Sickle Cell Anemia: The Whole Story Tim R. Randolph, PhD, MT(ASCP), CLS(NCA) Department of Biomedical Laboratory Science Doisy College of Health Sciences Saint Louis University Sickle Cell Anemia Objectives – By the end of this session the participants will be able to: Describe the molecular biology associated with the genetic mutation and protein polymerization Discuss abnormal lab findings associated with sickle cell disease and trait Discuss symptoms and treatment for patients with sickle cell disease and trait Thalassemias vs Hemoglobinopathies Thalassemia Hemoglobinopathies – Genetic mutation (435) – Genetic mutation (1065) Globin gene(s) Globin gene(s) – Lack of gene expression – Normal gene expression – Decreased normal Hb – Release of abnormal Hb Anemia Low oxygen saturation – Low RBC, Hb, Hct, MCH, & Hb polymerization MCHC – Vaso-occlusion Increased RBC divisions Hemolysis Smaller RBC – Anemia – Low MCV – Normal MCV, MCH, & Increases Hb/RBC MCHC – Normalization of MCH and MCHC Sickle Cell Anemia Hemoglobin S – Definition A genetic point mutation resulting in one nucleotide change and a single amino acid substitution that changes the Hgb molecule from Hgb A to Hgb S – Etiology Single nucleotide substitution (A >>T) resulting in a change in one codon (GAG>>GTG) at the 6th position on the beta gene and the substitution of a valine (+0) for a glutamic acid (-1) at the 6th position of the beta chain - (a b GLU>>VAL) 2 2 Sickle Cell Anemia Sickle Cell Anemia NORMAL 0 1 2 3 4 5 6 MET VAL HIS LEU THR PRO GLU ATG GTG CAC CTG ACT CCT GAG SICKLE ATG GTG CAC CTG ACT CCT GTG MET VAL HIS LEU THR PRO VAL Sickle Cell Anemia Deoxyhemoglobin S Polymer Structure Deoxyhemoglobin S Paired strands of deoxy Hb S Charge and size prevent 14-stranded polymer (crystal structure) 6b Glu from binding. (electron micrograph) Hydrophobic pocket for 6b Val Dykes, Nature 1978; JMB 1979 Wishner, JMB 1975 Crepeau, PNAS 1981 Sickle cell Anemia