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509 Cards in this Set
- Front
- Back
Name the erythropoesis steps
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cFU-E
Pro-normoblast Basophilic normoblast Orthocrhomic normoblast Reticulocyte RBC |
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Which RBC precursors are found in the blood normally? and with disease?
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Nml - RBCs and reticulocytes
Disease -- all the way back to pro-normoblasts |
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Production of RBCs by bone marrow per day?
Lifespan of an RBC? |
10^12
120 days |
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Methemoglobin
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Oxidized hemoglobin
Iron is ferric rather than ferrous Cannot carry oxygen |
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Things that increase hemeoglobin affinity for oxygen
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alkaline
cooler less DPG |
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Things that decrease hemoglobin affinity for oxgyen
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Acidosis
Increased temperature Increased DPG |
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Haldane effect
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deoxygenated hemoglobin has higher affinity for CO2 than oxygenated
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Bohr effect
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In presence of CO2, hemoglobin affinity for oxygen decreases
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Hematocrit
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% of total blood volume that is RBC volume
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Hemoglobin
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Amount of hemoglobin in the blood-- in grams/deciliter
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MCV
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Mean corpuscular volume
Hct x10/RBCs Normal = 80-100 femptoliters |
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MCH
MCHC |
Mean corpuscular hemoglobin
average mass of hemoglobin per RBC Mean corpuscular hemoglobin concentration concentration of hemoglobin in a give volume of pack RBCs These define chromicity |
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RDW
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Red cell distribution width
SD of red cell size/MCV indicates the variation in size of RBCs Normal is 11.5-14.5 Low is never bad |
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Anisocytosis
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Increased RDW
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Reticulocyte
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Immature RBCs, about 1% of circulation normally
Still have ribosomes |
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Anemia affect on reticulocytes
Measured by? |
With worsening anemia, reticulocytes are extruded from bone marrow earlier
RPI - reticulocyte production index Greater than 2 is a adequate response to an anemia |
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Anemia sings and symptoms
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Pale, jaundice, cold skin
Fatigue, SOB, syncope Low BP, rapid HR, breathing, heart murmur |
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Transferrin
TIBC TS |
transferrin -- protein that binds Fe in blood
transferrin iron binding capacity transferrin saturation Fe/TIBC normal -- 20-50% |
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Ferritin
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Protein that stores many atoms of Fe
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Iron deficiency anemia causes
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Decreased oral intake
Decreased absorption gastritis, bypass, bacterial overgrowth, celiac, antacids, tea, spinach Increased loss (bleeding) |
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Weird causes of iron deficiency anemia
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Exogenous EPO depletion of stores
Hemolytic anemia leading to iron loss into urine |
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Pica
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Eating weird stuff
Symptom of iron deficiency pagophagia--ice amylophagia - starch geophagia--dirt |
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Plummer-Vinson syndrome
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Iron deficiency anemia
Dyspagia Esophageal webbing Atrophic glossitis Angular cheilosis Koilonychia (spoon nails) |
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Iron deficiency anemia smear and labs
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Microcytic
Hypochromic Anisocytosis RPI <2, Fe, TS, Ferritin all down, TIBC up |
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Sideroblastic anemia smear
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Microcytic anemia
Basophilic stipling creating a ring Hypochromic Dimorphic populations |
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Sideroblastic anemia causes
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Congenital ALA deficiency
Pyridoxine/copper deficiency Lead, ETOH, chloremphenicol, isoniozid RA, myeloma, myelo/lymphoproliferative diseases |
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Treating sideroblastic anemia
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Remove toxins
Treat with pyridoxine Transfusions |
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Lead poisoning blood stuff
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Sideroblastic anemia of any MCV
Disrupts both heme and globin synthesis Increased iron and sideroblasts in marrow |
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Lead poisoning symptoms
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Anemia
Lead line in gums Motor neuropathy -- lead palsy Autonomic neuropathy -- ileus/abdominal pain - lead colic |
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Thalessemias
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Quantitative disorder of globin synthesis
Not enough is made (Hemoglobinopathies are qualitative) |
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Beta thalassemia
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Minor: one mutation in beta globin gene
microcytic anemia, usually normal longetivity Major: two mutations, marked hemolysis, extramedullary hematopoesis (facial bones, hepatospenomegaly, cardiac failure) |
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Thalessemias treatment
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Splenectomy
Transfusions Chelation Bone marrow transplant |
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Microcytic anemias
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Iron deficiency
Sideroblastic (lead poisoning) Thalassemias, hemoglobinopathies 1/3 anemia of chronic disease |
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Major categories of normocytic anemias
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Low reticulocyte -- hyproliferative with decreased production
High reticulocyte -- destruction of blood cells (reticulocyte) |
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Normocytic anemias with a low reticulocyte
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Hypoplastic states
2/3 of the anemias of chronic disease aplastic anemia others (renal, endocrine disease) |
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Normocytic anemias with a high riticulocyte count
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Hemolytic states
Autoimmune Drug-induced Mebraneopathies (hereditary spherocytosis, PNH) Enzymopathies Hemoglobinopathies Microangiopathic hemolytic anemias |
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Anemia of Chronic Disease
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Normo/microcytic
Normochronmic Associated with diseases w/ inflammation, infection, malignancy |
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Hepcidin
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Acute phase protein -- produced during inflammation
Decreased iron absorption in intestine Decreased iron release from macrophages Direct inhibition of erothropoesis |
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Iron studies in anemia of chronic disease
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Low iron
Low TIBC High ferritin |
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Treatment of anemia of chronic disease
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Treat underlying disease
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Aplastic anemia
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Absent hematopoetic precursors in bone marrow
Pancyotopenia including normocytic anemia Most dangerous are leukopenia and thrombocytopenia |
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Causes of aplastic anemia
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Primary - idiopathic, Fanconi's
Secondary -- radiation, chemotherapy (alkylators), chloremphenicol, antiepileptics, nifedipine, benzene, parvovirus, EBV, hepatitis (non-A, non-B, non-C) |
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Aplastic anemia treatment
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Remove cause (stop radiation, meds)
Transfusions Anti-thymocyte or antilymphocyte globulin Cylcosporin, cyclophosphamide Stem cell transplant |
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Renal disease mechanism of causing anemia
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Hypoplastic, normocytic anemia with low reticulocyte count
Caused by underproduction of erythropoetin |
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Endocrine causes of anemia
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Hypothryoidism
Panhypopituitarism Low testosterone |
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Primary myelofibrosis
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Metaplasia of the bone marrow--replacement with fibroblasts
Smear: teardrops, nucleated red cells, early white cells Usually with large spleen (extramedullary hematopoesis) Not possible to get aspirate from bone marrow, need to core |
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Myelophthistic anemia
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Infiltration of the bone marrow by fibrosis, tumor, granuloma
Smear: teardrops, nucleated red cells, early white cells Look for a cancer |
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Haptoglobin
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Binds to heme in vasculature
Preventing iron use by bacteria Heme-haptoglobin is taken up and disposed of by macrophages Used to monitor levels of intravascular hemolysis |
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Causes of intravascular hemolysis
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Transfusion reactions
G6P deficiency w/ oxidative stress Paroxysmal nocturnal hemolysis Infection (clostridial sepsis, severe malaria) Microangiopathy (aortic stenosis, artifical valve leak) |
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Shistocyte
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Fragment of a red blood cell
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Intravascular hemolysis
Clinical signs Labs |
Signs--
Pallor, fatigue, tachycardia Jaundice Blood tinged urine, plasma Labs-- Decreased haptoglobin, increased LDH Decreased RBC, hemoglobin, hct Increased bilirubin Increased reticuloucyte count |
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Extravascular hemolysis
Intrinsic causes |
Membrane defects
Defective hemoglobin Enzyme deficiencies |
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Extravascular hemolysis
extrinsic causes |
Liver disease
Hypersplenism Inflections (malaria) Oxidant agents (nitrites, dapsone) Autoimmune hemolytic anemia Intravenous immune globulin infusion |
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Extravascular hemolysis
Clinical Signs Labs |
Signs-
Pallor, tachycardia, fatigue, jaundice Labs- decreased RBC, hemoglobin, HCT increased bilirubin increased reticulocyte count |
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Differentiating between extravascular and intrasvascular hemolysis
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Haptoglobin will be decreased in intravascular
Hemoglobinuria or hemoglobinemia in intravascular only |
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Autoimmune hemolytic anemias
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Antibodies to RBC antigens
can be auto or cross reactive Distinguished from others by Coombs test |
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Coombs test
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Direct -- anti Ig antibodies are added to a tube of whole blood -- agglutination reveals that there were antibodies stuck to the RBC
Indirect -- Donor RBCs are added to patient serum, then anit Ig Abs are added, agglutination means that there were anti-RBCs-Abs in serum |
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Warm type autoimmune hemolytic anemias
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Idiopathic
SLE, RA, sjorgen's CLL, lymphomas Drug induced (methyldopa) |
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Warm type alloimmune hemolytic anemias
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Drug induced
Transfusion reactions |
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Cold type autoimmune hemolytic anemias
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Idiopathic
Infections (mycoplasma pneumonia, mononuclesosis) Lymphomas Paroxysmal noctural hematuria |
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Spherocyte formation
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Antibodies coat RBC
Splenic macrophages Fc receptors bind antibody Fragment red cell Producing spherocyte |
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Treating autoimmune hemolytic anemias
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Underlying condition
Splenectomy Steroids Immunosuppresion Anti-CD20 (rituximab) Folic acid |
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Hereditary spherocytosis
Cause Labs Treatment |
Genetic disorder, usually autosomal dominant
Spectrin deficiencies result in less membrane stability Splenic macrophages chomp of bits of cells Anemia with high MCHC, extravascular hemolytic anemia Splenectomy |
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Increased MCHC
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High mean corpuscular hemoglobin volume
Hereditary spherocytosis or acquired hemolytic anemias |
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PNH
Cause and pathophys |
Paroxysmal Nocturnal Hemoglobinuria
Acquired mutation in a hematopoetic stem cell making blood cells glycophosphatidylinositol deficient and complement vulnerable Acidity increases liklihood complement mediated intravascular hemolysis - this happens at night |
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PNH
Symptoms |
Wake up with blood tinged urine
Anemia Thrombosis Smooth muscle dystonia Decreased quality of life Can have problems with other lines |
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PNH treatment
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Transfusion
Fe and folate supplements Eculizmab (anti-complement antibody) Stem cell transplant |
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GP6D deficiency
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Deficiency of glucose-6-phosphate dehydrogenase
X-linked (affected males or female mosaics w/ mutation in RBCs) Extravascular hemolysis either after stress or all the time Hemoglobin oxidize to methHbg--sulfHbg--Heinz bodies |
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GP6D oxidative stress triggers
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Infections
Ketoacidosis Fava beans Drugs sulfonamides quinine and quinidine primaquine, cholorquine acetylsalicilic acid vitamin K chloremphenicol |
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Bite cells with Heinz bodies
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Heinz bodies cannot make it through the splenic sinus space and that part of the cell gets chopped off
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Most common enzyme deficiency in the world?
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G6PD
400 million |
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Pyruvate kinase deficiency
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Autosomal recessive
2nd most common enzyme deficiency Rigid cells are sequestered by spleen and hemolyzed |
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Drug induced hemolytic anemias
3 kinds |
Hapten
Innocent bystander - drug combines with plasma protein and sticks to RBCs becoming an antigen (quinidine) Anitgenic - drug induces Ab production that cross reacts with a platlet |
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difference between thalassemias and hemoglobinopathies
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Opathies -- qualitative disorders, hemoglobin does not function appropriately
Thalaseemias -- quantitative disorders, not enough hemoglobin |
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Sickle cell anemia mutation
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Valine for glutmine in Beta globin chain
S hemoglobin is more likely to aggregate, creating structural problems in RBCs |
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Sickle cell anemia RBC destruction
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Sickle cells lives only 10-20 days
Some destroyed intravascularly, most in spleen |
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Sickle cell clinical manifestation
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Anemia
Aplastic episodes (parvovirus) Delayed growth Pigment gallstones Vasooculusion -Avascular hip necrosis, priapism, pain, acute chest, stroke Leg uclers etc |
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Precipitating factors of sickle cell crisis
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Infection
Dehydration Oxygen deprivation (altitude, operations, OB delivery) Cold Heavy exercise |
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Prevalence of sickle cell anemia
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2 million Americas
1 in 5000 African Americans Homozygous - 0.3-1.3% African Americans Heterozygous - 8% of African Americans |
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Sickle cell disease penetrance
|
Heterozygotes - typically wildtype, sometimes small renal infarcts can lead to hematuria
Homozygotes - variable, from infant crises to almost normal |
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Sickle cell diagnosis
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Hemoglobin electrophoresis
Trait -- some S and some A Disease -- just S and no A |
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Sickle treatment
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Prophylaxis with hydration, oxygenation, warmth, vaccines
Crisis -- oxygen, hydration, analgesiacs Hydroxyurea- increase hemoglobin Stem cell transplant |
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Macrocytic anemias
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Increased MCV
Increasd reticulocyte production DNA synthesis abnormalities Others |
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Megaloblastic anemias
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Anemias where problem is DNA synthesis, end up with mature cytoplasm, immature nuceli
Macrocytic anemia B12 deficiency, folate deficiency, drug induced, some hereditary |
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Drugs causing megaloblastic, macrocytic anemias
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EPO
Hydroxurea, methotrexate, 5FU, capecitabine Azt Phenytoin, valproic acid omezoprole, rantindin trimethoprim-sulfamethoxazole |
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B12
|
Colbalomine
Cannot be produced by body Animal products (meat, milk, eggs) only dietary source Needs intrinsic factor to be absorbed |
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B12 deficiency
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Decreased oral intake (vegans, alcohol)
Decreased absorption deficiency in intrinsic factor pancreatic insufficiency gastrectomy, ileal resection gastritis crohn's disease neomycin, metformin, proton pump inhibitors |
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B12 deficiency anemias
|
Macrocytic anemias
Ovalocytes Hypersegmented PMNs Demyelination of spinal cord loss of some sensations (deep touch, vibration, ataxia, reflex abnormalities) |
|
Schilling's Test
|
Determining where B12 deficiency is coming from
Have to first give an IM shot to avoid deprived tissues from sucking up all the B12 Then give radioactive B12 by mouth, with oral intrinsic factor, give antibiotics and try again (absorptive issue) Looking for B12 in urine |
|
Folate sources
|
leafy greens, beans, fortified grains
Needed for thiamine synthesis and DNA replication/repair |
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Folate deficiency symptoms
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Macrocytic, megaloblastic anemia
Ovalocytes Hypersegmented PMNs Same as B12 deficiency histologically but lacks the spinal cord part |
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Why not just give folate?
|
Treatment of b12 deficiency with folate will treat anemia but not spinal cord degeneration
|
|
Folate deficiency causes
|
Decreased oral intake (alcoholics, poor diet, overcooked foods)
Decreased absorption (celiacs, bowel disease) Drugs (methotrexate, trimethoprim, phenytoin) Increase utilization (pregnancy, lactation, chronic hemolysis, exfoliative dermatitis) |
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Reticulocytes in macrocytic anemias
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Reticulocytosis alone can cause increased MCV
|
|
Labs to differentiate between folate and B12 deficiency
|
MMA- increased with B12 deficiency and normal with folate
Homocysteine - increased with both Can also test for serum folate level |
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Myelodysplastic disorders
|
Malignant change in hemotopoetic stem cell
Myeloid precursors in bone marrow are dysplasic Inadequate blood cell production Can become an actue leukemia (30-40%) Chromosomal changes important |
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MDS counts
|
Hypocelluarlarity in periphery
can be anemia, bicytopenia, pancytopenia Hypercellularlity in bone marrow |
|
Etiology of MDS
|
Idiopathic
Radiation Chemotherapy Benzene |
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MDS treatment
|
Supportive-transfusions, growth factors, iron chelation (prevent transfusion toxicity)
5-Azacytadine Lenalidomide Chemo Stem Cell transplant |
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Alcoholics and MCV
|
90% of alcoholic have increased MCV
Can be b12, folate deficient Liver disease results in lipids deposited into cell membrane Acetaldehyde may have direct effect on RBCs |
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Alcoholic blood smear
|
Macrocytic
Ovalocyte, hypersegmented PMNs Acanthocytes Target cells |
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Acanthocytes
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Star like cells, out pouchings in membrane from fat deposition from failing liver
|
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Howell-Jolly bodies
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Rements of DNA in circulating RBCs
Splenectomy, sickle cell |
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Pleger-Huet cells
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Hyposegement PMNs
Seen in MDS |
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Neutropenia define
|
Too few white blood cells
|
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Neutrophilia define
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Too many white blood cells
|
|
PMN precursors in the proliferation compartment of the bone marrow
|
Blast
Promyelocyte Myelocyte This are dividing and differentiating |
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PMN precursors in the differentiation compartment of the bone marrow
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Metamyelocyte
Band Neutrophil |
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Distribution of neutrophils in peripheral blood
|
50% circulating and 50% marginated
|
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Growth factor most important in PMN development
|
G-CSF
Myeloid precursor proliferation Induction of myeloid maturation Protection from apoptosis Enhancement of PMN function |
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Lifespan of a PMN
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8-12 days in bone marrow maturong
3-6 hours circulating 2-3 days in tissue |
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WBC Distribution
|
20% Myeloid precursors
75% storage pools 3% marginating pool 2% circulating pool |
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Pathogenesis of increased white blood cell counts
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Acute - demargination
Chronic -- changes in production and release from storage pools |
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Pathogenesis of decreased white blood cell counts
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Defect in production
Increased margination Increase sequestration |
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Normal differential
|
Neutrophils -- 35-65%
Bands -- 1-5% Monos - 4-8% Eosin/basos - 1-2% Lymphocytes 20-50% |
|
Normal lymphocyte % distribution
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T cells - 85%
2/3 CD4 1/3 CD8 B cells - 15% |
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ANC
|
Absolute Neutrophil Count
WBC X (% segs (PMNs) + % bands) |
|
Normal ANC
|
1500-6300
|
|
Risk of infection with low neutrophils
|
Rises with decreasing number of neutrophils
With ANC less than 1000, manage fever as outpatient ANC<500, admit and manage with IV antibiotics ANC <200 -- fungals and opportunistic a problem |
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Neutropenic infections sources/types
|
Most common is autoinfection
Gram negatives -- can rapidly progress to sepsis Fungal/mucor -- related to the duration, not depth of neutropenia |
|
Symptoms of infection in neutropenia patient?
|
Take low grade fever seriously
There may be no symptoms |
|
Causes of acquired, extrinsic neutropenia
|
Chemotherapy
Infection Drugs, toxins Immune mediated Hypersplenism Idiopathic |
|
Infections causes neutropenia
|
Anything overwhelming
typhoid, influenza, varicella, CMV, HIV, EBV, dengue, yellow fever, rubella Mechanism -- consumption, bone marrow suppression, egress, circulating antibodies |
|
Drugs that can induce neutropenia
|
Antimicrobials - penicillin, cephs, vanco, bactrim
Antihistamines - H2 blockers, cimetidine, rantidine Anticonvulsants Antipsychotics Procanimide Mechanism -- bone marrow suppression, maturation arrest, anti-neutrophil antibody production |
|
Neutropenia caused by bone marrow infiltration by
|
Tumor
Sarcoidosis Tuberculosis |
|
Nutritional deficiency causing neutropenia
|
B12. folate deficiency results in ineffective myelopoesis
|
|
Hypersplenism
Causes, mechanism of causing neutropenia |
Sequestration, immune, and infiltrative effects
Cirrohsis with portal HTN Felty syndrome Gaucher's disease Chronic hemolysis (hereditary spherocytosis, malaria) |
|
Felty syndrome
|
Hypersplenism
Leukopenia Rheumatoid arthritis |
|
Neutropenia acquired, intrinsic causes
|
Leukemia
MDS Myeloproliferative disorders Aplastic anemia -- also extrinsic -- immune mediated |
|
Idiopathic or
Chronic benign neutropenia |
Low ANC <1500, up 35% of those with incidentally discovered neutropenia
More common in African Americans (5%) Much more common in Africans (50%) |
|
Cyclic neutropenia
|
Autosomal dominant (ELA2)
15-30 day cycles of neutropenia |
|
Neutrophilia
|
> than 10^7 PMN/ml
Causes: stress, infection, inflammation |
|
Most common etiologies for neutrophilia in the community
|
Smoking
Obesity |
|
Shift neutrophilia
|
Moderate leukocytosis (15 - 20 x 10^9)
Demargination of neutrophils Mature forms only Prednisone, epinephrine, excercise, seizures |
|
Leukomoid reaction
|
Severe leukocytosis >50 x 10^9 cell/L
Demargination and increased production Mature and young forms in periphery Infection, inflammation, metastatic cancer, GCSF |
|
Leukoerythrobastic reaction
|
Early forms of white and red blood cells in periphery, nucleated RBCs, tear drops
Seen with myelophthysic (marrow infiltration) and myelofibrosis |
|
Leukemia on differential
|
Large increase in young forms -- acute
Increase in all forms with shift toward young - chronic |
|
Sever congenital neutropenia
|
AD (ELA2 and others)
Multiple subtypes with static neutropenia |
|
Kostmann congenital neutropenia
|
AR
Infantile agranulocytosis Presents with multiple severe infections |
|
Chediak-Higashi
|
AR (LYST gene)
Neutropenia, giant lysosomes, oculocutaneous albinism, lymphoma like syndrome Failure in phagolysosome formation (lyso enzymes do not get to phagosome) Treated with chemo, steroids, transplant |
|
Hyper IgE syndrome
|
Inherited
Problem with neutrophil chemotaxis Presents with dermatitis, pulmonary/sinus infections, staph, candida High IgE and IgD May use prophylaxis with antibiotics |
|
Leucocyte adhesion deficiency
|
Inherited
Problem w/ PMN rolling and adhesion Presents with neutrophilia, recurrent pus-less infections staph and fungal infections 75% mortality by age 5 with no treatment |
|
Chronic granulomatous disease
|
Inherited
Problem with neutrophil microbial activity -- lacks H202, superoxide burst Presents with recurrent pyogenic infections (staph, seratia, fungi) Managed with longerterm antibiotic prophylaxis |
|
Myeloperoxidase deficiency
|
Inherited
Usually not clinical problems unless diabetic --- then candidal infections |
|
Major cause of acquired neutrophil dysfunction?
|
Myelodysplastic disorders
|
|
Eosinophilia
causes Most common? Types? |
>1500 cells/ul for 6 weeks, severe is >5000
Most common - atopic in developed nations, parasites in developing Primary - clonal disease of myeloid lineage Secondary- infections, allergies, toxins, reactive to lymphomas |
|
Toxocaria canis
|
Human infection by roundworms of dogs
Dogs as pets suggestive of this potential cause of eosinophilia |
|
Hypereosinophilia syndrome
|
Dysregulation of normal eosinophil production signaling
Eosins must invade organs and cause end organ damage Sometimes reversible with treatment Steroids are used Must rule out cancers, other causes |
|
Cell line to return first after chemotherapy
|
Monocytes
Precursors to macrophages, DCs |
|
Monocytes elevated in
|
Infection
Autoimmune, connective tissue disorders Granulomatous disease (sarcoid, ulcerative colitis, etc) |
|
Highest monocyte counts seen in?
|
Hematologic malignancies
Chronic myelomonocytic leukemia Acute monocytic leukemia |
|
Lymphopenia
Define, suseptibilities, etiologies |
ALC < 1000 cell/ul (going to be mostly T helper cell loss, as that is most of the cells)
Suseptible to viral, fungal, mycobacterial, atypical infections Congenital, meds, infectious, hematologic malignancies (esp Hodgkin's), starvation |
|
Infectious causes of lymphopenia
|
HIV
TB Malaria |
|
Medication causes of lymphopenia
|
corticosteroids
immune-suppressive chemo xrt |
|
Lymphocytosis
define, causes |
>4000 cells/ul
Acute infection--pertussis, EBV, hepatitis Chronic infection - brucellosis, TB, syphillis Hypersensitivity rxn to drug Cancer - lymphomas, leukemias |
|
Deciding whether a lymphocytosis is malignant or not?
|
Based on clonality
B cells -- use flow to check kappa:lamba ratio (should be 70:30) T cells -- PCR/southern blot looking at t cell receptor Vastly altered kappa:lambda ratio - light chain restriction |
|
Signs concerning for chronic neutropenia
|
Recurrent bacterial infections (esp systemic)
Infections at unusual sites (osteomyelitis) Unusual pathogens Chronic gingivitis, aphthous ulcers |
|
Wiskott-Aldrich
|
Congenital lymphocytopenia
|
|
Reed-sternberg cell
|
Giant cells
Multinucleate or biolobed nuceli Bone marrow aspirates of Hogdkin's disease |
|
Five stages of hemostasis
|
1. Vasoconstriction
2. Formation of platelet plug 3. Thrombus formation via coagulation cascade 4. Termination of thrombus formation by control mechanisms 5. Removal of clot by fibrinolysis |
|
Role of endothelium in steady state
|
Intact endothelium is antithrombotic
Prostacylin and NO secreting keeps plts from aggregating |
|
Platelets
General description |
Anucleate
150k-400k is normal Life 7-10 days Alpha, dense, glycogen granules |
|
Platelets role in coagulation
|
Primary plug
Provide reactive phospholipid surface for coagulation cascade |
|
Alpha granules of platelets
|
Pro/anti-coagulation factors
vWF, fibrinogen, Factor V, Protein S, platelet factor 4, ADP, Ca2+ |
|
vWF
|
Bridging protein in platelet adhesion to subendo
Factor VIII chaperon to site of injury Made by endothelial cells and megakaryocytes monomers that are modified to multimers Stored in --Weibel-Palade in endo, alpha granules in plt Cleaved in plasma to smaller multimers by ADAMTS13 |
|
Fibrinogen in thrombus formation
|
Bridging protein platelet aggregation
|
|
Result of vascular endothelial damage
|
Vasoconstriction, reducing blood flow and allows procoagulant factors to bind
Platelets aggregate Coagulation cascade initation |
|
Platelets are activated by?
and activation results in? |
Exposure to subendothelial collagen and matrix proteins
Thrombin, collagen -- potent activators Activation results in degranulation, shape change, TxA2 secretion (vasoconstriction) |
|
Adhesion
define and mechanism |
Platelets bridging to surface
GPIb-IX (also IIb/IIIa) binds to vWF whcih connect to subendothelial collagen |
|
Platelet aggregation
Define, mechanism |
Platelet to platelet bridging
GPIIb/IIIa changes conformation with activation Resulting in high affinity for fibrinogen |
|
Bernard-Soulier syndrome
|
Lack of GP1b-IX-V receptor
Bleeding disorder |
|
Glanzmann thrombasenia
|
Deficiency in GPIIb/IIIa receptor
Bleeding disorder |
|
Platelet plug
|
Primary hemostasis
Collagen-vWF-activated plts-fibrinogen-other activated plts TxA2 production and vasoconstriciton Not enough--coagulation cascade occurs on plt surface to convert fibrinogen to fibrin |
|
Outcome of the coagulation cascade
|
Thrombin
Which convert fibrinogen to fibrin Fibrin polymerizes around platlets and stabilizes Creating the secondary hemostatic plug |
|
Dense granules of platelets
|
ADP
ATP Ca Serotonin |
|
Agonists of platelet aggregation
|
ADP
Epi Collagen Thrombin Serotonin Thromboxane A2 |
|
Platelet factor 3 activity
|
Exposure of phosphatidyl serine and phosphatidyl ethanolamine to platelet surface
Allows coagulation factors to bind |
|
Scott syndrome
|
Defect in platelet factor three
Bleeding disorder |
|
Coagulation cascade generally
|
Amplification cascade
Zymogen conversion to active serine proteases Protease actives subsequent zympogen |
|
Factors synthesized in liver
|
ALL
VIII is also made in endothelial cells vWF is made only megakaryocytes and endothelial cells |
|
First step in coagulation cascade
|
Vascular endothelial cell injury induces tissue factor production by monocyte or vascular endothelium
Circulating factor XII complexes with TF and is activated |
|
Action of TF/XII complex
|
Activates X to Xa
Activates IX to IXa Which activates X to Xa In the presence of VIII |
|
Factor VIII
|
Vastly accelerates the conversion of X to Xa
Carried in circulation by vWF Necessary cofactor, along with calcium, for IX to bind to platelet membrant |
|
Factor X
|
Converts II to IIa
(prothrombin to thrombin) In the presence of V |
|
Factor V
|
Secreted by platelets when the are activated, therefore it is at the site of injury
Helps hold IIa and X close together on platelet phospholipid membrane ---prothrombinase complex Vastly increases conversion to thrombin |
|
Thrombin role in thrombosis
|
Converts fibrin to fibrinogen
Converts XI to XIa, which converts IX to IX---thrombin burst--amplifies signal Also activates V and VIII Regulates (prevents breakdown and then activates anticoagulation) |
|
XIIIa
|
Helps crosslink fibrin into strong sheets
|
|
Cessation Coagulations
4 things |
1. Hemodilution of of activated factors by systemic circulation
2. Hepatic clearance -- activated factors are metabolized 3. Endogenous anticoagulants 4. Fibrinolysis |
|
Endogenous anticoagulants
|
Antithrombin
Protein C/protein S Tissue factor pathway inhibitor Protein Z |
|
Antithrombin
|
Made by liver, endothelial cells
Binds and inactivates Xa and IIa Activity vastly increased by heparin |
|
Activated protein C
|
With cofactor protein S
Inactivates Va and VIIIa Activated by thrombin after thrombomodulin has changed its conformation After thrombomodulin binding (on endothelial surface) thrombin cannot activate coagulation factors |
|
Tissue Factor Pathway Inhibitor
|
Made by endothelial cells
Binds to and inactivates Xa Xa/TFPI inactivate TF/VIIa complex |
|
Fibrinolysis process
|
Plasminogen made by liver and circulates
Plasminogen binds to fibrin Plasminogen activated to plasmin by TPA/UPA Plasmin cleaves fibrin into degradation products like D-dimers |
|
Alpha-2-antiplasmin
|
Major inhibitor of plasmin
Deficiencies result in bleeding disorders |
|
Plasminogen activator inhibitor-1
|
Major inhibitor of tPA
Stored in platelets Deficiencies result in bleeding disorders |
|
Testing for coagulation?
What tube? |
Plasma
Blue top tube Citrate is the anticoagulant -- binds Ca making it unable to be a cofactor for coagulation cascade |
|
Testing for cellular blood elements?
What tube |
Purple top EDTA (anticoagulant)
|
|
Platelet count where spontaneous bleeding is a problem
|
Usually not until under 10K
|
|
Psuedothrombocyptopenia
|
EDTA sometimes results in platelet clumping
Automated counter returns low platelet count that is artifactual Look at the smear! or run again with a blue top tube |
|
Platelets on smear
|
10 plts on a 100x field = 150K
20 = 300K |
|
Bleeding time
|
Measures the platelet/blood vessel wall interaction
How long does it take a person to stop bleeding? Hopefully less than 9 minutes. Not great at predicting surgical bleeding, operator dependent |
|
PFA-100
|
In vitro test of plt fnc (adhesion and aggregation)
How long does it take for stimulated platelets to occlude an aperture Collagen/ADP-- tests for vWF Collagen/epi -- tests for aspirin, other dysfunction |
|
Thrombocytopenia and platelet function studies?
|
Will increase time without their necessarily being a functional deficit
|
|
PT
|
Time to clot when (TF + phospholipid + Ca) are added to citrated plasma
"Extrinsic pathway" Prolonged by deficiencies in VII, X, V, II, I DHMC--12.2-14.8 sec |
|
INR
|
Standardization of PTs based on analysis of the thromboplastin reagent based on a WHO standard
Normal INR - 1 Normal for anticoagulates 2-3 |
|
PTT
|
partial thromboplastin time
Citrated plasma + Ca + phospholipid + contact activator glass, cellite, kaolin, ellagic acid "Intrinsic pathway" test Prolonged by Deficiencies in-- HMWK, pre-kalikrein, XII, VIII, IX, XI X, V, II |
|
Prolong aPTT with no risk of bleeding
|
Deficiencies in HMWK, pre-kalikrein, XII
|
|
Prolonged PT and normal PTT
|
Factor VII deficiency, polymorphism, inhitor
Early liver disease or Vit K deficiency Early warfarin |
|
Prolonged PTT and normal PT
|
Hemophilia -- A (def in VIII), B (IX), C (XI)
vWF disease Inhibitor of intrinsic pathway Heparin HMWK, pre-kal, XII deficiencies |
|
Prolonged PT and PTT
|
Common pathway/multiple factors effected
Severe liver disease Therapeutic warfarin Consumptive coagulopathy Hemodilution Sever Vit K deficiency Low fibrinogen or dysfunctional fibrinogen Direct thrombin inhibitors |
|
Mixing study
|
50:50 ratio of patient and pooled normal plasma
correction of prolonged clotting studies indicates factor deficiency --if prolongs again after time-- likely VIII inhibitor persistence indicates inhibitor |
|
Coagulation factor assays
|
How much factor is there compared to normal pooled plasma?
normal considered 50-150% except XII: 30-150% |
|
Thrombin clotting time
|
Exogenous thrombin added to plasma
Time to clot Detect fibrinogen abnormalities hypo, dys, heparin, thrombin inhibitors |
|
D-dimer
|
Fibrin breakdown product
Elevated in acute thrombosis Also DIC, cancer, infection, surgery, inflammation |
|
Quantitative platelet disorders
|
Decreased production
Increased consumption Sequestration in spleen |
|
Autoimmune thrombocytopenia
like ITP |
Autoantibodies against platelets
Self-limited in kids with viral infections Chronic and requiring immune suppression in adults |
|
Medication induced thrombocytopenia
|
Immune mediated
Quinine -- low plts and bleeding Heparin -- HIT, low plts and clotting |
|
Thrombocytopenia thrombotic purpura (TTP)
|
microangiopathic hemolytic anemia thrombocytopenia
fever neurologic changes renal failure Clotting Failure of ADAMT13 to cleave vWF resulting in too many large vWFs (autoimmune or medication induced) Treat with plasma exchange, immunosuppression) |
|
HELLP in pregnancy
|
Similar to TTP
hemolysis, elevated liver enzymes, low platelets |
|
Thrombocytopenia 2/2 sequestration
|
Splenomegaly
Enlarged spleen can have 90% of plts (normal sized has 30%) Happens in myeloproliferative disorders, portal hypertension, portal/hepatic thrombosis |
|
Thrombocytopenia 2/2 decreased production
|
Leukemia, MDS, aplastic anemia
Bone marrow infiltration Virus (HIV, heps are toxic to megakary) Toxins (alcohol, xrt, chemo, meds) Nutritional deficiencies (B12, folate) Hereditary (rare) |
|
Gaucher's disease
|
Lysosomal storage disorder
glucocerebrosidase builds up Bone marrow fills with fat not hematopoetic cells |
|
Acquired plt function disorders
|
Usually medication
aspirin, NSAIDs, anticoagulants SSRIs, herbal supplements Uremia (circulating toxin) MDS, myeloproliferative disorders Cardiopulmonary bypass |
|
Gray plt disorder
|
Absent alpha granules
|
|
Quebec platelet syndrome
|
Elevated uPA in plt granules
Granule contents degraded |
|
Delta granule disorders
|
Less ADP released
Hermansky-Pudlack Chediak-Higashi |
|
Scott syndrome
|
Defect in assembling coagulation factors on plt surface
|
|
vWF epidemiology
|
Most common inherited bleeding disorder
1% of population had deficiency Autosomal dominant Levels vary between normal individuals Type O blood has less |
|
vWF deficiency Type 1
|
Low levels of activity
70-80% of affected |
|
vWF deficiency Type 2
|
Normal levels
Reduced activity -- abnormal molecule or reduced number of high molecular weight multimers 20-30% of affected |
|
vWF deficiency type 3
|
Absent vWF factor and factor VIII activity
Rare |
|
Acquired vW disease
|
Due to autoantibody
Rare |
|
Bleeding phenotype of vWD
|
Ranges in severity
Mucocutaneous predominates (mennorhagia, epistaxis, easy brusing, GI bleeding, oralpharyngeal) Hemarthroses rare Excessive bleeding with trauma, surgery Long bleeding with minor cuts Worse with aspirin |
|
Lab testing in vWF
|
PT, TCT are normal
PTT may be normal or prolonged (2/2 factor VII effect) Prolonged bleeding time, PFA-100 Abnormal aggregation on ristocetin test (1,2,3 are slow to aggregate, 2b is fast) |
|
vWD type 2b
|
Gain of function
Hyperaggregation at low ristocetin doses Plts normal but thrombocytopenia common (pseudo vWD is a gain of funciton in GPIb) |
|
vWD treatment
|
DDAVP (desmopressin, synthetic vasopressin)
Stimulates release of vWF Good in 1 and mild 2, BAD in 2b Factor replacement Anti-fibrinolytics to stabilize clots Contraceptive for mennorhagia Avoid aspirin |
|
Hemophilas
Deficiency and inheritance |
Hemo A - VIII deficient -- X-linked
Hemo B - IX deficient -- X-linked --christmas disease Hemo C - XI deficient-- AR Parahemophilia - V deficient - AR |
|
Symptom of female carriers with hemophila a or b
|
menorrhagia
|
|
Hemophila A/B subtypes
|
80% A and 20 % B
Mild: 5-40% factor, bleed with trauma/surg, may have normal aPTT Mod: 2-5% factor, may bleed spontaneous, prolonged aPTT Severe: 0-1%, spontaneous bleeding common, prolonged aPTT |
|
Hemophila bleeding phentype
|
May be delayed because primary hemostasis is fncal
Hemarthroses common -- target joint Muscle hematomas CNS bleeds Bleeding after trauma, dental work, etc Hematuria |
|
Effect on hemophila on coagulation cascade
|
Markedly reduced thromin burst
|
|
Labs in hemophila
|
aPTT prolongs with factor less than 30%
Corrects with mixing Specific factor levels low PT normal, PFA normal |
|
Treatment of hemophila
|
Treat with recombinant factor replacement
(mild VIII may respond to DDAVP) Either for acute bleeding or Prophylaxis 3x/week to keep trough level >1% -- only considered in severe |
|
Complications of hemophila
|
Joint destruction (arthropathy)
HIV/Hep C -80% of severe hemophiliacs in 80s, 50% of all -no HIV since 1986 Inhibitors to missing factors these antibodies can complicate treatment -might have to bypass using VIIa |
|
Acquired hemophilia
|
Autoantibody to factor VIII
Bleeding disorder in previously healthy 1/million/yr Mostly idiopathic and in the elderly, sometimes w/ cancer, post partum |
|
FEIBA
|
factor
eight inhibitor bypass agent treats acquired hemophilia |
|
Fibrinolytic bleeding disorders
|
Typically delay (12-24 hrs later)
Mucocutaneous, GU Rare hereditary -- quebec plt disorder, alpha-2-antiplasmin, pai-1 deficiency, More commonly acquired -- cancer, liver disease, DIC, prostate surgery |
|
Labs in fibrinolytic bleeding disorders
|
Prolonged PT and PTT
Increased D-dimers (may look like DIC) |
|
Treating fibrinolytic bleeding disorders
|
Supportive plasma infusions
Anto-fibrinolytic drugs (epsion aminocaproic acid, tranexamic acid) |
|
Most common cause of bleeding due to vit K deficiency
|
Over anti-coagulation
|
|
Causes of vit K deficiency
|
Dietary -- poor intake, malabsorption, alcoholism
Meds - antibiotics, salicyates, herbs, vitamins a and e, comarins |
|
Labs in Vit K deficiency
|
Prolonged PT and PTT, correct with mixing
Normal plt studies Low II, VII, IX, X with preserved V |
|
Treatment of Vit K deficiency
|
Oral Vit K
- IV only in emergency b/c rare anaphylaxis - substantial restorate at 24 hours add FFP in emergencies, will temporarily correct |
|
Liver disease
|
Problems with synthesis of coagulants and anticoagulants
Bleeding is the result usually, although clotting can also happen |
|
Liver disease and coagulation labs
|
INR is part of the liver disease end stage assessment
Low factors levels including V but not VIII PT/INR may not accurately predict bleeding |
|
Treatment of coagulopathy of liver disease
|
Transplant
Supportive hemostatic treatments don't really work but...Vit K, FFP |
|
DIC
|
Disseminated intravascular coagulation
Insult results in excessive thrombin generation Activating both coagulation and anticoagulation Results in clotting and bleeding Insults-- infections, cancer, trauma, brain injury, snake bite, burns, etc |
|
DIC presentation
|
Bleeding at surgical, IV sites
Purpura fulminans -skin necrosis, usually with infection --> amputation Thromboses -- micro w/ end organ damage common, large venous/arterial less Sometimes asymptomatic-- usually with cancer pts |
|
Lab evidence of DIC
|
Prolonged PT and PTT
Elevated D-dimers Decreased fibrinogen Decreased plts Anemia RBC schistocytes Endogenous anticoagulants low (antithrombin, C, S) |
|
Treating DIC
|
Treat underlying cause
Support with plasma (factors), cryoprecipitate (fibrinogen), and plts RBCs Heparin will stop, but with high risk of bleeding |
|
MDS
general idea |
Mutated bone marrow cells that divide but do not mature normally
Dysfunctional cells with premature apoptosis Hypercellular bone marrow the peripheral cytopenias |
|
Cells proliferate quickly but are arrested at immature level of differentation
|
Acute leukemia
High grade lymphoma |
|
Cells proliferate and mature normally but accumulate because of additional divisions or problems with cell death regulation
|
Chronic leukemia
Myeloproliferative disorders |
|
Increased number of myeloblasts in bone marrow
|
Normally less than 5%
5-19% -- myelodysplasia >20% -- acute leukemia |
|
Presentation of MDS
|
Asymptomatic -- on CBC
Cytopenia symptoms -- infections, fatigue, bleeding 15% have autoimmune disorders incidence increases with age primary is idiopathic, secondary due to mutagenic insult |
|
Lab findings in MDS
|
Microcytic anemia-- most common
Multiple cytopenias common Smear -- macrocytes, acanthocytes, elliptocytes, nucleated RBCs, pseudo-pelger-huet, hypogranulated neutrophils |
|
MDS with 5q minus
|
Thrombocytosis in common
|
|
Bone marrow biopsy in MDS
|
Hypercellular with at least one dysplastic lineage
Megakaryocytes dysplasia -- clustered cells, micromegakaryocytes, abnormal disorder Erythroid -- delayed nuclear to cytoplasmic maturation, erythroid hyperplasia with megaloblastiod hyperplasia -ringed sideroblasts can be seen |
|
Peripheral findings of MDS
|
Cytopenias
PMNs -- hypogranular, segemental abnormalities Erythrocytes -- macrocytes, ovalocytes, anisopolkicytosis, basophilic stipling, nucleated froms Plts - large, hypogranular Monocytes - monocytosis |
|
MDS subtypes with less than 5% blasts
|
Refractory anemia +/- ringed sideroblasts
Refractory anemia with multiple lineage dysplasia +/- ringed sideroblasts 5q- syndrome |
|
5q minus in MDS prognostics
|
Good prognosis, lower risk of progression to AML
|
|
Poor cytogenic prognostics in MDS
|
Multiple cytogenetic abnormalities
Changes in 5 or 7 that are not 5q- secondary mds almost always has these bad markers |
|
Prognostic scale in MDS
|
Number of basts
Number of cytopenias Karyote Worst - 5 months median survival, best -- 5 years median survival |
|
Treatment of MDS
|
Treat when symptomatic
Supportive w/ transfusions, growth factors, immunomodulatory agents, demethylating chemotherapy, induction chemotherapy Bone marrow transplant is only cure |
|
Difference between acute and chronic leukemias in presentation
|
Sick at presentation with acute
Immature cells seen in bone marrow and peripheral blood in acute, mature in With chronic, bone marrow function until late stages |
|
Symptomatic presentation of AML
|
Infection
Fatigue, dyspnea Bruising, bleeding DIC, bone pain, myeloid sarcoma/chloroma, organomegaly, CNS/gingival, cutaneous infilitration |
|
Diagnosing AML
|
Bone marrow biopsy w/ >20% blasts
-hypercellular, monotonous population Determine lineage with cytochemical/flow Determine cytogenetics |
|
Cytochemical stains to determine linease
|
Myeloperoxidase + sudan black --granulocyte
Butyrate esterase--monocytic PAS - lymphocytic |
|
Surface marker for hematologic stem cells
|
CD34
|
|
Surface marker for myeloid lineage?
Surface profile of myeloid leukemia |
CD33
CD33+, CD34+ |
|
Surface markers for t cell lineage
|
CD3, CD4
|
|
Surface markers for a b cell lineage
|
C19, CD20, CD22
|
|
Favorable karyotypes in AML
|
t (8;12)
t (15;17) -- m3 inversion (16) - M4Eo |
|
Bad karyotypes in AML
|
Any 5 or 7 changes (including 5q)
Trisomy 8 Monsomy 7 |
|
Good prognosis mutations in AML
|
NPM1
|
|
Poor prognosis mutations in AML
|
FLT3
KIT P53 |
|
Classification of AMLs
|
AML w/ recurrent genetic abnormalities
AML w/ multilineage dysplasia AML/MDS that is therapy related AML, NOS divided into M0-7 based on histology |
|
Prognostics in AML
|
Age
ECOG h/o previous hematologic malignancy Cytogenetics |
|
t (8;12) AML1/ETO
|
AML w/ recurrent genetic change
10% of AML Younger adults, some kids Generally favorable prognosis RUNX1-CBFA2T1 fusion protein represses transcription of genes related to differentiation -- differentiation block - AML Associated with extramedullary disease (skin, cns, myeloid sarcs) |
|
inv(16)(p13;q22) AML
|
AML with recurrent genetic changes
Eosinophils affected Generally good prognosis CBFbeta/MYH11 fusion protein blocks transcription of differentiation related genes -- differentation block -- AML |
|
Acute Promyelocytic Leukemia (M3)
|
AML with recurrent cytogenetic changes
Differentiation block is at promyelocyte stage 5-8% of AML Most are t (15;17) -- 95% creating PML/RARalpha fusion others are also RARalpha mutants Large granules with Auer rods Extremely prone to clotting Responsive to all-trans retinoic acid |
|
Microgranular Acute Promeylocytic Leukemia
|
Subtype of acute promyelocytic leukemia
Appear agranular or hypogranular Butterfly or bilobed nuclei High WBC count |
|
AML w/ 11q23 (MLL) abnormalities
|
AML with recurrent genetic changes
Approximately 5% of AMLs, associated with topoisomerase inhibitors Mixed Lineage Leukemia gene involved in multiple translocations (9;11), (11,19) Intermediate prognosis |
|
AML w/ multiple dysplastic lines
|
Bad prognosis
Severe pancytopenia in elderly >50% dysplasia in at least 2 cell lines Can arise from MDS or not |
|
AML, therapy related
|
Generally poor prognosis
1) with ionizing radiation or alkylating agents (cyclophosphamide, chlorambucil) --presents as MDS years later 2) with topoisomerase 2 inhibitors (often associated with 11q23 changes) --presents as overt leukemia, sometimes as soon as 12 months out |
|
AML -- M0
|
Minimally differentiated
No myeloid maturation Blasts vary in size with 1-2 nucleoli myeloperoxidase, sudan back, PAS, NSE--negative No granules No Auer rods |
|
AML -- M1
|
Arrest at myeloblast stage
Blasts vary in size w/ 1-2 nucleoi >3% are MPO, sudan black + Can have granules, Auer rods |
|
AML-- M2
|
AML with Maturation
30-45% of all AML >10% pros, myelos, neutrophils in marrow usually have granules and Auer rods |
|
M4: Acute Myelomonocytic leukemia
|
Mixed monocyte/granulocyte population
15-25% of AML >20% blats >20% neutrophils + precursors >20% monocytes + precursors |
|
M5: Acute Monoblastic leukemia
|
80% of cells in monocytic lineage
monoblast, promonocyte, monocytes Gingival infiltration, extramedullary disease are clinical features |
|
M6: Acute Erythrocytic leukemia
|
Rare
Erythroleukemia >50% erythroid precursors in marrow >20% of myeloblasts are non-erythroid Pure erythroid leukemia 80% of precursors are erythroid |
|
M7: Acute Megakaryocytic leukemia
|
Can get bone marrow fibrosis
Two ages Infants, kids <3 w/ downs -- good prognosis t (1,22) Older adult usually de novo, occasionally MDS |
|
Initial stabilization concens in AML
|
Treat infections
Check cardiac fnc (adriamycin) Manage leukostasis Manage hyperuricemia Tumor lysis syndrome DIC |
|
Treatment of AML
|
Goal -- remission w/ fewer than 5% blasts in marrow
Myeloablative doses of chemotherapy resulting in transfusion dependent cytopenia for 3 weeks 70% remission 5-20% complications stop treat 15-% - resistant disease Followed by 3-4 doses of consolidation and/or autologous transplant Allogenic transplant used in high risk patients |
|
APML and DIC
|
Granules in acute promyelocytic leukemia contain procoagulants
TF activates factor VII Cancer procoagulant activates factor X 10-20% die of hemorrhagic events |
|
APML and ATRA
|
t (15,17) with PML/RARalpha fusion protein APMLs respond to high doses of all trans retinoic acid
these doses push through the mutant retinoic acid receptor to progress differentiation normally ATRA shortens DIC, with chemo puts 80-90% in remission |
|
Retinoic acid syndrome
|
Potentially fatal syndrome occuring in 20% of APML patients treated with ATRA
Fever, edema, pulmonary infiltrates, respiratory distress Usually in first 3 weeks, unclear etiology Stop ATRA temporarily, give steroids |
|
Hyperleukocytosis in ATRA treatment
|
Probably due to white cell maturation
Can cause leukostasis |
|
APML and arsenic
|
Second line therapy
Induces differentiation and apoptosis through interaction with PML/RARalpha fusion product |
|
Characteristics of myeloproliferative disorders
|
Increase numbers in one or more cell lines, clonal marrow expansion
Extramedullary hematopoesis w/ hepatosplenomegally Hypercatabolism (fevers, night sweats, weight loss) Loss of sensitivity to growth factors Predisposition to develop AML |
|
Mutations often seen in myeloproliferative disorders
|
Activating tyrosine kinase mutations
|
|
Chronic myeloid leukemia
Genetics Presentation |
Must be t(9;22)
Present with fevers, chills, weight loss, early satiety, splenomegaly |
|
CML
Bone marrow Smear |
Bone marrow -- hypercellular w/ increased myeloid:erythroid ratio
Peripheral-- immature myeloid cells, but few blasts |
|
CML labs
|
Elevated WBC and plts early, low late
Maybe elevated LDH |
|
CML pathogenesis
|
t(9;22) creates fusion product BCR-ABL
BCR-ABL is an unregulated tyrosine kinase that stimulates proliferation |
|
Natural history of CML prior to TKIs
|
Chronic phase - Counts/spleen easily controlled with hydroxyurea, pts well, can be cured with stem cell transplant (3 years)
Acute -- counts more difficult to control with hydroxyurea, spleen grows, constitutional symptoms reappear (1 yr) Blast -- AML/ALL - like, unresponsive to therapy/transplant, (3-6 months) |
|
Current treatment for CML
|
First line with dasatinib -- BCR-ABL tyrosine kinase inibitor
Monitor-- counts, t(9;22) by fish, Bcr-ABL mRNA by RT-PCR With treatment fail, try other BcrABL TKs...then stem cell transplant |
|
Important prognostic in CML
|
Remission at 1 yr
|
|
Polycythemia Vera
Diagnosis |
Increased hemoglobin, red cell mass
-this can fall late Low serum EPO Presence of Jak2 mutation Hypercellular mone marrow No other reason for the high red cells |
|
Polycythemia Vera
Presentation |
Median age 60
sweats, fatigue, weight loss, HA, visual disturbances, abd pain, thrombosis, puritis, erythromelalgia (neurovascular peripheral pain) splenomegally (70%), plethora (70%), haptomegally (40%) |
|
Polycythemia Vera
Treatment and prognosis |
Poor prognosis if untreated, good w/
Treatment of choice -- phlebotomy (to Hct-40) to the point of iron depletion and decreased proliferation Can develop resistant AML/ALL or meylofibrosis |
|
Essential Thrombocythemia
Diagnosis |
plts consistently >450K
increased/weird megakaryocytes in BM Not CML, inflammation, iron deficiency |
|
Essential Thrombocythemia
Genetics |
50% have JAK2 mutation, others have MPL (myeloproliferatie leukemia virus gene-- the thrombopoetin receptor)
|
|
Essential thrombocythemia
presentation |
HA, lightheadedness, syncope, atypical chest pain, visual changes, mild splenomegaly
Some clot, some bleed |
|
Essential thrombocythemia
Treatment and prognosis |
Low risk --
<60, no h/o thrombosis, plts <1000K No treatment High risk Hydroxyurea, sometimes aspirin, anagrelide Usually normal life span, rarely get clotting complication, AML, ALL, myelofibrosis |
|
Primary myelofibrosis
Diagnosis |
Collage fiber deposited in bone marrow
Anemia -- can be severe w/ teardrop cells Increased, abnormal megakaryoctes in BM Plts, WBC can be up or down |
|
Primary myelofibrosis
Prognosis and COD |
Worse with
Hgb<10 WBC<4 or >30 Plts <100 Monocytes >1.0 range is from 175 months to 26 months COD: transformation to MDS, AML, bleeding, infection |
|
Primary myelofibrosis
Treatment |
Stem cell transplant is curative
Hydoxyurea, transfusions, splenectomy |
|
Systemic symptoms of lymphoma
|
Fever
Weight loss Night sweats |
|
Function of T cells
|
Direct kills of organisms or infected cells
Modulation of immune response through helper and suppressor Ts |
|
Function of B cells
|
Produce antibodies
Antigen present to T cells |
|
Locations of maturation and differentiation of lymphocytes
|
Maturation to competence: thymus and marrow
Differentiation and antigen driven replication: lymph nodes, spleen, MALT, others LN in aggregate is the largest |
|
Seven divisions of lymph node
|
Capsule
Subcapsular sinus: afferent lymph enters this space Cortex with follicles Paracortex Medulla with cords and sinuses Medullary vessels: artery and vein |
|
Primary lymphoid follicle
|
Small B cells
Virgin or recirculating memory cells |
|
Secondary lymphoid follicle
|
Antigenic stimulation for differentiation
Creates germinal center with follicular dividing cells Surrounded by mantle of transient small lymphocyytes |
|
Sites of B cell homing
|
Primary and secondary follicles
--for stimulation and differentation/proliferation Medullary cords, plasma cells release Igs into efferent lymph |
|
Site of T cell homing
|
Paracortex
|
|
Normal lymphocyte circulation
|
Blood into
Lymph node Surveilling for presentation of specific antigen Leave through efferent lymphatics |
|
Small lymphocytes appearance
|
Small round blue dots
Round nucleus Clumped chromatin Small/not visible nucleous |
|
Small lymphocytes identities
|
T or B
Virgin or effector or memory |
|
Where are B cells in LN?
|
Primary follicles
Mantle zones of secondary follicles Medullary cords |
|
Where are T cells in LN?
|
Paracortex
A few in the germinal center |
|
Noncleaved cells in lymph node
|
Replicating population
Small and large (based on comparison with macrophage nucleus Expanding the number of antigen specific cells |
|
Small cleaved cells
|
Post mitotic plasma or memory cell precursors
Look a lot like lymphocytes but are irregularly folded and cleaved Nonproliferating |
|
Large cleaved cells
|
Bigger version of small cleaved
Replicaiton potential not clear |
|
Cells of the germinal center
|
Follicular cells
Non cleaved, large cleaved |
|
Immunoblast
|
Proliferating large cell outside of germinal center of lymph node
May be B or T Looks like dividing cell: vesicular chromatin, nulceoli visible |
|
APCs in LNs
|
To T cells - interdigitating reticulin cells
To B cells - dendritic reticulin cells |
|
Macrophages in lymph node
|
Main cell of medullary sinus
Abundant pale cytoplasm, oval nucleus, one nucleolus A few in germinal center |
|
Reactive hyperplasia
|
Proliferation in one or all of lymph node zones based on stimulus
Not cancer |
|
Follicular hyperplasia
Define Associated with |
Type of reactive hyperplasia
Expansion of germinal centers (can go into paracortex, medullary areas Collagen vascular disease Systemic toxo Syphillus |
|
Interfollicular hyperplasia
|
A reactive hyperplasia
Paracortical expansion Skin disease, viruses, drug reactions |
|
Sinus histiocytosis
|
Expansion of macrophages in the sinus
Indicative of adjacent cancer or infections |
|
Factors predicting lymphoma course
|
Dominant cell type (or transformed cell type)
Stage Patient's health status |
|
Working Formula and lymphoma?
|
Divides lymphoma into
low, intermediate, high grades Clinical Based on clinical history, dominant cell type, "follicularity"-- do the cells form normalish LNs |
|
WHO lymphoma classification
|
Cell of origin: B vs T/NK vs Hog
Peripheral vs precursor |
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Leukemia vs lymphoma
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Is most of the disease in the lymph organs or the bone marrow/blood?
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IHC profile in B cell small lymphocytic lymphoma
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Monoclonal light chain
CD19 CD20 CD5 CD10 negative |
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IHC profile in B cell small cleaved lymphoma
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Monoclonal light chain
CD19 CD20 CD10 CD5 negative |
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Indolent lymphomas, name some
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CLL
follicular marginal zone MALT |
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Indolent lymphomas general course, treatment goals
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Slowly progressive
Difficult to cure Goals of chemo are extension of life with good quality Only cure is allogenic HSCT |
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Aggressive lymphomas general course, treatment goals
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Grow rapidly
Can be rapidly fatal Immediate aggressive treatment with the goal of cure |
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Aggressive lymphomas name some
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ALL, Burkitt's
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Intermediately aggressive lymphomas name some
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diffuse large cell
peripheral T cell mantle cell |
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Staging in Lymphoma
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I -- involvement of a single LN region
II - multiple regions on same side of diaphragm III - disease on both sides of the diaphragm IV - multifocal extranodal involvement or regionally distant extrnodal invovlement A or B (symptoms) |
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B symptoms
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Night sweats
Fever Greater than 10% weight loss |
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Diffuse large B cell lymphoma
Pathology |
Originates from large replicating cells of germinal center and paracortex
Oval/cleaved cells with nucleoli and vesicular chromatin Diffiuse infiltration of LN CD19/20 positive May overexpress bcl-2/6 |
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Diffuse large B cell lymphoma prognosis
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Intermediate aggressiveness lymphoma
30-40% cure rate |
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Diffuse large B cell lymphoma presentation
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Children or adults (median age 64)
Present with an enlarging, painless mass in lymph node region Diffuse or localized |
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Prognostics in diffuse large B cell lymphoma
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Age (>60 bad)
Stage (III or IV) LDH elevation Poor performance status Extranodal involvement |
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Diffuse large B cell lymphoma treatment
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For localized: chemo + xrt
Advanced: Anthracycline based chemo R-CHOP used -- rituxin, cyclophosphamide, adriamycin, vincristin, prednisone Rituxin increases OS by 10% |
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Relapsed large B cell lymphoma treatment
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Chemo + autologous transplant
Transplant helps up cure rate by 20% |
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Follicular lymphoma pathology
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Cancer of small cleaved cells of germinal center
Clumped chromatin, irregular nuclear profile Retain follicular structure of LN but monotonous cells More large cells -- worse grade |
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Follicular lymphoma IHC/molecular changes
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t(14;18)
bcl-2 overexpression CD19, 20, 10, bcl2+ CD5, cyclinD1 - |
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Follicular lymphoma epi
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Most common of indolent lymphomas
22% of NH lymphomas Disease of adults >40 Typically presents as stage III or IV |
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Follicular lymphoma prognosis
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No curable
7-10 years, but highly variable Transformation to large cell has more aggressive course Prognosis as FLIPI score based on: Age >60, elevated LDH , stage III/IV, >4 LN sites, hemoglobin <12 |
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When to treat follicular lymphoma
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treat with gentle chemo including rituximab when
bulky, painful adenopathy organ system invovlement cytopenias severe B symptoms high FLIPI score |
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Marginal zone lymphoma pathology
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Origin is post germinal center memory B cell
CD20+, CD5-, CD10- Arising in muscosal tissue of GI tract, tear duct, salivary gland, lung |
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Marginal zone lymphoma prognosis
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Indolent
Curable |
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Marginal zone lymphoma AKA
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MALT lymphoma
Extranodal marginal zone B cell lymphoma |
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Marginal zone lymphoma treatment paradigm
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Same as follicular
Watch and wait until meets criteria |
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Gastric MALT lymphoma
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Marginal zone lymphoma arising from gastric mucosa
Usually with H pylori infection H pylori antigens drive T cell activation, B cell clonal proliferation -->lymphoma Can be cured with H pylori antibiotic treatment Presents like a peptic ulcer |
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Hairy cell leukemia pathology
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Unique cytoplasmic projections
CD19, 20, 103 + CD 5, 10 negative In bone marrow looks like fried egg Trap IHC (tartrate acid phosphotase) |
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Hairy cell leukemia presentation
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Indolent lymphoma
Cytopenias, fatigue, weight loss Splenomegaly |
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Hairy cell leukemia treatment and prognosis
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80% cure rate with
Purine analog cladribine Rituxin for refractory/relapsed |
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Burkitt's lymphoma pathogenesis
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Origin: small noncleaved cell of germinal center
t(8;14) results in upregulation of myc oncogenes |
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Burkitt's lymphoma pathology
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Diffuse infiltration of lymph node
Small round cells with vesicular chromatin and nucleoli Lots of ineffective mitosis = macrophages = "starry sky" 19, 20, 10+, 5- |
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Burkitt's general features
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Highly aggressive
High LDH, rapid doubling time Presents with bulky disease can involve CNS, bone marrow, extranodal sites |
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Burkitt's subtypes
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Sporadic
Immunocompromised Endemic |
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Endemic Burkitt's
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Africa
Jaw disease EBV related |
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Immunocompromised Burkitt's
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AIDS associated
Abdominal masses, marrow, lymph nodes 30% are EBV positive |
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Sporadic Burkitt's
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Children and young adults
Abdominal masses, marrow, LNs 30% are EBV positive |
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Burkitt's course
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Live only weeks if not treated
80-90% cure early stage, 60-80% with advanced stage |
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Poor prognostics in Burkitt's
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High LDH
CNS involvement Bone marrow involvement Tumors >10 cm Immunocompromised Burkitt's |
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Mantle cell lymphoma pathology
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Origin: lymphocyte of inner mantle zone
Looks like cleaved cell Nodal involvement either diffuse or expansion of mantle zone |
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Mantle cell lymphoma pathogenesis
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t(11:14) upregulates bcl-1 which increased cyclin D1 production
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Mantle cell lymphoma course
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Looks indolent, isn't
5 year survival 30-50% Allogenic HSCT can prolong but not cure Autologous may also help |
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T cell lymphomas
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Less common
More likely to be extranodal With nodal involvement are usually bad, and not as responsive to therapy as B cell |
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Mycosis fungiodes
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Indolent T cell lymphoma of the skin
Incurable with slow course |
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Anaplastic large cell lymphoma
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T cell lymphoma
Can have a 2;5 translocation with ALK gene ALK gene is a positive prognostic |
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Hogkins's disease pathology
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Reed-Sternberg cell
a minor population but diagnostic altered B cell CD15 and 30 positive Spread continguously via lymphatics |
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HD epi
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Less common than NH lymphoma
Biomodal age: late adolescents and 60s |
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HD subgroups
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Nodular sclerosis - most common neck/mediastinum, fibrous capsule and bands of expanding cells
Lymphocyte predominant - neck limited disease, young adults Lymphocyte depleted - oft retroperitoneal aggresive Mixed celluarlity - very aggressive |
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HD course
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80% cure rate
Dependent on stage, bulk, subtype ESR can be used as a marker of activity |
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Treatment of stage I/II HD
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Radiation only for some stage I
Abreviated Chemo + radiation |
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Treatment of advanced stage HD
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ABVD chemo, anthracylcine based
Concerns: secondary malignancies (breast, lung, MDS, sarcoma) Cardiac tox of anthracyclines |
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Primary refractory HD
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Disease that grows through treatment or recurs in 6 months
Often rapidly progressive to death |
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Follicular lymphoma grade 3
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Treated like a large cell
But still not curable |
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Follicular lymphoma chemo
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Rituxan, cytoxan, vincristine, prednisone
Fludarabine |
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Rituximab in follicular lymphoma
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Makes a 20+ different upfront in combo
Maintenance therapy can improve PFS by 2 years |
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If antibiotics do not work for gastric MALT?
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xrt to stomach
rituximab |
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Precursor T cell lymphomas
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Origin: immature T cells of thymus
Diffuse infilitration of thymus Disease of teenagers, boys>girls Aggressive and curable (70%) |
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Systemic symptoms of HD
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B symptoms
Pruitis Alcohol induced pain |
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Intratreament prognostic for HD?
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Negative PET after 2 cycles
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HIV and NH lymphoma
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60-160x increased risk of NHL
25-40% lifetime risk Mostly with <100 CD4s (except Burkitts) Burkitt's, diffuse large cell, primary CNS, primary effusional |
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Hep C and NH lymphoma
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Increased risk of marginal and diffuse B cell
Treating Hep C sometimes results in remission Thought to be due to chronic antigenic stimulation |
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ALL
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Acute lymphoblastic lymphoma/ lymphoblastic leukemia
Either T or B cell blasts Say lymphoma if its less than 25% blasts in marrow and there is a mass |
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ALL epi
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75% of cases are in <6 yo
80-85% are B cells in kids Of adult leukemias, ALL is 20%, 75% are B cell |
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ALL presentation
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Marrow symptoms -- fatigue, infection, bleeding
T cell precursor ALL may present with mediastinal mass |
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Pathology of ALL
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Blasts in marrow and cytopenias is periphery
Myeloperoxidase negative TdT positive, myelperoxidase negative T : CD3, 7 B: CD10, 19 Many cytogenetic abnormalities |
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ALL outcomes
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Better in kids: 80% cure
Adults: 40% cure |
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ALL treatment
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Rapid resistance is a problem
Use multidrug induction and then long consolidation CNS prophylaxis with XRT or intrathecal chemotherapy -25% CNS relapse without Many adults need allogenic transplant to survive |
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Chronic lymphocytic leukemia/ small lymphocytic lymphoma
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Indolent course, not curable
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CLL flow profile
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CD5+, CD19+, CD23+
Not much Ig or CD20 10-, cyclinD1- |
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CLL presentation
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Asymptomatic
Male (2:1) > 50 (median is 65) Lymphocytosis with small mature lymphocytes or Adenopathy |
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CLL when to treat?
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With B symptoms
Cytopenias Bulky/painful adenopathy Organ involvement Progressive splenomegaly, hepatomegaly Lymphocyte doubling time < 1 year |
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Complications of CLL
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Infections due to immunocompromise
Autoimmune disease ITP or hemolytic anemia Rickter's transformation to diffuse large cell |
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Prognosis of CLL
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Median is 9 years
Rai criteria - clinical Cytogenetics : 17p is p53 loss-- BAD Mutation status of IgVh: unmutated heavy chain indicates less mature cell = more aggressive Surface markers: CD38, Zap70-- bad |
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Treatment of CLL
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Prednisone, cyclophosfamide, fludaribine
Rituximab |
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Philadelphia chromosome in ALL
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Either a progression from CML or de novo
Use imatinib |
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Smudge cell
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Seen on smear
Fragile cell gets destroyed by process Characteristic of CLL |
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Do we treat CLL based on cytogenetics?
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Not yet
Remember early treatment has not been shown to help |
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Alemtuzumab
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CD52 monoclonal antibody
Use late in CLL Problems with infections |
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Bendumustine
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Nitrogen mustard
Used in CLL (in combos) |
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CLL refractory to fludarabine
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BAD
prognosis less than a year |
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Prolymphocytoid transformation
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Another CLL transformation
Larger cells, less distinct nucleoli, less dense chromatin Refractory |
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SPEP
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Serum protein elctrophoresis
Separates proteins by size |
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Ig increases will be seen on serum protein elctrophoresis as?
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Increases in the beta and or gamma regions
Spikes for monoclonal, more generalized increases for polyclonal |
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Polyclonal expansion states?
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Infection, inflammation, reactivity
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Monoclonal expansion states?
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Malignancy
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Urine electrophoresis
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Can see light chains here
Bence-Jones proteins when found in urine |
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Serum immunofixation
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Parallel runs of electrophoresis
Stain for different heavy chains and light chains Can characterize the gammaglobinopahy |
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MGUS
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Monoclonal gammaglobinopathy of unclear significance
No symptoms, no lytic lesions, plasma cells in marrow <10% 25% of patients will get a hematologic disorder Increasing prevalence with age (1% at 50, 8% at 80) |
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Multiple myeloma
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Neoplasm of plasma cells
Mature cells that have undergone class switching CD38 and 138 positive Il-6 is growth factor |
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Multiple myeloma cytogenetics
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Typically complex
Deletion 13 is bad |
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Mutiple myeloma Ig products
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Intact antibody
Free light chain Both |
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Multiple myeloma symptoms
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C - hypercalcemia
R - renal failure A - anemia B - bone lesions I - infections |
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Pathogenesis of lytic lesions in mutliple myeloma
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Il-6 and other cytokines increase osteoclast activity
Increased osteoclast activity results in hpercalcemia |
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Symptoms of hypercalcemia
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Nausea
Fatigue Renal insufficiency Constipation Mental status change |
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Hyperviscosity syndrome
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2% of multiple myelomas, mostly Ms and As related
CNS symptoms, CHF, renal insufficiency, bleeding Can be fatal |
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Plasmacytoma
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Solid tumor of plasma cells
Can be painful |
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Distribution in Igs of multiple myeloma
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60% IgGs
20% IgAs - worse prognosis Few IgDs Rest are light chains |
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Workup for multiple myeloma
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SPEP, UPEP
xrays CBC Bun Bone marrow biopsy |
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B-2-microglobulin and prognosis in multiple myeloma
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>4 bad
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Diagnosis of multiple myeloma
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Big M spike
Lots of plasma cells in marrow Hypogammaglobinemia Plasmacytoma Lytic lesions/end organ damage |
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Worse than MGUS but not multiple myeloma
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Smoldering myeloma
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Multiple myeloma prognosis
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Not curable
7 months untreated 3-5+ years with treatment Remission, relapse pattern Cytogenetics, staging can predict |
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Multiple myeloma treatment
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Alkylating agents and prednisone
Bortezomab/velcade - nfKB thalidomide, lanolidomide - immune modulatory ( decrease Il-6, induce apoptosis, disruption of BM microenvironment) Radiation to lytic, plasmacytomas Autologous transplant? |
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Waldenstrom Macroglobemia
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IgM disease
Post germinal center memory cell Ranging from gammopathy to lymphoplasmacytic lymphoma with IgM Hyperviscosity syndrome is a problem - plasmaphorese |
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Waldenstroma Macroglobemia treatment
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Only symptomatic
Rituxin Cytoxan, fludarabine, prednisone relvlimid, velcade also active |
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Risk of progression from MGUS to multiple myeloma
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1% per year
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Increased chance of MGUS progression
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IgA or IgM
Serum IgM protein size Abnormal FLC ratio |
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Multiple myeloma epi
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1% of new cancers
14% of hematologic malig Increases with age AA > caucasians |
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Amyloid AL
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Light chain deposition in tissues
With or without myeloma Prognosis is months if cardiac involvement Treat like myeloma |
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Fundoscopic with hyperviscosity syndrome
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Sausage-link, tortous retinal veins
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Leukoreduction
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Filtering out WBC from blood units
Must be <5 million Makes CMV safe Reduces febrile non-hemolytic transfusion reactions, HLA alloimmunization |
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Most/least frequent blood type
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O and AB
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Universal plasma donator
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AB
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Non-ABO antigens
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Rh, Kell, Kidd, Duffy...
Need exposure to have antibodies Pregnancy is one way to get exposed |
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Complications of incompatibility
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Hemolytic transfusion reaction
Hemolytic disease of the newborn Extravascular hemolysis |
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ABO forward and reverse typing
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Forward -- what will clump patients red cells
Reverse - what will patients serum clump |
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Solid phase antibody screen
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Looking for non-ABO antibodies
Antigens on plate well Plasma Anti-Ig tagged antibody |
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Immediate spin cross matching
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Tests for ABO
Add a little of patient serum to proposed donor sample If it clumps...don't use it |
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Anti-globulin cross matching
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Test for non ABO
Add donor red cells to patient serum Add anti-Ig antibody Look for clumping |
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Transfusion indications
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Symptomatic anemia
Usually not necessary if over 10 Usually necessary if under 7 |
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Gray area RBC transfusion recommendations
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Age 60-80, transfuse below 9
40-60, below 8 4 m - 40 years, below 7 Below 10 with age and recent MI |
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Platelet transfusion indications
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Correction of low or dysfunctional platelets
Prophylaxis: in hospital <5, out patient <20 Treatment of microvascular bleeding 2/2 uremia or plt harming drugs with Massive Transfusions |
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FFP indications
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replacement of coagulation factors
Prophy with abnormal coag studies Treat microvascular bleeding with abnormal coag studies THIS DOES NOT SEEM TO WORK |
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How much does hemoglobin go up in response to 1 unit of PRBCs
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1 g/dl
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How much does plt ct go up in response to unit of plts
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10-30K
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Risk of contracting HIV vs fatal hemolytic transfusion rxn?
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More likely to have a fatal hemolytic transfusion reaction
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Hemolytic transfusion reactions are reactions against?
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Red blood cells
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Hypersensitivity transfusion reactions are against what?
types? |
Plasma proteins
Anaphylactic Anaphylactoid Allergic |
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Transfusions complications related to WBCs
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Febrile transfusion reactions
Alloimmunization Transfusion related acute lung injury Graft vs host disease Immunomodulation |
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Post transfusion purpura
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Reaction against platlets
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Risk of some type of transfusion reaction?
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3-3.5%
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What to do when a transfusion rxn happens?
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Stop the transfusion
Evaluate and treat patient Send labs (bili, haptogloben, cbc) also on transfused blood Check for clerical errors Collect first urine |
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Pathogenesis of acute hemolytic transfusion reaction
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Antibodies in plasma recognize antigens on red cells
Phagocytes are activated Systemic activation of immune response |
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Factors effecting extent of hemolytic transfusion reaction
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Antibody titers
Antibody class Antigen concentration on cells Antigen position on cells Number of cells transfused |
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Components of hemolytic transfusion reaction and mediators
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Fever, chills - Il-1, 6, TNFalpha
Shock, inflammatory response- complement (C3a, 5a), bradykinin DIC -- coagulation cascade, thrombin Kidney failure |
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Pathogenesis of kidney failure in hemoytic transfusion reaction
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Hypotension - acute tubular necrosis
Immune complex glomerulonephritis DIC -glomerular capillary thrombosis Free Hgb-- leads to tissue damage and ischemia |
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Signs and symptoms of acute immune hemolysis
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Can be asymptomatic
Fever, chills Pain at iv site Red urine DIC Back (kidney) pain N/V Hypotension |
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Outcomes of ABO mismatch transfusions
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6% die
41% have morbility but survive 47% have no adverse effects |
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What is responsible for fatal transfusion reactions?
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50% administrative errors
30% technical errors |
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Delayed hemolytic transfusion reactions
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Occur 5-14 days later
Either a primary response to antigen or amnestic response with a latent population of memory cells Fever, chills, signs of extravascular hemolysis New alloantibody seen in serum Rarely needs treatment |
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Explain antibodies in delay hemolytic transfusion reaction
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Non intially
With transfusion, antibodies made Antibodies attach to RBCs (direct Coombs positive) More antibodies made, cells begin to lyse (direct and indirect positive) All cells destroyed, antibodies in blood (indirect positive, direct negative) |
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Delayed serologic transfusion reaction
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New antibodies detectable after transfusion but not hemolysis
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Allergic transfusion reactions
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Reaction to plasma proteins
Happens 1-3% of time Uticaria, flushing, puritis, wheezing dyspnea |
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Treating allergic transfusion reactions
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Stop transfusion
Give antihistamine Give steroids Give albuterol by neb |
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Anaphylactic or analphylactoid transfusion reactions
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Reaction to IgA or other plasma protein
Occurs 1 in 20K or 50K Dyspnea, larygneal edema, cynanosis, n/v/d, hypotension, shock, deah |
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Treating anaphylactic or analphlactoid transfusion reaction
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Stop transfusion, eval patient
Give epinepherine, antihistamines, steroids Support respiration and BP |
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Increased susceptibility to anaphylacic transfusion reaction
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IgA deficiency
1 in 700 May have antibodies against all IgAs or a subtype that they are missing Allergies to products that can be in blood (penicillin) |
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What do you do when a patient who has known anti-IgA needs a transfusion
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Autologus
Wash cells, plts Use IgA deficient donors |
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Febrile transfusion reaction
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Reaction to WBCs
Increase of 1C or 2F, chills, rigors, HA, n/v Happens in 1% of RBCs, more in plts -- less with leukoreduced |
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Treating ferbile transfusion reaction
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Stop transfusion
Rule out hemolysis Give antipyretics Steriods meperdine |
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Mechanisms of febrile transfusion reaction
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Classic -- recipients antibodies attack antigens on donor WBCs
Immune complex -- recipients antibodies react with antigens/proteins in donor and stimulate macrophages Cytokines -- donor macrophages produce cytokines in storage, which are transfused in |
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TRALI
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transfusion related acute lung injury
Donor antibodies, recipient cells, host actors = bilateral lung infiltrates Like ARDS but only 10% mortality |
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Pathophysiology of TRALI
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Donor antibodies lead to complement activaiton--->C5a ---> PMNs that activate and damage pulmonary vascular bed (also other vasculatures probably)
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Donors at risk for causing TRALI
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multiparous women
recipients of multiple transfusions |