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942 Cards in this Set
- Front
- Back
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What is the cellularity in the hollow of the bone?
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Cellularity is 100% in infants.
Cellularity decreases by 10% with each decade of life until age 70-80, It then remains at 20-30%. |
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Lymphoid and myeloid stem cells both come from...
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Pluripotent stem cells.
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What is the normal myeloid to erythroid ratio in the bone marrow?
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3:1
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Stromal cells include...
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Fibroblasts
Fat cells Endothelial cells These along with adhesion molecules and growth factors constitute the stromal matrix. |
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Where does hematopoeisis occur?
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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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What are the stages of erythropoeisis?
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Pronormoblast
Basophilic normoblast Polychromatophillic normoblast. Orthochromatic normoblast. Reticulocyte. |
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Why does the nucleus shrink throughout the hematopoeitic development?
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Chromatin condenses.
Nucleus:cytoplasm ratiodecreases with maturation. Cell also gradually changes from blue to red. |
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What is distinctly absent in a red blood cell?
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No nucleus
No cytoplasmic organelles No protein or lipid synthesis No oxidative phosphorylation |
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Red cells are are highly deformable. What sort of order of magnitude changes in size is it capable of?
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8 microns in a large vein to 2 microns in a capillary
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What is the significance of the biconcavity of a red blood cell?
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Deformability
High surface area for gas exchange. |
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What are the different white blood cells?
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-Granulocytes-
Neutrophils Eosinophils Basophils -Lymphocytes- T cell (thymus) B cell Natural killer (NK) cell -Monocytes- Tissue macrophages |
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A cell with pink granules is...
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An eosinophil until proven otherwise.
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What are the stages in the development of a neutrophil?
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Myeloblast
Promyelocyte Myelocyte Metamyelocyte Band Neutrophil (the only one that should normally be found circulating in the blood) |
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High circulating neutrophils are usually an indication of ...
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Bacterial infection.
Neutrophils are involved in oxidative and non-oxidative killing of bacteria and fungi. |
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Where are neutrophils found?
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Circulating in the blood and tumbling (loosely adhering) along endothelium.
There is both a circulating pool and a marginating pool. |
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What are Eosinophils?
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A granulocyte.
Bi-lobed nucleus Eosinophilic granules Parasitic infections Allergic reactions Vasculitis Some hematologic malignancies |
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What is a MAST cell?
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A tissue bound cell with the same precursor as a basophil.
Releases histamine and IgE. Increased in myeloproliferative disorders. |
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What are the growth stages of a lymphocyte?
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Lymphocytes have no morphologically distinct stages of maturation so we discern lymphoblasts from lymphocytes by acquisition and loss of surface antigens to differentiate in to B, T, and NK cells.
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How long do lymphocytes stick around for?
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Years.
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What sort of lymphocyte content do we normally find in peripheral blood?
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70% T cells
25% B cells < 5% NK cells no plasma cells |
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What markers identify B cells?
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CD10
CD19 CD20 CD79a sIg Kappa/gamma |
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What markers identify T-cells?
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CD3
CD4 CD5 CD7 CD8 |
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CD 38 is only expressed on...
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Very mature lymphocytes.
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What markers identify NK cells?
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CD16
CD56 |
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What markers identify T-cells?
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CD3
CD4 CD5 CD7 CD8 |
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What is the function of the spleen?
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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. ie. Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. |
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What is splenic sequestration?
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During periods of extensive red cell damage and splenic activity, blood may enter the spleen but be unable to exit .
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What % of the population will have an accessory spleen?
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10%
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TdT is a marker of....
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Stem cells
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CD38 is a marker of...
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Plasma cells.
Memory cells. |
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What are the subunits of a hemoglobin molecule?
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2 alpha chains
2 beta chains (aka non-alpha) 4 heme molecules (Fe bound to protoporphyrin 9) Total of four oxygen binding sites. Each chain has about 140 AA |
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The genes for alpha chains are on...
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Chromosome 16
Others are on chromosome 11 There are two copies of alpha and gamma genes per chromatid for a total of 4 genes per person. The redundancy is important to prevent lethal mutations. |
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Hemoglobin A has...
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2 alpha and 2 beta chains
(standard hemoglobin in adults) |
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Hemoglobin A2 has..
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2 alpha and 2 delta chains
Not very efficiently expressed so small concentration of A2. |
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Hemoglobin F has...
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2 alpha chains and 2 gamma chains.
Even adults have a small amount of fetal hemoglobin expressed in special RBC's called F cells. |
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What modifications can Hemoglobin A undergo?
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Post-translational modification.
Reactions can occur with various sugars and the amino groups of the globin chains. Results in glycated hemoglobin Most common is Hb A1c, where glucose is added to the beta chain. It is a good indication of how well a diabetic patients blood sugar is controlled. |
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Hemoglobin’s affinity for oxygen depends on ...
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The partial pressure of oxygen (pO2)
The higher the pO2 the higher the saturation in a sigmoid relationship. |
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What is P50?
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The amount of oxygen needed to saturate 50% of the hemoglobin
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Once an oxygen binds to one heme molecule what is the effect on the binding sites?
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It makes it easier for oxygen to bind to the other sites.
This is why the curve is sigmoidal. |
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Low pH causes a...
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right shift
The shift as a result of pH is called the Bohr effect. |
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What happens with high 2,3-BPG?
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Hb molecule goes from relaxed and oxygenated to tense and deoxygenated
Need a higher pO2 to saturate the same amount of Hb The curve therefore shifts to the right. |
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How does fever shift the curve?
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Right.
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Hb F curve is to the ...of a normal adult curve.
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Left
Hb F doesn’t release oxygen as easily as Hb A; so fetus needs more Hb to adquately oxygenate tissues. Newborns therefore have higher Hb values than when they’re older (and have Hb A). |
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P50 Hb F is about
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20mmHg
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P50 Hb A is about
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25mmHg
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Does oxygen delivery require energy consumption?
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No
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How does the RBC generate energy for itself?
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The embden-meyerhof pathway which is an anaerobic glycolytic pathway.
It results in manufacturing lactate from glucose. It takes 2ATP and makes 4ATP. It generates 2,3-BPG. It reduces methemoglobin to hemoglobin (Fe3+ to Fe2+) |
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What enzyme deficiency hurts the HMP shunt so there is no NADPH?
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G6PD deficiency. The most common RBC enzyme deficiency in the world.
Without NADPH, glutathione metabolism does not occur. H2O2 is not converted to water and oxidative damage results in hemolysis and hemolytic anemia. |
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What is the role of the spleen?
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Primary site of extravascular RBC destruction.
In splenectomized patients macrophages of Liver and Bone marrow assume this role. |
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RBC's may be retained in the spleen if...
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Shape is less adaptable (spherocytes)
Membrane is less flexible (older cells) There are inclusions or particles stuck to the membrane such as Heinz bodies (denatured Hb) or Howell-Jolly bodies (nuclear remnants). Seeing these features in circulating cells is an indication of poor spleen function. |
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The vast majority of normal physiological hemolysis is...
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Extravascular hemolysis which takes place within macrophages outside the vascular stream.
About 15% of Hb is broken down by intravascular hemolysis though. |
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How are RBC's broken down by the macrophages of the reticuloendothelial system?
(Extravascular hemolysis) |
Globins are broken down into amino acids.
Iron is bound to transferrin which carries it to the bone marrow and/or liver where any iron excess is stored as ferritin. Protoporphyrin is converted into bilirubin which is expelled from the macrophages in its unconjugated form (indirect billrubin). The unconjugated billirubin then travels to the liver which conjugates it into bilirubin glucoronides with UDP glucoronyl transferase. Billrubin glucoronides are eventually expelled either as stercobillinogen in the stool or urobillinogen in the urine. |
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What is intravascular hemolysis?
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Red cell lysis which occurs within the circulation.
15% of Hb catabolism follows this pathway Transfusion reactions also happen primarily in the vessels. |
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What is haptoglobin?
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Hp is the main Hemoglobin (Hb) binding glycoprotein involved in intravascular hemolysis.
It is an acute phase reactant and is made by the liver. It is absent in the newborn. It forms complexes with hemoglobin that will be degraded. The Hp/Hb complex is internalized by hepatocytes where globins and Hp are degraded into AA. The remaining heme is catabolized to bilirubin and iron. Low or absent plasma Hp is an indicator of recent or ongoing massive intravascular hemolysis because it represents either rapid saturation of Hp or rapid clearance of HB/Hp complexes. |
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What proteins can bind free heme or free hemoglobin from intravascular hemolysis and become important especially when the haptoglobin is saturated?
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Hemopexin
Albumin (methemalbumin) |
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What role do the kidneys play in managing intravascular hemolysis?
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Even under normal physiological conditions, some free Hb is reabsorbed into cells of the proximal tubules where globin and heme are degraded into a.a, iron and bilirubin just like in the liver.
In low chronic intravascular hemolysis, ferritin accumulates in the tubular cells which eventually die and pass in the urine. This can be detected with prussian blue stain which shows hemosiderin. During massive intravascular hemolysis, the tubular cells cannot handle the volume and Hb appears in the urine. (haemoglobinuria). This can lead to acute renal failure. |
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What does elevated billrubin do to the color of urine?
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It darkens it.
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The process of turning protoporphyrins into billirubin gives off...
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CO2
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What happens to conjugated billirubin excreted into the bowel through the bile?
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It reaches the distal ileum and colon and is reduced by bacteria.
Some of it can also be resorbed and go through the plasma to either the liver (into the bile again) or the kidneys for excretion in urine. |
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Is unconjugated or indirect billrubin bound to anything for transport to the liver?
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Yes.
Albumin. Billirubin is not soluble on its own. |
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Where do billirubin stones typically come from?
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The gallbladder.
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What happens if unconjugated billirubin reaches the basal ganglia?
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Kernicterus.
This causes neurological symptoms and in severe cases, brain damage. |
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What is hemolytic anemia?
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When the life-span of erythrocytes is shorter than normal, there is an imbalance between RBC catabolism and production.
The natural response is a compensatory increase in erythrocyte production so the hallmark sign of hemolytic anemia is reticulocytosis (an abundance of reticulocytes or immature RBC's). |
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Is it possible to have hemolytic anemia without an elevated reticulocyte count?
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Yes.
If there is myelosupression. Eg. Parvovirus B19 attacks RBC precursors in children. |
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What is the etiology of hemolytic anemia?
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Intrinsic red cell abnormalities
Extrinsic causes of hemolysis Immune mediated hemolysis Non-immune mediated hemolysis |
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What are some intrinsic red cell disorders that can cause hemolytic anemia?
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Hereditary Spherocytosis
Hereditary Elliptocytosis G6PD Deficiency Pyruvate Kinase Deficiency Unstable Hemoglobins Methemoglobinemia Thalassemia Sickle Cell Disease |
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What are some extrinsic causes of hemolysis?
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Immune mediated hemolysis:
Warm Reactive Autoimmune Hemolytic Anemia (AIHA). Cold Agglutinin Disease. Paroxysmal Cold Hemoglobinuria (PCH). Schistocytic hemolytic anemia (so named because of fragments made by mechanical destruction of RBC's as they travel): Hemangiomas (Kasabach-Merritt syndrome). Prosthetic heart valves. Microangiopathic hemolytic anemia (MAHA) including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. |
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What is the clinical presentation of hemolytic anemia?
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Pallor
Icterus, jaundice Fatigue Splenomegaly Gallstones Cholecystitis Dark urine May present with parvovirus associated aplasia. Family history. |
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What are the increased nutritional requirements for chronic hemolysis?
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Folic acid (10 day storage)
AA for globin chains B12 (10 year storage) No increased Fe requirement since it is “recycled” and stored in bone marrow. |
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If a patient with hemolytic anemia has a positive direct coombs test, what are the three main patterns that are possible?
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IgG only on surface of RBC
IgG and C3complement on the surface of the RBC. C3 only on surface cells, antibody on cells may be IgM. |
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What is Warm Reactive Autoimmune Hemolytic Anemia (AIHA)?
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IgG mediated.
Extravascular clearance primarily via the reticuloendothelial system (spleen). May be idiopathic or associated with SLE, lymphoid malignancies or immunodeficiency. |
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How do we differentiate an immune mediated hemolytic anemia from a non-immune mediated hemolytic anemia?
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Direct coombs (antiglobulin) testing to identify the presence of immunoglobulins or complement on the surface of the red cells.
In a direct coombs test, the patient sample is mixed with reagent that has antibodies against human immunoglobulins and complement. If agglutination forms, the test is +. |
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What is Cold Agglutinin Disease?
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An immune mediated hemolytic anemia which is IgM mediated.
Can be associated with Mycoplasma and EBV. Primarily intravascular lysis. |
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Which cells originate from lymphoid stem cells?
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B-cells
T-cells NK cells All others originate from myeloid stem cells. |
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What is Paroxysmal Cold Hemoglobinuria (PCH)?
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Another immune mediated hemolytic anemia.
It is an acute illness, often after viral URI. Inciting infections include measles, mumps, varicella, syphilis, Mycoplasma Caused by cold reactive IgG (Donath Landsteiner Antibody) It is primarily an intravascular hemolytic anemia. |
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How do we manage 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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What stimuli cause an increase in bone marrow activity?
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Infection
Low tissue oxygenation Activity is mediated by growth factors and decreased when demand is met. |
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What is indirect coombs testing?
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In indirect coombs testing we test for free antibodies in the patients serum.
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What are the two best sites for aspirating bone marrow?
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The pelvic girdle and the sternum.
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What are some terms associated with neutrophils?
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Polys
PMN (Polymorphonuclear neutrophil) Seg (segmented neutrophil) 3 lobes separated by a thread |
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What are the components of the hematopoietic system?
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Bone marrow and all blood corpuscles
Liver Spleen Lymph Nodes Thymus |
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Why can you not get a positive indirect coombs test on a baby?
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It takes about 6 months to develop antibodies against major antigens.
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What is a monocyte?
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Cells that circulate for 24 hours and then go into tissues to become macrophages.
They Ingest fungi, mycobacteria, and play a role in battling pyogenic bacteria. |
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Do we normally have antibodies against the minor antigens in our serum?
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No
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Platelets are made from...
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Megakaryocytes.
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The white pulp of the spleen consists of...
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lymphocytes around arterioles
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The red pulp of the spleen consists of...
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splenic sinusoids
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Where does the tip of a PICC line sit?
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In the SVC.
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What is a normal value for RBC? (red blood cell count)
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4.7 – 6.1 (M) millions/ μL 4.2 – 5.4 (F)
Red cells are highest at birth (RBC, Hb, Hct) 30% are Hb F At 3 months Hb F decreases to normal level (2%) 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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What is a normal value for HgB? (Hemoglobin)
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14 - 18 (M) g/dL 12 - 16 (F)
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What is a normal value for HcT? (Hematocrit)
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42 - 52 (M) %
37 - 47 (F) In general 3 times HgB. Tells you the volume of packed red blood cells in a given volume of whole blood. |
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What is a normal value for MCV? (Mean corpuscular volume)
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80 - 96 fL (1 x 10^-15 L)
Tells size of red blood cell The RDW value (sometimes called CV of the MCV) that is given with MCV tells the red cell distribution width or, in english, how varied the sizes of the red cells are. If the RDW is normal, all cells are similar size (whether they’re all big or all small) If RDW is increased, the cell size is NOT known. Normal RDW is 11.5 – 14.5 % |
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What is a normal value for MCH? (mean cell hemoglobin)
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27 - 31 pg (picograms)
Tells average weight of hemoglobin per cell. |
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What is a normal value for MCHC? ( Mean corpuscular hemoglobin concentration)
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33 - 37 g/dL
Tells average concentration of hemoglobin per cell. |
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In what situation would MCH and MCHC be pretty different?
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In microcytic anemia (Low MCV), the MCH is going to be the same but the MCHC will be high.
In a normal sized cell with low hemoglobin though, both the MCH and MCHC will be low. |
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Seperately from a CBC, we can order a reticulocyte count. What does this tell us?
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Measures the percentage of reticulocytes circulating in the blood by identifying preciptiated RNA in young cells with methylene blue stain. Reticulocytes can also be seen by Giemsa stain,
If there are a lot of reticulocytes in the blood, the MCV and RDW will be high because reticulocytes are bigger than mature RBC's. |
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The relative order of a normal WBC differential from most frequent to least frequent is...
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Segs (segmented neutrophils)
Bands (immature neutrophils) Lymphs Monos Eos Basos Other Mnemonic: Never let men eat bologna. |
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In what situation do we expect elevated bands?
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Infection.
This is sometimes called a bandemia or a left shift. |
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What is thrombocytopenia?
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Low platelets
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What is thrombocytosis?
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High platelets
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What is hypochromia?
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Low MCH
Translates as low color. |
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What are the causes of low MCV?
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Iron deficiency anemia
Hemoglobinopathies (sickle cell, thalassemias, etc) Anemia of chronic disease. Copper deficiency. Lead poisoning (decreased heme synthesis) Often associated with hypochromia. |
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What is basophilic stippling?
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Punctate basophilic precipitation of undegraded RNA "speckles" seen on RBC's.
A sign of ineffective hematopoiesis. Seen in lead toxicity. |
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What is the significance of a "target" or sombrero cell?
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This charcteristic shape is the result of redundant red cell membrane/ decreased cell volume.
It is seen in: Hemoglobinopathies/thalassemias. Iron deficiency anemia. Drug-induced hemolytic anemia. Liver disease. |
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What is a Schistocyte (helmet cell)?
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Helmet shaped cell seen in:
DIC TTP Caused by presence of too much fibrin. |
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What is an acanthocyte?
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Also sometimes called a thorn cell.
Usually an artifact but can signify liver disease. |
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What is a rouleax formation?
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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. Causes are plasma cell disorders like multiple myeloma, plasma cell leukemia or infection. Can occasionally be an artifact. |
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What are Howell Jolly Bodies?
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RBC inclusions that look like the RBC has a mole.
They are remants of nuclear chromatin normally removed by the spleen and are seen in surgically or functionally asplenic patients as well as dialysis patients. |
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What is a spherocyte?
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An RBC with no central pallor
seen in hereditary spherocytosis. They are smaller than normal RBC's. |
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What is the normal range of blast cells in a bone marrow aspirate?
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<5.0
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Why do we do flow cytometry on bone marrow aspirate?
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It helps us determine lineage.
We can also do cytogenetics or FISH for diagnostic purposes. FISH is only as good as what we are looking for though. |
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What phase of the cell cycle does the cell have to be in to do cytogenetics?
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Metaphase
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What do we do with the core we get during a bone marrow biopsy?
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Determine cellularity.
It should be 100-age except at the extremes. |
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What does a basic metabolic panel include?
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Sodium
Potassium Chloride CO2 BUN Creatinine Glucose Calcium |
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What does a comprehensive metabolic panel include?
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Basic metabolic panel
And: Total Protein Albumin AST ALT Alkaline Phosphatase Total Bilirubin |
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Can you add on an electrolytes test if the tube of blood you drew is a CBC?
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No.
Electrolytes are run on serum so the tube must be clotted. The CBC would have been drawn in an anticoagulated tube. |
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What is electrophoresis?
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A test used to separate and quantitate serum protein including hemoglobin.
Separates different proteins based upon their physical and chemical properties. Mobility of the protein depends on its molecular weight and charge. Blood is separated into cells and serum. Serum is applied to a gel, current is applied, and different proteins move at different rates/distances along the gel. Albumin should be the main protein. |
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How do we screen for sickle cell anemia?
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RBC mixed with reducing agent and observed under microscope for characteristic change in shape (sickle).
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How do we determine what sort of hemoglobin chains someone has?
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Different hemoglobins have different mobilities in electrophoresis.
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How does colder weather affect sickle cell patients?
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Vasoconstriction causes increased clotting and ischemia.
Left shift of the oxygen dissociation curve. |
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Why are sickle cell patients susceptible to encapsulated organism infection?
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Functional asplenia due to autosplenectomy.
The spleen infacts because of the sickle occlusion. |
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How do we designate sickle cell genotypes?
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SS: Homo sickle.
SBthal 0: Nonsense mutation, no functional beta globin. SBthal +: Missense mutation, some functional beta globin. SC: Slight abnormality, clinical course close to sickle trait. SA: Sickle trait |
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The best test for diagnosing sickle cell is...
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Hemoglobin electrophoresis.
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Direct billrubin is the same thing as...
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Conjugated billirubin
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What does 1 unit of whole blood yield in whole blood collection?
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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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What is cryoprecipitate made from?
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Fresh frozen plasma.
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What do we use packed red blood cells for? (PRBC)
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Transfuse (1 or 2 units) to treat anemia.
Hemoglobin (Hb) usually < 8 g/dL (Not hard and fast rule though) PRBC stored in fridge. 1 unit will increase the Hb by 1 g/dL and increase Hematocrit (Hct) by 3%. (numbers are doubled for peds) |
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How do we define massive transfusion?
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Replacement of 1x total blood volume (usually ~10 units of PRBC) in less than 24 hours.
After this, we can stop typing because we know what blood is in the system. Massive transfusion may be complicated by dilutional coagulopathy, hypocalcemia, hyperkalemia, arrhythmia. |
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What is the volume of a unit of blood?
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It is variable.
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How long can PRBC be frozen for?
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10 years.
(thaws in about an hour) |
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Platelets are stored....
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Constant motion.
Room temperature. Highest risk |
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When do we usually use platelets?
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Thrombocytopenia.
Platelet count < 20,000 / uL or platelet dysfunction. |
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What is plasma and when is it transfused?
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FFP and 24 hour plasma are now considered interchangeable.
Transfuse (2 units) to treat clotting factor deficiencies. Prolonged Prothrombin time (PT) and activated partial thromboplastin time (PTT). Will have normal levels of Factor VIII. Factor VIII levels degrade over several days. Factor VIII levels are 50-80% normal by 5 days. |
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How is serum different from plasma?
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It is not anticoagulated.
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What do we get from whole blood phlebotomy?
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Packed Red Blood Cells (PRBC)
Platelets Plasma |
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What do we get from apheresis?
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Same as whole blood.
(but more) WBC (Granulocytes, Monocytes, T-Cells, Stem Cells) |
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How does apheresis work?
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Blood is separated into its component parts:
Red blood cells Plasma Platelets Takes about 90 minutes. |
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What is Cryoprecipitated AHF (Cryo) and what is it used for?
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It is NOT concentrated FFP.
Cryo is made from FFP but provides a more concentrated form of: Fibrinogen Factor VIII von Willebrand Factor Factor XIII Fibronectin It can be used to treat bleeding from deficiency of these factors. 5 or 10 units of cryo are usually transfused to replace fibrinogen. |
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Is there such a thing as a pure blood product?
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No
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What is the H antigen?
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The H antigen is present on all human red blood cells.
One way to think of H is as the “O” antigen. H is the precursor of the A & B antigens. |
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What is the A antigen?
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It is basically an H antigen with a GALNAC (n-acetylglycosamine) substitution on its end.
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What is the B antigen?
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It is basically an H antigen with a GAL (galactose)substitution on its end.
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What are H, A and B antigens anchored to on the RBC surface?
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Ceramide
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What antibodies do people of various blood types express?
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Group A person =Anti-B
Group B person =Anti-A Group AB person =NO ABO antibodies Group O (H antigen) person = Anti-A & Anti-B |
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What makes A and B antigens "major"?
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A and B antigens are widespread environmentally – dust, food, intestinal bacterial flora etc.
This makes it almost impossible for a patient to be naive to them. |
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Who is considered a universal donor?
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O=universal donor for RBC's
AB=Universal plasma donor |
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What makes Rh a smaller concern in typing than ABO?
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Antibodies to D antigen (Rh) are NOT “naturally” occurring.
A person needs an exposure to foreign, non-self red blood cells to have an antibody response. Examples of exposures: Pregnancy Blood transfusion Sharing needles etc. |
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What is forward typing?
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Testing the PATIENT’S red cells for A or B antigen.
|
|
|
What is reverse typing?
|
Testing the PATIENT’S serum for the expected antibody.
|
|
|
What is Rh typing?
|
Testing the red cells for the D antigen.
This is why we need a red cell sample to do an Rh type. |
|
|
In the context of transfusion, what is a screen?
|
Checking the PATIENT’S serum for other antibodies against red cell antigens
other than ABO – !!Kell, Duffy and Kidd!! are all examples. |
|
|
What is crossmatching?
|
Mixing the PATIENT’S serum with a sample of DONOR red cells from the exact unit that we wish to transfuse.
If the red cells and serum mixture clumps (agglutinates), the unit is INCOMPATIBLE. |
|
|
In the standard FORWARD typing reagent kits, what are the colors of the bottles or wells?
|
Blue anti-A
Yellow anti-B Gray-Anti D |
|
|
How does the forward type test work?
|
We add the antibodies and sample to three long wells (A,B,D).
If they clump up they can't spin through the gel and remain in the original position. We read the test by stating that the blood has antigens that correspond with the stationary wells (top of the tube) and no antigens for those wells that moved (bottom of the tube). |
|
|
Why would O not be the universal donor if we still transfused whole blood instead of PRBC?
|
Because the plasma contains AB antibodies that would attack the native cells.
Group AB makes no ABO antibodies however which is why its the universal plasma donor. |
|
|
The direct coombs test which is used to evaluate hemolytic transfusion reactions or autoimmune hemolytic anemia is also called?
|
DAT
(Direct Antiglobulin Test) We take a red cell sample and check to see if it has IgG or C3d stuck on the cells. |
|
|
What is hemolytic disease of the newborn? (HDN)
|
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. |
|
|
Which immunoglobulins cross the placenta?
|
IgG (1 and 3)
|
|
|
What happen to the baby in hemolytic disease of the newborn?
|
Erythroblastosis Fetalis because of mothers antibodies against foreign red cells:
Anemia with possible organ failure. Edema (Hydrops) Jaundice Cardiac and liver failure. |
|
|
Who will have a positive coombs test (+DAT), mother or baby?
|
Baby.
Need a chord blood sample or something from the baby to do the test. |
|
|
Why does HDN not happen with ABO antigens?
|
It does.
It is simply not as severe. |
|
|
What other indications of HDN are there?
|
Fetal tachycardia due to fetal anemia.
Increased bilirubin & bile pigments in the amniotic fluid because of high hemolysis in the fetus. Peripheral smear of fetal blood will show spherocytes and nucleated red cells. |
|
|
Which tranfusion reactions are potentially life threatening?
|
Acute hemolytic reaction.
Transfusion-related acute lung injury (TRALI) Sepsis (Bacterial contamination of the product) Anaphylaxis |
|
|
What are some of the more common benign transfusion reactions?
|
Febrile non-hemolytic RXN
Urticarial (mild allergic RXN) Circulatory overload |
|
|
What is the most likely severe reaction with a platelet transfusion?
|
Sepsis.
They are stored at room temperature. |
|
|
What is the most likely severe reaction with a red cell transfusion?
|
Acute hemolytic RXN due to clerical error.
|
|
|
What is the most likely severe reaction with an FFP or Cryo transfusion?
|
TRALI
|
|
|
How do we know someone is having an acute hemolytic reaction?
|
+ Coombs test (DAT+)
ABO is the most severe but there can also be a delayed hemolytic transfusion RXN (Rh, Kidd, Kell, Duffy etc.) which presents 3-10 days after the transfusion. |
|
|
How do hemolytic transfusion reactions present?
|
S&S:
Fever and chills – Most common Renal failure DIC Back pain Lab: + DAT Hemoglobinemia Hemoglobinuria INCREASED: LDH ; Bilirubin DECREASED: Hemoglobin / Hematocrit ; Haptoglobin Peripheral smear shows schistocytes or spherocytes. |
|
|
What are spherocytes?
|
Ball shaped RBC's that can carry oxygen but are readily broken down by the spleen which "mistakes" them for old RBC's.
|
|
|
What infectious agents do we currently test donor blood for?
|
HIV.
HTLV 1 and 2. HBV. HCV. West nile. Syphillis.(Treponema) Chagas.(Trypanosoma) Only HIV an HCV are PCR based tests. |
|
|
What do we not test donor blood for that can be transmitted by a transfusion?
|
Basically anything.
Malaria Influenza Babesia vCJD CMV EBV and the list goes on...and on. |
|
|
What size is a normal reticulocyte compared to a mature RBC?
|
Macrocytic
|
|
|
What is a reticulocyte shift?
|
As the hematocrit decreases, reticulocytes are forced into the circulation early and constitute an increasing percentage of total RBC's.
|
|
|
What can cause reticulocyctosis (macrocytosis)?
|
Alcohol:
Probably acetaldehyde related. Liver disease: Probably due to increased lipid deposition on RBC membranes. Target cells usually also seen. Thyroid disease: Autoimmune thyroiditis associated with antiparietal cell antibodies. Spurious macrocytosis: Artifacts that occur to normal sized RBCs like misreading of clumps by machine. |
|
|
What are myelodysplastic syndromes?
|
Diseases in which the marrow doesn't make enough healthy blood cells.
AKA preleukemia and smoldering leukemia. Characterized by: Hypolobulated or hypogranular neutrophils. Large and/or abnormally granulated platelets. Monocytosis. Occasional blast forms. Common in geriatrics. Diagnosed on bone marrow morphology. |
|
|
What is megaloblastic anemia?
|
Anemia, often pancytopenia, with macrocytic RBC's and hypersegmented neutrophils.
Charcteristic delayed nuclear maturation and nuclear/cytoplasmic dyssynchrony result from slow DNA sythesis. The root cause is inadequate conversion of deoxyuridylate to thymidylate. |
|
|
What interferes with DNA synthesis thereby producing megaloblastic anemia?
|
Folate deficiency
Cobalamin deficiency Drugs that inhibit absorption of B12 and folate thereby inhibiting enzymes required for DNA synthesis. |
|
|
A shortage of B12 interferes with the normal biochemistry at two important points. What are they?
|
B12 is a cofactor in the conversion of methyl tetrahydrofolate (methyl THF) to tetrahydrofolate (THF), a process which also turns homocysteine into methionine.
The end product of this reaction, Tetrahydrofolate, is required for synthesis of deoxythymidine nucleotides which in turn are required to make DNA. In fatty acid synthesis, B12 is a cofactor in the conversion of methyl-malonyl-CoA to succinyl-CoA which is required for sequential two carbon elongations of the fatty acid chain. |
|
|
What are the two cobalamin dependant enzymes?
|
L-methylmalonyl-CoA mutase
Methionine synthase Methionine synthase also needs methyltetrahydrofolate as a cofactor which is derived from folic acid (folate). |
|
|
What are high dietary sources of B12 (cobalamin)?
|
Clams, Molluscs
Beef liver Breakfast cereals (100% fortified) Fish Mostly animal products. |
|
|
What are high dietary sources of folate (folic acid)?
|
Leafy green vegetables.
Breakfast cereals. |
|
|
Why do many hospitalized patients become folate deficient?
|
Overcooking of vegetables.
|
|
|
How long is B12 stored in the body ?
|
3-5 years
It is difficult to become dietarily deficient in B12 unless you are a very strict vegan. This is not the case with folate which is not stored for more than a few weeks. |
|
|
Where is folic acid absorbed?
|
Mostly in the proximal small intestine.
Some comes from bacteria in the large bowel though. |
|
|
What causes cobalamin deficiency?
|
Pernicious anemia (lack of IF)
Defect in IF Gastrectomy (partial or total) Gastric bypass Atrophic gastritis Acid blocking drugs Ileal resection Crohns disease Ileal cell diseases (Cbi-F, IGD) Bacterial overgrowth parasite or sprue in the jejunum. TCII-Cbl transporter defect in intestinal blood vessels. |
|
|
Why do many hospitalized patients become folate deficient?
|
Overcooking of vegetables.
|
|
|
How long is B12 stored in the body ?
|
3-5 years
It is difficult to become dietarily deficient in B12 unless you are a very strict vegan. This is not the case with folate which is not stored for more than a few weeks. |
|
|
Where is folic acid absorbed?
|
Mostly in the proximal small intestine.
Some comes from bacteria in the large bowel though. |
|
|
What causes cobalamin deficiency?
|
Pernicious anemia (lack of IF)
Defect in IF Gastrectomy (partial or total) Gastric bypass Atrophic gastritis Acid blocking drugs Ileal resection Crohns disease Ileal cell diseases (Cbi-F, IGD) Bacterial overgrowth parasite or sprue in the jejunum. TCII-Cbl transporter defect in intestinal blood vessels. |
|
|
What are the typical lab findings of B12 deficient and folate deficient megaloblastic anemias?
|
|
|
|
Why is red cell folate a useful measurement?
|
It provides an indication of the folate the RBC has been exposed to during its 3 month life.
Sort of like HbA1c for folate. One of the most sensitive ways to look for folate deficiency though is to look at the smears themselves for hypersegmentation of the neutrophils. |
|
|
Which cells exhibit megaloblastosis in megaloblastic anemia?
|
All proliferating cells including GI epithelium (buccal mucosa, tongue, small intestine), cervix, vagina, and uterus.
Changes are most striking in the blood and bone marrow though. |
|
|
What other indications are there of megaloblastic anemia?
|
Oval macrocytosis with or without anemia.
MCV higher than normal for the patient. Thrombocytopenia or leukopenia with immature forms. Basophilic stippling, leukoerythroblastic changes. Hypercellularity of the bone marrow. Nuclear/cytoplasmic dyssynchrony in the marrow. Kayorrexhis. Increased indirect bilirubin. Increased LDH. |
|
|
What are some of the secondary clinical manifestations of B12 or folate deficiency?
|
Glossitis.
Secondary malabsorption caused by megaloblastic GI changes. Weight loss. FTT. Infertility. Thrombosis Hyperpigmentation. Immune deficiency. |
|
|
What sort of neuropsychiatric manifestations can B12 deficiency cause?
|
Peripheral neuropathies
Dorsal column involvement (loss of position and vibratory sense, ataxia) Subacute combined degeneration of spinal cord. Psychiatric symptoms (dementia, psychosis) |
|
|
How do we treat cobalamin deficiency?
|
1000 ug B12 weekly by IM injection x 8 weeks then monthly for life.
Consider oral therapy with close monitoring. Folate 1 mg po per day Warning: Folate repletion without B12 repletion may normalize MCV and Hgb but allow neurologic manifestions to persist. |
|
|
What is a schilling test?
|
A test fromerly done to measure cobalamin absorption.
Part 1: Give radioactive cobalamin by mouth. After 1 hour, give injection of unlabelled cobalamin by injection (“flushing dose”) to saturate plasma B12 binders. 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 with poor absorption. If stool amounts were high, patients were given IF and then we measured again to see if IF helped. |
|
|
What is the significance of methylmalonic acid and homocysteine tests?
|
High MMA=B12 deficient.
High homocysteine=Either or both B12 or folate are deficient. |
|
|
Anemia in general is a reduction in oxygen carrying capacity resulting in decreased tissue oxygenation. How do we measure it ?
|
a decrease in RBC, Hgb or Hct
|
|
|
What classic signs suggest that an anemia is due to hemolysis or dysarthropoeisis?
|
JAUNDICE
SPLENOMEGALY MAXILLARY HYPERPLASIA |
|
|
Koilonychia (spooning of nails) suggests...
|
Iron deficiency.
|
|
|
Apart from size what is the key difference between macrocytic cells and microcytic cells?
|
Macrocytes are associated with defects in DNA synthesis.
Microcytes are associated with defects in Hgb synthesis. |
|
|
What can cause a microcytic Anemia?
|
Decreased Iron Availability.
Disordered Heme Synthesis. Disordered Globin Synthesis. |
|
|
How is iron absorbed?
|
In the proximal portion of the jejunum, NRAMP2/DMT transport receptors on the luminal surface of the intestinal cells facilitate absorption into the intestinal cells.
Hfe receptors on the vascular side of the cell then bind the iron to transferrin for transport to the bone marrow. There is a special transferrin receptor that accepts the iron in the bone marrow which can become dislodged in some microcytic anemias. |
|
|
What does an iron deficiency CBC look like?
|
High RDW
Low everything else. |
|
|
Apart from CBC what other lab tests show an iron deficiency?
|
IRON PROFILE:
Serum Iron (decreased) TIBC / Transferrin (increased) {only other situation where this pattern is pregnancy} % Iron Saturation of TIBC (Markedly decreased) Serum Ferritin (measurement of stored iron) SOLUBLE TRANSFERRIN RECEPTOR. FREE ERYTHROCYTE PROTOPORPHYRIN. |
|
|
In what order do the labs change in iron deficiency?
|
Serum ferritin (stored iron) goes down.
Serum iron decreases. TIBC increases. Excess protoporphyrin develops. |
|
|
Is it possible to have iron deficiency without anemia?
|
Yes.
|
|
|
In adults when we we find an iron deficiency what should we do immediately?
|
!!!LOOK for the bleed!!!
Usually from large bowel or excessive menstrual blood loss. |
|
|
Other than blood loss, what could be causes of iron deficiency anemia?
|
Increased requirements from Pregnancy or Lactation
Decreased Absorption (infrequent) Decreased gastric acidity. Small bowel disease. |
|
|
Is nutritional Iron deficiency common?
|
yes, very.
Most common in toddlers & adolescent girls. |
|
|
What are risk factors for infants to acquire an iron deficiancy?
|
Low birthweight.
Perinatal bleeding. Low hemoglobin at birth. High growth rate. Early cow’s milk and solid food intake. Frequent tea intake. (chelates iron and interferes with digestion). |
|
|
What is PICA?
|
Eating things that are not food in an attempt to replenish iron.
Can be a sign of iron deficiency with or without excessive milk intake. |
|
|
How do we differentiate between an iron deficiency anemia and microcytic hyperchromic anemia?
|
TIBC will not be increased in microcytic hyperchromic anemia.
Ferritin can be increased as an acute phase reactant in microcytic hyperchromic anemia. |
|
|
What non sideroblastic causes are there for microcytic hyperchromic anemia?
|
Can happen congenitally due to an inability to transport iron into red cells (low transferrin levels).
More commonly though, there is a defect associated with inflammatory diseases , IL-1 and IL-6 that causes iron to be accumulated and not recycled from the reticulendothelial system. |
|
|
What causes a sideroblastic anemia?
|
CONGENITAL:
X-linked or autosomal recessive mitochondrial disease. ACQUIRED: Drugs (isoniazid) Toxins (lead) Neoplasm (MDS) |
|
|
What is a distinguishing feature of sideroblastic anemias?
|
Iron accumulations in the mitochondria form a dotted blue ring around the nucleus.
These cells are called ring sideroblasts. |
|
|
What two microcytic hyperchromic anemias are most frequently seen in practice?
|
Iron deficiency.
Thallasemias. |
|
|
What beta globin genes on chromosome 11 contribute to hemoglobin manufacture?
|
Beta=HbA
Delta=HbA2 Gamma A and Gamma G=HbF |
|
|
What alpha globin genes on chromosome 16 contribute to hemoglobin manufacture?
|
Alpha 1
Alpha 2 |
|
|
What is a thallasemia?
|
They are disorders of globin chain imbalance. The chains are perfectly normal but the production of one is deficient in QUANTITY.
Whichever globin chain is not being expressed adequately carries the name of the disorder. |
|
|
What forms of hemoglobins are there in alpha thallasemia?
|
“Barts”-Gamma chain tetramer
(in fetus or very young child) “H”- Beta chain tetramer. Hemoglobin H is very unstable and produces a hemolytic anemia. |
|
|
Alpha thallasemias has varied clinical features determined by the number of alpha genes deleted out of the four. What are the different forms?
|
1 gene deleted:
Silent Carrier 2 genes deleted: “thalassemia minor” 3 genes deleted: hemoglobin “H” disease 4 genes deleted: Hydrops fetalis |
|
|
How do inheritance patterns for alpha thallasemias work?
|
In the the "alpha +" aka "-3.7 deletion" variety that is common in african ancestry:
Two silent carrier parents will produce an alpha thalassemia minor child. Homozygosity means two genes deleted but on different chromosomes. In the SEA (south east asian) variety both deletions are on the same chromosome and segregate together so reproduction even with a silent carrier can produce pretty substantial disease. |
|
|
What is the mechanism for alpha thallasemias?
|
Gene deletion
|
|
|
What are the characteristics of thallasemia minor (2 genes deleted) aka alpha thalasemia trait?
|
MICROCYTIC HYPOCHROMIC RED CELLS.
“TARGET” CELLS PRESENT DECREASED MCV NORMAL RDW MILD ANEMIA |
|
|
What are the characteristics of hemoglobon H disease? (3 alpha genes deleted)
|
MODERATELY SEVERE HEMOLYSIS
ELEVATED RETICULOCYTES RED CELL INCLUSIONS ON SUPRAVITAL STAINING |
|
|
Beta thalassemia has a simpler inheritance pattern than alpha thalassemia. How does it work?
|
HETEROZYGOTE-
Beta thalassemia minor (B-thalassemia trait) HOMOZYGOTE (or compound heterozygote)- Beta thalassemia major aka Cooley’s anemia |
|
|
The crux of the diagnosis for beta thallasemia other than family history is....
|
Elevated hemoglobin A2.
In a normal patient this is about 2% of the total Hb. It should be quite a bit higher in beta thallasemia patients. |
|
|
The characteristics of beta thalassemia minor aka beta thalasemia trait are?
|
Mild microcytic hypochromic anemia.
elevated Hb. A2. Low MCV. Normal RDW. |
|
|
The characteristics of beta thalassemia major aka beta thalasemia are?
|
VERY LOW HEMOGLOBIN
TRANSFUSION DEPENDENT BONE MARROW TRANSPLANT CAN BE CURATIVE |
|
|
What is hemoglobin E?
|
B-CHAIN MUTATION (B26lys..glu).
PREVALENT IN S.E. ASIA. MICROCYTIC HYPOCHROMIC ANEMIA. INTERACTS WITH B-THALASSEMIA. |
|
|
What happen to individuals who are compound heterozygotes for Hb E/ B-thal?
|
MODERATELY SEVERE ANEMIA
SPLENOMEGALY GROWTH DELAY TRANSFUSION REQUIREMENT |
|
|
What is the rule of threes?
|
RBC x 3 = Hb
Hb x 3 = Hct |
|
|
How does erythropoeisis work?
|
|
|
|
why does Hf have a higher oxygen binding affinity?
|
The interaction of globin chains with 2,3 BPG is less effective.
|
|
|
How is erythropoiesis regulated in the fetus?
|
During the last two thirds of preganancy, oxygen sensors trigger the release of erythropoietin in low oxygen situations.
Erythropoietin stimulates the bone marrow to make more red cells. |
|
|
When is the amount of gamma and beta chains produced roughly equivalent to each other?
|
Shortly after birth
|
|
|
What are the characteristics of fetal erythrocytes?
|
Macrocytic
Carry Hf Increased enzyme activity. Altered membrane antigen expression. |
|
|
What does a normal neonate CBC look like?
|
High hemoglobin
High MCV Reticulocytes Predominance of Hf RBC's |
|
|
What happens to a newborn's blood between 2 and 6 months? (early infancy)
|
“Physiologic” (adaptational) anemia.
Hemoglobin nadir (low point) @ 8-10 weeks. Hematopoietic recovery with increased reticulocytes at end of physiologic anemia. |
|
|
How does prematurity effect the normal development process of the blood?
|
Physiologic anemia develops earlier and nadir is lower.
Increased risk of iron deficiency anemia because of low birth weight and blood volume. (bigger babies are born with bigger iron stores) |
|
|
Why is there a heightened risk of developing iron deficiency anemia between 6 and 24 months of age?
|
Rapid somatic growth increases the iron requirements.
|
|
|
What is hydroxyurea?
|
An antineoplastic drug used in hematological malignancies, specifically polycythemia vera and essential thrombocytosis. It is also used to reduce the rate of painful attacks in sickle-cell disease and has antiretroviral properties in diseases such as AIDS.
It inhibits ribonucleotide reductase. In sickle patients it activates the gammaglobulin synthesis necessary for fetal hemoglobin through a nitric oxide and cyclic GMP mechanism. |
|
|
What happens in childhood around school age?
|
WBC differential shows increasing neutrophils and decreasing lymphocytes.
|
|
|
Why are adolescents at increased risk of iron deficincy microcytic anemia?
|
Much like infancy, rapid somatic growth causes an increased iron demand.
In addition, gender differences start to appear because of androgenic effects.Females are at greater risk because of menstrual blood loss. |
|
|
What are the most likely anemias in neonates?
|
HEMORRHAGE
Feto-MaternalBleeding Feto-Fetal Bleeding HEMOLYSIS Inherited Red Cell Disorders Alloimmune process Both types of anemia show high reticulocyte counts. |
|
|
What are hereditary membrane RBC disorders?
|
Spherocytosis.
(Most common hemolytic anemia) Defect is in proteins that link vertically with the lipid bilayer. Eliptocytosis |
|
|
What clinical features are associated with spherocytosis?
|
SPLENOMEGALY
NEONATAL JAUNDICE HEMOLYTIC ANEMIA CHOLELITHIASIS AUTOSOMAL DOMINANT (75%) RESPONSE TO SPLENECTOMY. INCREASED MCHC (one of the only states that does this) INCREASED OSMOTIC FRAGILITY MEMBRANE INSTABILITY |
|
|
What causes spherocytosis?
|
Highly variable condition.
Ankyrin deficiency most common autosomal dominant form. Decreased ankyrin provides fewer binding sites for spectrin which results in decreased spectrin in the membrane. Band 3 deficiency does not affect the stability of the cytoskeleton but results in membrane surface loss. Beta spectrin deficiency causes mild to moderate autosomal spherocytosis. Alpha spectrin and protein 4.2 deficiency cause autosomal recessive spherocytosis. |
|
|
What are the complications associated with hereditary spherocytosis?
|
“APLASTIC CRISES” (parvovirus B19)
FOLIC ACID DEFICIENCY INCREASED HEMOLYSIS CHOLELITHIASIS LEG ULCERS (Associated with chronic anemias of any etiology because of peripheral ischemia) |
|
|
Hereditary elliptocytosis is usually autosomal dominant and has many variants. It can even be asymptomatic. What usually causes it?
|
PROTEIN 4.1 SPECTRIN DEFECTS
|
|
|
Apart from spherocytosis and eliptocytosis, what other RBC defects are related to membrane pathology?
|
pyropoikilocytosis
stomatocytosis (rare dehydration of cells that leads to fishmouth shape) |
|
|
What enzyme deficiencies commonly cause hemolytic anemias?
|
PYRUVATE KINASE
G6PD |
|
|
What are the clinical features of pyruvate kinase deficiency?
(accumulation of 2,3 BPG) |
Most common glycolytic pathway enzymopathy.
Autosomal Recessive Neonatal Jaundice Chronic Severe-Moderate Hemolysis. Transfusion dependant. Variable response to splenectomy. (worst cases actually respond best) Very high reticulocyte count |
|
|
What are the clincal features of G6PD deficiency?
|
Most common enzyme deficiency.
X-Linked inheritance so mostly boys but not exclusively. Neonatal Jaundice. Infection induced hemolysis. Drug induced hemolysis. Fava bean hemolysis. Chronic hemolysis. Heinz body hemolytic anemia. |
|
|
What variants of G6PD deficiency are there?
|
B- variant (mediterranean) unstable enzyme Fava bean hemolysis
A- (african) paroxysmal oxidant hemolysis. |
|
|
What causes Heinz bodies in G6PD deficiency?
|
Hemoglobin denatures because the mechanism for protecting it is damaged.
The Heinz inclusions are denatured Hb. Blister cells aka Pyknocytes or Hemighosts are also seen and are red cells in which the Hb is concentrated in one half of the cell giving a blister appearance. |
|
|
What is the classic drug that exacerbates G6PD hemolysis?
|
Primoquin for malaria.
|
|
|
What is the early infancy anemia known as congenital pure red cell aplasia or diamond black fan syndrome?
|
An inherited red cell disorder.
The problem is actually in the bone marrow which does not make red cells. In some occasions it is because of a ribosomal protein mutation.(RPS19) Red cells have very high levels of adenosine deaminase in them which is diagnostically useful. MCV in these patients will be high because the cells are fetal red cells. Look for Hf. Reticulocytes will be low too because no RBC's are being made in the marrow. Clinical features include a typical facies and thumb anomalies. |
|
|
Is there hemolysis in the steady state of A- (african) G6PD deficiency?
|
No
|
|
|
What are some of the less common pediatric anemias?
|
Hereditary orotic aciduria (nucleotide synthesis enzyme)
Pearson syndrome (mitochondrial deletion with lactic acidosis) TRANSCOBALAMIN II DEFICIENCY (leads to intracellular vitamin B12 deficiency) |
|
|
What anemias are common in late infancy?
|
Nutritional iron deficiency anemia. (most common so therapeutic trial with iron is indicated)
Transient erythroblastopenia of childhood. (TEC) |
|
|
What are the diagnostic features in Transient erythroblastopenia of childhood. (TEC)?
|
Usually 6 months or older.
NORMOCYTIC NORMOCHROMIC (normal MCV) LOW RETICULOCYTES VERY LOW HEMOGLOBIN SPONTANEOUS RESOLUTION Compare with diamond blackfan of early infancy that has a HIGH MCV. |
|
|
In childhood anemia it is likely not nutritional, what do we look for?
|
Bleeding.
Anemia is likely secondary to other disease. |
|
|
What is the childhood disease Fanconi's anemia?
|
PANCYTOPENIA WITH CONGENITAL ANOMALIES
BONE MARROW HYPOPLASIA RADIAL/THUMB ANOMALIES ALTERED SKIN PIGMENT(HYPER OR HYPO PIGMENT) INCREASED RISK FOR MALIGNANCIES |
|
|
What physical abnormalities are associated with Fanconi's anemia?
|
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%) |
|
|
What anemias are associated with adolesecence?
|
IRON DEFICIENCY ANEMIA
SECONDARY TO OTHER DISEASE SPORTS ANEMIA |
|
|
What anemias can occur in pediatrics of any age?
|
Autoimmune hemolytic anemia
Microangiopathic hemolytic anemia. Hemoglobinopathies Sickle cell Etc. |
|
|
What is microangiopathic hemolytic anemia associated with?
|
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) |
|
|
What are the four sickle cell hemoglobinopathy syndromes?
|
Hb. S/S
Hb. S/C Hb. S/B-thal. (+/0) |
|
|
What is the epidemiology of hemoglobinopathies and how do we detect them?
|
Hb. S is most common in U.S., followed by C and E.
Hb. S and E are most common world wide. Electrophoresis or chromatography identifies variants with charge change. |
|
|
What are the classic physical findings of sickle cell disease?
|
Splenic sequestration.
Avascular necrosis. Stroke. Acute chest syndrome. Vasculitis. |
|
|
What things are important to remember about managing sickle cell in children?
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EARLY DIAGNOSIS (NEONATAL SCREENING)
HYPOSPLENIC FUNCTION PNEUMOCOCCAL VACCINE PROPHYLACTIC PENICILLIN DACTYLITIS (HAND FOOT SYNDROME) SPLENIC SEQUESTRATION STROKE PREVENTION |
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In summary, what are considered "pediatric" anemias?
(some can occur in adults too) |
TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD (TEC)
DIAMOND-BLACKFAN ANEMIA FANCONI’S ANEMIA NUTRITIONAL IRON DEFICIENCY ANEMIA ALLOIMMUNE HEMOLYTIC ANEMIA OF THE NEWBORN |
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Hall mark signs of iron deficiency are....
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EXCESSIVE MILK INTAKE
PICA |
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NEONATAL JAUNDICE
and /or FAMILY HISTORY OF SPLENECTOMY OR CHOLECYSTECTOMY should make you think about... |
Congenital hemolysis
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Short stature, thumb and radial anomalies, horseshoe kidney and microopthalmia should make you think about...
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Fanconi's anemia
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Thumbs and facies should make you think about...
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Diamond blackfan anemia
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Lactic acidosis and failure to thrive should make you think about...
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Pearson syndrome
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What is the mentzner index?
|
MCV / RBC
>13.5 IRON DEFICIENCY <11.5 THALASSEMIA TRAIT |
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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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Barts hemoglobin on newborn screen is...
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Consistent with alpha thalassemia trait
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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 |
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Platelets are seen breaking off
from the cytoplasm of a megakaryocyte. |
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How does regulation of Thrombopoiesis or platelet production occur?
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Thrombopoeitin (TPO) which can act on all levels of platelet precursors from stem cells to platelets themselves is a glycoprotein that binds to its receptor on platelets and megakaryocytes.
Thrombopoeitin is produced at a CONSTANT RATE by the liver. The inverse relationship between serum TPO levels and platelet mass exists because TPO concentration is regulated by the total mass of PLTs/megakaryocytes available to bind and degrade the protein. |
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What is the difference between eythropoeitin and thrombopoeitin?
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Eythropoeitin induces erythrocyte production.
TPO induces platelet production. |
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What is the structure of a platelet?
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What is contained in platelet alpha granules?
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Beta-Thromboglobulin
Factor V Factor XI Protein S FIBRINOGEN VON WILLEBRAND FACTOR PLATELET FACTOR 4 Platelet derived growth factor |
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What is contained in platelet dense bodies?
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ADP (activates neighbouring platelets)
Serotonin (Vasoconstrictor) ATP Calcium |
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What are the three big picture components of hemostatsis?
|
Vessels:
Vasoconstriction Platelets: Platelet adhesion Soluble factors: Fibrin formation through coagulation cascade. |
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What are the functions of platelets?
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Formation of mechanical plugs during normal haemostatic response.
Local release of vasoconstrictors. Catalysis of reactions in the soluble coagulation cascade. Initiation of tissue repair. Regulation of local inflammation. |
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What is platelet adhesion?
|
Platelets roll and cling to NON-PLATELET surfaces.
Reversible. Seals endothelial gaps. Requires VWF in arterioles. Collagen is also important. |
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What is platelet aggregation?
|
Platelets cling to EACH OTHER.
Irreversible. Platelet plugs form. Requires fibrinogen. Secretion of all platelet contents. |
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What is platelet secretion?
|
An irreversible process essential for coagulation which occurs during platelet AGGREGATION.
Platelets discharge the contents of their granules. |
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Where do platelets normally travel in the blood vessel?
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They get pushed out towards the vessel walls.
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Where does VWF come from and what does it do?
|
Both from endothelial cells and from platelets.
It seves as the bridge or adaptor between the platelet and the collagen. It has an end that binds collagen and one that binds glycoprotein 1b on the platelet. |
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What are the events of primary hemostasis?
|
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. |
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What do defects in GPIb cause?
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Bernard-Soulier Disease
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What do defects in GPIIbIIIa cause?
|
Glanzmann Thrombasthenia (weak platelets)
Drugs like rheopro do the same thing. |
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What causes an increase in the affiinity of surface GP2b3a for fibrinogen?
|
Ultimately intracellular calcium.
Agonists can act on G protein coupled receptors to cause this (not directly on GP2b3a). |
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What are some GP2b3a mechansim aggregation agonists?
|
Thrombin
TXA2 ADP Collagen PAF |
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What are some GP2b3a mechanism aggregation inhibitors?
|
Reversible:
Adenosine (increases cGMP) NO PGI2 Dipyridamole (increases cGMP and adenosine) Irreversible: Ticlopidine (ADP) Clopidogrel (ADP) ASA (Cox) |
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Where does aspirin act?
|
Cyclooxygenase inhibitor
Decreases thromboxane A2 production for the 5-7 day life of the platelet. |
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How do colpidogrel (plavix) and ticlopidine achieve platelet aggregation inhibition?
|
They block binding of ADP to agonist sites on platelets.
No ADP, No cGMP increase, No calcium to create conformational change in GP2b3a. Therefore, no increase in aggregation. |
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How do expensive coronary drugs like abcixemab (reopro) work?
|
Glycoprotein blockers.
Blocking the glycoprotein means no fibrinogen binding. |
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What allows the platelet plug to become a fibrin stabilized platelet plug?
|
Crosslinking of fibrin due to interaction with the coagulation cascade.
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How do we define thrombocytopenia and what are it's consequences?
|
Platelet count <150,000/ul
Bleeding following surgery or trauma with PLT counts < 50K Spontaneous hemorrhage with PLT counts < 10K Transfusion threshold is somewhere around 10,000 but this is not a hard and fast rule. |
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In general terms, what can cause thrombocytopenia?
|
Failure of platelet production
Increased consumption of platelets. Abnormal distribution of platelets. (availability) Dilutional Loss. |
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Is retroperitoneal hemorrage typically associated with thrombocytopenia?
|
No.
It is a massive bleed. Not the "oozey/bruisey" type of bleeding typically associated with thrombocytopenia. |
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What can cause selective megakaryocyte depression?
|
Rare congenital defects.
Drugs, chemicals, viral infections. |
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Failure of platelet production (thrombocytopenia) is most commonly part of a more generalized bone marrow failure. What can cause this?
|
Cytotoxic drugs
Radiation Marrow infiltration HIV infection |
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What is May-Hegglin anomaly?
|
A rare inherited form of thrombocytopenia which also causes inclusions in neutrophils.
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What is thromobocytopenia and absent radii syndrome?
|
Exactly what it sounds like.
Very rare genetic condidtion. |
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What is gray platelet syndrome?
|
A very rare condition which causes a distinct absence of dense granule content in platelets.
Platelets appear very pale. |
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What causes increased consumption of platelets?
|
Immune:
Autoimmune/idiopathic (ITP) Infections like HIV and malaria. Drug-induced immune responses. Heparin (HIT). Post-transfusional purpura. Disseminated intravascular coagulation (DIC). Thrombotic thrombocytopenic purpura (TTP). |
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What type of Immune Thrombocytopenic Purpura is less responsive to treatment?
|
Chronic
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What is going on here?
|
Peripheral smear in a patient with ITP showing an almost total absence of platelets.
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|
Giant platelet (larger than a normal red cell)
Found in: Increased platelet turnover. Myeloproliferative disorders. Myelodysplastic disorders. |
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What is the pathogenesis of ITP?
|
Autoimmune recognition causes increased platelet destruction in the spleen.
Recent evidence suggest immune cells also target megakaryocytes IN THE BONE MARROW. |
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How do we treat ITP?
|
Target the immune system with steroids, splenectomy or high dose Immunoglobulins. (This engages the Fc receptors and gives the macrophages something to munch on besides platelets)
Increase platelet production by giving thrombopoeitin receptor agonists to stimulate megakaryocyctes. |
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There are TONS of drugs that induce thrombocytopenia. Which ones are really important examples?
|
EtOH
Heparin Phenytoin Quinine Quinidine Sulfas |
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What is Heparin Induced Thrombocytopenia?
|
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 |
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What is the clinical pentad of thrombotic thrombocytopenic purpura?
|
Fever
Anemia Thrombocytopenia Renal dysfunction Neurologic deficits (FAT RN) Devastating disorder which is fatal if untreated. |
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What do we see on the blood film of TTP patients?
|
schistocytes + few platelets
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What is the pathophysiology of TTP?
|
The absence or impairment of ADAMTS13 (VWF cleaving enzyme) allows persistence of the ultralarge “sticky” forms of VWF.
These forms of VWF trap platelets and cause thrombi in vessels. The thrombi lead to end-organ damage, and the pentad of clinical features. |
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How does dilutional loss lead to thrombocytopenia?
|
Thrombocytopenia occurs in patients receiving massive transfusions (10-20 units) of PRBCs over a brief time frame.
eg. CABG It is due to the absence of viable platelets in stored PRBCs since platelets typically live 5-7 days. |
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What is the platelet distribution in normal patients?
|
~30% in spleen
~70% circulating This can be dramatically shifted towards the spleen if there is splenomegaly and cause thrombocytopenia. |
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What is pseudothrombocytopenia?
|
EDTA in CBC tubes can cause clumping of platelets which can be misinterpreted as thrombocytopenia.
Fibrin strands from a clot in the sample (as pictured) can also give falsely low platelet counts. |
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What is thrombocytosis?
|
a PLT count > 500K
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What are the mechanisms of thrombocytosis?
|
Reactive:
Cytokine driven (>80% of cases) autonomous/clonal/neoplastic aka Essential Thromboyctyosis. |
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What are the possible complications of thrombocytosis?
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Thrombosis in 15-20%
Bleeding in 3-5% (pardoxically, even though there are many platelets, they don't function well. Neither complication is typical in patients with reactive thrombocytosis. |
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What are the causes of Secondary (Reactive) Thrombocytosis?
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What is leukocytosis?
|
An absolute increase in the number of leukocytes in peripheral blood without reference to cell type or level of maturity.
In adults >10,000-11,000/mm3 |
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The majority of cases of leukocytosis are due to an increase in ...
|
Neutrophils.
First circulating neutrophils move to a site of injury or infection. In most cases this is followed by the release of stored leukocytes, commonly referred to as a "left shift“. |
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What are the pathophysiologic mechanisms of leukocytosis in patients with normally functioning bone marrow?
|
Infection
Inflammation (tissue necrosis, infarction, burns, arthritis etc.) Stress leukocytosis (overexertion, seizures, anxiety, anesthesia, epinephrine) Drugs (corticosteroids, lithium,beta agonists) Trauma (splenectomy is especially bad for this because the white cells no longer have a reservoir and they all circulate) Hemolytic anemia |
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What are the pathophysiologic mechanisms of leukocytosis associated with abnormal bone marrow?
|
Acute leukemias
Chronic leukemias Myeloproliferative disorders. |
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What is leukemoid reaction?
|
An excessive white blood cell response (> 50,000) associated with a cause outside the bone marrow.
This exaggerated WBC count is usually caused by relatively benign processes (infection or inflammation). Underlying malignancy is the most serious but least common cause of a leukemoid reaction. Down syndrome babies can have leukemoid reactions which resolve spontaneously. |
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Lymphocytes normally represent what percentage of WBC's (leukocytes)?
|
20-40%
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What is relative lymphocytosis?
|
Relative lymphocytosis occurs when there is a higher proportion (greater than 40%) of lymphocytes among the white blood cells but the absolute lymphocyte count (ALC) is normal.
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What are the criteria for absolute lymphocytosis?
|
>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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Why do children exhibit physiological relative lymphocytosis?
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Rapid tissue growth and development of the immune system.
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What causes absolute lymphocytosis?
|
Acute infection
(CMV, EBV, Pertussis, Hepatitis, Toxoplasmosis) Chronic infection (TB, Brucella) Lymphoid malignancy such as chronic lymphocytic leukemia. |
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What causes relative lymphocytosis?
|
Normal in young children.
Viral infection. Splenomegaly. |
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What causes very pronounced benign reactive Lymphocytosis?
|
Pertussis
Acute infectious Lymphocytosis (Coxsackie). Infectious Mononucleosis (EB) |
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What percentage of circulating leukocytes are normally eosinophils?
|
<5%
They last less than 24 hours in the circulation before they go to extravascular tissues. The storage pool of eosinophils in the marrow is about 5-times the circulating population. |
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What do eosinophils actually do?
|
Participate in immunologic and allergic events.
Play a role in phagocytizing antigen-antibody complexes. Associated with allergy and tissue invasive parasites. |
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What causes eosinophillia?
|
Allergic events
Parasitic infections Dermatological conditions Infections (scarlet fever, chorea, leprosy, genitourinary infections) Immunologic disorders (Rh arthritis, SLE, eosinophillia-myalgia syndrome) Myeloproliferative disorders (chronic myelo-genous leukemia, polycythemia vera, myelofibrosis) Adrenal insufficiency (addisons disease) Pleural and pulmonary conditions. (Löffler’s syndrome, pulmonary infiltrates and eosinophilla) |
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Basophilia is a VERY uncommon cause of leukocytosis. Basophils are inflammatory mediators of substances such as histamine. These cells, along with similar tissue-based cells (mast cells), have receptors for IgE and participate in the degranulation of white blood cells that occurs during allergic reactions, including anaphylaxis. What are possible causes of basophilia?
|
Viral infections like varicella and chronic sinusitis.
Inflammatory conditions like IBS, chronic airway inflammation, chronic dermatitis. Myeloproliferative disorders like chronic myelogenous leukemia, polycythemia vera, myelofibrosis. Endocrinological causes like Hypothyroidism, ovulation, estrogens. Alterations in marrow an reticuloendothelial compartements like chronic hemolytic anemia, Hodgkin’s disease or splenectomy. |
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What is neutropenia?
|
Decrease in the absolute neutrophil count (ANC) below accepted norms for age.
Term newborn (up to 1 week) < 3,000 Infant (1 week – 2 years) < 1,100 Child, adolescent, adult < 1,500 |
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What is benign ethnic neutropenia?
|
Approximately 25% to 50% of persons of African descent and some ethnic groups in the Middle East have benign ethnic neutropenia, with low leukocyte and neutrophil counts.
They have a normal bone marrow response and are not more susceptible to infection though. |
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How does altitude affect neutrophil count?
|
lower ANC above 5,000 ft
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How does neutrophil count correlate with risk of infection?
|
200-500 moderate to severe
(skin, mucous membrane) <200 Severe (sepsis, pneumonia, etc) |
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How do we evaluate neutropenia?
|
Marrow reserve ?
Normal - immune neutropenias, hypersplenism, infection Decreased - congenital neutropenias, marrow failure syndromes, chemotherapy, etc Primary hematologic disorder? Intrinsic defects in stem cells/granulopoiesis or extrinsic causes of neutropenia. |
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What is pseudo-neutropenia
|
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. Patients respond well to rapid mobilization of neutrophils from marginal pool with exercise and/or epinephrine. |
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What is infection induced neutropenia?
|
Common during viral infections, usually transient.
Proctated neutropenia can be seen with mononucleosis, hep B and HIV. |
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What is the mechanism for drug induced neutropenia?
|
Immune mediated or direct destruction of granulocyte precursors.
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|
What is cyclic neutropenia?
|
Autosomal disorder
Marked neutropenia every 21 days, nadir last 3-7days Patients are subject to recurrent severe infections. |
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What is Kostmann syndrome?
|
Severe congenital neutropenia
Present at birth ANC < 200/ul Predisposes to leukemia and preleukemic conditions. |
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What is lymphopenia?
|
Absolute lymphocyte count (ALC) of <1,000/mm3 in adults or <1,500/mm3 in children.
<1000 in kids is definately abnormal. Sometimes related to SCID, AIDS, aplastic anemia, steroids, chemo or radiotherapy, congenital lymphatic abnormalities. |
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What is the algorithm for diagnosing anemia?
|
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|
What are the main microcytic anemias?
|
Iron Deficiency
Anemia of chronic disease Thalassemias Sideroblastic anemia |
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|
What are the main macrocytic anemias?
|
B12 Deficiency.
Folate Deficiency. Inherited Megaloblastic Anemias. Drug-Induced (dilantin, sulfa, AZT, methotrexate) Other (Alcoholism, Hypothyroidism, Liver Disease, MDS, reticulocytosis) |
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|
What are the main normocytic anemias?
|
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 |
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|
How do we calculate mean corpuscular volume, MCV?
|
if HCT is in (L/L)x1000
and RBC is in millions/uL MCV=HCT/RBC MCV is in fL (normal:80-100fL) |
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How do we calculate mean corpuscular hemoglobin, MCH? (The amount of hemoglobin in an average red blood cell)
|
If hemoglobin is in g/dL and
RBC count is in millions/µL MCH=Hb/RBC MCH is in pg (normal: 26-33pg) |
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|
How do we calculate mean corpuscular hemoglobin concentration, MCHC?
(the color of the RBC) |
Hemoglobin is in g/dL
Hematocrit is in L/L MCHC=Hb/HCT Normal range: 32 - 36 g/dL Hyperchromic > 36 g/dL Hypochromic < 32 g/dL |
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What does RDW measure?
|
anisocytosis – variation or range in cell volume.
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What do the reticulocytes tell us in anemia?
|
How well the patient is compensating for the anemia.
Reticulocytosis: normally ↑ % in response to anemia. Reticulocytopenia: abnormal ↓ % in response to anemia. |
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What type of anemia is a Nutritional Fe deficiency?
|
Microcytic, hypochromic anemia.
|
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|
What is Ferritin?
|
A soluble protein-iron complex (apoferritin and Fe+3-phosphate core).
Synthesis of ferritin is stimulated by the presence of iron. |
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|
What is hemosiderin?
|
An insoluble protein-iron complex which is formed by lysosomal digestion of ferritin.
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What is conclusive evidence of Iron deficency?
|
Bone marrow Fe stores are depleted.
Serum ferrtin should be decreased but can be elevated for other reasons and is not an absolute indicator. |
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|
What is the typical M:E ratio in iron deficiency anemia?
|
About 0.8:1
The bone marrow compensates for the iron deficiency anemia by increasing red cell production which lowers the ratio. |
|
|
What is folate used for in the body?
|
Purine/pyrimidine synthesis
Methionine synthesis Methylation transfer reactions |
|
|
Hypersegmentation of neutrophils is an early sign of ?
|
B12 or folate deficiency.
|
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|
MCV > 120fL is generally diagnostic of..
|
B12 or folate deficiency.
The drug sulfasalazine is one of the only other differential items that cause this high of an MCV. |
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|
How do you tell B12 from folate deficiency on a smear?
|
You don't.
Hematologic features of B12 and Folate deficiency are indistinguishable. |
|
|
The giant myelocytes and bizarrely nucleated metamyelocytes found in a B12 or folate deficient patient's bone marrow are easily mistakeable for....
|
Leukemia
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|
Do megaloblasts mature differently from normoblasts?
|
Not really
|
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|
What bone maroow findings are associated with hemolytic anemias?
|
Hypercellular, with associated erythroid hyperplasia.
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|
What complications are associated with hereditary spherocytosis?
|
Transient Aplastic Crisis (TAC) caused by infections. (Parvovirus B19 about 90% of aplastic crises in HS)
Effective 'cure' for HS is a splenectomy. |
|
|
Parvovirus B19 infects...
|
Red cell precursors in the bone marrow.
Causes transient erythroblastopenia of childhood (TEC) which is similar to diamond blackfan anemia but does not start at birth because it is not congenital. Also causes erythema infectiosum or “Fifth Disease” with a slapped cheek appearance. Giant pronormoblasts with viral inclusions can be seen in bone marrow. |
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|
What is aplastic anemia?
|
A stem cell failure in the bone marrow.
All the hematopoietic elements fail resulting in marked panhypoplasia of the bone marrow and pancytopenia of the peripheral blood. Most cases are idiopathic. Paroxysmal Nocturnal Hemoglobinuria. Prognosis: variable and unpredictable, usually BAD. |
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|
In basic solutions (pH > 8) hemoglobin is negatively charged. In what order do the hemoglobin variants migrate to the anode?
|
Hyperspace
Breakneck Accelerating Fast Slow Crawl |
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|
In acidic solutions (pH <6.2) hemoglobin is positively charged. In what order do the hemoglobin variants migrate to the anode?
|
Carolina (fastest)
Sucks At Football (slowest) This test is used to confirm Hb S and Hb C. |
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|
Severe microcytic anemia with sickle cells is associated with the genotype...
|
HbS/B0
Sickle/Beta Thalassemia |
|
|
What are the mechanisms of chemotherapy induced nausea and vomitting?
|
Stimulation of chemoreceptor trigger zone (CTZ).
Peripheral mechanisms - Damage of GI mucosa - Stimulation of GI neurotransmitter receptors Cortical mechanisms - Direct cerebral activation - Indirect (psychogenic) Vestibular mechanisms Alterations of taste and smell |
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|
Where is the CTZ?
|
The area postrema in the brainstem.
The CTZ releases neurotransmitters, which activates brainstem vomiting center. |
|
|
The main neurotransmitter involved in chemotherapy induced nausea and vomitting is...
|
Serotonin
Also involved: Substance P Dopamine Histamine Acetylcholine Serotonin and substance P are specific to CINV. |
|
|
The ACUTE PHASE of nausea is the most common,
Begins 1 to 2 hours, peaks 4 to 10 hours and resolves within 12 to 24 hours. What are the most effective drugs against it? |
Serotonin antagonists (ant.)
Neurokinin ant. also work. |
|
|
DELAYED PHASE N/V begins 1 to 5 days after chemotherapy, peaks 48 to 72 hours and is generally of longer duration but lesser severity than acute phase N/V.
It is associated with high-dose cyclophosphamide, mitomycin-C, cisplatin, doxorubicin, and ifosfamide. What drugs work best against this type of N/V? |
Neurokinin-1 antagonists
|
|
|
When should we give 5HT3 antagonists for CINV?
|
30 minutes prior to chemo.
Increased efficacy with corticosteroids. Effective for acute N/V but not any more effective for delayed N/V than other therapies. |
|
|
What is the pharmacological effect of 5HT3 antagonists?
|
Blocks serotonin both centrally and peripherally.
|
|
|
What are the adverse effects of 5HT3 antagonists?
|
Headache
Constipation Diarrhea EKG changes – (underlying arrhythmias?) |
|
|
What are the 5HT3 antagonist antiemetic drugs?
|
Ondansetron (Zofran®)
Granisetron (Kytril®) Granisetron (Sancuso) Dolasetron (Anzemet®) Palonosetron (Aloxi®) !!Ondansetron (Zofran®) and Granisetron (Kytril®) only for highly emetogenic chemo as oral agents!! |
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|
How do Neurokinin-1(NK-1) receptor antagonists work?
|
Inhibit sSubstance P
Indicated for preventing acute and delayed CINV along with 5HT3 antagonists and corticosteroids. |
|
|
Granisetron (Sancuso) is a...
|
5HT3 antagonist patch
Lasts about 7 days and is put on about 24hours prior to chemo. |
|
|
Which 5HT3 antagonist is only available IV?
|
Palonosetron (Aloxi®)
|
|
|
What is Aprepitant (Emend)?
|
NK-1 Receptor Antagonist.
|
|
|
What are the adverse effects of Aprepitant (Emend)?
|
Asthenia/fatigue (18%)
Nausea (13%) Hiccups (11%) Diarrhea (10%) Somnolence |
|
|
What sort of drug interactions should we be cautious of when using Aprepitant (Emend)?
|
Decrease steroids by 50% IV or 25% PO because of synergy.
Caution with agents that are metabolized by CYP3A4 . |
|
|
What antiemetic drugs are dopamine receptor antagonists?
|
Phenothiazines:
prochlorperazin (Compazine®), promethazine (Phenergan®) Butyrophenones: droperidol (Inapsine®) Substituted benzamide metoclopramide (Reglan®) |
|
|
What are phenothiazines good for?
|
Effective for delayed nausea/vomiting.
|
|
|
What are some of the adverse events associated with phenothiazines?
|
akathisia – lorazepam can help
dystonia – diphenhydramine or benztropine can help sedation – more common with promethazine |
|
|
What is a consideration in choosing compazine vs. phenergan?
|
Prochlorperazine (compazine)is a more potent antiemetic in cancer patients but has a higher incidence of akathisia and dystonia than promethazine (phenergan).
|
|
|
How do substituted benzamides work?
|
Blocks dopamine in the CTZ and peripherally. Commonly used before 5HT3 blockers.
Increases esophageal sphincter tone. Improves gastric emptying. Increases transit through small bowel. Diarrhea is a major side effect but this can be helped by coadministration of dexamethasone. Other side effects: EPS (Bad) Restlessness Sedation Fatigue Nausea |
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|
The substituted benzamide metoclopramide (Reglan) has different effects based on dosing. How does this work?
|
10 mg PO q6h
(useful for mild nausea) 0.5 mg/kg IV q6h (blocks serotonin) |
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|
How are benzodiazepines like Lorazepam (Ativan) antiemetics?
|
Used for anticipatory nausea because of amnestic, anxiolytic and sedative properties.
Not effective for preventing emesis and are usually given with other antiemetics. |
|
|
Why are corticosteroids not given in acute myelogenous leukemia (AML)?
|
They may increase the differentiation of WBC.
(left shift) |
|
|
What are the side effects of corticosteroids?
|
Increases appetite, improve mood and sense of well being.
BUT.. Can cause mood changes, anxiety, euphoria, headache, metallic taste, abdominal discomfort. |
|
|
What do we know about Cannabinoids like Dronabinol (Marinol)?
|
Less effective than metoclopramide but more effective than phenothiazines.
Not effective with high emetogenicity. Adverse events include mood changes, dysphoria, memory loss, hallucinations, blurred vision, hypotension and tachycardia. Beneficial with younger patients. Dose is 2.5-5 mg po TID |
|
|
What type of nausea responds well to anticholinergics like scopolamine?
|
Nausea associated with movement.
Side effects: Cant see Can't spit Can't pee Can't...poop |
|
|
Bottom line, what do I use for acute CINV?
|
Day 1:
5HT3 + dexamethasone + aprepitant Day 2&3: Aprepitant + dexamethasone For delayed and rescue CINV: Metoclopramide Dronabinol (marinol) Phenothiazines |
|
|
What are the effects of CSFs (colony stimulating factors) on mature cells?
|
Increase chemotaxis
Enhance phagocytosis Increase cytotoxic killing Improve responsiveness to antigens. Enhance eosinophil function. |
|
|
What is Filgrastim (Neupogen®)?
|
G-CSF
(granulocyte colony stimulating factor) Supports proliferation of neutrophils and stimulates neutrophil function but has no effect on mature eosinophils and macrophages. Used for cancer patients receiving myelosuppressive chemo or BM/stem-cell transplant. Also used for peripheral blood stem cell collection and severe chronic neutropenia. Causes bone pain in lumbar, sternal and pelvic areas which responds to acetaminophen or NSAIDs. Begin 24-72 hours after chemo completion (SQ or IV) Continue until ANC > 1000 for 3 days or > 5000 for 1 day. |
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|
What is Pegylated Filgrastim (Neulasta)?
|
A large "chunk" of filgastrim.
Flat dose regardelss of weight. The larger structure slows clearance and allows only one dose. Cleared by neutrophils so as the white blood cells recover they are able to clear the drug. |
|
|
What is Sargramostim (Leukine®)?
|
GM-CSF
(Granulocyte-macrophage colony stimulating factor) Stimulates only CFU-GM and CFU-GEMM to increase neutrophils, macrophages, monocytes and eosinophils. Has more side effects than filgastrim on first dose because of multiple cell lines. eg. fever, headache, myalgia, arthralgia, pleural and pericardial effusions. May increase response to antifungal therapy because of macrophage involvement. Used for: Autologous bone marrow transplant. Treatment of BMT failure or engraftment delay (auto or allo BMT). Neutrophil recovery following chemotherapy for AML. Mobilization of peripheral blood progenitor cells. Peripheral stem cell transplantation. |
|
|
What is Erythropoietin (Procrit/Epogen)?
|
Enhances RBC production (including HCT) and decreases the need for RBC tranfusion.
Must have Hgb < 10 g/dL or HCT < 30%. Continue until hct > 30-33% or hct increases > 4 points in 2 weeks. Iron stores should be monitored and supplemented if serum transferrin < 20%. Takes 2-6 weeks to see response. Used for: End stage renal disease. AIDS patients on zidovudine. Anemia from cancer chemo. Anemia of prematurity. Myelodysplastic syndrome. BM/stem cell transplant. Preoperative blood collection. Adverse events: Hypertension (24%) Headache (16%) Clotting of vascular access. Iron deficiency anemia. Seizures. Long bone pain and cold sens. Pyrexia (38% of AZT patients) |
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|
Darbopoietin (AraNesp)
|
Larger than eythropoeitin with more carbohydrate groups for slower elimination.
Should be used in patients receiving chemotherapy with no intent for cure. |
|
|
What does the synthetic IL-11, Oprelvekin (Neumega) do?
|
Promotes megakaryocyte production.
Prevents severe thrombocytopenia. For the most part outdated because it does not reduce platelet transfusion under the current guidelines.(<10,000) |
|
|
What cell types cause leukemia?
|
Usually occurs with myeloid or lymphoid cells.
Can involve other cells, including cells in the erythroid or megakaryocytic lineage. |
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|
In general, the incidence of acute leukemias....
|
Increases with age.
Major upward trend begins at about 50. The exception is childhood ALL which also has a small peak at about 1-4 years. |
|
|
Acute myeloid leukemia is the same thing as...
|
Acute Myelogenous Leukemia
Acute Nonlymphocytic Leukemia |
|
|
What is the abnormal cell in AML?
|
The myeloblast.
Grow uncontrollably. Maturation is halted. Inhibit growth of normal cells in the marrow. |
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|
What are the risk factors for AML?
|
Prior chemotherapy with alkylating agents and epipodophyllotoxins.
Prior ionizing radiation particularly prenatally (less relevant now due to regulation) Exposure to benzenes Abnormal genetics: Down syndrome Neurofibromatosis Schwachman syndrome Bloom syndrome Familial monosomy 7 Kostmann syndrome Fanconi's anemia Primarily an idiopathic disease though. |
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|
How do we determine the lineage of cells in bone marrow to discern AML form ALL?
|
Flow cytometry
Cytogenetics and FISH can also be done on the aspirate to determine translocations and other genetic abnormailites. |
|
|
What do we use the bone marrow core sample?
|
Slice it up to determine the cellularity.
|
|
|
While we formerly categorized AML based on morphology under the FAB system we now classify...
|
Based on genetics under the WHO system.
Big groups are: AML with recurrent genetic abnormalities. AML with multilineage dysplasia. AML and myelodysplastic syndromes, therapy related. AML, not otherwise categorized. |
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|
The most importnat prognostic factor for AML is...
|
Genetics
|
|
|
How do we treat AML?
|
Don’t use surgery.
Don’t use radiation. Use chemotherapy – circulates in the blood like the leukemia cells do. |
|
|
What is the problem with chemotherapy?
|
Kills the good cells as well as the bad cells.
|
|
|
What is induction chemotherapy for AML?
|
First treatment patients get.
Called induction chemo because it trys to "induce" a remission. Standard of care is: Cytarabine (7 days) Daunorubicin (3 days) Sometimes Etoposide (3days) 7+3+3 Supportive care takes 4-6 weeks. |
|
|
What is tumor lysis syndrome?
|
When cells are destroyed they release:
Uric acid (nephropathy) Phosphorous Hypercalcemia Hyperkalemia etc. |
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|
What cardiac complications are associated with chemotherapy for AML?
|
Donarubicin is an anthrocycline and can cause cardiomyopathy (CHF).
|
|
|
How do we monitor chemotherapy for AML?
|
Repeat a marrow on day 14 (nadir marrow)
If no leukemia, await count recovery (~ 2 weeks) If leukemia still present, need additional chemo: "5+2+2” or different regimen. |
|
|
Why do we do a recovery marrow?
|
To make sure that the only cells that came back after the chemo were the good ones.
If we can’t see any leukemia cells, the patient is in remission. |
|
|
What is the chance an AML patient will relapse from complete remission if we stop treatment alltogether?
|
>85%
|
|
|
What is consolidation chemo aka intensification chemo treatment for AML?
|
We need to give additional chemotherapy to consolidate the remission that we’ve achieved with induction chemotherapy.
3 booster treatments ~4weeks apart of high dose ara-C (days 1, 3, and 5). Patients can be discharged on antibiotic pills but ~50% will return with fever while neutropenic. Outpatient transfusions as needed. |
|
|
What are bad prognostic factors for AML?
|
Increased age.
Secondary AML (toxin-induced) Certain genetic abnormalities like -5, -7, 11q23 (MLLgene). Not obtaining remission after induction chemotherapy. |
|
|
What is an MDR abnormality?
|
MDR stands for mutli drug resistant gene.
If MDR is active the cells will actively pump out the chemotherapy. Increased incidence of this protein with increased age. |
|
|
What is the problem with chemotherapy?
|
Kills the good cells as well as the bad cells.
|
|
|
What is induction chemotherapy for AML?
|
First treatment patients get.
Called induction chemo because it trys to "induce" a remission. Standard of care is: Cytarabine (7 days) Daunorubicin (3 days) Sometimes Etoposide (3days) 7+3+3 Supportive care takes 4-6 weeks. |
|
|
What is tumor lysis syndrome?
|
When cells are destroyed they release:
Uric acid (nephropathy) Phosphorous Hypercalcemia Hyperkalemia etc. |
|
|
What cardiac complications are associated with chemotherapy for AML?
|
Donarubicin is an anthrocycline and can cause cardiomyopathy (CHF).
|
|
|
How do we monitor chemotherapy for AML?
|
Repeat a marrow on day 14 (nadir marrow)
If no leukemia, await count recovery (~ 2 weeks) If leukemia still present, need additional chemo: "5+2+2” or different regimen. |
|
|
What is consolidation chemotherapy aka intensification chemotherapy for AML?
|
We need to give additional chemo to consolidate the remission that we’ve achieved with our induction chemo.
Three "booster treatments" ~4 weeks apart of HIGH DOSE ara-C given on days 1,3 and 5. Patients can go home on prophylactic antibiotic pills after 6 day hospitalization but ~50% will return with fevers while neutropenic. Outpatient transfusions as needed. |
|
|
What are bad prognostic factors for AML?
|
Increased age.
Secondary AML (toxin-induced). -5, -7, 11q23 MLLgene abnormality (<10% CR rate) Not obtaining remission after induction chemotherapy. |
|
|
What is an MDR gene abnormality and why is it important in AML?
|
MDR stands for multidrug resistance gene.
The protein actively pumps the chemo out of cells. Increased incidence with age. |
|
|
What are good prognostic factors for AML?
|
APL (acute promyelocytic leukemia):
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 |
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|
What sort of prognostic factor is normal cytogenetics in AML?
|
Considered an intermediate risk factor.
|
|
|
When do we recommend transplant in AML patients?
|
Whether we recommend this and when we recommend this depends on many variables:
1st CR if pt has poor cytogenetics. Otherwise, at the time of relapse – but need to get them into CR again. |
|
|
What is AML M3 (Acute Promyelocytic Leukemia)?
|
Comprises ~10% of AMLs
In > 90% of cases involves t(15;17) which is also 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. |
|
|
How is the treatment of acute promyelocytic leukemia different from standard AML treatment?
|
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 (Vitamin A). Acts on RAR-alpha (Retinoic acid receptor). Retinoic acid is a part of the normal differentiation of neutrophils from myeloblasts. The 15:17 translocation in these patients makes the RAR inacessible to vitamin A which can be overcome by supraphysiologic doses. ATRA helps decrease bleeding complications associated with APL and DIC. Improves CR rate. Because ATRA works by a different mechanism, we skip the day 14 marrow and just do a recovery marrow. |
|
|
What are the side effects of ATRA?
|
Hyperleukocytosis
and ATRA syndrome aka differentiation syndrome. Fever, pulmonary infiltrates, hypotension and dyspnea due to cytokines from granules. Treat with 2 to 3 day course of decadron. |
|
|
What other unique treatment for APL is used here at baptist?
|
CALGB 9710:
Arsenic trioxide improved overall survival and event-free survival. Overall treatment is for 2 years which is much longer than other AML regimens. |
|
|
What is the least common type of leukemia in children?
|
chronic lymphoid leukemia (CLL)
|
|
|
In broad terms what are the two types of lymphoid leukemia?
|
ALL
CLL |
|
|
In broad terms what are the two types of myeloid leukemia?
|
AML
CML |
|
|
What is the order of incidence of leukemias in children?
|
ALL ~80%
AML ~15% CML ~ 4% CLL <1% |
|
|
What do we see in acute leukemias?
|
Predominance of very immature WBC precursors.
The cells proliferate, and lack differentiation. |
|
|
What do we see in chronic leukemias?
|
Proliferation of relatively mature WBC’s; often indolent; more commonly seen in adults than children.
|
|
|
What are the sources of acute leukemias?
|
|
|
|
When is the peak incidence of ALL in children?
|
age 2-5 years
whites > blacks males > females |
|
|
What are the clinical manifestations of ALL in children?
|
fatigue
pallor bruising, bleeding fever lymphadenopathy hepatosplenomegaly mediastinal mass pain (musculoskeletal) |
|
|
What are the typical lab findings of ALL in children?
|
Leukocytosis or Leukopenia
Anemia Thrombocytopenia May see “blasts” on the blood smear. May see chemical abnormalities consistent with “tumor lysis” (increased uric acid, phosphorus, potassium, creatinine). |
|
|
How do we diagnose ALL in children?
|
>20-25% lymphoblasts in bone marrow.
Lumbar puncture also required for evaluation of CNS disease. |
|
|
What does a burkitt L3 lymphoblast look like?
|
|
|
|
How are childhood ALL's classified for diagnostic purposes?
|
Morphology (L1, L2, L3 – based on FAB criteria)
Cytochemical stains (ALL vs. AML) Immunophenotyping - monoclonal antibodies reacting with cell surface antigens (ALL vs. AML, T vs. B lineage) |
|
|
What are good prognostic factors for childhood ALL's?
|
Hyperdiploidy (>50 chromosomes per leukemia cell)
t(12;21) translocation (TEL-AML1 fusion gene, aka ETV6-RUNX1) Trisomies of chromosomes 4, 10, and 17 |
|
|
What are bad prognostic factors for childhood ALL's?
|
Hypodiploidy (<44 chromosomes per leukemia cell)
t(4;11) translocation (MLL-AF4 fusion) t(9;22) translocation (BCR-ABL fusion or Philadelphia chromosome) |
|
|
Precursor T cell ALL in children is associated with?
|
Males > Females
older age (5-12 years) high WBC count bulky adenopathy, mediastinal mass, hepatosplenomegaly CNS disease |
|
|
What are possible ALL emergencies?
|
Sepsis (infection)
Bleeding (from thrombocytopenia) Tumor lysis syndrome Hyperleukocytosis (very high WBC count) Tracheal compression/SVC syndrome |
|
|
What is combination chemotherapy for ALL in children?
|
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) |
|
|
What drugs are commonly used in ALL?
|
Steroids
(prednisone, dexamethasone) Vincristine Asparaginase Doxorubicin/daunorubicin (antharcyclines) Methotrexate Mercaptopurine Cytarabine Cyclophosphamide |
|
|
What are some of the newer drugs used for ALL?
|
Imatinib:
Targets BCR-ABL subtype Nelarabine: Targets T-cell subtype Rituximab: Targets CD-20 subtype Clofarabine: Targets all subtypes. |
|
|
What sort of CNS treatment do we use in ALL?
|
Intrathecal chemotherapy.
Radiation therapy. High dose IV methotrexate - penetrates CNS. |
|
|
How long does ALL treatment generally go on for?
|
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. |
|
|
Which of these patients with ALL has the best prognosis?
A. a 6 month old baby B. a 3 year old pre-schooler C. a 14 year old adolescent D. a 24 year old medical student |
B
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|
|
What is the difference in prognosis between adult ALL and pediatric ALL?
|
In PEDIATRICS, prognosis is generally GOOD, with ~80% overall event-free survival.
In ADULTS, prognosis is relatively POOR (Only 30-50%are cured) |
|
|
What are the prognostic factors for precursor B ALL?
|
|
|
|
Controversial poor prognostic factors in ALL include...
|
Black and Hispanic ethnicity
Obesity |
|
|
Risk assesment for ALL is done by...
|
Combining data about:
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 classified as low, standard, high, or very high risk. |
|
|
Late effects of ALL therapy include...
|
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) |
|
|
What do we know about ALL relapses?
|
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 relapse. |
|
|
The peak age for ALL is...
|
2-5 years.
|
|
|
What is chronic myelogenous leukemia? (CML)
|
A cancer of the white blood cells where the malignant cell is a relatively immature stem cell
The result is excess production of mature cells of multiple lineages |
|
|
What does the CBC look like in CML?
|
Elevated total white cell count.
Differential reveals elevated numbers of neutrophils, bands, myelocytes, metamyelocytes, eosinophils, basophils, platelets, RBC do not increase though which is counterintuitive. |
|
|
Steroids are only cytotoxic to...
|
Lymphoid leukemia cells
NOT myeloid leukemia cells. We only use them for ALL or CLL. Not for AML or CML. |
|
|
How do we diagnose CML?
|
Find the Philadelphia chromosome by cytogentics, FISH or PCR.
|
|
|
What is the philadelphia chromosome?
|
t(9;22)
Chromosome 9: abl gene (Abelson leukemia virus) Chromosome 22: bcr gene (breakpoint cluster region) If someone does not have 9;22 translocation they DO NOT have CML. |
|
|
How does the philadelphia chromosome cause CML?
|
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. |
|
|
Chromosome 22 can break in different regions within the bcr gene, resulting in different sizes of bcr-abl protein products. What are these sizes?
|
p190 (190 kDa protein):
seen in ALL p210 (210 kDa protein): seen in CML |
|
|
What are the different phases of CML?
|
Chronic phase:
<5% blasts in the marrow Accelerated phase: 5-20% blasts in the marrow Blast phase: >20% blasts in the marrow Just like any other acute leukemia. !!Can be myeloid or lymphoid on flow cytometry because the philadelphia translocation could be on either or both progenitors!! |
|
|
How do we treat CML?
|
Pre-Gleevec era:
High dose interferon Allogeneic stem cell transplant Now: Gleevec (imatinib mesylate) aka TKI (tyrosine kinase inhibitor) aka STI (signal transduction inhibitor) aka Small molecule inhibitor |
|
|
How is Gleevec taken?
|
Pill taken once a day that is generally well tolerated.
Side effects: Mild nausea and vomiting. Periorbital or pedal edema. Pleural effusions. |
|
|
How does Gleevec work?
|
Blocks ATP binding to the Bcr-Abl protein and this prevents binding of GRB-2.
|
|
|
What else does Gleevec bind to?
|
c-Kit
Works on GI stromal tumors PDGFR-alpha Seen in hypereosinophillia. |
|
|
What is one of the mechanisms by which Gleevec resistance develops?
|
T315I mutations.
|
|
|
Second generation tyrosine kinase inhibitors now exist. What are they?
|
Dasatinib
Nilotinib Neither are effective against the T315I mutation. |
|
|
How is the accelerated phase of CML treated?
|
Higher doses of Gleevec.
|
|
|
How is the blast crisis of CML treated?
|
Just like the 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. |
|
|
What is chronic lymphocytic leukemia (CLL)?
|
A cancer of the white blood cells in which the malignant cell is more differentiated than in CML.
Results in excess numbers of mature-appearing lymphocytes Continuum with SLL (small lymphocytic lymphoma) that has no circulating neoplastic cells and resides in lymph nodes. |
|
|
What will the CBC look like in CLL?
|
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. |
|
|
How do we diagnose CLL?
|
Peripheral blood sample for flow cytometry.
Do not need a bone marrow for diagnosis. (+) CD5, CD19, CD23 We are basically looking for B-cell (CD19/CD23) with avariant expression of a T-cell marker (CD5). (+/-) CD20 (weak expression) (+) surface immunoglobulin Light chain restriction Only kappa or lambda, not both. Send chromosomal studies to get information on prognosis. |
|
|
What are median overall survival rates for CLL?
|
|
|
|
When do we intitiate treatment on a patient with CLL?
|
Need to have symptoms:
Symptomatic lymphadenopathy. Symptomatic splenomegaly. “Symptomatic” counts which means anemia or thrombocytopenia as a result of CLL progression in the marrow. Stage III or stage IV disease Note: The absolute white cell count is NOT listed as an indication to treat. |
|
|
How does CLL impact the immune system?
|
Quantitative immunoglobulins often reveal patients to be pan-hypoglobulinemic.
If patients have persistent infections or infections severe enough to require hospitalization, we can treat treat with IVIG. The immune system can also be overactive which can result in autoimmune hemolytic anemia or immune mediated thrombocytopenic purpura. |
|
|
How can we tell if a CLL patient’s thrombocytopenia is from ITP or stage IV disease?
|
Do a bone marrow.
If there are megakaryocytes it is ITP.Give steroids. If there are no megakaryocytes because there is no more room for them in the marrow. Start Chemo. |
|
|
What is Richter’s transformation?
|
Development of diffuse large B cell lymphoma arising from one CLL clone.
May have B symptoms meaning one area of lymphadenopathy out of proportion to others. |
|
|
How do we demonstrate richters transformation?
|
PET scan will show transformed sites.
CLL is not PET avid DLBCL (Diffuse large B cell lymphoma) is very PET avid. Must document with biopsy (surgical) to prove transformed disease. |
|
|
What do we do if Richter's transformation occurs?
|
Treat with DLBCL regimen such as R-CHOP.
CLL chemo is ineffective. Pts are still left with underlying CLL after treatment complete. |
|
|
Apart from Richter's, what other transformation occur with CLL?
|
Transformation to prolymphocytic leukemia
>55% prolymphocytes Treatment is different from standard CLL treatment. |
|
|
How do we treat CLL?
|
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. |
|
What is this?
|
Hairy cell leukemia.
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. Clinically, notable for very large spleens, and dry taps on bone marrows. |
|
|
What does hair cell leukemia look like in the bone marrow?
|
Cells look like fried eggs
Marrow has lots of fibrosis. |
|
|
How do we treat hairy cell leukemia?
|
Purine analogs, specifically Cladribine.
|
|
|
Which chemotherapy drugs affect mitosis?
|
Vinca alkaloids
Taxanes |
|
|
Which chemotherapy drugs affect DNA synthesis?
|
Anti-metabolites
Epipodophyllotoxins Camptothecins |
|
|
Which chemotherapy drugs are cell cycle nonspecific?
|
Alkylating Agents
Anthracyclines |
|
|
Which chemotherapy agents are alkalating agents?
|
*=available orally
Cyclophosphamide* Ifosfamide Platinums: Cisplatin (CDDP) Carboplatin Oxaliplatin Nitrosureas: Lomustine* (CCNU) Carmustine (BCNU) Mechlorethamine Melphalan* (Alkeran®) Chlorambucil* (Leukeran®) Busulfan* (Myleran®) Thiotepa Procarbazine* Dacarbazine (DTIC) Temozolamide* |
|
|
How do alkylating agents work?
|
Bind to purines and render them unstable.
Template being replicated is misread or mispaired during DNA synthesis. or Cross-linking prevents DNA strands from unwinding. or Single or double-strand breaks in DNA occur. |
|
|
What happens to the alkylating agent cyclophosphamide in the body?
|
It is converted by hepatic microsomal enzymes to 4-hydroxycyclophosphamide (4-HCP).
4-HCP is converted to acrolein and phosphoramide mustard. Phosphoramide mustard alkylates DNA. Acrolein is responsible for causing hemorrhagic cystitis. |
|
|
What happens to ifosfamide in the body?
|
Almost the same thing as cyclophosphamide.
Parent drug is converted to acrolein and ifosforamic mustard. There is more acrolein formed with ifosfamide than cyclophosfamide so more hemorrhagic cystitis. |
|
|
What is the difference between cyclophosphamide and ifosfamide in terms of application?
|
Cyclophosphamide:
leukemia, lymphomas, solid tumors. bone marrow transplant. graft-versus-host-disease Rheumatic disorders & autoimmune nephritis Ifosfamide: solid tumors |
|
|
The main difference between cyclophosphamide and ifosphamide in terms of side effects is that...
|
Cyclophosphamide produces more myelosupression than hemmoragic cystitis which makes myelosupression the dose limiting toxicity.
Ifosfamide produces more hemmoragic cystitis than myelosupression which makes hemmoragic cystitis the dose limiting toxicity. Cyclophosphamide produces Syndrome of inappropriate anti-diuretic hormone (SIADH). Ifosfamide can cause CNS, pulmonary and cardiac toxicity. |
|
|
How is hemmoragic cystitis caused?
|
Acrolein binds to thiol in bladder wall.
Prevent with vigorous hydration (≥2 L/day) & MESNA Test urine for heme. |
|
|
What is MESNA?
|
Uroprotectant containing sulfhydryl group that is useful for PREVENTING hemmoragic cystitis.
|
|
|
What are the important pharmacokinetics of the platinums?
|
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 ) |
|
|
What is the most active single agent in cervical cancer?
|
Cisplatin
|
|
|
What is the most active single agent in colon cancer?
|
Oxaliplatin
|
|
|
What other cancers do we treat with platinums?
|
Testicular, ovarian, metastatic bladder, lung and other solid tumors.
Non-Hodgkin’s lymphoma. |
|
|
What are the toxicities of cisplatin in descending order of importance?
|
Vomiting (limiting)
Nephrotoxicity (limiting) Peripheral neuropathy Neurotoxicity Ototoxicity |
|
|
What are the toxicities of carboplatin in descending order of importance?
|
Myelosuppression (limiting)
Neurotoxicity Vomiting |
|
|
What are the toxicities of oxaliplatin in descending order of importance?
|
Cold induced peripheral neuropathy (limiting).
Myelosuppression |
|
|
What is Amifostine (Ethyol)?
|
Free radical scavenger that is metabolized to an active free thiol.
Binds to cisplatin and prevents damage to normal tissue in alkaline phosphatase related mechanism. side effects: HYPOTENSION and NAUSEA and VOMITING. Also used to prevent radiation-associated xerostomia |
|
|
What are the oral alkylating agents?
|
Chlorambucil (Leukeran)
-chronic lymphocytic leukemia Busulfan (Myleran) -leukemia and transplant **Melphalan (Alkeran) -multiple myeloma Temozolomide (Temodar) -brain tumors and melanoma |
|
|
Which anthracyclines are red?
(orange when diluted) |
The rubies.
Doxorubicin Daunorubicin Idarubicin Epirubicin The rest are blue. |
|
|
How do anthracyclines work?
|
Inhibition of topoisomerase II.
Intercalation between DNA base pairs, interfering with DNA synthesis. Formation of free radicals that damage DNA and cell membranes. |
|
|
What is the most active agent against breast cancer?
|
Doxorubicin.
|
|
|
What are the main toxicities of anthracyclines?
|
Myelosuppression
Cardiotoxicity Extravasation injury (Treat with Wydase and cold) !!Mitoxantrone has less free radical formation; therefore, less risk of cardiotoxicity, extravasation injury, N/V, mucositis!! |
|
|
When does cardiotoxicity start to become a major problem with anthrocyclines?
|
cumulative doses > 550mg/m2
|
|
|
What is Dexrazoxane (Zinecard®)?
|
Cardioprotectant
Disrupts iron-anthracycline complex. |
|
|
What is Liposomal doxorubicin (Doxil®)?
|
Liposomal delivery system for Doxorubicin not as readily taken up by cardiac tissue.
Lowers risk of cardiotoxicity. |
|
|
What is Mitoxantrone?
|
Relatively new.
Similar to anthracyclines. Decreased side effects. Blue-green urine discoloration. |
|
|
What side effect should we watch out for with the anthracycline bleomycin?
(big in testicular cancer) |
Pulmonary toxicity
|
|
|
What is the anthracycline Mitomycin C commonly used for?
|
The shake and bake procedure.
|
|
|
Which antimetabolite drugs have an antifolate mechanism?
|
Methotrexate* (MTX)
Pemetrexed (Alimta) |
|
|
Which antimetabolite drugs are purine analogs?
|
Mercaptopurine* (6-MP)
Thioguanine* (6-TG) Fludarabine Cladribine |
|
|
Which antimetabolite drugs are pyrimidine antagonists?
|
Cytarabine (Ara-C)
Gemcitabine (Gemzar®) Fluorouracil (5-FU) Capecitabine* (Xeloda®) |
|
|
How does methotrexate work?
|
Inhibits dihydrofolate reductase and therefore purine and thymidilate synthesis.
No thymine, no DNA synthesis. Goes hand in hand with Leucovorin which is administered after the methotrexate and "Rescues" cells we dont want to kill by providing 5-formyl tetrahydrofolate. Uptake of leucovorin by healthy cells > cancer cells. MTX causes Myelosuppression, mucositis and nephrotoxicity. (crystallization of MTX) !!Avoid nephrotoxic meds (NSAIDs, sulfa)!! MTX can accumulate in fluid and leach out over time. Make sure CXR is obtained prior to dose to verify there is no pleural effusion. |
|
|
What is Pemetrexed (Alimta)?
|
Similar to MTX but works on multiple enzymes.
Good for asbestos mesothelioma. cutaneous reactions – prevent with dexamethasone Supplement folate and B12 to prevent hematologic and gastrointestinal toxicity. |
|
|
What is Cytarabine (Ara-C)?
|
Arabinose analog of cytosine.
Phosphorylated to active component within cancer cells. Inhibits DNA polymerase. Used for: Acute leukemias. Non-Hodgkin’s lymphoma. No significant activity against solid tumors. Low dose toxicities: ~100 mg/M2/day Myelosuppression Alopecia Gastrointestinal Rash—plantar-palmer syndrome High dose toxicities: ~3 g/M2 q12h nausea CNS toxicity chemical conjunctivitis acral erythema Good for "liquid tumors". |
|
|
Gemcitabine (Gemzar®) is similar to Ara-C in MOA and structure. It is effective for solid tumors and achieves cellular concentrations 20X higher than Ara-C. What are its toxicities?
|
Fever and flu-like symptoms.
Peripheral edema. Myelosuppression. Generalized rashes. Mild N/V NOT neurotoxic. Intermittent dosing more effective than continuous dosing. |
|
|
What is Clofarabine (Clolar)?
|
Pyrimidine antagonist used for relapsed pediatric ALL.
Main toxicity is a skin rash. (hands) $36,000 for 5 days of therapy. |
|
|
What is Nelarabine (Arranon)?
|
Pyrimidine antagonist used for T-cell ALL or T-cell lymphoblastic lymphoma.
|
|
|
What does fluorouracil get metabolized into?
|
FdUMP
Binds to thymidylate synthase. Leucovorin enhances action of this drug. Fluorouracil is used for treatment of solid tumors including breast, colorectal and other GI tumors. Also used for actinic keratoses and noninvasive skin cancers. |
|
|
What are the toxicities associated with fluorouracil?
|
Myelosuppression (bolus)
Bloody diarrhea (CI) Mucositis (CI) Dermatologic (nail banding) Ocular Nausea and vomiting (mild) Cardiotoxicity (rare) |
|
|
What is Capecitabine (Xeloda®)?
|
Oral prodrug of fluorouracil
More diarrhea and skin rash. |
|
|
What is Mercaptopurine (6-MP)?
|
Purine analog
Metabolized by xanthine oxidase. Decrease dose by 75% if used with allopurinol. |
|
|
What is Thioguanine (6-TG)?
|
Purine analog.
No dose reduction required with allopurinol |
|
|
Fludarabine & cladribine are purine analogs. What should I be cautious about with these?
|
Immunosuppressive → risk of opportunistic infections.
|
|
|
Which chemotherapy drugs are mitotic inhibitors?
|
Vinca alkaloids:
Vincristine (Oncovin®) Vinblastine (Velban®) Vinorelbine (Navelbine®) Taxanes: Paclitaxel (Taxol®) Docetaxel (Taxotere®) |
|
|
What is the mechanism of action of mitotic inhibitors?
|
Spindle poisons” which bind to tubulin.
Vinca alkaloids: Inhibit microtubule assembly Interfere with formation of mitotic spindle Cells accumulate in mitosis Taxanes: Promote microtubule assembly Interfere with microtubule disassembly. |
|
|
What is the main toxicity of vincristine?
|
Neurotoxicity.
Do NOT give Intrathecally. GI smooth muscle paralysis causes constipation. |
|
|
What is the main toxicity of Vinblastine/Vinorelbine?
|
Myelosuppression
|
|
|
How do we deal with extravasation of vinca alkaloids?
|
Use warm compresses & hyaluronidase .
|
|
|
What are the main toxicities of Taxanes?
|
Myelosuppression
Mucositis Peripheral neuropathy (cumulative) Premedicate with dexamethasone, H1 (benadryl)- & H2 (zantac)-antagonist. Hypersensitivites are caused by oily solutions the taxanes come in. |
|
|
What can cause an anterior mediastinal mass?
|
Thyroid
Thoracic aorta Thymoma Teratoma Terrirble lymphoma |
|
|
Blunting of the costophrenic angle on x-ray (meniscus) is a sign of...
|
Pleural effusion
|
|
|
What are
Ixabepilone (ix-a-BEP-i-lone) and Ixempra® (ix-EM-pra) ? |
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 which accounts for its activity in taxane resistant patients. Neurotoxicity and oily solution just like paclitaxel. |
|
|
What are Epipodophyllotoxins?
|
Etoposide (VP-16) and teniposide (VM-26)
Same mechanism as red anthracyclines.(Topo II inhibition) Myelosupression is limiting toxicity. |
|
|
What are Camptothecins?
|
Irinotecan (GI cancer) & topotecan
Inhibit topoisomerase I Clinical uses: Ovarian cancer Lung cancer CML, MDS Cervical, ovarian cancer Colorectal cancer Main topotecan toxicity is myelosuppression. Main Irinotecan toxicity is severe diarrhea. Treat acutely with scopolamine or atropine. Prevent with 5HT blockers and antihistamines. Treat chronic dehydration with loperamide. |
|
|
What is L-asparaginase?
|
Degrades asparagine found in the serum.
In lymphoid malignancies the lymphocytes rely on serum asparagine. Without 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, if so give Erwina asparaginase or peg-asparaginase (more expensive) Peg-asparaginase is a larger molecule therefore given less frequently. |
|
|
What is Hydroxyurea (Hydrea)?
|
Used for CML and in some sickle cell patients.
Blocks ribonucleotide reductase. Increases Hf production by unknown mechanism. Causes "gentle" myelosuppression to lower white count before hardcore chemo. This reduces "tumor lysis" syndrome. Doses 50 mg/kg/d (aprx 500 mg PO BID & titrate to WBC effect) |
|
|
What is Bortezomib (Velcade)?
|
Selective, reversible inhibitor of the proteosome.
Used for Multiple Myeloma, NHL, ? leukemias. Adverse events: peripheral neuropathy, fatigue, malaise, weakness, GI effects, thrombocytopenia. We adjust dosing based on peripheral neuropathy and thrombocytopenia. |
|
|
What is All-trans retinoic Acid ,"ALTRA" (Vesinoid)?
|
Used with APL
Matures promyelocytes blasts inducing a CR May cause retinoic acid 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. |
|
|
What is Retinoic acid syndrome?
|
Fever, dyspnea, pleural effusion, peripheral edema, hypotension.
treat with dexamethasone 10 mg IV BID x 3 days |
|
|
What is arsenic trioxide (trienox)?
|
Used for APL.
Retinoic acid syndrome (differentiation syndrome) QTC prolongation. |
|
|
What are the risks of the mutiple myeloma drug thalidomide?
|
Thromboembolism especially in combination with steroids.
Should use anticoagulation. Drowsiness. Peripheral neuropathies. pts / prescribers / dispensers must enroll in STEPS |
|
|
What is Lenalidomide (Revlimid)?
|
Used for MDS (low dose) and MM (high dose).
Main toxicity is myelosupression. |
|
|
What do Hypomethylating Agents do?
|
Cells need methyl groups to grow
Removes methyl groups leading to cancer cell death |
|
|
What are examples of methylating agents?
|
Azacitadine (Vidaza)
Decitabine (Dacogen) Both are used for MDS. |
|
|
How do Histone Deacetylase inhibitors work?
|
Cancer cells can have too much HDAC which allows the cell to grow unregulated (unable to die).
The ultimate goal is cell death through normal cell regulation. |
|
|
What is an example of a histone deacetylase inhibitor?
|
Vorinostat (Zolinza)
Used for cutaneous T-cell lymphoma (CTCL). Causes,Anemia, Thrombocytopenia and GI symptoms. |
|
|
What is Temsirolimus (Torisel™)?
|
mTOR inhibitor blocks mRNA translation and halts progression from G1 to S phase.
Treatment of advanced renal cell carcinoma. !!!Premedicate with antihistamine.!!! |
|
|
What is the mechanism of monoclonal antibodies in treating cancer?
|
Destroys tumor cells through activation of complement and antibody-dependent cell-mediated cytotoxicity.
Means of targeting cytotoxic radioisotopes, toxins, or drugs to tumors. |
|
|
What are the monoclonal antibodies used in chemo named?
|
All end in "Mab"
Momab (radiolabeled) Eg. tositumomab Zumab (human) Eg. alemtuzumab Ximab (chimeric with murine & human) Eg. cetuximab |
|
|
What toxicities are associated with monoclonal antibodies?
|
Infusion-related toxicity (65-80%): SOB, increased temp, chills, nausea, asthenia, and HA.
premedications: acetaminophen, diphenhydramine, hydrocortisone Hypotension (10%)-recommend holding anti-hypertensives. |
|
|
What are the 1st generation monoclonal antibodies?
|
Rituximab:
Targets CD20 on B lymphocytes. Acute infusional related RXN's. Very commonly used. Gemtuzumab ozogamicin: Targets CD33 in refractory AML. Alemtuzumab: Anti-CD-52 antigen found on B and T lymphocytes. Used for B-cell chronic lymphocytic leukemia. Profound immunosuppression, "liquid AIDS". |
|
|
What are the big radiolabelled Mab's?
|
ibritumomab
tositumomab |
|
|
What are the two types of tyrosine kinase (TK) inhibitors?
|
Monoclonal antibodies.
Small molecule inhibition. |
|
|
What do tyrosine kinases do?
|
Regulates cellular proliferation, differentiation, function, & survival.
Receptor & non-receptor TKs like FLT3, VEGF, ABL, c-KIT, etc. Activity is tightly controlled in normal cells which makes it easy to target cancer cells. |
|
|
What are the small molecule TK inhibitors?
|
Imatinib (Gleevec®)
Gefitinib (Iressa®) Erlotinib (Tarceva®) Sunitinib (Sutent®) Sorafenib (Nexavar®) |
|
|
What are the monoclonal antibody Tk inhibitors?
|
Cetuximab (Erbitux®)
Trastuzumab (Herceptin®) Bevacizumab (Avastin®) |
|
|
How does the monoclonal antibody trastuzumab (Herceptin) work?
|
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. (do not give with doxirubicin) |
|
|
What is bevacizumab (Avastin)?
|
Monoclonal 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 |
|
|
What is cetuximab (Erbitux)?
|
Monoclonal antibody against epidermal growth factor receptor (EGFR).
Used for metastatic colorectal cancer. Causes acneform rash. Panitumumab (Vectibix) is very similar. |
|
|
What is erlotinib (Tarceva)?
|
Tyrosine kinase inhibitor used as salvage treatment of non-small cell lung cancer.
Causes acneiform rash, diarrhea, interstitial lung disease. |
|
|
What is gefitinib (Iressa)?
|
Tyrosine kinase inhibitor used for non-small cell lung cancer in patients who are benefiting or have benefited from gefitinib.
Skin rash, ocular symptoms, pulmonary symptoms. |
|
|
What are the toxicities of tyrosine kinase inhibitors?
|
Skin rash (72%)
Diarrhea (35%) Nausea/vomiting Myelosuppression Pulmonary symptoms (SOB, cough, fever) with acute onset or worsening. |
|
|
What are tyrosine kinase inhibitors used for in CML?
|
They inhibit Bcr-Abl tyrosine kinase.
Bcr-Abl is the abnormal gene product that is caused by the Philadelphia chromosome in chronic myeloid leukemia (CML). Also inhibits tyrosine kinase for platelet derived growth factor (PDGF), stem cell factor (SCF) and c-kit. |
|
|
The main side effects of tyrosine kinase in CML are...
|
Musculoskeletal pain.
Fluid retention (periorbital). QT prolongation. |
|
|
What is Imatinib (Gleevec)?
|
Used to treat Philidelphia 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 which can only be treated with transplant. Dasatanib and Nilotinib are similar alternatives but CANNOT overcome T315I resistance. |
|
|
Sorafenib inhibits...
|
Raft kinase
Used for advanced renal cell carcinoma in adults. |
|
|
What is Sunitinib used for ?
|
Gastrointestinal stromal tumors (GIST) after disease progression or intolerance to imatinib (Gleevec).
|
|
|
The difference between latency and chronic infection is that..
|
No active viral replication in latency.
Replication goes on even in the absence of symptoms in chronic infection. |
|
|
Parvovirus B19 causes....
|
Hydrops fetalis
Erythema infectiosum (fifth disease) Aplastic crises in hemolytic subjects. Seronegative RA syndrome. Chronic anemia in immunocompromised hosts. Arthropathy that mimics RA. |
|
|
What percentage of adults have antibodies for parvovirus B19?
|
About half.
Prevalence rises rapidly during school years because shedding and transmission only occur in the 50% of children who are asymptomatic and those that are presymptomatic. |
|
|
What cells does parvovirus B19 infect?
|
Erythroid progenitor cells.
|
|
|
What gives a positive monospot test besides mono?
|
Lymphomas
ALL Have to send VCA (viral capsid Ag) IgM test which only hangs out for about 8 weeks to confirm EBV. |
|
|
Cold hemolytic anemias are caused by..
|
IgM
Do not respond to steroids. |
|
|
Warm hemolytic anemias are caused by..
|
IgG
May respond to steroids. |
|
|
People recovering from mono should not engage in contact sports because...
|
The spleen is enlarged and could rupture.
|
|
|
What organisms are patients susceptible to after bone marrow transplant in phase 1? (<30days)
|
HSV
Facultative G-'s Staph. Strep. Candida Aspergillus |
|
|
What organisms are patients susceptible to after bone marrow transplant in phase 2? (30-100 days)
|
CMV
EBV Staph Candida Aspergillus Pneumocytis jiroveci Toxoplasma Strongyloides |
|
|
What organisms are patients susceptible to after bone marrow transplant in phase 3? (>100days)
|
VZV
CMV EBV Encapsulated (pneumoco etc.) Aspergillis Pneumocystis jiroveci Toxoplasma Strongyloides |
|
|
What are the viral causes of pneumonia in immunocompromised hosts?
|
CMV
(particularly in allogeneic BMT patients) VZV and HSV (dissemination) RSV Influenza Parainfluenza |
|
|
What are some non-infectious causes of fever and pulmonary infiltrates in immunocompromised hosts?
|
Idiopathic pneumonia
ARDS Alveolar Hemorrhage Leukemic Infiltration Lymphoma Pulmonary Emboli Aspiration Drug Induced Lung Injury (especially bleomycin) |
|
|
What are the major risk factors of CMV infection in BMT recipients?
|
Seropositive status (donor or recipient)
Older age Conditioning regimens other than cyclophosphamide. !!!!GvHD!!!!!!! |
|
|
What is the characteristic finding of CMV pneumonia on H&E stain?
|
Owls eye cells
|
|
|
What does CMV most commonly coinfect with?
|
Fungi (including PCP)
and Pseudomonas |
|
|
How do we treat CMV?
|
Antiviral like Gancyclovir
Foscarnet for salvage/intolerance CMV Ig or IVIg for HSCT recipients. |
|
|
How do we provide CMV prophylaxis for patients undegoing bone marrow transplant?
|
MUST use combined therapy :
GCV + IVIG |
|
|
What is the difference between CMV prophylaxis and "preemptive therapy".
|
More targeted therapy for brief periods given with:
‘induction’ therapy ALA therapy Defined lab evidence of infection. |
|
|
What is the typical abnormal blood finding in parvovirus B19?
|
Hb is down.
|
|
|
The most likely cause of ITP is...
|
!!!!DRUGS!!!!
|
|
|
The most common thrombocytopenia caused by HIV is...
|
ITP
|
|
|
Is VZV vaccine indicated in immunocompromised patients?
|
No.
(Not yet) |
|
|
What is the trigger for coagulation?
|
Tissue factor
|
|
|
What is tissue factor?
|
A transmembrane protein found everywhere except the bloodstream.
Tissue factor deletion is lethal. |
|
|
What does tissue factor do?
|
Tissue factor is a cofactor for Factor VIIa activity which activates factor X in a static sytem or factor IX in a flowing system.
TF-VIIa is inhibited by TFPI (tissue factor pathway inhibitor) |
|
|
What is thrombin?
|
Major coagulation effector enzyme required for fibrin clot formation.
Converts Fibrinogen to Fibrin Activates Factor XIII FXIIIa crosslinks Fibrin Activates Platelets |
|
|
How is fibrin crosslinked?
|
FXIII activated by thrombin first gamma crosslinks two fibrins end to end and then alpha crosslinks multiple fibrins by their alpha chains.
|
|
|
What are the different states fibrin can exist in?
|
Fibrinogen:
Soluble, digested by plasmin. Fibrin (polymer): Weak clot, easily digested by plasmin. Gamma crosslinked Fibrin: Strong clot, can be digested by plasmin Alpha crosslinked Fibrin: Strong clot, resists plasmin digestion |
|
|
Factor II is also known as...
|
Prothrombin
|
|
|
How does TF-VIIa ultimately activate thrombin?
|
|
|
|
What do factors VII, IX, X and II have in common?
|
Vitamin K dependent proteins.
All gamma carboxylated. All of these factors are low or absent in vitamin K deficiency or warfarin anticoagulation. |
|
|
The conversion of FII (prothrombin) to thrombin is increased 300,000 fold by the presence of the cofactor....
|
Factor Va
|
|
|
The conversion of factor V to factor Va is activated by....
|
Thrombin.
This is what makes the process a positive feedback because Fva leads to the production of thrombin from FII (prothrombin). |
|
|
Apart from conversion of factor V to factor Va what other positive feedback loop is thrombin involved in ?
|
The conversion of factor VIII to factor VIIIa.
FVIIIa is a cofactor for FX to FXa which in turn activates the production of thrombin from FII (prothrombin). |
|
|
What are the natural anticoagulants that limit the coagulation cascade?
|
Antithrombin 3
aka Heparin Cofactor and The protein C system: Protein C Protein S Thrombomodulin |
|
|
What happens if we mix thrombin and antithrombin 3?
|
Antithromobin 3 acts as a suicide substrate and TAT (Thrombin-antithrombin) is formed.
|
|
|
What happens if we mix FXa with AT3?
|
XAT (X-antithrombin)
|
|
|
What happens if we mix FIXa with AT3?
|
IXAT (IXAT)
|
|
|
How does heparin work?
|
It accelerates the inhibition of clotting factors by antithrombin.
|
|
|
What is the molecular weight of unfractionated heparin?
|
30-35,000
Big polymer. |
|
|
The molecular weight of LMWH is about...
|
5-10,000
|
|
|
Both heparin and LMWH are antithrombotic but they are different in that...
|
Unfractionated heparin but NOT LMWH accelerates the inhibition of thrombin by AT3.
Both accelerate the inhibition of FXA by AT3. The inhibition of FIXa is not affected by either. |
|
|
What happens to excess thrombin (IIa) from the coagulation cascade that is not inhibited bt AT3?
|
It binds to the cofactor thrombomodulin on the endothelial cell surface to form the complex thrombomodulin IIa.
This complex acquires the ability to activate protein C (PC) to it's activated form aPC. It also loses the ability to activate factors V, X, and platelets as well as the ability to covert fibrinogen to fibrin. |
|
|
What does activated protein C (aPC) do?
|
Cleaves FVa (the 300k fold amplifier from the cascade) into the inactive form FVi.
A Protein S cofactor is also required for this to happen in humans but not bovines. The protein C system is thus a negative regulator of the coagulation cascade, |
|
|
How does fibrinolysis work?
|
Triggered by aPC.
Plasmin is the effector enzyme. Relatively non-specific serine protease. Fibrin specificity is conferred by activation mechanism. |
|
|
How does aPC activate fibrinolysis?
|
aPC left over from downregulating the coagulation cascade binds aPC receptors on the endothelial cell which triggers changes that release tissue plasminogen activator (tPA) from the endothelium.
tPA then converts plasminogen to plasmin which begins chewing up the fibrin. Interstingly, fibrin is a cofactor in the conversion of plasminogen to plasmin by tPA which means that there must be plasmin substrate for plasmin to form. |
|
|
What does plasmin chew up fibrinogen into?
|
FDP
|
|
|
How do the coagulation cascade, the protein C system and the fibrinolytic system interact?
|
|
|
|
Decreased thrombin/plasmin ratio will cause....
|
Defective hemostasis.
|
|
|
What does warfarin do?
|
Essentially induces vitamin K deficincy,
|
|
|
What does Heparin do?
|
Activates antithrombin 3 system?
|
|
|
How does liver disease cause defective hemostasis?
|
Produces a deficiency of basically all of the clotting factors except factor VIII.
|
|
|
What are examples of hemostasis defects caused by deficiency in a single factor?
|
Hemophilia
or Immune inhibitors of single factors. |
|
|
Shear forces in a blood vessel increase as a function of...
|
Linear velocity
Viscosity Decreased vessel radius Turbulence |
|
|
The stickiness of subendothelial VWF increases with...
|
Increased shear rate.
|
|
|
What must happen for hemostasis to occur?
|
Thrombin activity must exceed plasmin activity.
Platelet procoagulant function must be normal. |
|
|
Thrombosis risk is conversely related to....
|
Bleeding risk.
|
|
|
What is Virchow’s triad?
|
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 |
|
|
Why are atherosclerotic plaques a focus of thrombosis?
|
Tissue factor exposure by smooth muscle cells.
They are also high shear settings where VWF and platelets become involved followed by thrombus growth through the coagulation cascade. |
|
|
What are considered thrombophillic conditions?
|
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 |
|
|
In broad terms, what are the causes of thrombosis?
|
Increased thrombin generation as in coagulation factor inhibitor deficiencies.
Decreased plasmin generation. Increased platelet procoagulant function as in thrombocytosis or activated platelets. |
|
|
What three forms of tissue factor can cause DIC?
|
TF on extravascular smooth muscle cells. (vessel injury)
TF patch on luminal vessel wall. (Endothelial damage and thrombosis) TF on circulating monocytes. This is the most common cause of DIC and results form activation by LPS during sepsis. |
|
|
What happens during the first stage of DIC, the hypercoagulable state?
|
AT3 is adequate to control the coagulation cascade.
But:- Factors V and VIII are being activated to FVa and FVIIIa by thrombin. Procoagulant effectiveness is increasing so more thrombin is being produced for a given stimulus. Circulating platelets are activated and the risk of thrombosis is increased. We can try and control the risk by giving low dose heparin to: Amplify AT3 effectiveness. Shut down thrombin generation. Reduce risk of thrombosis. We can also try GP IIb/IIIa inhibitors to block platelet aggregation. And ASA, Clopidogrel (Plavix) to block platelet activation. |
|
|
What happens in the second stage of DIC, "Early or Mild DIC/Consumption Coagulopathy"?
|
AT3 has been consumed
and excess thrombin is being produced. The protein C system becomes activated so aPC inactivates FVa and FVIIIa. FV and FVIII deficiencies result. ( a hemophillia-like disorder) Activated platelets are removed from the circulation (Thrombocytopenia). Risk of bleeding is therefore increased. In this stage we can replace missing coagulation factors V and VIII by giving cryo (FVIII and Fibrinogen) and platelets (FV). We can also replace AT3 with concentrate or bank plasma. Both low dose heparin to control thrombin generation and antiplatelet agents will increase risk of bleeding. |
|
|
What happen in the third stage of DIC, Late or Severe DIC/Consumption Coagulopathy?
|
aPC inhibitor has been consumed.
Fibrinolysis has been activated. Free Plasmin dissolves hemostatic plugs, reduces the thrombin/plasmin ratio, digests most coagulation factors and fibrinogen as well as platelet surface receptors Defective hemostasis and rebleeding of old wounds occurs. In this state we need to inhibit the highly destructive plasmin with AMICAR which causes a high risk of fatal thrombosis. We also need to inhibti thrombin with heparin and friends which increases the risk of fatal bleeding. Lastly, we need to replace coagulation factors with concentrates: Cryoprecipitate Platelets AT3 Prothrombin complex |
|
|
What sort of mortality do we expect with DIC?
|
Stage 1 1%
Stage 2 5% Stage 3 60% |
|
|
How can we prevent the DIC chain of events from happening?
|
Use prophylactic heparin in high risk settings to prevent stage 1 or hypercoagulable state.
|
|
|
Very generally, the three stages of DIC are...
|
Thrombotic.
Bleeding. Re-bleeding. |
|
|
Do peripheral blood counts decrease with age?
|
No.
Marrow can sustain normal peripheral blood counts throughout the human lifespan, but… Diminished reserve capacity in times of stress as a consequence of decreased marrow cellularity. |
|
|
What are common causes of anemia in the elderly?
|
Iron deficiency.
Anemia of chronic disease (ACD). Chronic kidney disease. B12 or folate deficiency. Unexplained anemia . |
|
|
Reduced hemoglobin in the elderly has a relationship with...
|
Increased Mortality.
Increased cardiac disease. Decreased muscle mass, Increased disability. Increased falls and fractures Also associated with cognitive impairment. |
|
|
What should we worry about with iron deficiency anemia in the elderly?
|
GI bleed (colon cancer)
|
|
|
Why does the incidence of cancers increase with age?
|
Longer duration of carcinogen exposure.
Decreased DNA repair ability. Increased genomic instability. Decreased tumor suppressor activity. Decreased immune surveillance. |
|
|
Do older adults tolerate agressive chemotherapy?
|
Yes.
Selected patients respond well to very agressive chemo. but As a group, older adults experience inferior outcomes and can experience increased toxicity related to treatment. Patients >65 are 16 times more likely to die of cancer. |
|
|
What accounts for the outcome disparity for older cancer patients?
|
Research Bias and
Under-Treatment. Tumor Biology. Physiologic Changes in the host. Impairment in physical function. Increased comorbidities. |
|
|
What are examples of diseases in which up front “dose attenuation” results in inferior outcomes when treating for cure ?
|
AGGRESSIVE NHL
Small cell lung cancer Breast cancer |
|
|
What are examples of diseases in which age related changes in tumor biology influence outcome?
|
Unfavorable changes:
Acute Leukemias (More MDL) Agressive NHL Favorable changes: Breast cancer and possibly prostate cancer. |
|
|
What age related physiological changes affect the pharmacology of cancer treatment?
|
Decreased intestinal absorption.
Decline in renal excretion. Changes in volume of distribution. Altered metabolism by cytochrome P450. |
|
|
What factors into treatment decisions in the elderly?
|
Characteristics of Patient
Characteristics of Tumor Characteristics of Treatment |
|
|
What are the four possible chronic myeloproliferative neoplasms ?
|
Chronic myelogenous leukemia (CML):
Proliferation primarily of neutrophil series. Polycythemia vera: Proliferation primarily of erythroid series Essential thrombocythemia: Proliferation primarily of megakaryocytic series. Primary myelofibrosis (PMF): Proliferation of all series with predominant marrow fibrosis. |
|
|
What is the natural progression of CML?
|
Acute phase.
Accelerated phase. Blast phase. |
|
|
The defining feature of CML is...
|
Philadelphia Chromosome
t(9;22)(q34;q11) Fusion of BCR (22q11) and ABL (9q34) genes. |
|
|
The bone marrow and peripheral blood findings in CML...
|
Are almost exactly the same because of hypercellularity and elevated M:E ratio in the marrow.
|
|
|
How do we know when a CML patient is in the blast phase?
|
Blasts > 20% in PB or BM
|
|
|
How is it possible for CML to progress to a lymphoblastic leukemia?
|
Because it is a malignancy of STEM CELLS.
|
|
|
How do we calculate Absolute neutrophil count?
|
ANC =
(Segs + Bands) X WBC Segs and bands given as a percentage. |
|
|
What is a Pseudo Pelger-Huet cell?
|
A finding consistent with myelodysplastic syndromes.
MDS are associated with ineffective and disordered hematopoiesis as well as other bizarre types of cell maturation including this funny looking type of neutrophil. |
|
|
What does a ringed sideroblast look like?
|
|
|
|
What are the main clinical differences between myelodysplastic syndromes and myeloproliferative disorders?
|
|
|
|
A normal blast count in the bone marrow is...
|
<5%
>20% means acute leukemia. |
|
|
Othe than Auer rods and surface antigens, what is used to detemine lineage of cells in AML?
|
Myeloperoxidase -
myeloid Non-specific esterase - monocytic |
|
|
What is the diagnostic algorithm for leukemia?
|
|
|
|
What is an autologous transplant?
|
Collected from and infused into the same person.
|
|
|
What is a syngenic transplant?
|
Collected from an identical twin.
|
|
|
What is an allogeneic transplant?
|
Collected from another member of the same species whether related or unrelated (NMDP).
|
|
|
Where do we collect stem cells for transplant?
|
Bone marrow
Peripheral blood after priming or mobilization with granulocyte colony stimulating factor. Umbilical blood. |
|
|
What is the transplant-related mortality within 3 months of autologous stem cell transplant?
|
<5%
|
|
|
What complications are associated with autologous stem cell transplant per se?
|
DMSO toxicity
Graft failure |
|
|
What complications are associated with the conditioning regimen for autologous stem cell transplant ?
|
N/V/D+mucositis
Pancytopenia Infection Hair loss Liver (venoocclusive disease of the liver VOD) Lung (diffuse alveolar hemorrhage DAH, interstitial pneumonitis) Heart, Renal, Neurotoxicity, etc. + Long-term complications |
|
|
What is the average hospital stay for autologous stem cell transplant?
|
3-4 weeks
|
|
|
In what diseases can we not use autologous HSCT?
|
Bone marrow failure states such as aplastic anemia, myelofibrosis or sickle cell.
|
|
|
What are the common indications for autologous HSCT?
|
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. |
|
|
What are the benefits of Allogeneic transplant over AutoHSCT?
|
Guarantee of a clean graft.
Can be used in marrow failure states. |
|
|
What are the disadvantages of Allogeneic transplant compared to AutoHSCT?
|
Donor matching
Graft versus host disease (T-cell mediated process) Largely due to GVHD and increased infections, mortality is much higher. (10-20% by day 100) |
|
|
What is the likelihood of matching with a full sibling for alogeneic transplant?
|
1 in 4
If no sibling match, it is possible to find a donor from the NMDP or international registries. Some HLA types are ethnically conserved. |
|
|
How long does it typically take from transplant to engraftment?
|
about 2 weeks
|
|
|
What are the most common sites in descending order for GVHD?
|
Skin
Liver GI |
|
|
What are usually the earliest signs of liver GVHD?
|
Increased conjugated bilirubin and alkaline phosphatase.
Best diagnosis is liver biopsy but is difficult in thrombocytopenia because of bleeding risk. |
|
|
What is the problem with T-cell depletion to prevent GVHD?
|
Increased risk of recurrence of the underlying neoplasm.
|
|
|
Do how do we treat GVHD?
|
Pulsed steroids first.
Increased immune suppression such as cyclosporine, tactolimus, mycophenylate. ATG Other experimental measures. |
|
|
What is considered the upper age limit for autologous transplant?
|
70
65 for allogeneic but these are not hard and fast rules. |
|
|
How does radiation damage cells?
|
Damaging the DNA in cells.
|
|
|
What are the sources of radiation that we use?
|
High-energy photons from cobalt, cesium or linear accelerators.
Linear accelerators are the most common. |
|
|
Is radiation a focal or systemic treatment?
|
Radiation is considered local.
Only cells in the area being treated are affected. Standard of care is often combined modality with radio, chemo and surgery. |
|
|
What are examples of diseases in which radiation is given pre-operatively?
|
Esophageal cancer.
Head and neck cancer. Rectal cancer |
|
|
In radiation oncology, what is simulation?
|
Simulation (sometimes referred to as a marking session) is the first part of treatment planning which is crucial and awesome etc. etc.
|
|
|
What is radiation measured in?
|
The unit Gray is currently used. One Gray is equal to 100 rads.
one cGray (cGy) = one rad. |
|
|
How do we minimize radiation dmage to normal tissues?
|
Total dose of radiation is divided into several smaller doses or fractions given over several weeks.
|
|
|
What restricts the amount of radiation we use?
|
The tolerance of the normal tissue.
|
|
|
What is internal radiation therapy?
|
Also known as brachytherapy. Brachytherapy means short-distance therapy. The two main types of brachytherapy are interstitial radiation and intracavitary radiation.
|
|
|
External beam radiation is more common than brachytherapy. What is it?
|
The radiation is focused from a source outside the body onto the area affected by the cancer.
|
|
|
What makes a patient an immunocompromised host?
|
Neutropenia (ANC <500)
↓ Ab Production ↓ Cell mediated immunity Disrupted Barriers |
|
|
What sorts of diseases cause immunocompromise?
|
Note distinct absence of HIV under cell-mediated immunity.
Slide is from 1981. |
|
|
Numerically, how do we define immunocompromise?
|
Deficncy in cell mediated immunity is a CD4 count <200 cells/cu mm
Neutropenia is ANC<500 Hypogammaglobulinemia is an IgG level <800 mg/dl The more severe the defect the greater the risk of infection so this is not a cutoff but a continuum. |
|
|
What sort of susceptibilities do patients exhibit with decreasing levels of cell mediated immunity?
|
|
|
|
What should be the primary goal of treating infection in immunocompromised hosts?
|
Prevention of infection.
|
|
|
Most bacterial infections that afflict immunocompromised hosts come from...
|
The patients themselves
(endogenous) Just over 50%. In contrast, most fungal infections are exogenous. |
|
|
What antibiotics are commonly used to prophylax immunocompromised hosts?
|
Fluoroquinolones.
moxifloxacin, cipro, or levofloxacin. |
|
|
How do we recognize infection in immunocompromised hosts?
|
FEVER
(becomes an increasingly more sensitive but less specific sign as neutrophil count decreases) rubor calor tumor dolor |
|
|
What is considered a significant fever in immunocompromised hosts?
|
Single temperature > 38.3°C (101°F)
or Temperature > 38°C (100.4°F) for > 1 hr or on two or more ocasions per 24 hour period. |
|
|
What are the most common sites of infection in immunocompromised hosts?
|
|
|
|
What causes fever and skin lesions in the immunocompromised host?
|
Bacteria:
Staph G- (pseudomonas, aeromonas, serratia) Nocardia TB Viruses: HSV VZV Fungi: Aspergillus Mucoraceae Candida Cryptococcus |
|
|
What organisms apart from those that can cause skin maifestations with fever can also cause CNS symptoms with fever in the immunocompromised host?
|
Bacteria:
Enteric G-'s Fungi: Zygomycetes Viruses: Papovaviruses Parasites: Toxoplasma Strongyloides |
|
|
Patients with a dysfunction of in phagocytic cells like acute leukemias tend to get...
|
!!Extracellular pathogens!!
Pyogenic bacteria Aspergillus and zygomyctes. Candida. |
|
|
Patients with cell mediated immunity dysfunction like HIV patients tend to get infected with....
|
Intracellular pathogens.
Viruses Parasites Mycobacteria Candida and different fungi. and selected bacteria which are intracellular. |
|
|
Patients with antibody dysfunction tend to get infected with...
|
Encapsulated bacteria.
S. pneumoniae Neisseria Etc. |
|
|
As a general rule patients who undergo solid organ transplant have a dysfunction of....
|
Cell mediated immunity.
This makes them susceptible to intracellulars like nocardia, toxoplasma, crypto, pneumocystis etc. This takes about a month though so for the first month they are susceptible to the same organisms as everyone else. |
|
|
What are considered primary lymphoid tissues?
|
Bone marrow
Thymus |
|
|
What are considered secondary lymphoid tissues?
|
Lymph nodes
Spleen Tonsils Clusters of lymphoid tissue in the GI and pulmonary tracts |
|
|
How do normal B cells mature?
|
Mature in the bone marrow
Enter peripheral blood and migrate to secondary lymphoid tissues. |
|
|
The cortex of a lymph node consists of...
|
Primary follicles
Secondary follicles |
|
|
The paracortex of a lymph node consists of...
|
T cells
Dendritic APC's High endothelial venules |
|
|
The medulla of a lymph node consists of...
|
Plasma cells
Medullary sinuses |
|
|
The Sinuses of a lymph node contain....
|
APC's (macrophages etc.)
|
|
|
The B cells found in primary follicles in the cortex of a lymph node are...
|
Naive B-cells
|
|
|
The B-cells found in secondary follicles in the cortex of a lymph node are...
|
B cells that are proliferating after encountering an antigen.
Naïve B cells get pushed to the periphery and form the mantle zone. |
|
|
The germinal centers of secondary follicles in the cortex of a lymph node have dark zones and light zones.
What is contained in each? |
Dark zone: centroblasts
Light zone: centrocytes The dark zones are darker because the immature centroblasts have more nuclei. The light zones are lighter because the cells are not dividing as rapidly. |
|
|
What destroys B cells with “wrong” antibodies when they reach germinal centers of secondary follicles in the lymph node?
|
Tingible body macrophages
|
|
|
How are T-cells made?
|
Lymphoid stem cells migrate from the marrow to the thymus via peripheral blood.
|
|
|
When does thymus function cease?
|
Never.
Even though it involutes function continues after puberty. |
|
|
What happens in the thymic cortex?
|
Thymic epithelial cells interact chemically and physically with lymphocytes to help them differentiate.
The T-cell precursors (lymphoblasts) rapidly proliferate as they head towards the medulla. The closer they get to the medulla the less they proliferate and the more they resemble a mature T-cell. Only about 5% of these cells actually make it into the medulla because of positive selection and negative selection. |
|
|
What happens in the thymic medulla?
|
Final development of selected lymphoblasts into lymphocytes.
|
|
|
When negative selection of lymphocytes happens outside the thymus it is called....
|
Peripheral tolerance.
It is called central tolerance if it happens in the the thymus. |
|
|
What determines if a T-cell will stay in the thymus or migrate to various places in the body such as the epithelium of the GI tract?
|
If the TCR is made from alpha and beta genes, the T-cell stays in the thymus.
If the TCR is made from gamma and delta genes, the T-cell migrates. |
|
|
Small lymphocytic lymphoma is on a continuum with....
|
Chronic lymphocytic leukemia.
It becomes CLL when there are white cells circulating in the blood. |
|
|
Burkitt's lymphoma is on a continuum with...
|
Burkitt's leukemia.
|
|
|
Acute lymphoblastic lymphoma is on a continuum with...
|
Acute lymphoblastic leukemia
It is called lymphoma if there is no bone marrow involvement. |
|
|
What are some of the common non-hodgkin lymphomas?
|
High grade (Highly Aggressive):
Burkitt’s Lymphoma/Leukemia Pre-B cell ALL/Lymphoma Pre-T cell ALL/Lymphoma Adult T cell Lymphoma (HTLV-1) Intermediate grade (Aggressive): Diffuse large B cell lymphoma Anaplastic large cell lymphoma. Mantle cell lymphoma Low grade: 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. |
|
|
Which lymphomas are on a continuum with leukemias?
|
Burkitt’s Lymphoma/Leukemia
Pre-B cell ALL/Lymphoma Pre-T cell ALL/Lymphoma CLL/SLL |
|
|
Mantle cell lymphoma can be either...
|
Intermediate grade or low grade.
|
|
|
What is follicular lymphoma?
|
Most common low grade non-Hodgkin lymphoma.(~20%)
Incidence increases with age. (Median 60-70 years of age). Characterized by SMALL CLEAVED CELLS. B-Cell lineage (CD20+) The larger the number of centroblasts, the more aggressive the follicular lymphoma. |
|
|
What are the different grades of follicular lymphoma?
|
Grade I:
0-5 centroblasts/hpf Grade II: 6-15 centroblasts/hpf Grade IIIa: Centrocytes present Grade IIIb: solid centroblast sheets. Acts like intermediate grade lymphomas. |
|
|
What do the lymph nodes look like in follicular lymphoma?
|
Mantle zone is lost.
Follicles start to merge together. Polarization of germinal center is lost. Paracortex is lost. |
|
|
What translocation is associated with follicular lymphoma?
|
t(14;18)
|
|
|
How do we treat follicular lymphoma?
|
Not cureable but very treatable.
Highly variable treatment. "mowing the grass when it gets too long" |
|
|
What are the adverse prognostic factors for follicular lymphomas according to FLIPI (Follicular Lymphoma International Prognostic Index)?
|
Age > 60 years
Ann Arbor Stage III-IV Hb < 12 g/dl Number of nodal areas >4 LDH > upper limit of normal |
|
|
What is Diffuse Large B Cell Lymphoma?
|
Most common intermediate grade lymphoma.
Comprises ~30% of all new NHL diagnoses. CD19+, CD20+ B cell lineage Cells are larger than a normal lymphocyte. No standard cytogenetics. Normal architecture of lymph nodes is destroyed. Often very responsive to chemotherapy |
|
|
How we treat large B-cell lymphoma?
|
R-CHOP
|
|
|
What is R-CHOP?
|
R: rituximab (Rituxan)
C: cyclophosphamide (Cytoxan) H: Hydroxy-doxorubicin (doxorubicin) O: Oncovin (vincristine) P: Prednisone |
|
|
What are the negative prognostic factors for diffuse large B-cell lymphoma?
|
Age > 60 yo
ECOG > 2 (preformance in daily living scale. 0 is best 4 is the worst) LDH > upper limit of normal >1 extranodal site Stage III/IV disease |
|
|
What is burkitt's lymphoms (leukemia)?
|
One of the fastest growing tumors that exist.
Doubling time is 24 to 48 hours. |
|
|
What are the three types of Burkitt's lymphoma?
|
African: affects jaw or facial bone
“American”, or endemic: affects lymph nodes in abdomen, GI tract Immunodeficiency-associated Burkitt's lymphoma. |
|
|
What are AIDS defining malignancies?
|
Immunodeficiency-Associated Burkitt’s Lymphoma.
Kaposi’s sarcoma (HHV-8) Systemic NHL, primary effusion lymphoma, CNS lymphoma. Cervical cancer (HPV) |
|
|
What are the typical pathological findings of Burkitt's lymphoma?
|
Starry sky appearance.
~100% Ki-67 staining CD20(+), CD10(+), CD5(-) |
|
|
What translocations are associated with Burkitt's lymphoma?
|
t(8;14)
t(2;8) t(8;22) All have a cytogenetic abnormality involving chromosome 8: !!!!c-myc!!!! |
|
|
What is important about the treatment of Burkitt's lymphoma?
|
Treatment is very complex and long and must begin immediately. Much of it is given intrathecally.
Extremely high risk for spontaneous tumor lysis syndrome. |
|
|
What are the sanctuary sites for Burkitt's lymphoma?
|
Brain and testicles.
(The two brains) |
|
|
What is a myeloproliferative disorder?
|
Clonal proliferation of a cell line derived from the myeloid stem cell.
|
|
|
What are the different myeloproliferative disorders?
|
Chronic idiopathic myelofibrosis can be thought of as proliferation of fibroblasts even though this is not technically true.
|
|
|
How is normal red blood cell production regulated?
|
Normoxia:
vHL protein targets HIF-1a for destruction by ubiquitin proteosome. No HIF-1a/HIF-1b complex Epo gene not transcribed Hypoxia: HIF-1a is not degraded. HIF-1a/HIF-1b complex binds to and stimulates transcription of Epo gene. Epo (Erythropoeitin) causes increased production of RBC's in the marrow. |
|
|
vHL (Von hippel-Lindau) protein which targets HIF-1a
for destruction by proteosomes (ubiquitination) is activated by.... |
Oxygen.
|
|
|
Why do we sometimes see erythrocytosis after renal transplant?
|
The native kidneys can sometimes keep producing erythropoietin despite negative feedback from the new kidney.
|
|
|
Carbon monoxide shifts the dissociation curve to the....
|
Left
|
|
|
What are some genetic causes of polycythemia?
|
|
|
|
What is polycythemia vera?
|
A Clonal disorder in which RBC production is independent of erythropoietin and its receptor.
Do not need Epo to form RBCs so blocking the Epo receptor which is completely normal does not “turn off” RBC production. Circulating Epo level will be low. The problem is ususally in the JAK/STAT pathway where JAK-2 (Janus activating kinase-2) becomes a constituitively active tyrosine kinase due to a valine/phenylalanine substitution at position 617. The substitution promotes cytokine hypersensitivity or cytokine independent growth which leads to erythrocytosis. |
|
|
What sort of lab values do we expect in polycythemia vera?
|
Elevated hemoglobin and hematocrit.
Elevated RBC mass. Increased marrow cellularity. ~60% of patients will have a platelet count > 400K ~40% of patients will have a WCC > 12K This is because both platelets and WC are of the same lineage. |
|
|
What sort of signs and symptoms do we expect in polycythemia vera?
|
“Congestion”:
HA, visual changes Dizziness Paresthesias Facial plethora Pruritis after a warm bath Bleeding, bruising Thrombosis: MI, DVT, PE, CVA, Budd-Chiari syndrome (hepatic vein occlusion) Hepatosplenomegaly Erythromelalgia (painful red hands) |
|
|
The risk for thrombotic events in polycythemia vera increases with....
|
Age
White cell count (marker). |
|
|
Transformation risks for polycythemia vera include...
|
Myelofibrosis
AML |
|
|
How doe we treat polycythemia vera?
|
Phlebotomy.
(Goal Hct < 45% for males; < 42% for females) Hydroxyurea. Low dose ASA. |
|
|
What is essential thrombocythemia?
|
A clonal disorder which is
Independent of thrombopoietin or its receptor (c-Mpl). TPO levels are normal or elevated because of decreased TPO clearance but this is NOT the cause. JAK2 mutation similar to polycythemia vera seen in ~50% of ET patients. |
|
|
How do we diagnose essential thrombocythemia (thrombocytosis)?
|
Sustained platelet count ≥450K.
Hyperplasia of megakaryocytes on bone marrow biopsy. Absence of t(9;22) to rule out CML and absence of other causes of secondary thrombocytosis. |
|
|
What do the blood counts look like in essential thrombocytosis?
|
Elevated platelet count
Normal white blood cell count Normal hemoglobin |
|
|
Why do patients with essential thrombocytosis bleed despite the elevated platelet counts?
|
The platelets function abnormally.
|
|
|
What sort of thrombosis events are common in essential thrombocytosis?
|
CVA
TIA MI priapism Splenomegaly Erythromelalgia |
|
|
What are the progression risks for essential thrombocytosis patients?
|
myelofibrosis
AML |
|
|
How do we treat essential thrombocytosis?
|
Hydroxyurea
Aspirin |
|
|
Which leukemias are considered myeloproliferative disorders?
|
CML
Chronic eosinophillic leukemia. |
|
|
What is chronic idiopathic myelofibrosis?
|
“Scarring” of the bone marrow
Reticulin and/or collagen fibrosis Decreased cellularity of bone marrow Often have “dry taps” |
|
|
How does chronic idiopathic myelofibrosis present?
|
!!Marked splenomegaly!!
Hepatomegaly present as well. Extramedullary hematopoiesis can be found in unusual places including: Pleural effusions Pericardial effusions Ascites Central nervous system |
|
|
What do the blood counts look like in chronic idiopathic myelofibrosis?
|
!!Leukoerythroblastic!!! picture:
Pseudo-Pelger-Huet cells Giant platelets All of these are signs of marrow replacement. Patients are usually anemic. WCC and platelet count may be high or low. |
|
|
What is the risk of leukemic transformation in chronic idiopathic myelofibrosis?
|
Usually myeloid.
Can be lymphoid, erythroid, megakaryocytic, or mixed lineage. JAK2 mutations also seen in ~50% of patients. |
|
|
How do we treat chronic idiopathic myelofibrosis?
|
We dont have a very good treatment.
Palliative: Hydroxyurea Splenectomy Appropriate acute leukemia treatments with transformation (prognosis worse than de novo leukemia patients) |
|
|
What are myelodysplastic syndromes?
|
Disorders of ineffective hematopoiesis with hypercellular but abnormal bone marrows and peripheral cytopenias.
Patients usually present as a result of their cytopenias (similar to AML). |
|
|
What is the typical clinical presentation of myelodysplastic syndromes?
|
Recurrent infections
Fatigue, pallor Bleeding Usually don’t have splenomegaly (unlike myeloproliferative disorders) |
|
|
How do we diagnose myelodysplastic syndromes?
|
Bone marrow biopsy and aspirate.
Look for dysplastic cells eg.nuclear/cytoplasmic dyssynchrony. Look for an increased number of blasts: < 5% blasts: Normal >20% blasts: Acute leukemia 6-19% blasts: MDS Also evaluate chromosomes (with cytogenetics and sometimes FISH) because this helps with prognosis. |
|
|
How does the International Prognostic Scoring System for myelodysplastic syndromes work?
|
0=low
0.5-1.0=intermediate 1 1.5--2.0=intermediate 2 2.5-3.5=High Age is not incorporated. Older people do worse. |
|
|
The two greatest risk factors for developing AML from MDS are...
|
Age.
IPSS score. |
|
|
What is 5q- syndrome?
|
Clinical course tends to be relatively more benign than other MDS.
Overall these patients are more responsive to certain treatments like: Thalidomide Lenalidomide |
|
|
How do we generally treat MDS?
|
Supportive care:
Antibiotics, transfusions, growth factors ( EPO, GCSF), Iron chelators like Exjade to bind iron which gets excreted in urine and bile. Chemotherapy: Different from AML chemotherapy. Monitor for transformation to AML. (outcomes are worse for patients with AML arising from MDS) |
|
|
What is a plasma cell dyscrasia?
|
Genetic mutations result in increased numbers of plasma cells with increased amounts of antibody production which can cause end organ dysfunction.
There is a continuum of disorders depending on amount of excess protein present. |
|
|
What is the continuum of plasma cell dyscrasias?
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MGUS
(Monoclonal Gammopathy of Undetermined Significance) Multiple Myeloma Plasma Cell Leukemia |
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How do we diagnose plasma cell dyscrasias?
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Measure the number of plasma cells by bone marrow biopsy and aspirate.
Measure the amount of protein (antibody): Comprehensive panel (Total protein elevated in excess of albumin). Serum quantitative immunoglobulins. Serum protein electrophoresis. (SPEP) Serum immunofixation. Serum free light chains. |
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What does the alpha peak on SPEP represent?
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Alpha-1 antitrypsin, etc
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What does the alpha 2 peak on SPEP represent?
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Haptoglobin, etc
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What does the beta peak on SPEP represent?
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Transferrin
Some immunoglobulins |
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What does the gamma peak on SPEP represent?
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Most immunoglobulins
!!!Not just IgG!!! |
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A sharp peak in the gamma region on SPEP means monoclonal antibodies is called an M-spike. How can we tell if it is IgG, IgM or IgA?
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We can't.
All these antibodies have gamma globulin chains. This is why we do (IEP) immunoelectrophoresis. |
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What is a normal kappa lambda ration on a serum free light chain test?
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2:1
Ratio will be altered dramatically with monoclonal antibody production. |
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How does multiple myeloma damage bones?
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Increased osteoclast activation leads to lytic lesions in bone often seen in:
Calvarium Spine Ribs Pelvis Long bones |
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How are the kidneys damaged by mutliple myeloma?
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Deposition of immunoglobulin.
Cast nephropathy “Myeloma kidney”. Infiltration of kidney by plasma cells. |
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What do we see in the bone marrow of a multiple myeloma patient?
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Increased plasma cells.
(offset nucleus and lots of golgi) |
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What do we see in the peripheral blood of multiple myeloma patients?
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Normochromic normocytic anemia.
Rouleaux formations. Circulating plasma cells usually only seen with plasma cell leukemia. !!!Hypercalcemia!!! which also contributes to renal failure. |
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What are the symptoms of hypercalcemia?
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Stones: kidney stones
Bones: increased bone rebsorption. Groans: constipation. Moans: psychiatric issues. |
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How do we treat plasma cell dyscrasias?
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Depends on where the patient falls along the continuum.
Observation Oral chemotherapy Intensive IV chemotherapy Bisphosphonate for bones and hypercalcemia. |
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What SPEP pattern do we see in infectious mononucleosis?
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Spike on albumin peak.
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What SPEP pattern do we see in Hypogammaglobulinemia ?
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Flattened or absent gamma peak.
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What cells fight fungal infection?
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Monocytes
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If someone on coumadin eats a lot of leafy vegetable their INR will...
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Be lower.
Because of the consumption of vitamin K. |
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The target PTT with heparin therapy is....
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70-90 seconds
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Lepirudin, a direct thrombin inhibitor is made from...
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Recombinant leech saliva
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What is a normal platelet count?
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150-350 K
Usually requires < 50K before bleeding occurs. |
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What is a normal Bleeding Time (BT)?
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2-9 minutes
Platelet aggregation studies now used more frequently. |
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What is a normal aPTT (Activated Partial Thromboplastin Time )?
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21 - 35 seconds
aPTT is sensitive to intrinsic Pathway abnormalities: XII, XI, IX, VIII, X, V. Less sensitive to II, fibrinogen. Less sensitive to II, fibrinogen |
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What is a normal PT (prothrombin time)?
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10-14 seconds.
Sensitive to Extrinsic Pathway abnormalities: VII, X, V, II, fibrinogen. Useful in Vitamin K deficiency: II, VII, X |
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What parts of the clotting cascade do PT and aPTT measure?
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D-dimers are an indication that...
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Thrombin has been activated and coagulation is actually occuring.
This is an advanatge because traditional FDP assays cannot distinguish between plasmin action on fibrinogen (fibrinogenolysis) and fibrin (fibrinolysis). This means traditional FDPs can be elevated when there is no clot present and plasmin is just cleaving fibrinogen. |
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What are the classic findings of DIC?
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Elevated PT and aPTT with thrombocytopenia and elevated D-dimers.
Schistocytes in blood smears Decreased concentrations of all coagulation factors including V/VIII. Petechiae and ecchymoses of skin and mucous membranes. Shock. |
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What study will be elevated in Von Willebrands disease or treatment with Heparin?
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aPTT
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What is linitis plastica?
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'leather-bottle' stomach due to poorly differentiated adenocarcinoma infiltrating the gastric wall.
This gastric carcinoma does not ulcerate or protrude into the gastric lumen. |
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Which leukemia is highly associated with DIC presentation?
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APL
t(15;17) |
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What is the clinical pentad of TTP?
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MAHA
Neurologic abnormalities Renal Insufficiency Fever Thrombocytopenia |
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What IS TTP?
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Deficiency of vWF metalloproteinase (ADAMTS13).
Enzyme deficiency results in accumulation of very-high-molecular weight multimers of vWF, promoting platelet aggregation. The outcome is a consumptive thrombocytopenia with schistocytes in blood smears. |
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What are the clinical features of the hemolytic uremic syndrome?
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MAHA
Thrombocytopenia Renal Insufficiency Bloody diarrhea (happens because of the O157:H7 or shigella causative agent and is a great way to tell HUS from TTP) |
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What are the main microangiopathic hemolytic anemias?
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A deficiency in FXII and vwf is...
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Von willebrands disease,
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What are the functions of VWF?
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Carrier protein for FVIII which increases its serum half life
Binds to GpIb receptor on platelets causing their adhesion to damaged endothelium. |
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What is the vWD panel we do after ruling out platelet problems with platelet count, PT, aPTT?
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Factor VIII activity – decreased in vWD
vWF antigen – decreased in vWD Ristocetin cofactor activity – decreased in vWD vWF multimeric analysis – qualitative test of vWF |
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How does multimeric analysis of vwf help us to subtype the disease in vWD?
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Type 1 – Generalized decrease
Type 2 – Loss of high molecular weight multimers. Type 3 – Multimer absence. !!type 1 and type 2 are typically asymptomatic!! |
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What is factor VIII?
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Synthesized in liver.
Circulates bound to von Willebrand Factor as stable complex. Activated by IIa (and Xa!): Enhances activation of X by IX 200,000 fold. Inactivated by Protein C. |
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What is hemophilia A?
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!!Factor VIII deficiency!!
X-Linked recessive - Xq28 mutation with high rate of spontaneous mutation (30% of hemophilia A patients have no family history) A pattern of bleeding (joint/muscle) and easy bruising emerges in neonatal period. |
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What is hemophilia B?
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Factor IX deficiency.
X-linked recessive, 1:30,000 male. Most families have unique mutations. |
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What are the main differences between vwd, hemophilia A and hemophilia B?
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What is factor V leiden deficiency?
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Mutation in Factor V renders the cofactor resistant to proteolysis by activated Protein C.
Predisposes to recurrent venous thromboembolism so warfarin prophylaxis is indicated. Autosomal Dominant, point substitution mutation which intereferes with the function of the MNL1 restriction enzyme. Dx: DNA mutational analysis |
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What are the natural anticoagulants and thrombolytics?
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What are some primary or genetic causes of hypercoagulability?
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Factor V gene mutation.
Antithrombin III deficiency. Protein C or S deficiencies. |
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What are some secondary or acquired causes of hypercoagulability?
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Tissue damage (surgery, fracture, burns), Cancer, DIC, etc.
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What is antiphospholipid antibody syndrome?
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Autoimmune hypercoagulability caused by antibodies to cardiolipin and lupus anticoagulant.
Associated with pregnancy complications and fetal loss. Most often diagnosed because of incidental paradoxical elevated aPTT. |
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What does tissue factor do?
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Forms a complex with Factor VII to activate factors X and IX.
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What does a BUN to creatinine ratio greater than 20:1 mean?
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pre-renal failiure.
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What does diarrhea do to serum electrolytes?
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Raises Na and Cl
Lowers K and Bicarb |
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The best test for following warfarin is ...
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prothrombin (FII) time (PT)
Goal is INR of 2.0-3.0 |
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The best test for following heparin is...
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aPTT
goal is 70-90 seconds. |
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What does unfractionated heparin do?
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Binds to antithrombin to accelerate inactivation of factor Xa
It can also bind to and inactivate thrombin. |
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What does low molecular weight heparin do?
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Binds to antithrombin and inactivates Xa, but is too short to bind to thrombin.
Has little effect on aPTT so the dose is rarely titrated but we can measure anti-Xa activity if necessary. |
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What is the mechanism for heparin induced thrombocytopenia??
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Heparin binds to platelet factor 4
This complex binds to an activated platelet surface An IgG antibody binds to the heparin/PF4 complex Results in platelet clearance; ie: thrombocytopenia |
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What is the mechanism for heparin induced thrombocytopenic thrombosis?
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Heparin binds to platelet factor 4
This complex binds to an activated platelet surface An IgG antibody binds to the heparin/PF4 complex Results in platelet clearance; ie: thrombocytopenia Fc portion of IgG further activates platelets, resulting in thrombosis. |
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How do we treat HIT or HITT?
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Direct thrombin inhibitors
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How can we LOWER the INR in a patient on coumadin (warfarin)?
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Vitamin K
FFP Contains fibrinogen and all the clotting factors, but has low amounts of factors V and VIII (these don’t store well) Cryo Contains fibrinogen, vWF, VII, and XIII |
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What coagulation factors are in the extrinsic (tissue factor) system?
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Factor VII
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What coagulation factors are in the intrinsic (tissue factor) system?
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XII
XI IX VIII |
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How do both the intrinsic and extrinsic system connect with the final common pathway?
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They work on Factor X.
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What is included in the common pathway?
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X
V II (prothrombin) Fibrinogen |
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INR is an internationally standardized equivalent of...
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PT
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What does factor XIII do?
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Stabilizes fibrin by crosslinking it.
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How do we differentiate hemophilia A from VWD?
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Hemophillia A is x linked (male patients)
VWF is autosomal dominant. Hemophillia A has only decreased XIII coagulant but normal VWF. VWF will have a prolonged bleeding time. |
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Two things can increase the synthesis of factor XIII. What are they?
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Desmopressin
Estrogen (birth control pills) |
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Hemophilia A is a deficiency of...
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Factor XIII
The Factor VIII gene is located near the tip of the long arm of the X chromosome and a missense, frameshift mutations, deletions or inversions (intron 22) can cause it to be damaged. |
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Hemophillia B or christmas disease is a deficiency of...
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Factor IX
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What clotting tests are elevated in hemophilia?
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Only the PTT is prolonged.
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The incidence of hemophilia A is about...
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1 in 5000 male births
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How is it possible for a female to be affected by hemophilia?
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Lyonization of healthy X.
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What are the clinical manifestations of hemophilia?
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!!!Joint bleeds!!!!
(Target joints are those into which repeated bleeding occurs) Deep muscle bleeds. Hematomas. Post-surgery/Post-trauma complications. Dental extraction complications. Intracranial hemorrhage |
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How do we classify the severity of hemophilia A?
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What is hemophilic arthropathy?
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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. |
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How do treat hemophilia?
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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. Cryo for factor VIII or FFP for factor IX are a last resort in remote areas. Synovectomies, joint replacements/fusions. PREVENTION, PREVENTION, PREVENTION |
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How are the plasma derived concentrates made?
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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. Recombinant human factor VIII and IX can also be made from trasfected mammalian cell lines and require no viral attenuation. |
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What are the complications associated with hemophilia treatment?
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Development of inhibitors (alloantibodies) to Factor VIII and less commonly, Factor IX.
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 |
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At what age do we begin prophylactically treating hemophilia patients?
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1-2 years
Maintain trough FVIII:c/FIX:c > 1-2% |
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What is acquired hemophilia?
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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. |
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What is by far and away the most common bleeding disorder?
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VWD
!!!Autosomal dominant!!! Affects men and women equally. |
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What are the two functions of VWF?
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Promotes platelet adhesion to damaged endothelium
Chaperone molecule for Factor VIII which dramatically lengthens its half life. |
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What are the main differences between Hemophilia A, Hemophilia B and VWD?
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Bleeding time is prolonged in VWD. Normal in both hemophilias.
Muscle, joints, post-trauma, post-op bleeding is hemophilia. Mucous membranes, skin cuts, post-trauma, post-op bleeding is VWD. Hemophilia is sex linked but VWD is autosomal dominant. |
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How do we treat VWD?
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DDAVP = Desmopression=1-deamino-8-D-arginine vasopressin = synthetic analog of ADH L-vasopressin.
Releases stored Factor VIII and VWF from endothelial cells. Given IV or intranasally. Humate P – Intermediate purity factor VIII concentrate which contains both VWF and factor VIII. |
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What is AMICAR?
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Stabilizes fibrin clots.
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How do we treat TTP to replace the ADAMST13 enzyme?
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Plasmapheresis to remove the inhibitor and plasma replacement.
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What % of patients on opiod analgesics will develop addiction?
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< 1% of patients receiving pain therapy with opioid analgesics.
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Dependance is...
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When withdrawal symptoms appear upon stopping the drug
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Tolerance is...
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When a particular dose loses its effectiveness.
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What is nociceptive pain?
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Pain from somatic and visceral structures.
Somatic - sharp, localized, throbbing, pressure-like Visceral - diffuse, irritating, cramping. |
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What is neuropathic pain?
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Pain from the peripheral or central nervous system
Burning, sharp, shooting. eg. Shingles. |
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What should we watch for with NSAIDs?
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Decrease in renal function
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What are the advantages of non-acetylated salicylates?
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Less GI tox & better for sparing platelets
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How does acetaminophen achieve its antipyretic and analgesic effects?
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Inhibits prostaglandins in CNS and peripherally blocks pain impulse generation.
Metabolized in liver. |
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NSAIDs (cox inhibitors) have dose response curves plateaus with an analgesic ceiling. they are especially helpful for bone pain. What are their limitations?
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Gastropathy
Anti-platelet effect Renal toxicity Drug interactions |
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When do we use selective cox-2 NSAIDs?
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History of GI ulcers
Elderly Low platelet count < 50K Receiving anticoagulation Receiving corticosteroids Coagulopathy Prior intolerance to non-selective NSAID |
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What is celoxicib (celebrex)?
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Used for acute and chronic pain.
100-200 mg PO daily max dose. but Familial adenomatous polyposis (FAP) 400 mg PO BID, this high dose does not produce the cardiac drawbacks that caused withdrawal from the market. Many drug interactions that should be watched (warfarin, CYP450) Caution in pts with sulfonamide allergy because contains a sulfa part. |
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What is Tramadol (Ultram)?
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Binds to the mu-opiate receptors but also binds to norepinephrine and serotonin.
Less addictive than "real" opiates. May lower seizure threshold. Must be adjusted in renal failure. |
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How do you convert someone on oxycodone to IV morphine equivalent?
|
10mg Oxycodone po=15mg morphine po=5mg morphine IV
So... from oral oxycodone to IV morphine divide by 2. |
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What are some adverse effects of morphine?
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sedation, urinary retention, decreased respirations, CONSTIPATION (Use with laxitive)
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What is Hydromorphone (Dilaudid)?
|
Approximately 6 times more potent than morphine.
both IV and PO. Useful alternative in liver/renal failure patients. Less nausea/vomiting and pruritis relative to morphine. |
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What is fentanyl?
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100 times as potent as morphine; titrate slowly
1 mg IV morphine = 10 mcg fentanyl. Least likely opiate to induce histamine release. Watch administration of fentanyl patch with heating pad or high fevers because it ups the dosing considerably. Also available as transmucosal "lollipop". |
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What is meperidine?
|
NOT recommended for pain management unless no other options.
Toxic metabolite normeperidine is CNS toxic and can cause seizures. Useful for post-anesthesia and amphotericin B related rigors. |
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Methadone is an....
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Opioid agonist & NMDA antagonist
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What is the MOA of heparin?
|
Complexes with Antithrombin III accelerating its ability to inactivate factors IIa, Xa, and IXa.
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Gabapentin is used for...
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Neuropathic pain.
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Do we have to check aPTT when giving sq prophylactic heparin or low molecular weight heparin?
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No
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What choices do we have for low molecular weight heparin?
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Enoxaparin (Lovenox)
Dalteparin (Fragmin) Fondaparinux (Arixtra) |
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What do we use Enoxaparin (Lovenox) for?
|
Indicated in the treatment and prophylaxis of venous thromboembolism (VTE).
New data suggests we can dose this once a day. |
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What is the approved use of Dalteparin (Fragmin)?
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Prevention of VTE
NOT approved for treatment of VTE |
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Fondaparinux (Arixtra) is not technically a heparin. Where does it act?
|
It is an Anti Xa inhibitor.
It does not act on AT3 like other heparins. Good option for heparin-induced thrombocytopenia (HIT) Can also be used for VTE prophylaxis. |
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What is the MOA of warfarin?
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Inhibits the production of vitamin K dependent clotting factors (II, VII, IX, X).
Takes about 5 days so heparin bridging therapy is used. Can cause skin necrosis – bruising on buttocks, thighs, penis, breasts. |
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How do we monitor warfarin therapy?
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INR (PT)
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What is the target INR for warfarin therapy?
|
2.0-3.0
Up to 3.5 for some states like mitral valves or systemic embolism. |
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One of the main interactive consideration with Warfarin is that...
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It is highly protein bound
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Why do we give mutivitamins or Vitamin K with warfarin if it decreases the efficacy?
|
It reduces interactions with other drugs.
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When do we transfuse plasma or prothrombin complex concentrate rather than just give vitamin K to reverse the effect of warfarin?
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INR > 20 or rapid reversal
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How long does it take for the effect of aspirin to go away?
|
The life of the platelet.
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What is the MOA of ticlopidine (Ticlid)?
|
Inhibits platelet activation and aggregation but mechanism is different from any other antiplatelet drug.
Can cause reversible neutropenia. |
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What is the MOA of Clopidogrel (Plavix)?
|
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 because it is irreversible. |
