Sickle Cell Anemia

Hemoglobin Synthesis Hemoglobin synthesis 25% 25% 0.5% 1.5%

48% a a g d b

a a g d b

25% 25% 0.5% 1.5% 48% Chromosome 16

Chromosome 11 Hemoglobins in normal adults a b a g a

d b a g d

a a HbA HbF HbA2 98%

~1% <3.5% Hemoglobinopathy definition An inherited mutation of the globin genes leading to a qualitative abnormality of globin synthesis

Thalassemia definition An inherited mutation of the globin genes leading to a quantitative abnormality of globin synthesis Geography of Hemoglobinopathies Hemoglobin Electrophoresis

Separation of various hemoglobins with electrophoresis on cellulose acetate, pH 8.6. Hemolysates represented are AA (normal adult), SC (hemoglobin SC disease), SSF (homozygous sickle disease, SS, with increased F), AS (sickle trait), and AC (C trait). Hemoglobin Analysis by HPLC Sickle Cell Anemia Wide spectrum of disorders 1 / 600 African Americans affected 1 / 8 African Americans - sickle trait

Hb SS ~ 60% of sickle cell disease Hb SC and Sb-thal ~ 40% Sickle trait S/; 8% of African-Americans; 8% of African-Americans Asymptomatic Partial protection from malaria Sickling may occur in renal medulla decreased urinary concentrating ability, hematuria Rare complications at high altitude

(splenic infarction) Sudden death following strenuous exercise (rare) Genetic and Laboratory Features of Sickle Hemoglobinopathies

(Modified from Steinberg, M., Cecil Medicine 2007) SS SC Pathophysiology of Sickle Cell Anemia HbS Polymer Vaso-occlusion NO

Arginine Hemolysis (Modified from Steinberg, M., Cecil Sickle Cell: Molecular Basis Glutamate Valine at 6th position b globin

Sickle Hb forms polymers when deoxygenated Polymerized sickle Hb injures RBC membrane and distorts its shape Distorted RBC is hemolyzed Sickle Cells Electron Microscopy Sickle Cell: Pathophysiology Deoxygenation of mutant Hb leads to

K+ efflux cell density / dehydration polymerization Sickled cells adhere to endothelial cells Endothelial factors vasoconstriction Blood flow promotes vaso-occlusion Vicious cycle with decreased blood flow, hypoxemia / acidosis, increased sickling Some cells become irreversibly sickled FACTORS THAT INCREASE Hgb S

POLYMERIZATION Decreased oxygen Increased intracellular hemoglobin S concentration (SS > SC, S-thal) Increased 2,3-DPG Decreased pH Slowed transit time through the circulation Endothelial adhesion FACTORS THAT DECREASE Hgb S POLYMERIZATION

Lower concentration of Hb S (compound heterozygosity for thal) Increased HbF levels Genetic basis Hydroxyurea Clinical Features of Sickle Cell Anemia Painful episodes Pneumococcal disease Renal abnormalities

Osteopenia Acute chest syndrome Splenic infarction Nutritional deficiencies Placental insufficiency Splenic sequestration Stroke

Pulmonary hypertension Osteonecrosis Priapism Retinopathy Leg ulcers Gallstones Clinical Features of Sickle Cell Anemia Associated with higher hemoglobin

Associated with lower hemoglobin Painful episodes Acute chest syndrome Osteonecrosis Proliferative retinopathy Stroke Priapism

Leg Ulcers Complications of Sickle Cell Disease Skin ulcer Pneumonia Stroke

Osteonecrosis Sickle Cell Avascular Necrosis Sickle Cell Avascular Necrosis Pulmonary Hypertension Sickle Cell Dactylitis Priapism Sickle Cell Splenic Complications

Splenic Sequestration Autosplenectomy Sheth, S. et al Pediatr Radiol 2000 Sickle Cell Anemia treatment Opiates and hydration for painful crises

Pneumococcal vaccination Retinal surveillance Transfusion for serious manifestations (eg stroke); exchange transfusion Hydroxyurea Stem cell transplant Hemoglobin C Glutamate lysine at 6th position in beta chain

Hb tends to crystallize Prevalent in west Africa Homozygous state chronic hemolytic anemia Compound heterozygosity with Hb S produces sickle phenotype Hemoglobin C Homozygous: target cells, tactoids

Hemoglobin SC Other hemoglobinopathies Unstable hemoglobins Heinz body formation Multiple mutations reported; dominant inheritance Hemolytic anemia (may be precipitated by oxidative stress) Heinz bodies (supravital stain)

Other hemoglobinopathies Hemoglobin M Congenital methemoglobinemia, cyanosis Hemoglobin with low oxygen affinity Right shifted dissociation curve, decreased EPO Mild anemia (asymptomatic) Hemoglobin with high oxygen affinity Left shifted dissociation curve, increased EPO Erythrocytosis

These all have dominant inheritance Many benign/; 8% of African-Americansasymptomatic mutations described The Thalassemias Syndromes in which the rate of synthesis of a globin chain is reduced beta thalassemia - reduced beta chain synthesis alpha thalassemia reduced

alpha chain synthesis THALASSEMIA Diminished or absent synthesis of normal globin chains ( or ); genetically ); genetically heterogeneous Heterozygous state protects from malaria, hence more common in southern European, African, Asian peoples Unbalanced globin chain synthesis causes microcytosis, ineffective erythropoiesis

and hemolysis Thalassemia Single globin gene missing normal CBC Two -globin genes

missing: microcytosis, minimal anemia One -globin gene missing: microcytosis, mild anemia

Three globin genes missing: microcytosis, hemolysis, moderate to severe anemia Two -globin genes missing:

transfusiondependent anemia Decreasing globin chain production Increasing globin chain imbalance causing: ineffective erythropoiesis (precipitated chains) hemolysis ( tetramers or Hb H) Worsening anemia

Four globin genes missing: fetal demise Alpha thalassemia aa // aa aa // a /aa //

- /a /- // - /- /- /; 8% of African-Americans - /- Normal Mild microcytosis Mild microcytosis Hemoglobin H disease Hemoglobin Barts Hydrops Fetalis Hgb H disease

H Hgb H inclusions (supravital stain) Hydrops fetalis (note gross edema) Hydrops fetalis Beta thalassemia major

No beta chain produced (no HbA) Severe microcytic anemia occurs gradually in the first year of life (as gamma chain production stops) Marrow expansion Iron overload Growth failure and death Beta thalassemia major Thalassemia

Beta thalassemia major Male 18 years Beta thalassemia major treatment Transfusion Iron chelation Stem cell transplant

-Thalassemia Minor b/ /b0 or b/ /b+ Microcytosis, target cells Mild anemia often asymptomatic Decreased HbA production Increased proportion of Hb A2

-Thalassemia Intermedia b+/ /b0 (small amount of b / chain production) Chronic anemia Splenomegaly Often transfusion-dependent Hemoglobin E

b mutation (glutamine lysine at amino acid 26) Altered mRNA splicing, unstable mRNA Heterozygous in 30% of SE Asians Homozygous Hb E: microcytosis, hypochromia, little or no anemia Hemoglobin E /; 8% of African-Americans b-thal causes thalassemialike phenotype

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