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41 Cards in this Set
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Blood and Lymph- Hemoglobinopathies by Turnicky
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Blood and Lymph- Hemoglobinopathies by Turnicky
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Hemoglobinopathies are....
Qualitative vs Quantitative |
Abnormalities in hemoglobin synthesis leading to impaired binding or transport of oxygen
Qualitative: defect in formation of the Hb molecule. Properties of that Hb may lead to pre-mature hemolysis. Quantitative: Decreased synthesis of globin with resultant decrease in hemoglobin formation. |
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Anemia due to abnormal globin synthesis...structural vs synthesis... name conditions for each
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Abnormality in the structure or synthesis of the globin chains: the heme portion is normal
Structural: mutations involving amino acid deletions or substitutions -Sickle cell anemia as an example Synthesis: genetic defect that cause reduced synthesis of structurally normal globin chains -The thalassemias |
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Name the types of hemoglobins, and when you have them...
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-At birth Hb F (alpha2;gamma2) is predominant
-At six months of age Hb F gene becomes inactive and by one year of age Hb A (alpha2; beta2) becomes the major Hb -A (alpha2 beta2); A2 (alpha2 delta2); F(alpha2 gamma2) -A is major (95-95%), A2 minor (2-3), Fetal (.8-2.0) -no S or C -Clinical manifestations are determined by the amount of variant Hb present -Frequently not manifest until after 6 mo when the HB F gene becomes inactive. |
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What do you see in diabetics that's used to monitor glucose control?
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-Hb A1c is a minor Hb formed by post-translational addition of glucose to the beta chain.
-Increased levels produced in diabetics with increased blood glucose levels -Tool for monitoring glucose control |
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Altered Solubility
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amino acid substitution results in a molecules that polymerizes into insoluble, rigid aggregates of Hb resulting in hemolytic anemia.
-Hb S; Hb C |
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Altered Stability
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amino acid substitutions/deletions can disrupt normal conformation disturbing binding of heme to globin or disrupt the stability of the globin subunit resulting in an unstable hemoglobin
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Altered Function
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aa substitutions of the globin chain may affect O2 affinity
-High affinity: Decreased O2 delivery to tissue producing erythrocytosis -Low affinity: Premature O2 release -No affinity: Hb in reduced state (fe+3), Cyanosis, HbM. |
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How do you identify the varieties of hemoglobin?
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Hb electophoresis:
Each Hb has an electric charge of a different degree. Subjecting dissolved blood to an E- field, components move at different rates forming bands, each band is then quantitated as a %, which indicates the severity of any abnormality |
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hemoglobin S aka sickle cell anemia...
what is the scientific designation, what does it mean? |
Scientific designation for hemoglobin S:
-B6 Glu>Val -The mutation is the beta chain affecting the amino acid in the sixth position. The amino acid glutamic acid is replaced by valine -Change in net charge; hence altered electrophoretic mobility Solubility of HbS in the doxy state is markedly reduced: -S molecules polymerized into rigid aggregates. -After polymerization the cells assume a crescent shape. |
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What factors contribute to sickling?
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-Hypoxia, acidosis, hypertonicity and temperatures>37o promote deoxygenation and the formation of HBS polymers
-The spleen, kidney retina and BM provide the above microenvironment -Sickling also depends on HbS concentration within the red cell (MCHC) and -Intracellular Hb composition of normal Hb (%A, %A2, %F) -Sickled cells may return to normal biconcave shape upon reoxygenation. With repeated sickling the red cell membrane becomes leaky and rigid leading to irreversible sickled cells (Removed by spleen,liver, BM) -May initiate vaso-occlusive crises (Impaired cell deformability; Increased cell adherence to endothelium) Most common worldwide hemoglobinopathy -Africa certain regions 40% (Increased in regions with P. falciparum) |
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What does the bone marrow look like with sickle cell anemia? What accounts for the majority of clinical signs?
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Anemia: chronic extravascular hemolysis resulting in hyperplastic BM; thinning of cortex, to compensate for increased red cell turnover
Vaso-occlusive crisis: -Blockage of microvasculature by rigid sickled cells -Spontaneous event resulting in hospitalization -Triggered by infection, decreased O2 pressure, dehydration, or reduced blood flow |
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What else happens in vaso-occlusive crisis?
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Pain, low grade fever, tissue necrosis.
-Infarction of tissue: GI, liver, bone, lung, spleen -Aseptic necrosis of femoral head -Dactylitis: infarction of metacarpals/tarsals (swelling of hands and feet) -Recurrent priapism Slowing of blood flow in occlusive areas may result in thrombosis -Stroke (subclinical infarction in 30% of children) -Blindness -Chronic leg ulcers -Placental infarctions |
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What is a common cause of death in the young patients of sickle cell?
What can follow? |
Bacterial infection:
-Encapsulated microorganisms (strep. Pneumoniae and -Hemophilus influenzae) Pneumonia common, meningitis prevalent Aplastic crisis: temporary cessation of erythropoiesis in the setting of chronic hemolysis leading to worsening of anemia -Follows viral, bacterial infections |
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What is the MOST common cause of death in children?
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Chest syndrome: resembles pneumonia
-Fever, chest pain, pulmonary infiltrates from: -Pulmonary edema -Fat embolism from infarcted BM -Infection -Unknown causes |
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Older children/adults with splenic hypofunction present with what?
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-Basophilic stippling
-Howell-Jolly bodies -siderocytes |
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What are the diagnostic tests for sickle cell anemia? What's the therapy?
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-Hb electrophoresis (usually done to dx)
-Solubility test (rapid test) -Sickling test (confimatory) -DNA PCR testing for mutation -Beta chain position #6: substitution of Glutamic acid to Valine Aimed at suppressing formation of Hbs polymerization (nothing effective long term) -Transfusion -In aplastic crisis; Splenic sequestration -Decreasing vaso-occlusion: -Hydration; prophylaxsis for infection |
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Hydroxyurea
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-Reduces sickling by reactivating fetal genes and elevating levels of HbF
-Fewer vaso-occlusive events Side effects: cytopenias |
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Sickle cell Trait. Symptoms? Why is it important to diagnose?
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-Heterozyous condition (one normal gene)
-The one normal gene confers enough normal Hb to prevent symptoms or anemia Important to diagnosis because of genetic complications: -One of four children born to parents who each have the trait will have sickle cell disease -Two of four will have the trait |
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What is the second most prevalent hemoglobinopathy?
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Hemoglobin C
Beta (6) Glu>Lys usually asymptomatic -The danger is the combination of C trait with another abnormal hemoglobin |
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What do you see intracellularly in hemoglobin C disease?
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Disease (homozygous)
-.02% of US blacks Many target cells >90% Hb C Often asymptomatic; variable hemolysis Intracellular Hb crystals found |
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What heterozygous state is almost as severe as homozygous sickle cell disease?
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Hemoglobin S/C:
-Both beta chains are abnormal and no HbA is formed -Both sickling and HbC crystal formation leading to vaso-occulsive crisis. |
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Hemoglobin E... who gets it, what is the change? what happens to o2 affinity?
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-Most prevalent amongst SE Asians
-Beta (26) Glu to Lys -Target cells/microcytosis -Heteroz: no anemia; microcytosis only -Homoz: mild anemia -Decreased O2 affinity (shift to the right); -Danger is combination with other abnormal hemoglobins |
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Thalassemia is what. and the variants.
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Decreased globin chain synthesis
-Structural gene delections or -Mutations in controlling sites preventing gene expression. Alpha thalassemia: -Impaired alpha chain synthesis Beta thalassemia: Impaired beta chain synthesis Beta Variant HPFH: failure in the switch of the gamma chain to the beta chain after birth. Only HbF produced. |
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What do you always see in alpha and beta thalassemia? what else is there?
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-Hypochromic microcytosis (ALWAYS SEE THIS)
-Basophilic stippling -Increased Hb A2 -Increased RBC mass with low Hb conc. |
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What do you see in the CBC?
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-RBC count elevated
-MCH and MCHC decreased -MCV decreased (<67 fl think thal.) -Normal RDW (IDA is large RDW) -All the cells are similar sized -Peripheral smear: Target cells Still in doubt? Erythrocyte Proto-phorphyrin test: Normal (abnormal in all anemias) -(elevated in IDA) |
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Why is there an elevated RBC count?
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Diminished synthesis of a globin chain:
-Too few cells with normal hemoglobin -Marked tissue hypoxia Compensatory erythropoietin driving marked marrow hyperplasia and even greater ineffective erythropoiesis releasing increased numbers of red cells into the circulation -Cells with excess alpha or beta chains. -There is a relative excess of globin chains from the chain not effected resulting in production of red cells with abnormal hemoglobin containing an excess of a particular globin chain. These Hbs are unstable and precipitate resulting in extravascular removal in the spleen (continuous chronic hemolysis) |
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Beta Thalassemia: HomozygousThalassemia Major (Cooley’s Anemia)
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-Infant protected until 6mo when HbA replaces HbF as the major Hb
-Severe anemia: cardiac failure in 1st decade -Chronic hemolysis with gallstones, gout and icterus -Splenomegally -Extramedullary hematopoiesis -BM hyperplasia with facial deformities -Lack of Beta chain production -Compensatory production of excess free alpha chains precipitate in the red cells resulting in chronic hemolysis and significant anemia. -Dramatic reduction in HbA with reduced O2 carrying capacity -Marked ineffective erythroid hyperplasia |
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What is stimulated because of the erythroid hyperplasia? what can this cause? how do you treat?
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-The erythoroid hyperplasia stimulates iron absorption in the gut leading to iron toxicity.
-Transfusion therapy prolonging life to 3rd decade -Secondary Hemochromatosis -Cardiac siderosis -Pancreatic iron overload with DM -Hepatic cirrhosis Bone marrow Transplantation Death in 2nd or 3rd decade |
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Beta Thalassemia:Heterozygous Beta Thalassemia Minor..always a problem?
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-One normal beta gene is present directing nearly normal beta chain synthesis
-RBC survival near normal except in stress or pregnancy when moderate Hypo/micro anemia develops. -Usually only a mild Hypo/micro anemia CBC values still persist: Elevated rbc number, decreased MCH, decreased MCV -But to a lesser extent -Target cells, Basophilic stippling *Frequently confused with IDA. |
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Alpha Thalassemia-named according to how many mutations of the 4 alpha genes...
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Silent Carrier (1 of 4.. asx)
Alpha Thal Trait (2 of 4) Hemoglobin H Disease (3 of 4) Hydrops fetalis with Hb Bart’s (4 of 4) |
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Name the genotype, and findings for each:
Silent Carrier Alpha Thal Trait Hemoglobin H Disease Hydrops fetalis with Hb Bart’s |
Silent Carrier: genotype: aa/a-
findings: normal or slight microcytosis, no dz Alpha Thal Trait: genotype -a/-a or --/aa findings: mild hypo/micro anemia, target cells, baso stippling (mimicks IDA) Hemoglobin H Disease: genotype: --/-a -findings: mod to marked hypo/micro anemia, target cells, baso stippling, servere hemolytic anemia, Hb H. Hydrops fetalis: genotype: --/-- (no alpha chains, only beta) -findings: fatal; servere anemia, numberous NRBCs, Hb Bart's |
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Hb Bart’s has
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very high O2 affinity with no release to tissues.
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Hemoglobin Dissociation Curve
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Shift left- increase affinity for oxygen from Hb (capillaries at lungs)
Shift right- decreased affinity for oxygen (capillaries at tissues) At 60mmHg the curve is almost flat, indicting little change in sat. above this -So, PaO2 of 60 or more provides >90% sat -<60, curve is steep, small changes in PaO2 greatly reduce the SaO2 Steep mid-section results in additional delivery of large volume of O2 in response to tissue hypoxia |
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Hypoproliferative Anemia
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-A heterogeneous group of acquired or hereditary disorders characterized by Bone Marrow HYPOCELLULARITY
-Much of the normal marrow is replaced by fat -Defect is due to depletion, damage, or inhibition of stem cells -Pleuripotent: Aplastic Anemia with decrease in all 3 cell lines with peripheral pancytopenia -Unipotent: only one cell line affected, eg pure red cell aplasia |
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Aplastic Anemia
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Pluipotential stem cell disorder with Peripheral pancytopenia
Variable etiology: -Bone Marrow Matrix Defects (stromal) -Immunologic Suppression -Deficient Growth Factors -Abnormal or deficient stem cells mostly idiopathic (80%) |
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Aplastic Anemia: Lab
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-Pancytopenia is typical
-NRBCs and teardrop cell NOT typical, if seen suggests marrow replacement (myelophthisic anemia); no architectural damage. -Relative reticulocyte count maybe normal but corrected retic count is always low. -Erythropoietin often increased Therapy: Remove causative agent if known -Hematopoietic growth factors are used, but do not result in sustained response. -Immunosuppressive therapy -Antilymphocyte globulin, cycloporine |
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Aplastic Anemia: Pure Red Cell Aplasia
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-Selective decrease in erythroid precursor cells in BM and peripheral anemia
-No disturbance of granulopoiesis or thrombopoiesis. -Corrected Reticulocyte count is low |
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Bone Marrow Replacement Disorders
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Bone marrow failure with resultant peripheral cytopenias not the result of aplastic anemia or a stem cell defect
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Myelophthisic Anemia
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-BM infiltration by tumor, fibrosis or granulomas
-Release of immature cells in peripheral blood: NRBCs, tear drop cells & neutrophilic left shift: -Called a leukoerythroblastic picture -Anemia with normal, increased, or decreased leukocytes and platelets -The abnormal replacement disrupts the normal marrow architecture allowing release of immature cells. Anemia, thrombocytopenia or pancytopenia may be seen -In aplastic anemia, the marrow architecture is preserved and numerous immature cells are not observed in the peripheral circulation. Pancytopenia is characteristic. |
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Myelodysplastic Syndrome (MDS)... what is the most consistent finding?
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-Clonal pluripotential stem cell disorder
-Previously call pre-leukemia -BM maturation abnormalities characterized by BM hypercellularity with peripheral cytopenias, with anemia -Frequent chromosomal abnormalities -Anemia most consistent finding, often macrocytic by indices, but dimorphic on smear review. |