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140 Cards in this Set
- Front
- Back
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Idiopathic thrombocytopenic purpura
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Is not really idiopathic! This is an autoimmune condition that is secondary to splenic destuction of opsonized platelets. Usually follows viral URI.
Usually present with recurrent epistaxis and multiple petechiae and some ecchymoses with normal PT and PTT and low platelet count |
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Von Willebrand Factor Disease
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Functions of vWF:
- binding to platelets' GPIb receptor and to sunendothelial collagen and to other matrix proteins --> this binds proteins to damaged vessels. - causes platelet - platelet binding - carrier of Factor VIII in plasma Can confirm by Ristocetin assay - it binds to vWF and causes platelets to aggregate Bleeding Time increased and PTT may be also increased |
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Glanzmann's Thrombasthenia
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Fibrinogen is the man that is holding platelets together. Caused by genetic defficiency in IIb-IIIa receptors.
Fibrinogen cannot bind to these receptors and hence no platelet aggregation can take place. Dx: decreased bleeding time |
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Bernard Solullier Syndrome
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Due to defficiency in GpIb receprors that vWF (von for one!) is binding to.
Platelets are abnormally large. Dx: decreased platelet count and increased bleeding time |
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Reactive Polycythemia
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An increase in Hematocrit of RBC count without a true increase in the amount of RBCs. This usually happens as a result of dehydration, vomiting, diarrhea or diuresis
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Absolute Polycythemia
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Is a normal increase in the amount of RBCs as a result ot increased Erythropoetin secretion.
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What produces intermittent hemolytic anemia?
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G6PD and Pyruvate Dehydrogenase Defficiency
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ALL
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Acute Lymphoblastic leukemia
- mainly in children - arise from mutations, translocations and hyper and hypoploidy of committed stem ccells (85% B cells) and (15% T cells) Associated with ionizing radiation Clinically: thrombocytopenia, neutropenia, anemia Risk group assignment is based on the type of mutation (t(12,21) tel-aml - good, t(9,22) bcl-abr - bad) High sucess rate with chemotherapy Adults have worse prognosis |
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A parasitic infection induces what kind of cellular response?
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Eosinophils - promote Ab - dependant cell mediated toxicity
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Viruses elicit what kind of response?
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TH1 response and mononucleosis
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Granulocytosis with Left Shift
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In acute inflammation (such as bacterial infections) there is an increase in the neutrophil count in peripheral blood. Since the body is in a hurry to release these PMNs, they have not all completely matured into the multi-lobed nuclei. This phenomenom is called a "left shift."
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When is myeloperoxidase stain used?
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To stain neutrophils - can also asses their oxidative burst, basence of which is idicative of Chronic Granulomatous Disease
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Schuffner dots are indicative of what?
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Plasmodium Vivax/Ovale infection - Malaria
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What is the drug of choice for Malaria?
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Chloroquine
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Erythropoetin
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Secreated in in peritubular capillaries in kidneys
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Reticulocyte Count
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Measure of effective erythropoesis
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Newbord physiologic anemia
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Due to replacement of HbF with HbA.
After this occurs, the infant's body gets the signal to increase RBC production. This temporary and expected drop in the blood count (called physiological anemia of the newborn) is considered normal and no treatment is needed. |
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Anemia
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A decrease of RBC mass. However, O2 saturation is normal and arterial PO2 is also normal
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MCHC
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RBC intracellular Hb concnetration - decreased in microcytic anemia and increased in spherocytosis
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Peripheral blood smear in thalassemia
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Decreased MCV and increased RBC count
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Total Iron Binding Capacity
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Measures the blood's capacity to bind iron with transferrin.
Increased in iron defficiency, decreased in anemia of chronic disease and sideroblastic anemia |
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Serum Ferritin
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Decreased in iron defficiency, increased in anemia of chronic disease, siderobastic anemia and normal thalassemia
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Microcytic anemia
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Iron defficiency anemia
Thalassemia Anemia of chronic disease Sideroblastic anemia |
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What are the most common causes of microcytic anemia by age group?
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Child: Meckel's diverticulum
Female<50: menorrhagia Man<50: peptic ulcer disease Man/woman>50: colon cancer |
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Describe stages of Fe defficiency anemia
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Decreased Ferritin, Decreased Fe and percent saturation, increased TIBC, Normocytic and then microcytic anemia
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Anemia of chronic disease
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MC anemia in alcoholis and in malignancy
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Alpha Thalassemia Trait
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AR: two alpha globin gene deletions - nromal electrophoresis
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HbH
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Three alpha globin gene deletions, hemolytic anemia because of 4 beta globin chain Hb accumulation
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Hb Barts disease
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Most serious form of alpha thal - results in hydrops fetalis
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Give examples of absolute polycythemia with appropriate stimulus of tissue hypoxia
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here Erythropoetin is high!
- COPD - High altitude - Cyanotic Congenital heart Disease - Hypoventilation syndromes (sleep apnea) - left shifted Hb curve |
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Give examples of absolute polycythemia with inappropriate stimulus of tissue hypoxia
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- Polycythemia Vera (low erythropoetin)
- Renal disorders (increased Epo) - Cushing's syndrome (increased Epo) - Uterine leiomyoma (increased Epo) |
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Give examples of relative polycythemia
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Here we don't have an actual increase in the RBC mass!
Usually a response to decreased plasma volume |
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Febuxostat and Allopurinol are used for what?
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Used in conjunction with chemotherapy to reduce the potential consequeces of increased uric acid from purine breakdown as cells lyse. These drugs prevent the development of uric acid stones or hyperurecemia
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In a neonate patient - rapidly rising Billirubin, jaundice, anemia and small spherocytes in the smear. Direct Coombs test is positive
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Hemolytic disease of a newborn - usually due to either Rh or ABO incompatibility
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What two genetic blood dyscrasias tend to manifest after 6 months of age?
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Sickle Cell anemia and Beta thalassemia - because after 6 mo a baby will be making adult hemoglobin (2 alpha and 2 beta) instead of fetal hemoglobin (2 alpha and 2 gamma)
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Heinz bodies
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Oxidation of iron from ferrous
to ferric form leads to denatured hemoglobin precipitation and damage to RBC membrane. Leads to formation of bite cells. Seen with alpha-thalassemia, G6PD deficiency. |
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What is Anemia?
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A reduction below the normal limits of the total circulating red cell mass resulting in diminished oxygen transport capacity of the blood and reduced oxygen delivery to the peripheral tissues (i.e., too few red blood cells in the circulation)
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Describe RBC Homeostatis
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RBC are produced in the bone marrow, exit into the circulation, get pumped by the heart and finally sequestered by the spleen.
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What is MCV?
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Mean Corpuscular Volume (MCV): The average size or volume of all the individual RBC’s in the sample. A population may, on average be in the normal range (“normocytic”), smaller than normal (“microcytic”), or larger than normal (“macrocytic”). Some types of anemia are characterized by typical changes in the MCV.
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What is RDW?
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Red Cell Distribution Width (RDW): A measure of how heterogeneous in size an RBC population is; i.e., if all the RBC’s on average are exactly the same size (have the same MCV), the RDW is small; if the distribution of RBC sizes around the mean is wide, the RDW is large.
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What are the majority of these cells (name)?
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Reticulocytes: the youngest red cells in the peripheral blood, having just completed their maturation in the marrow; their count is a measure of the ability of the marrow to produce new RBC’s
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Desribe signs and symptoms of anemia
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1. Pallor of skin and mucous membranes
2. Rapid heart rate (tachycardia) 3. Rapid breathing (tachypnea) 4. Easy fatigability with exertion 5. Headache 6. Fever |
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Describe four most common physiological compensatory mechanisms in anemia
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1. “Shift to the right” of the hemoglobin/oxygen dissociation curve; with increasing 2,3 DPG the hemoglobin releases oxygen in the peripheral tissue more readily at a given pO2
2. Shunting of blood from “non-essential” tissues: skin, mesenteric bed, kidneys 3. Increased cardiac output (e.g., increased heart rate) 4. Erythropoietin secretion by the kidneys to boost RBC production in bone marrow |
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Describe Erythropoietin Response to declining concentrations of Hb
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As Hb declines kidneys produce more Epo
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Describe three main (general) mechanisms of anemia
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1. Excess red cell loss (bleeding)
2. Shortened red cell survival (hemolysis) 3. Decreased red cell production (bone marrow failure |
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What is the major cause of RBC loss?
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Almost always synonymous with bleeding; clinically these bleeds may run a spectrum from acute, traumatic--sometimes massive--bleeds to slower, chronic RBC losses
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Describe s/s and lab findigs with RBC loss through bleeding
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With increasing total blood volume loss, increasing symptoms: at 20%, tachycardia, postural hypotension; at 40%, severe shock
Labs: initially a CBC will be normal (no anemia) as in large bleeds whole blood, not just RBC’s, is lost; the intravascular ratio of RBC’s to plasma is not changed (so normal hb and hct) |
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Describe Hemolytic Anemia
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Red cell survival is markedly shortened in these conditions with premature removal primarily by the spleen. As anemia develops, erythropoietin secretion rises and this drives a compensatory erythroid hyperplasia in the bone marrow to increase RBC production in order to make up for the increased RBC clearance. The reticulocyte count is always elevated.
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What are the laboratory markers of increased RBC turnover?
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1. Elevated lactic dehydrogenase (LDH)
2. Variably elevated bilirubin (unconjugated) 3. Decreased haptoglobin |
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Describe five major types/causes of hemolytic anemia
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Intrinsic red cell defects (inherited):
- Membrane defects - Enzyme deficiencies - Hemoglobin disorders Extrinsic red cell defects (acquired): - Immune mediated hemolysis - Physical causes of hemolysis (microangiopathy) |
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What is Hereditary Spherocytosis?
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Most common membrane defect; 1/5000 in No. European population.
Autosomal dominant. Most commonly presents in early childhood with symptoms of anemia. Develop splenomegaly. |
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Describe the pathophysiology of Hereditary Spherocytosis
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Genetically heterogeneous: most common mutations are in the genes for ankyrin and band 3 (there are others)
These lead to destabilization of spectrin, influx of sodium into the cell, instability of the membrane with intravascular membrane loss due to shearing stresses, and the inability of the RBC to maintain a normal biconcave shape; these cells are inflexible and are removed by the RE system of the spleen |
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Describe Lab findings, disgnosis and treatment plan in Hereditary Spherocytosis
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Peripheral blood:
Usually mild normocytic anemia, Reticulocytosis Spherocytes in smear Bone marrow: Compensatory erythroid hyperplasia Diagnosis: Combination of family history, typical clinical presentation, and CBC findings leads to suspicion for HS; confirmatory test: osmotic fragility Course: Patients have chronic mild to moderate anemia improved by splenectomy (although the RBC defect remains) |
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What time of anemia this smear corresponds to?
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Hereditary Spherocytosis:
we see mild normocytic anemia, reticulocytes and spherocytes in smear. Spherocytes appear very round with NO CENTRAL PALLOR |
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What is Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency?
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X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase, a metabolic enzyme involved in the pentose phosphate pathway which maintains the supply of reduced glutathione in the cells that is used to mop up free radicals that cause oxidative damage.
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Describe Clinical Presentation of G6PD
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Ethnically distributed: most common in African, Mediterranean, Middle Eastern, and Asian populations.
X linked inheritance. Episodic anemia beginning in childhood: patients are non-anemic prior to exposure to oxidizing stresses; however, following such exposures (drugs, chemicals, infections), the patients become anemic. |
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Name a few agents that can cause oxidative stress in G6PD and lead to hemolysis
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1. Drugs
Anti-malarials: primaquine, chloroquine, pentaquine Anti-bacterials: sulfamethoxazole, sulfanilamide Many others, including analgesics (e.g., ASA) Chemicals 2. Diet: fava beans (“favism”) 3. Mothballs (para-aminobenzoic acid) 4. Infections Many viral and bacterial infections, especially when severe 5. Viral hepatitis 6. Pneumonia There is varying sensitivity to these oxidative agents among different ethnic groups; the clinical presentation of G6PD deficiency is probably due to the nature of the specific mutation |
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Describe Lab findings in G6PD
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Peripheral blood:
Normal hb/hct prior to oxidative exposure, then mild to severe anemia (depending on G6PD variant) develops shortly after. Reticulocytosis. Bite cells and blister cells in the peripheral smear. Bone marrow: Compensatory erythroid hyperplasia driven by erythropoietin during the anemia phase; normal bone marrow findings when not anemic. |
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How do we diagnose G6PD?
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Heinz body preparation from blood sample to screen; quantitation of G6PD level in RBC’s by specialty lab to confirm.
Heinz bodies are inclusions within red blood cells composed of denatured hemoglobin. They are formed by damage to the hemoglobin component molecules, usually through oxidation. |
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What type of anemia is this blood smear characteristic of?
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G6PD.
Here we see Bite cells. They appear when an abnormal hemoglobin aggregate (Heinz body) is nibbled out of a red cell's cytoplasm by the spleen leaving a bitten apple appearance. |
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What type of anemia is this blood smear indicative of?
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G6PD because we see bite cells. Bite cells appear when an abnormal hemoglobin aggregate (Heinz body) is nibbled out of a red cell's cytoplasm by the spleen leaving a bitten apple appearance.
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When testing for G6PD what is important to remember regarding the timing of the test?
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Since reticulocytes have the highest levels of G6PD--even in deficient patients--do not collect a blood sample in the acute setting to measure G6PD levels for G6PD deficiency diagnosis (will not reflect the patient’s baseline level)
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Describe clinical presentation of Sickle Cell Anemia
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- Found almost exclusively in blacks
- Onset in infancy, within first year of life. - Chronic moderate to severe anemia. - Clinically recognized “crises”: - Splenomegaly initially followed eventually by splenic auto-infarction; this predisposes to infections, particularly by encapsulated bacteria. - Skeletal changes seen in X-rays, especially in skull bones. |
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Describe Pathogenesis of Sickle Cell Anemia
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Beta globin chain gene mutation induces an amino acid change from glutamic acid (negative charge) to valine (neutral charge).
- In homozygotes, this alters the hydrogen bonding between and the stability of the globin chain interaction. - In conditions of deoxygenation, acidosis, dehydration, etc., HbS polymerizes--at first, reversibly but eventually irreversibly--which damages the RBC membrane (causing calcium influx, water loss, and increased cell stickiness), induces the sickle shape, and leads to both premature clearance by the spleen and vaso-occlusion. |
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What two factors contribute to the "sickling" of HbS in Sickle Cell Anemia?
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1) a high total amount of intracellular hb (i.e., intracellular dehydration) and
2) an elevated proportion of HbS; when other hemoglobins (i.e, HbA or HbF) are present in sufficient quantity (e.g., heterozygous HbS) they interfere with the ability of HbS molecules to polymerize and sickle. |
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What type of anemia might be responsible for these skeletal changes?
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Sickle cell anemia. Expanded medullary cavity. The diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a hair-on-end appearance
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Describe lab findings in Sickle Cell Anemia
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Peripheral blood:
- Moderate to severe normocytic anemia with high RDW - Sickled cells and target cells in peripheral smear - Reticulocytosis - Hyperbilirubinemia Bone marrow: - Erythroid hyperplasia (except in aplastic crisis; see later); may develop bone marrow fibrosis. |
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How do we diagnose Sickle Cell Anemia?
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Hemoglobin electrophoresis test
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What type of anemia this smear corresponds to?
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Sickle cell anemia - we see sickled cells and target cells in peripheral smear. We also see normocytic anemia with high RDW and reticulocytes.
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What are the three types of crises seen in Sickle Cell Anemia?
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1. “Sequestration crises”: Occurs in children with intact spleens; sudden massive splenomegaly with increased sequestration of RBC’s; profound anemia; usually transient.
2. “Aplastic crises”: Infection with parvovirus arrests erythroid maturation in the marrow so RBC production stops; this, together with continued rapid clearance of sickled cells from the blood by the spleen, leads to profound anemia. 3. Episodic “painful crises” involving joints, abdomen, and chest. |
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What is the therapy in Sickle Cell Anemia?
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Overall, about 50% survival by age 50.
Therapy: Supportive; alkylating agents (e.g., hydroxyurea) to increase HbF |
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What is microangiopathic anemia?
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A heterogeneous group of anemias that result from intravascular (not spleen mediated) RBC destruction due to collisions with or trauma from intravascular lesions or abnormal endothelial cells.
It can result from DIC (when multiple microthrombi are formed), in malignant hypertension ( due to narrowed arterioles, scarred endothelium) or mechanical heart valves (create shear stress) |
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In what type/types of anemia we see this type of blood smear?
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We see schistocytes here - irregularly shaped, jagged and asymmetrical cells without central pallor.
Several microangiopathic diseases, including disseminated intravascular coagulation and thrombotic microangiopathies, generate fibrin strands that sever red blood cells as they try to move past a thrombus, creating schistocytes (cutting through a guitar string effect) |
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Name the major types of Anemias of Decreased Production
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1. Nutritional anemias (
Iron deficiency anemia, Megaloblastic anemia) 2. Anemia of chronic disease 3. Anemia of chronic renal failure (CRF) 4.Aplastic anemia (AA) |
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What pathophysiological feature is common to all anemias of decreased production?
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In these anemias the marrow is incapable of producing new RBC’s to replace the senescent cells cleared from the blood; erythropoietin levels and bone marrow morphology vary widely from subtype to subtype, but the reticulocyte count is low in all of them.
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What is a typical distribution of iron within the body?
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Hemoglobin - 2.4 gm (63%)
Ferritin - 1.0 gm (33%) Myoglobin - 0.2 gm (4%) |
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Describe the mechanism of iron absorption
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The absorbed Fe, after temporary storage in the mucosal cell, is passed into the plasma and bound to transferrin, which delivers it to storage sites (macrophages)
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Describe three stages of Iron Deficiency Anemia
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1. “Iron depletion”: Fe loss exceeds Fe absorption, Fe stores are drawn down, but there are no hematologic consequences yet (i.e., no anemia, no microcytosis)
2. “Iron deficient erythropoiesis without anemia”: Fe is close to depleted and serum markers of iron homeostasis are abnormal, but there is no anemia 3. “Iron deficiency anemia”: Anemia is now present, with subsequent microcytosis |
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Name three main causes of Iron Deficiency Anemia
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1. Nutritional (in iron poor diet, eg. vegans and during periods of increased growth)
2. Bleeding 3. Malabsorption (eg. post-gastrectomy) |
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What are peripheral blood lab findings in Fe Deficiency Anemia?
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Mild to moderate microcytic anemia with high RDW and
low reticulocyte count (because not enoiugh iron for making RBCs) hypochromic RBC’s in PB smear. Serum iron studies: 1) low serum iron, 2) low serum ferritin, 3) high transferrin; low transferrin saturation (serum iron / transferrin) Thrombocytosis |
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Describe Bone Marrow lab findings in Fe Deficiency Anemia
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Erythroid hyperplasia driven by erythropoietin, but ineffective, i.e., not productive of new RBC’s (can’t complete maturation without available iron so precursors undergo apoptosis in marrow); no detectable storage iron by Prussian blue stain
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What type of anemia does this blood smear correspond to?
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Fe Deficiency Anemia - we see microcytic hypochromic anemia with many "bicycle tire cells" - indicative of iron deficiency
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Is this s hyperplastic or hypoplastic bone marrow?
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This is an erythroid hyperplasia observed in Fe Deficiency anemia, however non-productive in the absence of iron
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What is Megaloblastic Anemia?
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“megalo-”: large; “blastic”: immature - means this anemia present with many "iimature" looking large cells in the smear, mainly due to Folate and Vitamin B12 deficiency. Vitamin B12 and folate are critical to the biosynthesis of DNA; bone marrow is dependent on having a continually available source of the building blocks for cellular constituents. When B12 or folate become deficient, DNA synthesis slows and cell division stops
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Name main sources of Vitamin B12 (Cobalamin)
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Dietary source: animal proteins.
Large body stores relative to consumption: 2-5 mg. Absorption: after ingestion, B12 travels to duodenum and binds to intrinsic factor secreted by the parietal cells of the stomach. The complex travels to the terminal ileum where it is absorbed; the B12 is passed into the serum where it is carried by transcobalamin. |
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What are the main functions of Vitamin B12?
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Function: methyl donor intermediary in the synthesis of thymidine.
Also has a role in myelin synthesis in CNS. |
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What are main causes of Vitamin B12 Deficiency?
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1. Pernicious anemia (autoimmune gastritis): most common in U.S. Here gastric parietal cells are lost due to autoantibodies, so no intrinsic factor is secreted leading to no absorption of B12; neurologic component to PA also present (neuropathies, cerebellar signs, etc.)
2. Post-gastrectomy: B12 deficiency typically follows after 4-5 years 3. Intestinal disorders: ileal resection, malabsorption syndromes, tapeworms 4. Chronically low intake |
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Name the sourses of Folate
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Dietary source: green vegetables; since the 1990’s, added as a supplement to many food staples
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Name the function of Folate in the body
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Absorption: proximal jejunum
Function: final intermediary in synthesis of thymidine |
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Name the main causes of Folic Acid Deficiency
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1. Dietary deficiency: relatively low body stores; those with poor diets and who avoid green vegetables are at risk.
2. Intestinal diseases: malabsorption syndromes, etc. 3. Increased requirements: pregnancy, infancy, hemolytic anemia, malignancy. |
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Labs in Megaloblastic Anemia
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Peripheral blood:
- Moderate to marked macrocytic anemia with high RDW - Low reticulocyte count - Macroovalocytes in smear - Leukopenia and thrombocytopenia Bone marrow: - Hypercellular with erythroid hyperplasia |
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What type of anemia this blood smear characteristic of?
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Megaloblastic Anemia - we see many macroovalocytes here
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What are the treatments for Megaloblastic anemia?
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1. Must identify specific deficiency, i.e., folic acid or B12.
2. Folic acid supplements given to B12 deficient patients will correct the anemia but won’t reverse the neurologic changes 3. Folic acid: oral supplementation except with deficiency due to GI tract disease B12: parenteral supplementation (intramuscular) |
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Name the main causes of Anemia of Chronic Disease (ACD)
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1. Infections (viral, bacterial, fungal, parasitic)
2. Malignancy (solid tumor, hematologic) 3. Autoimmunity (rheumatoid arthritis, SLE, vasculitis, sarcoidosis, inflammatory bowel disease) 4. Chronic rejection after solid organ transplantation 5. Chronic kidney disease and inflammation |
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Describe pathogenesis of Anemia of Chronic Disease
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Multifactorial:
1. Variably shortened RBC survival 2. Erythropoietin resistance 3. Disordered iron metabolism due to elevated IL-6 stimulated production of hepcidin from liver. Hepcidin blocks iron release from macrophage stores so that it can’t be taken up by RBC precursors; they, in effect, develop intracellular iron deficiency despite abundant storage iron Hepciden blocks transfer of dietary iron from GI mucosal cells into the plasma by degrading ferroportin. |
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Describe lab findings in Anemia of Chronic Disease
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Mild to moderate normocytic anemia with normal RDW; sometimes microcytic so may be confused with Fe deficiency.
Low reticulocyte count Serum iron studies: low iron, low transferrin, high ferritin. Bone marrow: normocellular to hypocellular with variable erythroid compartment, though usually not erythroid hyperplasia. |
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These are RBC precursors - in what type of anemia we see these cells?
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In ACD, erythroid precursors are deficient in iron because of the block in iron transfer into them; they will lack the blue granules (seen with Prussian blue staining) normally found in these cells
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Describe the pathophysiology of Anemia of Chronic Renal Failure
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1. Diminished EPO secretion by the failing kidney
2. Ineffective erythropoiesis (like ACD) 3. Shortened RBC survival in toxic plasma (BURR CELLS) 4. Increased bleeding (and therefore RBC loss) |
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What type of anemia is this smear characteristic of?
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Anemia of Chronic Renal Failure.
Labs: Normocytic with normal RDW Low reticulocyte count Echinocytes (“burr cells) in smear. |
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Describe the pathophysiology of Aplastic Anemia
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Stem cell failure leading to the loss of normal myeloid precursors; the marrow becomes incapable of synthesizing new blood cells
30% of cases occur after known toxic exposure (e.g., drugs, hepatitis, chemicals, etc.), 70% are idiopathic |
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What type of anemia is this bone marrow sample indicative of?
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Moderate to severe normocytic anemia with normal RDW.
Low reticulocyte count. Thrombocytopenia and neutropenia, usually. Bone marrow: Marked hypocellularity; rare hematopoietic cells; abundant stroma and fat |
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What is Thalassemia?
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Thalassemia is caused by the decreased synthesis of primarily normal globin chains
Two major subtypes (there are also others): Alpha thalassemia Beta thalassemia |
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What is Beta Thalassemia?
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Decreased synthesis of beta globin chain.
Primarily caused by mutations in the regulatory (non-coding) portion of the beta globin chain gene; the transcribed mRNA is abnormal and has a very short half-life. Translation into protein can’t occur. Since there are 2 beta alleles, a person may inherit one normal and one mutated beta gene (heterozygous beta thal, beta thal trait, or thal minor) or 2 mutated alleles (homozygous beta thal or thal major). |
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Describe pathophysiology of Beta Thalassemia
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In homozygotes, no beta chain can be made but normal amounts of alpha chain are. These free alpha chain begin to self-associate and form aggregates in the precursor RBC cytoplasm. This causes two problems:
The aggregates are toxic to the cell, so intramedullary RBC precursor death occurs (“ineffective erythropoiesis”) RBC’s that manage to complete maturation are quickly cleared by the spleen because of the abnormal cytoplasmic contents (i.e., both poor RBC production and decreased survival contribute to he anemia) In heterozygotes, although one beta allele is mutated and normal levels of beta chain can’t be quite made, a sufficient quantity can be synthesize by the one normal allele to nearly compensate. These patients have mild or no anemia. |
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What are clinical presentations of Beta Thal?
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Homozygous thal:
Severe anemia that presents in infancy with failure to thrive, lethargy, irritability, jaundice, splenomegaly, bony abnormalities. Transfusion therapy is initiated early. Heterozygous thal: These patients are frequently asymptomatic and may be discovered incidentally; the condition may be suspected because of a known family history. The mild anemia may produce correlative mild symptoms. |
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Beta Thal Lab Findings
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Peripheral blood:
Marked microcytic anemia (MCV 50 - 70 fl) with high RDW Circulating RBC precursors Target cells and markedly hypochromic RBC’s on peripheral smear Bone marrow: Marrow hypercellularity with marked erythroid hyperplasia; the marrow expansion induces the bony abnormalities seen on X-ray |
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What anemia does this smear correlate to?
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Homozygous Beta Thalassemia
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What anemia does this smear correlate to?
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Homozygous Beta Thalassemia
Peripheral blood: Mild or absent anemia, microcytic with normal RDW Elevated RBC count Target cells on smear |
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How is Beta Thal Diagnosed?
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Homozygous:
Clinical presentation suggests the diagnosis; confirmation by CBC and hemoglobin studies (Hb F >90%, Hb A2 elevated, no Hb A). Parents with heterozygous condition may be known. Heterozygous: Little symptomatology; family history may be known. In suspected heterozygotes, a CBC will reveal microcytic RBC’s and hemoglobin studies show mildly elevated Hb F (1-4%) and Hb A2 (4-8%). Important to inform patient for genetic counseling purposes. |
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What is Alpha Thalassemia?
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African, Middle Eastern, and Asian ethnicity
Pathogenesis: Loss of alpha alleles on chromosome 16 due to large deletions of coding regions (vs beta thal: point mutations in regulatory portion of gene). Excess beta chains complex and cause both intramedullary cell death and increased RBC clearance 4 alpha alleles (vs 2 beta alleles), so 4 different alpha thal syndromes... |
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What are Lab findigs in Alpha Thalassemia?
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Peripheral blood
2 deletion: mild microcytic anemia; target cells on smear; no abnormal hemoglobins on electrophoresis 3 deletion: moderate microcytic anemia; schistocytes on smear; mild hyperbilirubinemia; Hb H seen on electrophoresis Bone Marrow Varying degrees of erythroid hyperplasia in all |
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What is a clinical corse for Alpa Thalassemia?
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One and two deletion: typically asymptomatic or mildly symptomatic; no therapy
Three deletion: occasional transfusion therapy is required to maintain a near normal level of hemoglobin and hematocrit. Signs of chronic hemolysis may manifest: splenomegaly, mild jaundice. The disease is not life shortening, however. |
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Name the five steps of hemostatic response
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1. Initiation (happens when subendothelial cells become exposed due to injury)
2. Localization (due to circulating platelets) 3. Propagation/Amplification (due to caogulation factors) 4. Termination (due to coagulation factor inhibitors) 5. Elimination (due to fibrinolytic system) |
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What happens during the Intiation phase of 1ry hemostatis?
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Endothelial wall becomes damaged, exposing subendothelium. This leads to a transient vasoconstriction – endothelin secretion by endothelium.
Exposed subendothelial components - vWF and collagen are now ready to activate platelet (localization is a step II) |
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Describe the contents of platelet granules that are relased upon activation
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ADP
Serotonin (which produces vasoconstriction) Fibrinogen, vWf, activated factor V |
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What mediates the attachment of platelets to subednothelial collagen?
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vWF (paramount!, platelet glue) as well as collagen. There are thousands of vWF (GP-Ib) and Collagen (GP-VI) receptors of the surface of the platelets.
This makes sure that there are adequate mechanisms in place for platelet attachment in hemostasis. |
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What is Willebrand Factor and why is it important in hemostasis?
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Von Millebrand factor is the most important component of Primary Hemostatic Response:
1. its a multimer composed of repeating subunits. 2. It is the platelet glue 3. There are many vWF diseases. 4. There are two pools of vWF: a) In subendothelium b) In plasma (here it does not work as a platelet glue, but rather a carrier protein for pro-cofactor factor VIII |
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Name different types of platelet activators
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1. Subendothelial vWF subjected to shear stress – “strong"
2. Collagen – “strong” 3. ADP: secreted from platelet dense granules – “weak” 4. Thromboxane A2: A prostaglandin – “weak” 5. Thrombin: the product of the coagulation cascade – “STRONGEST" |
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Explain how Aspirin (and other similar antiinflammatories) inhibit platelet activation (localization step II)
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Thromboxane A2 (Prostaglanding A is a weak activator). The pathway of thromboxane synthesis is inhibited by aspirin and other non-steroidal inflammatory agents.
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Describe platelet activation events
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1. in response to activators (vWF, Collagen and Thrombin) platelets form pseudopods which results in a marked increase in surface area.
2. Platelets release ADP, Serotonin, Fibrinogen, vWf and activated factor V. 3. Platelets initiate receptor – mediated intracellular signaling cascades: Synthesis and release of thromboxane A2, G protein – coupled thrombin receptor pathways, ADP receptor mediated pathways 4.Receptors for procoagulant proteins become activated and platelets join by formation of a fibrinogen-GpIIb-IIIa complex |
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What is Fibronogen
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Is a plasma protein that also is found in platelet alpha-granules.
Mediates platelet aggregation by bridging GpIIb-IIIa receptors. Is the substrate for blood clot formation. |
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Describe Von Willebrand’s disease
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Von Willebrand’s disease - reduced or abnormal synthesis of vWF which leads to poor platelet adherence to the site of injury. There are several types: Type 1: quantitative loss, Type 2- qualitative reduction, Type 3- almots no production at all.
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Describe Bernard-Soulier syndrome
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Bernard-Soulier Syndrome - expression of low levels or defective GpIb-V-IX complexes which leads to decreased vWF binding.
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Describe Glanzmann’s thrombasthenia
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Expression of low levels or
defective GpIIb-IIIa complexes which lead to decreased fibrinogen binding and poor platelet aggregation. |
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Describe physiologically relevant coagulation pathway components
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Physiologically-relevant Hemostatic Enzyme Complex Formation:
A series of vitamin K-dependent “zymogen” to vitamin K-dependent serine protease conversions initiated by exposed Tissue factor and small, circulating concentrations of Factor VIIa (the only factor present in an active form) |
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Name common constituents of coagulation complexes
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Vitamin K-dependent serine proteases
Protein cofactor Calcium ions Appropriate membrane surface - activated platelets - subendothelial cells, typically fibroblasts - damaged, intact endothelium |
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Name coagulation factors that are activated by the Vitamin K
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Precursors of 7, 9, 10, 2 and proteins C and S (mnemonic 1972 SC)
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Where does Factor V come from?
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Factor Va is both plasma-
and platelet-derived. In plasma it circulates as a procofactor, whereas it is stored in platelet alpha-granules in an active form. |
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Why is it important to form coagulation complexes?
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1. localization of procoagulant activity
2. amplification of the response 3. modulation – protection of complex from inhibitors. |
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Describe the role Thrombin plays in 2ry hemostatis
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Thrmobin is the most potent pro-coagulant. it activates factors 5, 7, 8, 11, 13, platelets, endothelial cells and fibrinogen
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Describe the conversion of Fibrinogen to Fibrin
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Fibrinogen is composed of D and E domains. D domains are made of longer alpha and beta chains and the E domain is made up of all the chains coming together in the middle.
Thrombin cleaves between 18-21 aa off of these small peptide chains. The E domain becomes “sticky” and now can bind the D domains to generate fibrinopeptide chains. You can measure these peptides in a clinical setting and see if someone has ramped up their Thrombin activity. |
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What reinforses Fibrin clots?
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Fibrin cross-linking between D domains catalyzed by Factor XIIIa.
Therefore in Factor 13 deficiences we will see unstable fibrin clots. |
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What are Gla domains and which coagulation factors have them? Why are they important?
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Gla domains are functional Domains of the Vitamin K-dependent Zymogens/Serine Proteases (factors 7,9,10 and proteins S and C)
(Thrombin (factor 2) is the exception!) Gla domains get their name because they contain several gamma- carboxyglutamic (Gla) resides. Gamma-carboxylation is a vitamin K-dependent post-translational modification. It is inhibited by Warfarin (coumadin) and other Dicoumarol analogues. |
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How can one develop Warfarin Toxicity?
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Decreased synthesis of functional coagulation factors II, VII, IX and X can lead to life-threatening bleeding.
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What are the constitutive mechanisms of termination of 2ry hemostasis?
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1. Inactivation of factor VIIa and factor Xa by tissue factor pathway inhibitor (TFPI).
2. Inhibition of thrombin and factors Xa, VIIa and IXa by antithrombin III (1972 mnemonic) |
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Describe the mechanism of action of TIFP
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TFPI shuts down the
extrinsic pathway by initially forming an inhibitory complex with free FXa . A TFPI/FXa complex then reacts with a TF/FVIIa complex effecting its inhibition, as well. |
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Describe the mechanism of action of Antithrombin III
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ATP III inhibits Vit, K dependant proteases (1972)
1. Heparan sulfate proteoglycans (polysaccharides), expressed on the luminal side of vascular endothelial cells, bind both the protease and ATIII. 2. Heparan polysaccharides also induce a conformational change in ATIII, which increases its ability to recognize factor Xa. ATIII inhibits factor Xa more effectively than it inhibits thrombin. |
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Describe “Clotting-initiated" processes in termination of 2ry hemostatis
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Thrombin binds to thrombomodulin expressed on endothelial cells and activates protein C to activated protein C, which
proteolytically inactivates factors Va and VIIIa. |
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Describe how Thrombin can be pro-coagulant and anti-coagulant at the same time.
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Becomes
an “anticoagulant” after binding to thrombomodulin expressed on the endothelial cell surface. |
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What is Factor V Leiden disorder?
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Results from a single base substitution leading to the
replacement R506 → Q. This substitution results in a cofactor with increased resistance to inactivation by APC. Increases risk of venous thrombosis 3-8 fold for heterozygous and 30 to 140-fold for homozygous gene substitutions. |
