (why?) |
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Thymic epithelial cell (TEC) has an MHC (major histocompatibility complex) molecule on its surface
TEC presents a peptide produced from processing an antigen Thymocyte recognizes the MHC protein (self) and the antigenic peptide (nonself) via the T cell receptor Signal for spontaneous apoptosis is turned off |
Positive selection in normal T cell development
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Central tolerance:
Any thymocyte that has a high affinity for the self MHC molecule and a peptide found on the antigen presenting cells in the thymus gets apoptosis induced Peripheral tolerance: Many tissue specific antigens are not present in the thymus Similar mechanism that occurs outside the thymus, except: Cells do not undergo apoptosis, but anergy (unresponsiveness) Why is this helpful? Fewer autoimmune problems Molecular mimicry may play a role – sometimes the T-cell will end up destroying same cells b/c it looks like a non-self cell – how autoimmune occurs |
T cell development and negative selection
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T cells primarily stay in thymus if
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T cell receptor is produced from alpha and beta genes
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T cells primarmily migrate to various places in the body, such as the epithelium of the GI tract (to help with mucosal defenses) if
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T cell receptor is produced from gamma and delta genes
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Burkitt’s Lymphoma/Leukemia
Pre-B cell ALL/Lymphoma Pre-T cell ALL/Lymphoma Adult T cell Lymphoma (HTLV-1) |
High grade (Highly Aggressive)
NHL |
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Diffuse large B cell lymphoma
Anaplastic large cell lymphoma Mantle cell lymphoma |
Intermediate grade (Aggressive) NHL
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CLL/SLL
Lymphoplasmacytic lymphoma Plasma cell myeloma Follicular lymphoma Mantle cell lymphoma Marginal zone B cell lymphoma T cell large granular lymphocyte leukemia Mycosis fungoides NK cell LGL |
Low grade NHL
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Most common low grade non-Hodgkin lymphoma
22% of all new NHL diagnoses Incidence increases with age Median age 60-70 years of age |
Follicular Lymphoma
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“Small cleaved cells”
Mature-appearing Flow cytometry: CD20+ CD10+ bcl-2+ CD5- |
Follicular Lymphoma
B cell lineage (think of the CD20+) |
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consist of centrocytes,
the small cleaved cells, and centroblasts, larger cells that divide more The larger the number of centroblasts, the more aggressive |
Follicular lymphoma
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0-5 centroblasts/hpf
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Grade 1 Follicular Lymphoma
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6-15 centroblasts/hpf
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Grade 2 Follicular Lymphoma
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centrocytes present OR
solid sheets of centroblasts Acts more like intermediate grade lymphomas |
Grade IIIa/Grade IIIb
follicular lymphoma |
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Overall lymph node architecture is recognizable but…
Mantle zone is lost Follicles start to merge together Polarization of germinal center is lost Paracortex is lost |
Follicular lymphoma
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Approximately 85% of patients with (condition) will have t(14;18)
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Follicular lymphoma
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Not curable
But is very treatable, ie: responsive to chemotherapy “Reset the clock”, “mow the grass” No definite standard of care Treatments may range from watchful waiting to stem cell transplantation |
Follicular lymphoma: treatment
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FLIPI
5 adverse prognostic factors: Age > 60 years Ann Arbor Stage III-IV Hb < 12 g/dl Number of nodal areas >4 LDH > upper limit of normal |
Follicular Lymphoma International Prognostic Index
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|
Most common of the intermediate grade lymphomas
Comprises ~30% of all new NHL diagnoses |
Diffuse large B cell lymphoma
|
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CD19+, CD20+
B cell lineage Cells are larger than a normal lymphocyte No standard cytogenetics Normal architecture is usually effaced Often very responsive to chemotherapy |
Diffuse Large B Cell Lymphoma
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|
Standard treatment is R-CHOP:
|
DLBCL
R: rituximab (Rituxan) C: cyclophosphamide (Cytoxan) H: Hydroxy-doxorubicin (doxorubicin) O: Oncovin (vincristine) P: Prednisone |
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|
One of the fastest growing tumors that exist
# of person’s cells doubling time is 24 to 48 hours |
Burkitt’s Lymphoma (Leukemia!)
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3 types:
African: affects jaw or facial bone “American”, or endemic: affects lymph nodes in abdomen, GI tract Immunodeficiency-associated |
Burkitt’s Lymphoma/Leukemia
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Infection with malaria causes excess production of B cells, which are infected with EBV
Tumor cells originate from a single EBV infected B cell |
African Burkitt’s Lymphoma
Noted that areas of high rates of Burkitt’s also had high rates of malaria Children with sickle cell trait were mostly free of both malaria and Burkitt’s lymphoma |
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|
Usually 4-7 years of age
Male : female 2:1 Incidence is 50 times higher than in US Involves bones of the jaw and other facial bones; kidneys, GI tract, other extranodal sites EBV is almost always found |
African Burkitt’s Lymphoma
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Usually what we see in the US
Occurs worldwide regardless of climate Accounts for 1-2% of lymphomas in adults and up to 40% of lymphomas in children Involves the abdomen, ovaries, kidneys, omentum, Waldeyer’s ring, and other extranodal sites 15-30% of cases will be EBV(+) |
Sporadic Burkitt’s Lymphoma
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Primarily occurs in patients affected with HIV – this then becomes AIDS-defining
Also seen in allograft recipients, congenital immunodeficiency states Accounts for 30-40% of all of NHL in HIV (+) patients Other AIDS-defining malignancies: Kaposi’s sarcoma Systemic NHL, primary effusion lymphoma, CNS lymphoma Cervical cancer |
Immunodeficiency-Associated Burkitt’s Lymphoma
|
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|
Diagnose with tissue
Starry sky pattern – big time board question ~100% Ki-67 staining CD20(+), CD10(+), CD5(-) |
Burkitt’s Lymphoma
|
|
|
All have a cytogenetic abnormality involving chromosome 8: c-myc
t(8;14): Ig heavy chain gene on chr 14 t(2;8): Kappa light chain gene on chr 2 t(8;22): Lambda light chain gene on chr 22 |
Burkitt's Lymphoma
|
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Treatment must begin immediately
These patients are at extremely high risk for spontaneous tumor lysis syndrome These like to go to CNS – must give intrathecal, so that CNS does not become a sanctuary site; testicles are other sanctuary |
Burkitt's Lymphoma
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Clonal proliferation of a cell line derived from the myeloid stem cell
|
Myeloproliferative Disorders
|
|
|
vHL protein targets HIF-1a
for destruction by proteosomes (ubiquitination) No HIF-1a/HIF-1b complex Epo gene not transcribed |
Regulation of Normal Red Blood Cell Production - normoxia
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|
HIF-1a is not degraded
HIF-1a/HIF-1b bind to Epo gene Stimulate transcription of Epo |
Regulation of Normal Red Blood Cell Production - hypoxia
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Appropriate causes of erythrocytosis
|
Hypoxia:
COPD R to L cardiac shunt Sleep Apnea High altitude Increased affinity for Hb: Chronic CO poinsoning New kidneys keep secreting Epo: After renal transplant |
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Clonal disorder
RBC production is independent of erythropoietin and its receptor Do not need Epo to form RBCs Blocking Epo receptor does not “turn off” RBC production The Epo receptor has no mutations Epo level will be low |
Polycythemia Vera
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|
|
>80% of (condition) patients
Valine substituted for phenylalanine at amino acid position 617 of JAK-2 (Janus activating kinase-2) Results in constituitively active tyrosine kinase activity Promotes cytokine hypersensitivity, or cytokine independent growth Causes erythrocytosis |
Polycythemia Vera: JAK-2
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|
|
Elevated hemoglobin and hematocrit
Elevated RBC mass ~60% of patients will have a platelet count > 400K ~40% of patients will have a WCC > 12K Why? Bone marrow overall cellularity is increased |
Polycythemia Vera: Lab values
|
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“Congestion”:
HA, visual changes Dizziness Paresthesias Facial plethora Pruritis after a warm bath Bleeding, bruising Thrombosis: MI, DVT, PE, CVA, Budd-Chiari syndrome Hepatosplenomegaly Erythromelalgia – painful red hands |
PV: Signs and Symptoms
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|
|
Increased red blood cell mass
Isotopic studies “Very much” increased Hb and Hct Other causes of polycythemia are ruled out And one or more of the following: Platelet count > 400K WCC > 12K Low Epo levels Bone marrow biopsy: Prominent erythroid and megakaryocytic proliferation Fibrosis |
Polycythemia Vera: WHO Criteria for Diagnosis
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Polycythemia Vera: Natural History
|
Thrombotic events:
MI, CVA, DVT, PE Risk increases with age and white cell count (marker) Risk of transformation: Myelofibrosis AML Depending on age and previous treatments |
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Polycythemia Vera: Treatment
|
Phlebotomy
Goal Hct < 45% for males; < 42% for females Hydroxyurea Aspirin 81 mg |
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Transient processes
Acute blood loss Recovery from thrombocytopenia Acute infection or inflammation Response to exercise Drug reactions Sustained processes Iron deficiency Hemolytic anemia Asplenic state Chronic inflammatory or infectious diseases Cancer |
Thrombocytosis: General
|
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Clonal disorder
Independent of thrombopoietin or its receptor (c-Mpl) TPO levels are normal or elevated Decreased clearance JAK2 mutation seen in ~50% of patients |
Essential Thrombocytosis
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|
|
Sustained platelet count ≥450K
Hyperplasia of megakaryocytes on bone marrow biopsy Absence of t(9;22)(CML) and other causes of secondary thrombocytosis |
Essential Thrombocytosis: Diagnosis
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ET: Blood Counts
|
Elevated platelet count
Normal white blood cell count Normal hemoglobin |
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ET: Natural History
|
Bleeding due to abnormal platelet function
Thrombosis CVA, TIA, MI, priapism Splenomegaly Erythromelalgia Risk for progression to myelofibrosis or AML |
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ET: Treatment
|
Hydroxyurea
Aspirin |
|
|
Clonal disorder
Excess number of circulating eosinophils Some patients will respond to Gleevec (imatinib) |
Chronic Eosinophilic Leukemia
|
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|
“Scarring” of the bone marrow
Reticulin and/or collagen fibrosis Decreased cellularity of bone marrow Often have “dry taps” |
Chronic Idiopathic Myelofibrosis: Bone Marrow
|
|
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Marked splenomegaly – trying to be hematopoietic
Hepatomegaly present as well - hematopoietic Extramedullary hematopoiesis can be found in unusual places: Pleural effusions Pericardial effusions Ascites Central nervous system |
Chronic Idiopathic Myelofibrosis: Clinical Presentation
|
|
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Chronic Idiopathic Myelofibrosis: Blood Counts
|
Leukoerythroblastic picture:
Pseudo-Pelger-Huet cells Giant platelets All signs of marrow replacement Patients are usually anemic WCC and platelet count may be high or low |
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|
Chronic idiopathic myelofibrosis:
factors |
JAK2 mutations also seen in ~50% of patients
Risk of leukemic transformation Usually myeloid Can be lymphoid, erythroid, megakaryocytic, or mixed lineage |
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Chronic Idiopathic Myelofibrosis: Treatment
|
Palliative
Hydroxyurea Splenectomy Appropriate acute leukemia treatments with transformation (prognosis worse than de novo leukemia patients) |
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|
Ineffective hematopoiesis
Cells do not progress through the normal stages of maturation Peripheral blood: cytopenias Bone marrow: hypercellular, with abnormal cells How do you think patients will present? |
Myelodysplastic Syndromes
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MDS: Clinical Presentation
|
Recurrent infections
Fatigue, pallor Bleeding Usually don’t have splenomegaly (unlike myeloproliferative disorders) |
|
|
Bone marrow biopsy and aspirate
Look for dysplastic cells Look for an increased number of blasts < 5% blasts: Normal >20% blasts: Acute leukemia 6-19% blasts: (condition) (does not need to be present but is diagnostic) Also evaluate chromosomes (with cytogenetics and sometimes FISH) Helps with prognosis |
MDS: diagnostic
|
|
|
Two greatest risk factors for developing AML
from MDS are: |
Age
IPSS score |
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Cytogenetics: (MDS type)
Clinical course tends to be relatively more benign Overall more responsive to certain treatments Thalidomide Lenalidomide |
MDS: 5q- Syndrome
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MDS: Treatment
|
Supportive care
Antibiotics, transfusions Growth factors: EPO, GCSF Iron chelators (Exjade [deferasirox]) Binds iron which gets excreted in urine and bile Chemotherapy Different from AML chemotherapy Monitor for transformation to AML Remember outcomes are worse for patients with AML arising from MDS |
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|
Genetic mutation results in increased numbers of (condition cells) with increased amounts of antibody production
Excess antibodies can cause end organ dysfunction Get continuum of disorders depending on amount of excess protein present |
Plasma cell dyscrasias
|
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Plasma Cell Dyscrasias: A Continuum
|
MGUS (monoclonal gammopathy of undetermined signifance) to
Mutliple myeloma to Plasma cell leukemia |
|
|
Plasma Cell Dyscrasias: Diagnosis
|
To measure the number of plasma cells:
Bone marrow biopsy and aspirate To measure the amount of protein (antibody) Comprehensive panel Total protein elevated in excess of albumin Serum quantitative immunoglobulins Serum protein electrophoresis Serum immunofixation Serum free light chains |
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|
Tells us how much immunoglobulin a patient has
IgG 3404 mg/dl IgA 260 mg/dl IgM <12 mg/dl (for example) Can we tell if this is a monoclonal excess of IgG by this information? No |
Quantitative Immunoglobulins used in concert with SPEP
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|
|
Clonal disorder
One narrow peak All the proteins are the same so they travel the same distance on the electrophoresis gel Quantitates the M spike 0.40 g/dl, for example Can we tell if this is IgG (or IgA or IgM)? No |
SPEP: Monoclonal Gammopathy used in concert with quantitative immunoglobulins
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|
|
Run patient’s serum on gel
Stain for different antibodies using specific reagents Confirms clonality Tells us which antibody is in excess IgG kappa, for example |
IEP: Monoclonal Gammopathy
|
|
|
Get quantification of amount of light chains in the serum
Free kappa, serum: 1720.0 mg/L Free lambda, serum: 1.8 mg/L Free kappa/lambda ratio: 15.9 (normal 2:1) For example |
Serum Free Light Chains
|
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MDS End Organ Damage: Bones
|
Increased osteoclast activation
Leads to lytic lesions in the bones Calvarium Spine Ribs Pelvis Long bones |
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MDS End Organ Damage: Kidneys
|
Deposition of Ig
Cast nephropathy "Myeloma kidney" Infitration of kidney by plama cells *Think Bence-Jones proteinuria |
|
|
MDS End Organ Damage:
Bone Marrow |
Increased numbers of plasma cells in the marrow
Normochromic normocytic anemia Circulating plasma cells usually only seen with plasma cell leukemia Classic changes seen on peripheral smear - Rouleaux formation due to extra monoclonal proteins |
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|
MDS End Organ Damage: Electrolytes
|
Hypercalcemia
Due to osteoclast activation Contributes to renal dysfunction “Stones, bones, groans, and moans” (applicable to all hypercalcemic states) Stones: kidney stones Bones: increased bone rebsorption Groans: constipation Moans: psychiatric issues |
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Plasma Cell Dyscrasias: Treatment
|
Depends on where the patient falls along the continuum
Observation Oral chemotherapy Intensive IV chemotherapy |
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|
Transmembrane protein
Found everywhere Except in the bloodstream Deletion is lethal (can create mouse with 1% tissue factor, but can’t live w/o any) Cofactor for Factor VIIa activity Factor X activation – static system Factor IX activation – flowing system TF-VIIa is inhibited by TFPI |
Trigger is Tissue Factor
|
|
|
TF-VIIa is inhibited by
|
TFPI - Tissue factor pathway inhibitor
|
|
|
Major coagulation effector enzyme
Converts Fibrinogen to Fibrin Activates Factor XIII FXIIIa crosslinks Fibrin Activates Platelets |
Thrombin
|
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|
Soluble, digested by plasmin
|
Fibrinogen
|
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Weak clot, easily digested by plasmin
|
Fibrin
|
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|
Strong clot, can be digested by plasmin
|
Gamma crosslinked Fibrin
Linear linking between fibrin segments with Factor XIIIa |
|
|
Strong clot, resists plasmin digestion
|
Alpha crosslinked Fribrin
3-D linking between fibrin segments with Factor XIIIa |
|
|
Vitamin K-based clotting factors and anti-coagulant factors
|
II, VII, IX, X
Protein C and Protein S |
|
|
Thrombin and AT3 in the presence of what creates what?
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UF Heparin
Thrombin anti-thrombin |
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FXa and AT3 in the presence of what creates what?
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UF and LMW Heparin
X anti-thrombin |
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FIXa and AT3 in the presence of what creates what?
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nothing
IX anti-thrombin |
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Thrombin and Thrombomodulin combine to create (part of protein C system)
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TM IIa
Loses the ability to activate factor V, X, platelets and fibrinogen to fibrin |
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TM-IIa is used to convert what?
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Protein C to aPC
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What does aPC do?
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aPC kill the amplifier FVa to FVi in the presence of Protein S (and some VIIIa)
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Triggered by aPC
Plasmin is the effector enzyme Relatively non-specific serine protease Fibrin specificity is conferred by activation mechanism |
Fibrinolysis
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aPC goes to aPC receptor on endothelial cell - endothelial cell releases
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tPA
converts Plasminogen to Plasmin |
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Plasmin converts what to what
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Fibrin to FDP (d-dimers)
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Severe deficiency of a single factor
Hemophilia Immune inhibitors Combined deficiency of many factors Vitamin K deficiency (2, 7, 9, 10) Liver disease (everything but 8) Anticoagulation Warfarin Heparin Argatroban, Refludan, Angiomax Excess Fibrinolysis Liver disease Thrombolytic therapy |
Decreased thrombin/plastin ratio - defective hemostasis
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Flow velocity
Laminar versus turbulent Vessel diameter Blood viscosity |
Shear forces
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Pressure difference across the vascular defect
Pressure gradient |
Hydraulic forces
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In a closed space, as bleeding continues, external pressure rises to match internal pressure
Effectiveness depends on pressure difference If external pressure rises above a critical value all blood flow ceases and other structures are compromised giving a “compartment syndrome” – particularly in the limbs |
Tamponade
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If external pressure rises above a critical value all blood flow ceases and other structures are compromised giving a
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“compartment syndrome” – particularly in the limbs
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Shear forces increase as
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Linear velocity increases
Activated coagulation factors are washed away Viscosity increases Vessel radius decreases Flow changes from laminar to turbulent High flow rates Vessel irregularities |
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Virchow's triad
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Alteration in the vessel
Damaged endothelium Exposes tissue factor Exposes collagen/VWF Alteration in the blood Increased thrombin generation Decreased plasmin response Stasis Valve pockets Area of hypoxia |
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Atherosclerotic plaques as focus
Tissue factor exposure by smooth muscle cells (at base of ulcerated plaque) Platelets are central High shear setting vWF involved Coagulation involved in thrombus growth |
Arterial thrombosis
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Inherited
Protein C, Protein S, AT3 deficiencies FV Leiden, G20210A mutations Congenital Factors II, VII, VIII, IX, XI, VWF, homocysteine Acquired Age Lupus anticoagulant, DIC Obesity, sedentary lifestyle, smoking Malignancy, surgery, pregnancy HIT/HITT |
Thrombophilic Factors
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TF on circulating monocytes
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Activation by lipopolysaccharide – sepsis
Disseminated intravascular coagulation - DIC |
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AT3 is adequate to control the coagulation cascade
But:- Factors V and VIII are being activated to FVa and FVIIIa by thrombin Procoagulant effectiveness increases More thrombin produced for a given stimulus Circulating platelets are activated Risk of thrombosis is increased |
DIC Stage 1
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DIC Stage 1 (The Hypercoagulable State – this would almost be considered pre-DIC) Treatment
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Control coagulation to regulate process
Low dose heparin Amplifies AT3 effectiveness Shuts down thrombin generation Reduces risk of thrombosis Anti-platelet agents GP IIb/IIIa inhibitors block platelet aggregation ASA (aspirin), Clopidogrel (Plavix) block platelet activation |
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AT3 has been consumed
Excess thrombin is produced The protein C system becomes activated aPC inactivates FVa and FVIIIa FV and FVIII deficiencies result Activated platelets are removed from the circulation Thrombocytopenia Risk of bleeding is increased (FV and FVIII deficiency and lack of platelets) |
DIC Stage 2 (Early or Mild DIC/Consumption Coagulopathy)
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DIC Stage 2 (Early or Mild DIC/Consumption Coagulopathy) Treatment
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Replace missing coagulation factors V and VIII
Cryoprecipitate FVIII and Fibrinogen Platelets FV Replace AT3 Concentrate or bank plasma Then low dose heparin to control thrombin generation Increases risk of bleeding Antiplatelet agents Increases risk of bleeding |
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aPC inhibitor has been consumed
Fibrinolysis has been activated Free Plasmin Dissolves hemostatic plugs Reduces the thrombin/plasmin ratio Digests most coagulation factors Digests Fibrinogen Digests platelet surface receptors Defective hemostasis and rebleeding of old wounds |
DIC Stage 3 (Late or Severe DIC/Consumption Coagulopathy)
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DIC Stage 3 (Late or Severe DIC/Consumption Coagulopathy) Treatment
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Need to replace coagulation factors
Plasma Concentrates Cryoprecipitate Platelets AT3 Prothrombin complex Need to inhibit Thrombin Heparin and friends High risk of fatal bleeding Need to inhibit plasmin AMICAR High risk of fatal thrombosis |
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What is the most frequent site of bleeding in hemophilia patients?
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Joints/Hemarthrosis
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What do you do to stop the bleeding in the psoas muscle of a patient with severe congenital Factor VIII deficiency?
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Use rFVIII
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Most common hemophilia?
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Hemophilia A/Factor VIII deficiency
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Factor VIII gene located near the tip of the long arm of X chromosome
Missense or frameshift mutations, deletions or inversions Defect is an absence or low level of Factor VIII Incidence is 1 in 5,000 live male births |
Hemophilia A
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Recurrent bleeds leading to persistent inflammation, soft tissue, bone destruction
Recurrent pain, chronic arthritis Decreased range of motion and mobility Eventual physical impairment, long-term disability, psychosocial consequences |
Hemophilic Arthrophathy
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synovitis and increased blood flow to the joint may lead to
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epiphyseal overgrowth and limb length discrepancy
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Factor IX deficiency
Same clinical manifestations as Hemophilia A Less common (1 in 25,000 births) X-linked mutation/deletion in Factor IX gene (first described in Christmas family) |
Hemophilia B
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Bleeding Time/PFA-100 – normal (tests skin, vessels and primary hemostasis)
Platelet Count - normal Prothrombin Time – normal (extrinsic pathway) Activated Partial Thromboplastin Time – long Factor VIII Assay Severe <1% Mild >5% |
LABORATORY FINDINGS IN HEMOPHILIA A
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Hemophilia Treatment Centers
Plasma derived or Recombinant factors to replace the missing factor Clotting factor concentrates are given to prevent bleeding and to limit existing hemorrhage Synovectomies, joint replacements/fusions PREVENTION, PREVENTION, PREVENTION |
Treatment of Hemophilia
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-purified from the cell culture of transfected mammalian cell lines
-require no further viral attenuation |
Recombinant human factor VIII and IX
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-large starting pool of carefully screened donor plasma
-Affinity chromatography using monoclonal antibodies -Viral inactivation procedures (pasteurization, solvent-detergent treatment, ultrafiltration) are effective against HIV and hepatitis viruses. |
Plasma-derived concentrates
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Development of inhibitors (alloantibodies) to Factor VIII and less commonly, Factor IX (about 10-20%)
Infectious Hep B (70-90% prior to vaccine) Hep C (>90% in pts treated prior to 1985) HIV (By 1984, >90% of severe Hemophilia A) CMV, Parvovirus B19 |
Complications of hemophilia treatment
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development of neutralizing and clearing anti-factor VIII (FVIII) antibodies in individuals without a preexistent congenital FVIII deficiency.
uncommon - incidence of 0.2 to one cases per million population per year Older adults Postpartum 50% with underlying autoimmune DO (lupus, rheumatoid arthritis), malignancy 50% idiopathic |
Acquired Hemophilia
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Heterogeneous group of inherited or acquired bleeding disorders
Bleeding due to reduced level or abnormal function of (name) The most common bleeding disorder Most types have autosomal dominant inheritance |
von Willebrand's Disease
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Promotes platelet adhesion to damaged endothelium and to other platelets
Carrier molecule for Factor VIII (increases half-life of Factor VIII) |
Hemostatic function of vWF
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DDAVP = 1-deamino-8-D-arginine vasopressin = synthetic analog of ADH L-vasopressin
Releases stored Factor VIII and VWF from endothelial cells (you get tachyphylaxis – lose drug effect) Humate P – Intermediate purity factor VIII concentrate which contains both VWF and factor VIII |
Treatment of vWD
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Drug that stabilized fibrin clot- stops fibrinolysis
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Amicar
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behavior pattern of overwhelming involvement with obtaining and using a drug. Will occur in < 1% of patients receiving pain therapy with opioid analgesics.
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Addiction
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withdrawal symptoms appear upon stopping drug
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Physical dependence
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when a particular dose loses its effectiveness
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Tolerance
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Therapeutic principles of pain managment administration
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Select appropriate drug
Select appropriate dose Select appropriate interval and route Prevent persistent pain and relieve breakthrough pain Titrate dose Use adjuvant measures Prevent, anticipate, and manage side effects |
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Defined as 1-2,3-4 on a 0-10 point VAS
Acetaminophen Non steroidal anti-inflammatory drugs (NSAIDs) Mild opioids combinations (Darvocet) |
Mild pain
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Defined as 5-6 on a 0-10 VAS
Small doses of morphine or oxycodone alone Combination agents may work |
Moderate pain
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Defined as 7-10 on 0-10 VAS
Morphine is drug of choice |
Sever/debilitating pain
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Step 1 analgesic, co-analgesic
Analgesic and antipyretic effects Mechanism: inhibits prostaglandins in CNS and peripherally blocks pain impulse generation Onset of action is 30 – 60 minutes Duration of action is 4 hours Metabolized in liver, excreted in urine Well tolerated without common toxicities expected with NSAIDs Available in many different dosage forms Max daily dose is 4 grams |
Acetaminophen
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Analgesic, antipyretic and anti-inflammatory effects
Inhibits cyclo-oxygenase (COX) enzyme that releases PG known to sensitize or activate peripheral nociceptors Vary in COX-2 selectivity Dose-response curve plateaus All the drugs in this class exhibit an analgesic ceiling effect Particularly helpful in bone pain |
NSAIDs
Limitations: Gastropathy Anti-platelet effect Renal toxicity Drug interactions |
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Patients where an NSAID is indicated with:
History of GI ulcers Elderly Low platelet count < 50K Receiving anticoagulation Receiving corticosteroids Coagulopathy Prior intolerance to non-selective NSAID |
Cox-2s
Celecoxib (Celebrex) Familial adenomatous polyposis (FAP) 400 mg PO BID Many drug interactions that should be watched (warfarin, CYP450) Caution in pts with sulfonamide allergy |
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Binds to the mu-opiate receptors but also binds to norepinephrine and serotonin
50-100 mg PO every 4-6 hr (max 400 mg/day) Needs to be adjusted in renal dysfunction (CrCl < 30 ml/min) Limited by N/V, constipation, and dizziness; may lower seizure threshold |
Tramadol (Ultram)
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Gold standard for pain management
Multiple dosage forms PO (IR and SR), IV, PR (rectal) Active metabolite morphine-6-glucuronide Well tolerated Release of histamine Adverse events: sedation, urinary retention, decreased respirations, CONSTIPATION (must put them on a laxative) Initial dosing is based on severity of pain usually 1 mg IV q4h as needed Inexpensive |
Morphine
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Slightly more potent than morphine
Fewer dosage forms PO (IR and SR) Multiple combination products Milder side effect profile relative to morphine Street value must be considered (Hillbilly heroin) |
Oxycodone
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Approximately 6 times more potent than morphine
Usual starting dose is 0.2 mg IV q3h prn Available as both IV and PO product No PO SR dosage form Useful alternative in liver/renal failure patients No active metabolite Less nausea/vomiting and pruritis relative to morphine |
Hydromorphone (Dilaudid)
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Available: IV, PO (IR & ER); 10x more potent than morphine
Changing from IV to PO 10 x IV dose divided in two doses Changing between immediate release and extended release 2 times the IR dose Really only used in pain clinic or by oncologists |
Oxymorphone (Opana)
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100 times as potent as morphine; titrate slowly
1 mg IV morphine = 10 mcg Unique dosage forms IV, transdermal (absorbed more under heat), lozenge Least likely to induce histamine release It is not known whether the dose requires adjustment for renal or hepatic failure; Renally eliminated and hepatically metabolized |
Fentanyl
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Cheap form of pain management
Dosing is complex because of longer half lives with administration Should only be dosed with advisement of practitioner with experience (pain control or palliative care) |
Methadone
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Major Adverse Effects of Narcotics
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CNS
Respiratory System Urinary Effects CV Effects CONSTIPATION!!!! Must give bowel stimulant not just stool softener Sennakot with docusate 2 tablets at bedtime or Miralax at bedtime |
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complexes with Antithrombin III accelerating its ability to inactivate factors IIa, Xa, and IXa.
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Heparin
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Monitoring:
check aPTT (activated partial prothrombin time) at 6 hours and adjust dose to keep aPTT within the therapeutic range Recheck aPTT every 6 hours for 1st 24 hours then every morning unless outside therapeutic range |
Monitoring of unfractionated heparin
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Improved bioavailability and more predictable pharmacokinetics
Do not have to monitor aPTT Longer half life Good for treatment of home DVT or uncomplicated PE Use in caution in obese patients and those with renal insufficiency |
LMW Heparin
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Enoxaparin (Lovenox)
Dalteparin (Fragmin) Fondaparinux (Arixtra) |
LMW Heparin choices - all administered SQ
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inhibits the production of vitamin K dependent clotting factors (II, VII, IX, X)
It will take at least 5-7 days to reach steady state Most bridge therapy with heparin product when treating If load patients with (drug) – protein C and protein S will be gone (natural anti-coagulants) could produce hypercoagulable state Skin necrosis – bruising on buttocks, thighs, penis, breasts Adverse events: bleeding |
Warfarin
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Check international normalized ratio (PT-INR)
The goal INR depends on the indication A fib goal 2-3 Mechanical Heart valves aortic position 2.0—3.0 mitral position 2.5 – 3.5 or 2.0—3.0 + ASA 80-100 mg additional RFs, or systemic embolism despite adequate anticoagulation 2.5-3.5 + ASA 80-100mg Bioprosthetic heart valves Aortic or mitral position 2.0—3.0 for 3 months followed by ASA 162 mg daily History of systemic embolism 2.0—3.0 for 3-12 months followed by ASA 162 mg daily |
Monitoring of Warfarin
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Drug Interactions with Warfarin
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Highly protein bound
H2 blockers/PPIs Antibiotics Antiepileptic Agents Barbiturates Carbamazepine Phenytoin Lipid lowering agents Antifungal agents Leukotriene Inhibitors Antidepressants |
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MOA: inhibits cyclooxygenase which inhibits formation of
Thromboxane-TXA2 (vasoconstrictor; irreversible) inhibits platelet aggregation and activation Increases risk for bleeding prostacyclin (PC; vasodilator; reversible) Major Adverse effects: GI Bleed, renal insufficiency Doses: 81-325 mg PO daily Used for post-heart attack and stroke |
Aspirin
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MOA: inhibits platelet activation and aggregation but mechanism is different from any other antiplatelet drug
Onset of action is 24-48 hours Side effects: diarrhea, rash, reversible neutropenia (2%) Drug interactions: Substrate of CYP3A4 inhibits CYP2C19 strong Dose: 250 mg twice daily with food Monitoring: CBC with diff q 2 weeks for 1st 3 months |
Ticlopidine (Ticlid)
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MOA: blocks ADP receptors inhibits platelet activation and aggregation
Prevents activation of GPIIb/IIIa Platelets that are affected last the rest of the platelet life Steady state: 3-7 days Drug interactions: minor CYP3A4 Dose: load 300 mg and then 75 mg daily with or without food MP: routine CBC monitoring not necessary |
Clopidogrel (Plavix)
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