Congenital RBC Disorders fsm.ac.fj

"Pleasure in the job puts perfection in the work." -- Aristotle HEMATOLOGY Congenital RBC disorders Dr. Venkatesh M. Shashidhar Senior Lecturer in Pathology Fiji School of Medicine Road Map & Objectives:  Over view of CBC  Over view of congenital RBC disorders  Thalassemias - α , ß,  Hemoglobinopathies - Sickle cell disease  Pathogenesis & Laboratory diagnosis  Discussion. C.B.C / FBC / Hemogram  Haemoglobin - 15±2.5, 14 ±2.5 - g/dl  PCV - 0.47 ±0.07, 0.42 ±0.05 - l/l (%)  Haematocrit, effective RBC volume - better  RBC count - 5.5 ±1, 4.8 ± 1 x1012/l  MCHC - Hb/PCV - 30-36 - g/dl  Hb synthesis within RBC  MCH - Hb/RBC - 29.5 ± 2.5 pg/l  Average Hb in RBC  MCV - PCV/RBC 85 ± 8 - fl CBC Analyzer Report Blood Smear - Normal Blood Smear - Normal RBC disorders (Anemias) : “Anemia is decreased red cell mass affecting tissue oxygenation” Low Hb <13.5 (males)*, <11.5 (females)*  Acquired disorders:  Decreased production  Increased loss  Congenital disorders:  Membrane, Hb & enzyme disorders. Congenital RBC Disorders:  Membrane Disorders:  Spherocytosis, Elliptocytosis  Hemoglobin Disorders:  Hemoglobinopathies - Sickle cell, HbC etc.  Thalassemia Syndromes - , ,   Enzyme disorders:  G6PD, PK deficiency Geographical Distribution: Introduction to Haemoglobins: MOLECULAR PATHOLOGY :  Normal adult blood contain 3 types of Hb.  The major component is HbA - α 2ß2. (>95%)  The minor component fetal Hb - α 2 γ 2 (90%,<2%) and Hb A2 - α 22 (1-3.5%) Structure & Synthesis of Haemoglobin: Hb in adult Structure Normal % Hb A α2 ß 2 96-98 Hb F Hb A2 α2 γ2 α2δ2 0.5-0.8 1.5-3.2 GENE CLUSTER & HB SWITCH MUTATIONS EFFECTS OF EXCESS  CHAINS Jaundice Gall Stones Iron over load Hb Electrophoresis – New born pH 8.6 _ pH 6.3 C S A F S F A Barts + Prenatal Diagnosis:  Family study – Parent Hb electrophoresis.  Foetal blood sampling – Second trimester  Chorionic villus biopsy – First trimester DNA studies.  PCR, Gene mapping, RFLP etc.  Gene Therapy – Gene insertion in umbillical blood stem cells and then transplantation. Summary:  Defective Membrane, Hb or enzyme  Decreased life span & hemolysis – chronic anemia, jaundice, gall stones  Increased erythropoiesis – marrow expansion  Thalassemia – Globin Quantitative disorder  Hemoglobinopathy – Globin Qualitative dis.  Blood Film & Hb Electrophoresis B.M biopsy, DNA studies (PCR, RFLP etc) Thalassemia Syndromes “Defective Globin Chain Production Leading to Decreased Normal Hb and Hemolysis” ,  Thalassemia Syndromes:  Group of disorders with decreased production of  or  chains.  Features:      Low Hb – depending on type. Microcytic Hypochromic RBC Unlike IDA, uniform - low RDW Target forms typical. No pencil forms. Heinz bodies – globin deposits. Thalassemia Syndromes:  Etiologically , ,  thalassemia, HbH dis.  Clinically classified into  Hydrops fetalis() – IU death  Thalassemia major () – transfusion dep  Thalassemia intermedia () – spleenomegaly, Fe  Thalassemia minor () - symptomless. Management of Iron overload  Thalassemia Major.  Subcutaneous infusion of Desferrioxamine. auto - infusion pump  8-12h x 5 / week.  Note Normal development. Thalassemia Major:  Marrow Expansion. Skull bone enlargement. Bone deformity:  Marrow Expansion  Rarifaction  Prominent epiphysis -Thalassemia:  Decreased production of  chains.  Classification  0 – (four gene deletion) - Hydrops fetalis  + 2/3 gene deletion – Thal. Intermedia, HbH dis.  0 trait, + trait – Thal Minor, HPFH  No  thalassemia major.  HbH inclusions can be demonstrated in some cases. (less in trait, more in intermedia) Hydrops Fetalis: -Thalassemia: Thalassemia Trait: Blood Smear & HbH Preparation -Thalassemia  Decreased  globin chains. Excess  chains  Varying clinical types – Trait, Intermedia & Major.  Trait is symptomless – Microcytic polycythemia.  Major is severe transfusion dependent hemolytic anemia.  Combinations with Sickle, HbD etc common. Thalassemia Major: Thalassemia Major: ß Thalassemia Major: Hemoglobinopathies Sickle cell anemia Qualitative Globin chain disorder. HbS, HbD, HbC etc. Sickle Cell Disease:  HbS (α 2ß2s ) – Polymerizes to form crystals when Oxygen tension is low. Vaso occlusion.  SS (disease) SA is trait (symptom free)  Clinically severe hemolytic anemia punctuated by crisis.  Crisis - hemolytic & vaso-occlusive  Hand-foot syndrome, vesceral sequestration  Avascular bone necrosis, Retinopathy etc. SCD  Hemolysis:  Anemia  Jaundice  Gall Stones  Vaso occlusion  Retinopathy  ARDS  Hematuria  Autosplenectomy  Bone necrosis  Leg ulcers. Sickle Cell Disease: Sickle Cell Disease:  Chronic leg ulcers.  Microinfarction in the lower limbs due to sickling in capillaries. Sickle Cell Disease:  Hand Foot Syndrome – Dactylitis affecting bone growth. Summary:  Membrane, Hb and Enzyme diseases.  Varying genetic abnormality & presentation  Trait (carriers) Disease (patients)  Thalassemias Quantitative Globin chain dis.  Hemolytic anemia + Iron over load.  Hemoglobinopathies – Qualitative Globin dis.  Hemolytic anemia + Crisis. Thank You... Shashi The only person who never makes a mistake is the person who never does anything…! - Theodore Roosevelt Her. Spherocytosis: Hereditary Elliptocytosis: G6PD Deficiency: G6PD Deficiency Anemia: Hb Barts levels in Cord blood in  thalassemia Phenotype Equivalent No % Barts of Functional Genes 4 0 3 2 1 0 0-1 2-8* 10-40 ~80 Normal  thal trait (mild)  thal trait (severe) Hb H disease Hb Barts Hydrops Higgs DR et al Blood 73, 1081, 1989 * Some references mention upto 15%