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220 Cards in this Set
- Front
- Back
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What does anemia typically result from? |
-Increased RBC loss (RBC destruction or excessive blood loss) -Decreased production of RBCs |
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What are causes of IDA? |
-Increased iron demand -Excessive loss (menstruation, chronic bleed) -Decreased absorption -Iron poor diet (elderly, milk babies) |
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What is serum iron measuring? |
Transferrin bound iron |
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Serum ferritin is directly proportional to... |
storage iron (marrow iron) |
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What is hepcidin and what is its function? |
Is a positive acute phase reactant that regulates iron absorption. When it binds to ferroportin it inactivates it Adequate iron stores = increased hepcidin Iron stores dropped = decreased hepcidin |
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Optimal iron absorption occurs when iron is in which state? |
Ferrous iron (2+) |
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What is hemosiderin? |
Insoluble storage form of iron that is less readily available than ferritin. Breakdown product of ferritin. |
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What are the five conditions associated with microcytic, hypochromic anemia? |
-IDA -AOI/ACD/ACI -SA -Hemoglobinopathies -Thalassemias |
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What is the general cause of Iron Deficiency Anemia? |
Iron deficiency |
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What is the general cause of Anemia of Inflammation? |
Decreased Fe absorption/release from cells Iron is "trapped" in macrophages because of increased hepcidin production |
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What is the general mechanism of AOI? |
1-Cause of inflammation 2-Inflammation stimulates liver to produce hepcidin 3-Stimulates sequestration of iron in macrophages, inhibits Fe export 4-Inhibits EPO production: decreased proliferation/differentiation of RBC 5-No iron results in reduction of Hgb levels = anemia |
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What are some examples of underlying inflammatory conditions that can lead to AOI? |
-Chronic infections -Autoimmune diseases -Malignancy -Inflammatory diseases -Increased cytokine release (due to infection such as infectious mono) |
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What is the general cause of Sideroblastic anemia? |
Inadequate iron utilization/incorporation into heme |
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What are some causes of sideroblastic anemia? |
Hereditary: -Rare X-linked -Stem cell dysfunction (decreased heme synthesis, thrombocytopenia, neutropenia) Acquired: -Drugs/alcohol -Lead poisoning |
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What does lead poisoning interfere with and how? |
Interferes with heme synthesis in three ways -ALA to porphobilingen -Corprophyrinogen to protoporphyrinogen III - Protoporphyrin IX (ring) to Heme |
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What enzyme incorporates Fe2+ into protoporphyrin IX ring to produce heme? |
Ferrochelatase |
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What will the RBC morphology typically look like in IDA? |
Microcytic (low MCV) Hypochromic (low MCHC) Marked anisocytosis Target cells Ovalocytes |
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% Transferrin saturation = |
(serum iron / TIBC) * 100% |
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What is TIBC? |
Total amount of iron that can be bound to transferrin |
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IDA Increased/Decreased: Serum iron- sTfRs- TIBC- %Saturation- Serum ferritin- Marrow iron- Sideroblasts/cytes- |
Serum iron- decreased sTfRs- increased TIBC- increased %Saturation- decreased Serum ferritin- decreased Marrow iron- decreased Sideroblasts/cytes- decreased |
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IDA Increased/Decreased: MCV- MCHC- Hepcidin- ZPP- Hgb- M:E ratio- WBC/PLT- |
MCV- decreased MCHC- decreased Hepcidin- decreased ZPP- increased Hgb- decreased M:E ratio- decreased (increased erythroid) WBC/PLT- increased (maybe) |
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AOI Increased/Decreased: Serum iron- sTfRs- TIBC- %Saturation- Serum ferritin- Marrow iron- Sideroblasts- |
Serum iron- decreased sTfRs- N to decreased TIBC- decreased %Saturation- decreased Serum ferritin- increased Marrow iron- increased Sideroblasts- decreased |
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AOI Increased/Decreased: MCV- MCHC- Hepcidin- ZPP- BM cellularity- Marrow Retics- |
MCV- decreased MCHC- decreased Hepcidin- increased ZPP- increased BM cellularity- erythroid hypoplasia Marrow Retics- decreased |
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What will the RBC morphology typically look like in AOI? |
Normo- to microcytic Normo- to hypochromic |
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TIBC will be ___________ in AOI because transferrin is a _______________. |
TIBC will be decreased in AOI because transferrin is a negative acute phase reactant. |
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What will the RBC morphology typically look like in Sideroblastic anemia? |
Dimorphic population Normo- to microcytic Normo- to hypochromic Target cells Basophilic stippling Pappenheimer bodies |
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SA Increased/Decreased: Serum iron- sTfRs- TIBC- %Saturation- Serum ferritin- Marrow iron- Sideroblasts- |
Serum iron- increased (can lead to Fe overload) sTfRs- decreased TIBC- N to decreased %Saturation- increased Serum ferritin- increased Marrow iron- increased Sideroblasts- increased (ringed) |
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SA Increased/Decreased: MCV- MCHC- Hepcidin- ZPP- BM cellularity- |
MCV- decreased MCHC- decreased Hepcidin- increased ZPP- increased BM cellularity- erythroid hyperplasia (ineffective erythropoiesis, *ringed sideroblasts, myeloid/megakaryocytic precursors abnormal) |
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Lead poisoning can cause __________. What laboratory findings would also be found in this case? |
Lead poisoning can lead to SA. -Increased lead level -Coarse basophilic stippling -Accumulation of iron and RBC protoporphyrin -Increased urinary ALA, coproporphyrinogen |
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What is the pathophysiology of Hemochromatosis and what are the typical lab findings? |
Accumulation of iron in the tissues (Typically does NOT lead to anemia) -Normal erythropoiesis -Increased liver enzymes -Increased iron studies (TIBC N) |
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What are some typical causes of hemochromatosis? |
Hereditary: -Recessve, mutant gene for Fe regulation/absorption -Absorb 2-3X as much dietary iron Secondary: -Acquired/Secondary to other inherited anemias -Repeated transfusions- leads to increased iron |
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What is the treatment for hemochromatosis? |
Therapeutic phlebotomy Chelation therapy |
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What are porphyrias, what are they caused by, and what symptoms can result? |
A group of rare diseases (usually hereditary) that result in errors in heme biosynthesis. Each disorder caused by a specific enzyme defect that results in an accumulation of a specific porphyrin. May result in hemolytic anemia. |
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Megaloblastic anemias are caused by... |
-Vitamin B12 deficiency -Folate deficiency |
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Megaloblastoid anemia is caused by... |
Drugs that interfere with DNA synthesis or inhibit folate |
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What are the functions of vitamin B12? |
-Aid in folate metabolism -Degradation of certain fatty acids (this results in neurological damage) |
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What is the name for Vitamin B12? |
Cobalamin |
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What is the function of Intrinsic factor? |
Needed for Vitamin B12 absorption Secreted by parietal cells, binds to dietary B12 in intestine, and transports to Ileum mucosal cell |
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What is the function of Folate? |
-Required for DNA synthesis (B12 is required for folate conversion) |
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What are the major causes of Vitamin B12 deficiency? |
-Dietary deficiency of animal protein (esp. kids) -Increased demand -Diseased Ileum -Competing organisms (D. latum- fish tapeworm) -Gastric failure (loss of parietal cells/IF) -Pernicious anemia (autoimmune anti-IF and anti-parietal cells) |
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What are the major causes of Folate deficiency? |
-Diet (alcoholism, elderly) -Chronic hemolysis -Malabsorption syndromes (Celiac disease) -Increased demand (pregnancy, nursing, kids, malignancy, dialysis) |
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What is the classic RBC morphology in megaloblastic anemias? |
-Megaloblastic changes (asynchronous) -Macrocytic -Ovalocytes -Anisocytosis -Dacryocytes -Basophilic stippling -H.J. bodies -Cabot rings |
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VitB12 deficiency Megaloblastic anemia: MCV- MCHC- Bone Marrow- WBC- PLT- Serum B12- |
MCV- increased MCHC- Normal Bone Marrow- Erythroid hyperplasia, Ineffective erythropoiesis, Mild hemolysis (increased bilirubin, LDH) WBC- decreased PLT- decreased (maybe) Serum B12- decreased |
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What are the major anemias caused by impaired production of RBCs? |
IDA, AOI, SA, Porphyrias, Megaloblastic anemias, Aplastic anemia, Congenital dyserythropoietic anemia, Myelophthisic anemia, Anemia of Chronic Renal disease, Anemia of Liver disease, Endocrine disorder anemia, Anemia of Viral infections |
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What is the classic WBC morphology in megaloblastic anemias? |
Neutropenia Hypersegmented PMNs Large granulocyte precursors (ex huge bands) |
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What is the classic PLT morphology in megaloblastic anemias? |
Megakaryocytes may be: -abnormally large -decreased degranulation -bizarre nuclear morphology |
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Folate deficiency Megaloblastic anemia: MCV- MCHC- Bone Marrow- WBC- PLT- Serum/RBC Folate- |
MCV- increased MCHC- Normal Bone Marrow- Erythroid hyperplasia, Ineffective erythropoiesis, Mild hemolysis (increased bilirubin, LDH) WBC- decreased PLT- decreased (maybe) Serum/RBC Folate- decreased |
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Macrocytic ovalocytes and symptoms of neurological damage are indicative of? |
Megaloblastic anemia caused by B12 deficiency |
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A positive test for anti-IF and/or anti-parietal cells is associated with what condition? |
Pernicious anemia Autoimmune disease that causes vit B12 deficiency-megaloblastic anemia. |
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What is stomatitis and what condition is it associated with/caused by? |
Stomatitis is sores in the mouth usually associated with megaloblastic anemia due to the rapid cell turnover. |
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What can you measure for early detection of megaloblastic anemia and how do they indicate the cause? |
Methylmalonic acid (MMA) Increased in B12 deficiency Homocysteine Increased in B12 deficiency Increased in Folate deficiency |
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What is aplastic anemia? |
Failed production of RBCs, PLTs, and WBCs due to damage of hematopoietic stem cells. |
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What condition will have relative lymphocytosis and why? |
Aplastic anemia Because you have low WBCs but lymphs are the last population to decrease so looks like you have increased lymphs. Will progress to low levels of lymphs too and patient will have increased infections |
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Aplastic Anemia increased/decreased: WBC- RBC- PLT- EPO- Bone Marrow- |
WBC- decreased RBC- decreased PLT- decreased EPO- increased Bone Marrow- hypocellular |
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What will the RBC morphology typically be in aplastic anemia? |
Macrocytic (slightly) Normochromic |
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Patients with aplastic anemia have __________PLT levels which leads to _______________. |
Low PLT levels Leads to petechiae and bleeding |
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What are the causes of aplastic anemia? |
-Idiopathic (unknown) -Acquired radiation, chemical exposure, drugs, chronic viral infection, rare causes (pregnancy, PNH) -Hereditary Fanconi's anemia, Diamond Blackfan |
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Fanconi's anemia is what kind of anemia? What are the characteristics? |
Hereditary aplastic anemia -Fragile, unstable stem cell chromosomes -Physical abnormalities (often skeletal) -High incidence o Leukemia -Most die in their 20's |
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Congenital Pure Red Cell Aplasia is what kind of anemia? What are the characteristics? |
Hereditary aplastic anemia (also called Diamond Blackfan) -Defective stem cells cannot commit to RBC precusors (but can commit to all other cell lines) -WBC/PLT normal -Minor physical abnormalities |
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What are some treatment options for aplastic anemia? |
-Stem cell transplant -Supportive therapy (maintain Hgb, PLTs) -Immunosuppressive therapy (sometimes caused by infection so may help) |
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What is Congenital Dyserythropoietic Anemia? |
An uncommon hereditary condition that results in changes in erythroid cell nuclear membrane and chromatin pattern (Erythropoiesis is messed up) **3 types of CDA |
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What are three common characteristics of CDA? |
Common characteristics: -RBCs destroyed in bone marrow (increased indirect bilirubin, ineffective erythropoiesis) -Bizarre RBCs (ex multinucleated erythroblasts) -Morphology: Oval macrocytes, basophilic stippling, cabot rings |
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Bizarre RBC precursors with nuclear bridges can sometimes be seen in what condition? |
CDA (Congenital Dyserythropoietic anemia) |
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What is myelophthisic anemia? |
Anemia associated with bone marrow infiltration |
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What is the cause of myelophthisic anemia? |
Marrow infiltration by abnormal or tumor cells -Crowds out normal blood cell precursors -Damages stem cells Usually leads to Extramedullary hematopoiesis -Increased immature cells in circulation |
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What is the typical WBC, RBC, and PLT morphology in myelophthisic anemia? |
-Marked poik -Dacryocytes -Schistocytes (from treatment) -Megakaryocyte fragments -Giant PLTs -Leukoerythroblastosis (both nRBC and myeloid precursors in circulation) |
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What are the possible mechanisms of Anemia of Chronic Renal Disease? |
-EPO deficiency or suboptimal response -Toxin build-up due to kidney disease- hemolysis -Blood loss due to decreased/dysfunctional PLT -Chronic inflammation (iron unavailable) -Dialysis- folate depletion |
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What is the typical RBC morphology in Anemia of Chronic Renal Disease? |
Hypoproliferation Normocytic (starting out) Normochromic (starting out) Marked anisocytosis Burr cells Acanthocytes Howell Jolly bodies Pappenheimer bodies |
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You would have high serum creatinine and BUN levels in what condition? |
Anemia of Chronic Renal Disease |
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What are the possible mechanisms of Anemia of Liver Disease? |
-Hemolysis due to acanthocytes (rigid, lack permeability) -Blood loss due to decreased coagulation factors (most are produced by liver) -Hypersplenism- PLTs sequestered, chronic bleeding, decreased RBC survival |
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What is the typical RBC morphology in Anemia of Liver Disease? |
-Hypoproliferation -Normocytic -Normochromic -Round macrocytes (NO megaloblastic changes) -Acanthocytes -Target cells (increased, defective membrane lipids/cholesterol- affects RBC membranes) |
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What is the mechanism of Endocrine Disorder Anemia? |
Other hormones besides EPO play a role in the regulation of erythropoiesis Examples: -Pituitary hormones control androgens (account for differences in Hgb between sexes) -Hypothyroid decreases demand for oxygen |
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What is the mechanism of Anemia of Viral Infections? |
Infections can affect the process of RBC production Examples: -Measles- iron sequestered in macrophages -Parvovirus B19- aplastic crisis -HIV- hypoproliferative anemia -(Bacterial, fungal, parasitic infections too) |
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What cause of anemia would not reflect anemia in the RBC values and why? |
Anemia due to acute blood loss Because when bleeding losing plasma and cells at same rate and body has not had time to respond and retain fluid portion Once fluid retention takes place though, would see low Hct (more plasma, fewer cells) |
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What is hydremia and what are the characteristics? |
Relative Anemia caused by an increase in plasma volume -Total RBC mass (mg/kg body weight) and oxygen carrying ability unaffected -H&H decreased due to plasma increase (will "appear" anemic) |
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What are some typical causes of hydremia? |
Pregnancy Hyperproteinemia Massive IV or FFP transfusion (Things that increase fluid) |
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What are some indicators of Increased RBC destruction (hemolysis)? |
-Increased serum indirect bilirubin -Decreased haptoglobin -Hemoglobinemia (excess Hgb in plasma) -Hemoglobinuria -Hemosiderinuria -Schistocytes -LDH isoenzymes 1 and 2 |
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What are some indicators of Increased RBC production? |
-Retics/RPI -Erythroid hyperplasia in BM (if BM responding normally) |
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What steps would you take to establish presence of/determine the cause of hemolysis? |
1. Coombs Test (DAT) 2. Negative DAT- peripheral blood smear 3. Further laboratory investigations depending on RBC morphology |
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What are the four main groups of Intrinsic Abnormalities causing RBC destruction? |
-Hereditary spherocytosis (HS) -Hereditary Elliptocytosis (HE) (includes HPP and SAO) -Hereditary Stomatocytosis -Hereditary Xerocytosis Classified by RBC morphological abnormality |
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Defect in the spectrin/ankyrin membrane complex can be in the ________ or ________ interaction and is associated with _________ and ___________ respectively. |
Defect in vertical interaction associated with Hereditary spherocytosis. Defect in horizontal interaction associated with Hereditary Elliptocytosis (mild). (Severe horizontal defect=HPP) |
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What is the cause of hereditary spherocytosis and how does it lead to anemia? |
Spectrin/ankyrin defect in the vertical interaction Leads to decreased RBC survival because are rigid and less deformable- hemolyzed in the spleen (extravascular) |
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What is the severity of HS, the classic presentation of HS and what is the treatment? |
-Varies from silent carrier to severe hemolysis -Presentation: Jaundice, Splenomegaly, Anemia -If moderate to severe hemolysis, can treat with splenectomy (but still have membrane defect) |
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HS increased/decreased: MCV- MCHC- Retics- DAT- Folic Acid- Indication of hemolysis- |
MCV- N to decreased MCHC- increased Retics- increased DAT- negative Folic Acid- decreased Indication of Hemolysis- Extravascular so usually no Hgbemia, Hgburia, Hemosiderinuria) |
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What is the typical RBC morphology in HS? |
Polychromasia Anisocytosis Spherocytes |
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What is the principle of the Osmotic fragility? |
When in hypotonic solution, water is drawn into the cell by osmosis and will eventually lyse if hypotonic enough. Cells that are already spherical cannot take in as much water before lysis occurs = increased osmotic fragility. |
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Spherocytes have ________osmotic fragility. |
Increased |
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Target cells have _________ osmotic fragility. |
Decreased |
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Normal RBC populations begin to lyse in saline solutions of about _________%. |
0.45% |
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% hemolysis can be calculated in relation to osmotic fragility by using this equation... |
( O.D. sample supernatant / O.D. supernatant of water tube ) * 100% |
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What is the procedure for the osmotic fragility test?
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1. Draw sample in Heparin tube (NOT EDTA)
2. Add blood to series of increasing saline dilutions up to pure water 3. Incubate RT 30 mins 4. Centrifuge, measure supernatant at 540nm to determine amount of Hgb released 5. Calculate/graph % hemolysis |
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What is the cause of hereditary Elliptocytosis and how does it lead to anemia? |
Hereditary spectrin/ankyrin defect (involving alpha or beta spectrin chain) in horizontal interaction (affects deformability, ability to regain normal shape) Can lead to severe hemolysis = anemia |
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What is the treatment for HE? |
Splenectomy |
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What conditions have been linked to various blood group antigens? |
Different types of HE |
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What are the different types of HE? |
-Spherocytic HE (hybrid of HE and HS) -SE Asian Ovalocytosis (SAO) -Hereditary Pyropoikilocytosis (HPP) |
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Hereditary Elliptocytosis: MCV- MCHC- Retics- Osmotic Fragility- RBC morphology- |
MCV- N to increased MCHC- N Retics- increased Osmotic Fragility- N Elliptocytes Mildly heat sensitive RBCs (maybe) |
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What is the proposed significance of SAO and what is the typical RBC morphology? |
Proposed to be a protective effect against malaria "Spoon"-shaped ovalocytes with transverse bar across central pallor space |
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What is the cause of HPP? |
-Defect in alpha or beta spectrin chain, caused by mutation
-Decreased synthesis of alpha spectrin |
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Hereditary Pyropoikilocytosis: MCV- MCHC- RBC morphology- |
MCV- very decreased MCHC- increased (usually) Elliptocytes Spherocytes Bizarre micro poik (RBC budding, fragments, bizarre shaped RBCs) |
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What population does HPP usually affect and what is a typical presentation of HPP? |
Black population most affected Presentation: -facial bone abnormalities (BM expansion) -gallbladder disease -slowed growth |
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What is unique/characteristic of RBCs in HPP? |
Thermal instability -cells fragment at 45C (normal cells fragment at 49C) |
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What is another name for Hereditary Stomatocytosis? |
Hydrocytosis |
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What is the cause of Hereditary Stomatocytosi? |
Deficiency of stomatin (in most patients)
-membrane protein theorized to regulate ion channel Na+/K+ pump failure -influx of Na+ exceeds eflux of K+ = water in |
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What is the treatment for Hereditary Stomatocytosis? |
Splenectomy (Would eliminate macrophages that eat abnormal RBCs so increased chance of RBC survival) |
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Hereditary Stomatocytosis: MCV- MCHC- Osmotic Fragility- 2,3 BPG- RBC morphology- |
MCV- increased MCHC- decreased Osmotic Fragility- increased 2,3 BPG- decreased Stomatocytes |
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How does Hereditary Stomatocytosis lead to anemia? |
-Mild to severe hemolysis = anemia -Decreased 2,3 BPG = functional anemia (Increases Hgb affinity for oxygen so less oxygen delivered to tissues |
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What are some causes of Acquired Stomatocytosis? |
-Acute alcoholism -Drug therapy -Liver disease -Cariovascular disease -Marathon running (transiently, occassionally) (little hemolysis, may be drying artifact) |
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What is the defect in Hereditary Xerocytosis? |
Unkown RBC permeability defect that causes cells to lose K+ Cells become dehydrated |
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What is the treatment for Hereditary Xerocytosis? |
Splenectomy does NOT correct hemolysis (Because cells are not specifcally sequestered in the spleen) |
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Hereditary Xerocytosis: MCV- MCHC- Osmotic Fragility- 2,3 BPG- RBC morphology- |
MCV- increased MCHC- increased Osmotic Fragility- decreased 2,3 BPG- decreased Stomatocytes Target cells "Puddle" cells (Hgb all on one side) Macrocytes ? |
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What is the defect in Acanthocytosis and what are the causes? |
Defect: Abnormal membrane lipids (contain excess cholesterol) Causes: -Abetalipoproteinemia- hereditary (low density lipoproteins absent) -Liver disease -Malnutrition -Certain blood groups -Vitamin E deficiency |
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What is the mechanism of Anemia of Alcoholism? |
Can be a hemolytic anemia -decreased deformability of RBCs Can be a megaloblastic anemia -Folate deficiency due to poor diet and ethanol interference with folate metabolism (Ethanol has a direct toxic effect on precursor cells, marrow cellularity, RBC morphology) |
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What is the most common hereditary X-linked enzyme deficiency that causes anemia? |
G6PD Deficiency |
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How does G6PD deficiency result in anemia? |
G6PD is responsible for NADPH generation and without NADPH RBCs are vulnerable to oxidative injury- decreased survival |
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What are some causes of oxidative injury (introduction of oxidative agents) related to G6PD deficiency? |
Drugs Infections Favism Neonatal jaundice |
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What is the cause/mechanism of hemolysis in G6PD deficiency? |
1. Heinz body formation from oxidative agents in older cells causes hemolysis 2. G6PD deficiency mostly in older cells 3. Hemolysis stops after older cells destroyed 4. So number of reticulocytes affects the rate of hemolysis (self-limiting) |
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What is the typical presentation of G6PD deficiency? |
-Most patients never experience clinical symptoms -Can have chronic, detectable anemia -Can have slightly reduced RBC lifespan (normal RBC morphology because BM compensates) -Can have episodic hemolytic crisis: moderate to severe anemia |
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What are the lab findings, RBC morphology during a hemolytic crisis with a G6PD deficiency? |
Normocytic Normochromic Bite cells (Morphology depends on severity of hemolysis) Heinz bodies (supravital stain) Increased Retics |
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What is the principle of the G6PD screening test and what are the results? |
Looking for fluorescence from NADPH under UV light G6PD deficient cells cannot generate NADPH so they do NOT show fluorescence |
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What is the most common hereditary Embden-Meyerhof pathway enzyme deficiency associated with anemia? |
Pyruvate Kinase (PK) deficiency |
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What is the cause of hemolysis in PK deficiency? |
Unknown ATP is decreased since Embden-Meyerhof pathway is main source of cellular energy |
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What is the principle of the PK screening test and what is the result? |
Looking for fluorescence from NADH under UV light. PK deficient cells cannot convert NADH to NAD so they DO show fluorescence. |
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What are the laboratory findings/RBC morphology with PK deficiency? |
Anemia can be fully compensated to very severe Increased Retics Increased 2,3-BPG Morphology not prominent factor |
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What is the treatment for G6PD and PK deficiency? |
G6PD avoid fava beans, treat infections early... PK Supportive therapy only Splenectomy does not stop hemolysis but can slightly increase Hgb |
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What is Paroxysmal Nocturnal Hemoglobinuria (PNH)? |
Acquired myeloproliferative disorder Defect in pluripotent stem cell - GPI anchor protein deficiency Results in episodic hemolysis at night |
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What is the mechanism of hemolysis in PNH? |
-Membrane defect -GPI anchor protein deficiency -GPI missing means that cells can fix complement -Especially likely to happen in low pH or reduced ionic strength environments (AT NIGHT!) -Results in intravascular hemolysis |
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What are the typical causes of hemolysis in PNH? |
Low pH Reduced ionic strength Infections Vaccinations Transfusions X-ray dye Strenuous exercise (possibly) (related to reduced pH?) |
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What is the typical presentation of patients with PNH? |
-Mild to severe anemia (may evolve into aplastic anemia, bone marrow failure) -Nocturnal hemoglobinemia -Nocturnal hemoglobinuria (Only 25%) -Hemosiderinuria (may lead to IDA) -Thrombosis (PLT activation by complement) -Increased infections/complications |
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Paroxysmal Nocturnal Hemoglobinuria: RBC- PLT- WBC- |
RBC- dual population: normal and neoplastic cells PLT- thrombocytopenia (low PLT) WBC- Neutropenia and dysfunction |
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How do you test for PNH? |
Flow cytometry Analyze RBCs and Granulocytes for surface expression of GPI anchoring proteins |
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What is Microangiopathic hemolytic anemia (MAHA)? |
An extrinsic abnormality damaging RBCs RBCs pass through fibrin strands or damaged vessels and are fragmented |
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What are the disorders associated with MAHA? |
-Disseminated Intravascular Coagulation (DIC) (acute condition) -Thrombotic Thrombocytopenic purpura (TTP) -Hemolytic Uremic Syndrome (HUS) |
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What is the hallmark of MAHA? |
Schistocytes |
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What are the precipitating factors of TTP? |
Immunological disease Infectious disease Pregnancy Hereditary |
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What is Thrombotic Thrombocytopenic Purpura and what are the laboratory findings? |
MAHA
Hemolytic anemia with schistocytes Thrombocytopenia (hemorrhage) Neurological signs (fluctuating) Fever Progressive renal disease |
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What is the mechanism of anemia in TTP? |
Small PLT aggregates on endothelial cells that cause occlusion of capillaries (microclots) (Microclots can enter the brain)! Proposed mechanism: ADAMTS13 deficiency ADAMTS13 (Protease) normally cleaves Von Willebrand factor (transmembrane glycoprotein) into smaller fragments, but with deficiency PLTs aggregate on full length VWF |
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What is Hemolytic Uremic Syndrome and what are the laboratory findings? |
Hemolytic anemia (similar to TTP) MAHA Thrombocytopenia Acute renal failure |
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What is the typical cause of HUS? |
Typically found in young children Typically found following Enteric infections -toxins targets kidney, trigger DIC -cause PLT activation |
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How is HUS distinguished from TTP? |
By severity of renal failure and absence of neurologic symptoms (HUS-acute renal failure, TTP-progressive failure) |
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What is the treatment for TTP? |
FFP transfusion (for some cases) Anti-PLT drug (ex aspirin) Steroid treatment |
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What is the treatment for HUS? |
Dialysis Transfusion (Condition may be recurrent) |
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What are some other causes of Non-Immune hemolytic anemia? |
Malignant hypertension DIC/HELLP Syndrome (Coag disorder) Chemotherapy induced Heart valve replacement (less of an issue now) March Hemoglobinuria (usually no schistocytes) Drugs and chemicals Venoms (cause coagulation/occlusion of capillaries) Burns Microorganisms (Malaria, Babesia, Bartonella, Clostridia, Strep) |
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What are some examples of Auto-immune hemolytic anemias? |
Warm reactive (at 37C)-most common, IgG, DAT+ Cold reactive (at 4C or 25C)- IgM Cold Agglutinin disease syndrome Paroxysmal Cold Hemoglobinuria (PCH) Drug Induced |
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What are the characteristics of Cold Agglutinin disease syndrome? |
-Anti-I -Secondary forms asscoiated with infection -Induced by cold weather -Can result in intravascular hemolysis due to complement fixation -DAT+ at 15-32C (usually only + for complement) -MCHC > 36 |
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What are the causes of MCHC > 36? |
-Cold agglutinin -Spherocytes -Icterus -Lipemia -Intravascular hemolysis |
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What are the characteristics of Paroxysmal Cold Hemoglobinuria? |
-More common in kids -Associated with viral disorders -IgG binds to RBCs at LOW temps- causes complement fixation -Donath-Landsteiner antibody (classic) (anti-P) |
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How do you test for PCH? |
Donath-Landsteiner test Blood sample in two tubes: Tube 1: incubate at 37C Tube 2: incubate at 4C then 37C Centrifuge and observe for hemolysis (+ in tube 2 = PCH) |
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What are the possible mechanisms of drug induced hemolytic anemia? |
-Immune complex formation (drug and ab complex activates complement) -Hapten (drug bound to RBC stimulates anti-drug antibody production) -Membrane modification- drug binds to cell and causes protein adsorption- stimulates auto-antibody production) |
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What are some examples of Alloimmune hemolytic anemia? |
Transfusion reaction -Immediate (usually ABO) -Delayed (previously formed ab just low titer) HDFN |
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How can you test for detection of Fetal-Maternal Bleed? |
Kleihaure Betke (Acid Elution slide test) Hgbs eluted from RBCs in acid bath Hgb F will elute at slower rate (cells retain Hgb) Adult Hgb will elute at faster rate (cells lose Hgb) Using stain for Hgb, can distinguish maternal/fetal cells and volume of bleed |
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What is the defect in hemoglobinopathies? |
There is a defective globin chain amino acid sequence (substitution, deletion, or addition) |
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Hgb A is made up of what globin chains? |
alpha2 beta2 (>95% of Hgb in adults) |
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Hgb A2 is made up of what globin chains? |
alpha2 delta2 (~2% of Hgb in adults) |
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Hgb F is made up of what globin chains? |
alpha2 gamma2 (1-2% of Hgb in adults) |
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What is the most common hemoglobinopathy and what is the defect? |
Hemoglobin S
Beta chain defect 6th amino acid glutamic acid substituted with valine |
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What is the mechanism of anemia in Hemoglobin S hemoglobinopathy? |
Hgb S is less soluble when deoxygenated and forms long, stiff bundles of Hgbs that deform RBC (sickle shape) Sickling occludes microvasculature Sickle cell crisis |
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What is the proposed reason for why the frequency of the Hgb S gene is greatest in regions with Malaria? |
Parasites utilize oxygen in RBCs (Infested RBC = deoxygenated = sickle cell RBC) |
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What are two major promoters of sickling? |
Hypoxia Low pH (decreases Oxygen affinity) |
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Why does Hgb S not usually manifest in children 6 months old and younger? |
Because it is a Beta chain defect Majority of their Hgb will be Hgb F (alpha2 gamma2) |
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What are the types of Sickle cell crisis that result in anemia? |
Vaso-occlusive crisis- auto-splenectomy, increased infections Aplastic crisis- BM suppressed by infections, can't compensate Hemolytic crisis- shortened RBC lifespan Sequestration crisis- massive pooling of sickle RBCs in spleen |
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What is the RBC morphology for a patient Homozygous for Hgb S? |
Normocytic to Microcytic Normochromic to hypochromic Sickle cells Target cells Basophilic stippling HJ bodies Polychromasia nRBCs |
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Homozygous for Hgb S: WBC- PLT- Tube solubility test- Bone marrow- |
WBC- often neutrophilia (shift to the left) PLT- often thrombocytosis Tube solubility test- positive Bone marrow- Erythroid hyperplasia |
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What is the Hgb electrophoretic pattern for a patient Homozygous for Hgb S (sickle cell anemia)? |
Hgb S *NO Hgb A Increased Hgb F Normal Hgb A2 |
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What is the RBC morphology for a patient Heterozygous for Hgb S? |
Normal morph -Some sickling (under extreme conditions of hypoxia) -Possible target cells |
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Heterozygous for Hgb S (sickel cell trait): WBC- PLT- Tube solubility test- Bone marrow- |
WBC- normal PLT- normal Tube solubility test- positive Bone marrow- normal Generally asymptomatic |
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What is the Hgb electrophoretic pattern for a patient Heterozygous for Hgb S (Sickel cell trait)? |
20-40% Hgb S * >60% Hgb A Normal-Increased Hgb A2 Normal Hgb F |
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How do you tell the difference between homozygous and heterozygous Hgb S? |
Hgb electrophoresis Heterozygous WILL HAVE Hgb A |
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What is the treatment for Hgb S anemia? |
Supportive therapy Hydroxyurea (increases amount of Hgb F) Bone marrow transplant |
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What hemoglobinopathy is the second most common in the US and what is the defect? |
Hgb C Beta chain defect 6th amino acid glutamic acid is substituted with lysine |
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What are the lab findings/RBC morphology in Hgb C disease (homozygous)? |
Hemolytic anemia Noromcytic to microcytic Normochromic to hypochromic Target cells Crystal cells Envelope cells Polychromasia (maybe nRBCs) |
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What are the lab findings/RBC morphology in Hgb C trait (heterozygous)? |
Asymptomatic |
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What is the most common double heterozygous hemoglobinopathy and what is the defect? |
Hgb SC Beta chain defects Amino acid substitution on 2 globin chains |
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What is the clinical presentation of Hgb SC hemoglobinopathy? |
Resembles Mild Sickle Cell disease Mild to severe Hemolytic anemia Moderate Splenomegaly Less frequent vaso-occlusive complications |
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What are the lab findings/RBC morphology in Hgb SC? |
Tube solubility test- positive Noromcytic to microcytic Normochromic to hypochromic Few Sickle cells Target cells Hgb SC Crystal cells Polychromasia |
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What is the Hgb electrophoretic pattern for Hgb SC? |
Hgb S Hgc C Hgb F normal NO Hgb A |
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What is the screening test for Hgb S and what is the principle? |
Hgb Tube Solubility test (Sickledex) -When Hgb S is deoxygenated it crystallizes and creates cloudy red suspension -Normal Hgb remains clear (Reagents: Saponin to lyse RBCs, buffers, Sodium hyrosulphite reducing agent) |
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What are some sources of false positives with Hgb Tube solubility? |
Hyperproteinemia (ex myeloma) Polycythemia Other abnormal Hgbs (Hgb C, Hgb Barts) |
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What are some sources of false negatives with Hgb Tube solubility? |
Anemia (not enough Hgb present in sample) Low Hgb S concentration (ex infant) Reagent deterioration |
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What is the procedure for hgb electrophoresis? |
-Hemolysate (lyse cells) is applied to solid supporting strip (usually cellulose acetate) -Buffered to alkaline pH (8.4 - 8.6) -Electrical current applied for specified time |
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What is the next step if you get an abnormal pattern Hgb electrophoresis and when is this necessary? |
Perform Hgb electrophoresis on different substrate and acidic pH. Always necessary when you get an abnormal Hgb pattern |
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What methodologies are used for Newborn hemoglobinopathy screenings in the US? |
Isoelectric focusing (IEF) (most common) HPLC Molecular DNA based (most effective) |
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Roughly how many other abnormal Hgbs exist and what are some examples? |
Hundreds exist -Hgb D -Hgb G -Hgb O-Arab -Hgb D-Punjab -Hgb C-Harlem -Hgb E -Hgb M (unstable) |
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What are the characteristics of Hgb E and what is the significance? |
Beta chain defect Mild anemia Microcytes Target cells Resembles a thalassemia because of decreased Hg production |
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What is the defect in Hgb M and what is significant about it? |
Unstable Hgb Alpha or beta chain defect - substitution Prevents Fe oxidation (30-50% Methemoglobin) so oxygen cannot bind Hydroxide ion takes place of oxygen Sample is brown Heinz bodies |
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What are screening tests for unstable Hgbs? |
Heinz bodies Heat denaturation Isopropanol precipitation (stress RBCs and look for Hgb precipitation. Normal RBCs won't have much precipitaiton) |
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What is a thalassemia and how are they classified? |
Decreased production of one or more globin chains Classified by which globin chain has decreased production |
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What are the two families of globin chains? |
Alpha family: alpha and zeta chains (a and z) Beta family: beta, delta, gamma, and epsilon chains |
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Each normal Hgb contains ____________ and ___________. |
Contains: Two alpha family genes Two beta family genes |
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The genes for alpha family chains are on what chromosome? The genes for beta family chains are on what chromosome? |
Alpha family: chromosome 16 (one zeta gene, TWO alpha genes) Beta family: chromosome 11 (one of each: beta, delta, gamma (G+A), epsilon) |
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What globin chain/Hgb is affected in Beta-thalassemias? |
Beta chain production is affected Therefore, Hgb A production is affected Patient may have increased Hgb A2 or Hgb F to compensate |
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When beta chain production is decreased, what are the effects? |
-Total Hgb is reduced, body compensates by making more Hgb A2 or Hgb F -Accumulation of free alpha chains (these are very unstable and denature/precipitate =*RBCs destroyed in bone marrow) |
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Beta/Beta = Beta0 = Beta+ = Beta++s = |
B/B = normal genes inherited, one from each parent B0 = abnormal gene- NO beta chains produced B+ = abnormal gene- decreased production of beta chains B++s = abnormal gene- mildly decreased production of beta chains (associated with silent carrier) |
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Beta++s/Beta is what Beta-thalassemia? What are the characteristics? |
Silent carrier beta-thalassemia -Heterozygous beta mutation- only slightly decreased levels of beta chain production -Normal alpha/beta ratios -Asymptomatic |
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Homozygous for silent carrier Beta-thalassemia results in? |
Moderate microcytic, hypochromic anemia Increased Hgb F Increased Hgb A2 (Rare genotype) |
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Beta-thalassemia minor is what genotype? |
Heterozygous (B+ / B) OR (B0 / B) |
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What is the RBC morphology in Beta-thalassemia minor? |
Microcytic Hypochromic Anisocytosis Target cells Ovalocytes Basophilic stippling Polychromasia (smear- cannot differentiate from other micro/hypochromic anemia) |
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Beta-thalassemia minor: Anemia- Retics- Osmotic fragility- Bilirubin- Bone marrow- Serum Fe studies- |
Anemia- mild to moderate Retics- increased Osmotic fragility- decreased Bilirubin- increased/high Bone marrow- Erythroid hyperplasia Serum Fe studies- normal |
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Beta-thalassemia major is what genotype? |
Homozygous (B+ / B+) OR (B+ / B0) OR (B0 / B0) |
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What is the RBC morphology in Beta-thalassemia major? |
Microcytic Hypochromic Anisocytosis Target cells Ovalocytes Basophilic stippling Polychromasia Many nRBCs (morph really messed up) |
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Beta-thalassemia major: Anemia- Retics- Osmotic fragility- Bilirubin- Bone marrow- Serum Fe studies- |
Anemia- severe Retics- increased (many nRBCs) Osmotic fragility- decreased Bilirubin- increased/high BM- Erythroid hyperplasia (marrow expansion) Serum Fe/Ferritin increased (Fe overload) |
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What are the big differences in B-thal major from B-thal minor? |
B-thal major patients have all of the same symtoms as B-thal minor just much more severe -Many nRBCs -Hemolysis due to free alpha chains -Extramedullary hematopoiesis -Hgb A2 and Hgb F increased -Marked bone changes -Serum Fe/ferritin increased |
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Why is serum Fe and ferritin increased in B-thal major? |
Because of increased iron absorption and increased RBC destruction |
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Patients with B-thal major have a grave prognosis. Why? What are some treatment options? |
Grave prognosis because of iron overload, bone marrow expansion, and anemia. Can give chelating drugs for iron toxicity, BM transplant, and possibly drugs to stimulate gamma gene (make more Hgb F) |
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What is Beta-thalassemia intermedia? |
Inbetween major and minor Homozygous for mild decrease gene mutation OR doubly heterozygous for mild mutations Clinical manifestations range from mild to severe |
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What is Delta Beta thalassemia? |
-Similar to B-thal intermedia -Cannot produce Hgb A OR Hgb A2 in normal quantities -Increase in gamma chain synthesis -Increased Hgb F to compensate -Results in mild microcytic/hypochromic anemia |
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What is Hereditary Persistence of Fetal Hemoglobin (HPFH)? |
-Rare Beta chain family defect -Closely related to Delta Beta Thalassemia -Continued synthesis of high levels Hgb F in adult life -No other symptoms of thalassemia |
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What is Hemoglobin E? |
Beta chain defect with diminished production |
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What is Hemoglobin Lepore? |
Delta Beta chain fusion with diminished production |
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What is the genotype for the silent carrier alpha-thalassemia? |
-a / aa One of four alpha genes is defective Most patients asymptomatic |
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What is the genotype for alpha-thalassemia minor and what is the clinical manifestation? |
Heterozygous (-- / aa) OR (-a / -a) Two of four genes are defective Results in mild microcytic hypochromic anemia (Very similar to B-thal minor) |
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What is Hemoglobin H disease? |
-- / -a alpha-thalassemia (3 of 4 alpha genes defective) |
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What is the clinical manifestation of Hemoglobin H disease? |
Similar to Beta-thal major but less severe Alpha chain production severely decreased Many free beta chains Free chains form tetramers: *Hgb barts: gamma 4 tetramer (only trace amts) *Hgb H: beta 4 tetramer (VERY unstable Hgb- forms Heinz bodies) |
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What is Hydrops Fetalis? |
-- / -- alpha-thalassemia All four alpha genes defective Incompatible with life |
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What is the clinical manifestation of Hydrops Fetalis? |
*Very high level of Hgb Barts (gamma 4) Fatal Hgb Barts has extremely high affinity for oxygen so oxygen won't release to tissues Fetal death occurs by tissue hypoxia |
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What is Hemoglobin Constant Spring? |
Alpha chain defect with diminished production |
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What are some examples of Thalassemias inherited in combination with hemoglobinopathies? |
Hgb S / B-thal Hgb S / a-thal Hgb C / B-thal (Abnormal Hgb chain AND decreased production) |
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What are other typical lab findings with Thalassemias? |
Decreased osmotic fragility Heinz body detection (supravital stain) Hgb electrophoresis |
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What is critical in the diagnosis of Beta-thalassemias and what are the results? |
Hgb Electrophoresis Decreased Hgb A Increased Hgb A2 and/or Hgb F |
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What are the results of Hgb electrophoresis for alpha-thalassemias and what does it tell you? |
ALL normal Hgbs affected (all contain alpha chains) so will not see shift as you will in Beta-thalassemias (all proportionally decreased) *Will detect abnormal Hgbs though (Hgb H and Hgb Barts) |
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What are the methods to quantitate Hgb F? |
-Acid Elution Slide Test (Kleihauer Betke) -Alkali Denaturation (Hgb F only Hgb not denatured) -Flow cytometry (monoclonal anti-Hgb F ab) -HPLC (can quantitate Hgb F and Hgb A2) |
