Hemoglobinopathy & Sickle Cell Anemia PDF

Hemoglobinopathy Sickle Cell Anemia Dr: Walaa Mamoun Al safi  Hemoglobinopathy Hb : haem + globin chains Normal adult blood contains three types of hb: major HbA = dominant after 3-6 months of age Molecular structure ( 2 alpha , 2beta). The minor Hbs : HbF (...

Hemoglobinopathy Sickle Cell Anemia Dr: Walaa Mamoun Al safi  Hemoglobinopathy Hb : haem + globin chains Normal adult blood contains three types of hb: major HbA = dominant after 3-6 months of age Molecular structure ( 2 alpha , 2beta). The minor Hbs : HbF ( 2alpha, 2gamma) HbA2 ( 2alpha , 2delta)  Hemoglobinopathy Embryonic haemoglobin: Hb Gower ( Zeta 2, E2) Hb Portland ( Zeta2, Gamma 2) Hb Gower2 ( 2Alpha, 2E). Fetal haemoglobin : Hb F ( 2Alpha, 2Gamma)  The First human genes to be discovered , sequenced and explained  located on ch. 11(ß )and 16(α)  Usually there are four genes that code for alpha globin and two genes that code for beta globin  Haemoglobinopathy  The genetic defects of Hb are the most  common genetic disorders world wide.  They occur in tropical and subtropical areas. Hemoglobinopathy  Hemoglobinopathy  Quantitave Disorder: Reduced or absent synthesis of α or ß globin chains.  Qualitative Disorder: Synthesis of an abnormal Hb e.g: Hb S, Hb C, Hb D and Hb E  Definition and Molecular Basis of Disease Sickle cell disease (SCD): a recessively inherited chronic hemolytic anemia Caused by a single nucleotide substitution in the β globin gene on chromosome 11at position 6th. – Hemoglobin S (most common): GTG  GAG results in substitution of valine (hydrophobic) for glutamate (hydrophilic) – Many other variant hemoglobins are described Mutant hemoglobin polymerizes under low oxygen conditions and form bundles that distort red cells into the classic sickle shape.  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  Pathophysiology Deoxygenation polymerization of hemoglobin sickling of red cells endothelial damage/activation RBC and leukocyte adhesion to endothelium, vasoconstriction vascular occlusion, organ ischemia and end- organ damage 10  Pathophysiology Severity of disease varies widely among individuals and disease type: SS disease is most severe SC and S-beta thal0 disease portend intermediate severity SA (one normal allele=trait) is generally asymptomatic Factors That Increase Hb 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 Hb S Polymerization Lower concentration of Hb S (compound heterozygosity for α thal) Increased HbF levels – Genetic basis – Hydroxyurea Sickle Cell Anemia and Malaria Children with sickle trait (heterozygotes) have a milder course of P. falciparum. However, children with SS disease have more severe courses with a very high mortality rate.  Prognosis Over the past 30 years in US/Europe, median survival has increased from 14yrs to 45-55yrs for SS disease Figures not available for Africa but estimated 50% of affected die before 5yrs WHO estimates that SCD complicates up to 9% of under 5 deaths in West Africa  Clinical Features of Sickle Cell Anemia Painful episodes Renal abnormalities Pneumococcal disease Osteopenia Acute chest syndrome Nutritional deficiencies Splenic infarction Placental insufficiency Splenic sequestration Pulmonary hypertension Stroke Osteonecrosis Priapism Retinopathy Leg ulcers Gallstones  Types of sickle cell crises Painful crisis Sequestration Acute chest Hemolytic Aplastic  Vaso-occlusive/pain crisis Occurs in 60% of SS patients when vaso-occlusion tissue ischemia May be triggered by infection, temperature extremes, dehydration or stress but usually w/o identifiable cause. Characterized by severe pain often in extremities, involving the long bones, or the abdomen. May last hours to days. Number of pain crises/year varies widely between individuals with some patients w/ constant low level pain. sickle cell anemia  Infection By by age of 5 years , 90% are asplenic due to microinfarcts. This makes children especially vulnerable to infection/sepsis with encapsulated organisms, esp. Strep pneumoniae (400x higher risk vs. general population) Sickle Cell patients are also more susceptible to osteomyelitis (Salmonella and Staph spp.)  Acute Chest Syndrome Characterized by new respiratory distress, CXR infiltrate, hypoxia(O22g/dL decrease in Hb from baseline, often w/ thrombocytopenia Occurs in children 2 episodes splenectomy Sickle Cell – Splenic Complications Splenic Sequestration Autosplenectomy Sheth, S. et al Pediatr Radiol 2000 pathology.mc.duke.edu/.../spleen1.jpg  Aplastic Crisis Caused by infection with 1-Parvovirus B19 which invades young erythroblasts in bone marrow 2-folate deficiency. Often presents with fever, URI sx and drop in Hb RBC life expectancy in SS disease is 10-20 days, thus decrease in RBC production has profound effect. Bone marrow recovery typically within 7-10 days Management: Transfusion if symptomatic with Hb drop.  Anemia Compensated anemia at baseline Baseline Hb normally 8-9 g/dl Overtransfusion can predispose to transfusion transmitted infections and iron overload Management Transfuse for Hb < 5g/dL or 5y/o who have severe complications of SCD Effective because increases HbF, decreases leukocytes, platelets and reticulocytes CBC must be monitored regularly when on therapy for leukopenia Laboratory Findings and Diagnosis Hemolytic anemia: low hemoglobin, high reticulocyte count, elevated LDH and decreased haptoglobin Peripheral blood smear: Sickle cell anemia Sickle cell anemia sickle cell anemia Diagnosis: Sodium metabisulfite Screening for SCD with sodium metabisulfite – Add Na metabisulfite to blood – Seal mixed sample in airtight container or under coverslip – Look for sickling under microscope Does not differentiate trait from disease Diagnosis: Hemoglobin Electrophoresis  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