Hematology - Hemoglobinopathies
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- 3 Classifications of Hemoglobinopathies
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QUALITATIVE: a.a. substitutions/deletions cause structural change in globin chain
QUANTITATIVE: genetic defects causing decr. synthesis of normal globin chains (thalassemias)
COMBINED DISORDERS: individ. is doubly heterozygous for 2 structural variants or str. var. & a thalassemia - Etiology of Sickle Cell Disease (HbSS)
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-Most common hemoglobinopathy
-Most prevalent in central africa, and in African-Americans
-Autosomal recessive
-Caused by single base mutation in 6th aa on the β-globin chain causing substitution of valine for glutamic acid - Pathophysiology of Sickle Cell Disease (HbSS)
- HbS polymerizes under reduced O2 tension making tactoids. Rigid sickle-shaped RBCs result, causing hypoxia & infarctive crises that can be painful. Recurrent deformations of RBC can lead to permanent sickle shape or hemolysis, reducing lifespan of cell
- 3 CRISES of Sickle Cell Disease (HbSS)
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APLASTIC crisis: bone marrow overworked as result of stress to produce new RBCs
HEMOLYTIC crisis: ACUTE increase in severity of existing anemia
VASO-OCCLUSIVE/PAINFUL crisis: hallmark of Sickle cell anemia, episodes of pain caused by blockage of microvasculatue by sickled cells - Other clinical findings of Sickle Cell Disease (HbSS)
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1st signs appear around 6 mos age (correlates w/ transition to b-chain)
reduced RBC life span (10-20 days!)
Chronic hemolytic anemia w/ many complications - Lab findings of Sickle Cell Disease (HbSS)
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SEVERE anemia (Hb only 6-8 g/dL)
normocytic, normochromic
aniso, poik, target cells, schizocytes, drepanocytosis, Howell-Jolly, Pappenheimer, polychromasia - How is Sickle Cell Disease Dx'd?
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SCREENING TESTS: solubility tests (Sickledex/Sicklesol)
-tube test precipitates abnormal HbS, making soln turbid
DEFINITIVE: cellulose acetate electrophoresis, citrate agar electrophoresis - What is Sickle Cell Trait (HbAS)
- Heterozygous condition, most common in US (~8% african americans)
- Clinical features of Sickle Cell Trait (HbAS)
- Pt's usually asymptomatic but sickling potential still exists
- Lab findings of Sickle Cell Trait (HbAS)
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NORMAL peripheral blood smear
Screening tests POSITIVE
some HbS on electrophoresis - Hemoglobin C disease Incidence
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Common in West African blacks
Small % of African Americans affected - Pathophysiology of HbC disease
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aa substitution on beta chain (Lysine for glutamic acid)
decrease in Hb solubility; intracellular crystals form (bars of gold)
RBC's become rigid - Clinical features of HbCC disease
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Pt's asymptomatic but joint/abdominal pain possible.
splenomegaly
chronic hemolytic anemia - Lab findings of HbCC disease
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MODERATE anemia
NORMOCYTIC, NORMOCHROMIC
codocytes, HbC crystals possible (bars of gold)
slight increased retics
Electrophoresis confirms HbC disease - Hemoglobin C Trait (HbAC) features
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2-3% American blacks affected
Pt's asymptomatic
electrophoresis to confirm - Hemoglobin SC disease features
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a. both β-chains abnormal (substituted w/ 2 different a.a's)
b. resembles mild sickle cell anemia
c. target, folded RBC's on smear (clam shaped)
d. POSITIVE screening tests
e. electrophoresis shows abnormal Hgb - Hemoglobin S/β-thalassemia features
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a. person has structural Hb variant (HbS) AND a quantitative defect
b. severity of clinical & lab findings depends on severity of thalassemia inherited
1. β0 thalassemia produces no β-chains
2. β+ produces less β-chains - Definition of Unstable Hemoglobins
- disorders characterized by precipitation of denatured abnormal Hbs as artifacts called HEINZ BODIES
- Features of Heinz Bodies
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consisted of denatured hemoglobin
attach to inner surface of RBC membrane, affecting permeability and decreasing deformability
inclusions pitted by splenic macrophages leaving cell w/ less Hb and membrane => eventual RBC destruction - Pathophysiology of Unstable Hemoglobins
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problems result from aa substitutions that affect stability of hemoglobin molecule.
-substitution of aa around heme pocket
-" at contact pts between α & β chains
-" of polar for nonpolar aa
-deletions or elongations of 1° structure - Clinical findings of unstable hemoglobin
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1. INHERITED disorder
2. ALL Pt's heterozygous
3. Severity of anemia depends on degree of instability of the Hb molecule - Features of Hb w/ INCREASED O2 affinity
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-bind O2 more readily => less release to tissue
-left shift in O2 dissoc curve
-Don't result in anemia; [Hgb] and Hct increase to compensate - Features of Hb w/ DECREASED O2 affinity
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-release O2 very easily to tissue
-right shift in O2 dissoc curve
-normal to decreased [Hgb] and slight anemia