RBC disorders Lecture III Hemolytic Anemia II (1).ppt

Hematopoietic & Lymphoid Systems RBC disorders: Lecture III Hemolytic Anemia II Dr. Ghassan Balousha MD. PhD 1  Anemia Classification (according to mechanism of production) II. Increased Rate of Destruction (...

Hematopoietic & Lymphoid Systems RBC disorders: Lecture III Hemolytic Anemia II Dr. Ghassan Balousha MD. PhD 1  Anemia Classification (according to mechanism of production) II. Increased Rate of Destruction (Hemolytic Anemias) A. Intrinsic (intracorpuscular) abnormalities of RBCs: 1. Hereditary a. Disorders of RBC membrane cytoskeleton (e.g., spherocytosis, elliptocytosis) b. RBC enzyme deficiencies 1) Glycolytic enzymes: pyruvate kinase, hexokinase 2) Enzymes of hexose monophosphate shunt: glucose-6-phosphate dehydrogenase, glutathione synthetase c. Disorders of hemoglobin synthesis 1) Deficient globin synthesis: thalassemia syndromes 2) Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia 2. Acquired a. Membrane defect: paroxysmal nocturnal hemoglobinuria B. Extrinsic (extracorpuscular) abnormalities: 1. Antibody mediated a. Isohemagglutinins: transfusion reactions, erythroblastosis fetalis (Rh disease of the newborn) b. Autoantibodies: idiopathic (primary), drug-associated, SLE 2. Mechanical trauma to RBCs a. Microangiopathic hemolytic anemias: thrombotic thrombocy-topenic purpura, DIC 2 3. Infections: malaria  Thalassemia Quantitative abnormalities of Hb synthesis: 1. α-thalassemia: α-globin chain synthesis is reduced 2. β-thalassemia, β-thalassemia β-globin chain synthesis is either: – absent (β0 thalassemia), thalassemia or – decreased (β+ thalassemia) thalassemia Inherited as an autosomal codominant: 1. Heterozygous: (thalassemia minor or trait) – asymptomatic or mildly symptomatic 2. Homozygous: (thalassemia major) – symptomatic with severe hemolytic anemia Common among Mediterranean, Mediterranean African, & Asian 3  Normal Hemoglobin HbA: 2 α & 2 β chains α chains: encoded by two α-globin genes located on chromosome 16 (4 genes in total) β chains: encoded by a single β-globin gene 4 located on chromosome 11 (2 genes in total)  Clinical classification of thalassemias Clinical Genotype Disease Nomenclature Thalassemia Homozygous β0-thalassemia Severe, requires blood 0 (β /β0); transfusions regularly major Homozygous β+-thalassemia + + (β /β ) increased levels of HbF Thalassemia Heterozygous Asymptomatic with mild or 0 + β /β or β /β no anemia; RBC abnormalities minor seen increased level of HbA2 5  β-Thalassemia 1. β0-thalassemia, β0- associated with total absence of β- globin chains in the homozygous state 2. β+-thalassemia, β+- characterized by reduced (but detectable) β-globin synthesis in the homozygous state. more than 100 different mutations (mainly single base changes) 6 Pathogenesis of β-thalassemia major Hemolytic anemia: caused by – Reduced synthesis of β-globin: – leads to inadequate HbA formation – Hb concentration (MCHC) is lower (hypochromic) hypochromic – Hemolysis caused by excess insoluble unpaired α-globin – Mature RBCs are susceptible to phagocytosis by spleen Ineffective erythropoiesis: – intramedullary BM destruction of immature RBCs – associated with inappropriately increased absorption of dietary 7 iron and iron overload How is Thalassemia major diagnosed? 1. Peripheral blood smear: Severe microcytic hypochromic RBCs Target cell Poikilocytosis (abnormally shaped (RBCs) Anisocytosis (unequal size) reticulocytosis 8 Target cell Normal cell 9 How is Thalassemia major diagnosed? 2. Hb electrophoresis: – reduction or absence of HbA – increased levels of HbF – HbA2 level may be normal or increased 3. Prenatal diagnosis by DNA analysis Treatment: Blood transfusions: – reduce the skeletal deformities – increase survival into the second or third decade Iron chelators: for iron overload Bone marrow transplantation at an early age is the 10 treatment of choice  What are the complications? Skeletal deformities: deformities due to hyperplasia of erythroid progenitors (excessive erythropoiesis) Extramedullary hematopoiesis and hyperplasia of the mononuclear phagocytes produces: – Splenomegaly – Hepatomegaly – Lymphadenopathy Growth retardation & cachexia: cachexia due to ineffective erythropoiesis severe hemosiderosis: hemosiderosis due to iron overload 11 Cardiac failure from secondary hemochromatosis Pathogenesis of β-thalassemia major 12 Thalassemia: x-ray film of the skull showing new bone formation resembling a crew-cut. 13 Beta-thalassemia major: Skull bossing due to expansion of the red bone marrow in skull 14  Thalassemia minor: Clinical Course Clinical features: – mild microcytic hypochromic anemia – patients have a normal life expectancy Diagnosis: Hb electrophoresis: – reduced amounts of HbA (α2β2) – increased level of HbA2 (α2δ2) Prenatal diagnosis by DNA analysis 15  Clinical & genetic classification of thalassemias Clinical Nomenclature Genotype Disease α-Thalassemia: 1. Silent carrier -α/αα (loss of 1 gene) Asymptomatic; no RBC abnormality -α/αα (Asian);-α/-α Asymptomatic; like thalassemia 2. α-Thalassemia trait (black African) minor (Loss of 2 genes) Severe anemia, 3. HbH disease -/-α (loss of 3 gene) β-globin tetramers (HbH) γ4 tetramers (Hb Bart) 4. Hydrops fetalis -/- (loss of 4 gene) Lethal in utero 16 hydrops fetalis 17  Immunohemolytic Anemias Anti-RBC antibodies Diagnosis: Coombs antiglobulin test 1. Direct Coombs test: based on the capacity of antibodies raised in animals against human immunoglobulins to agglutinate RBCs A positive result indicates that the patient's RBCs are coated with human antibodies that can react with the antihuman immunoglobulin serum. 2. Indirect Coombs test: test detects antibodies in the patient's serum and involves incubating normal RBCs with the patient's serum, followed 18 by a direct Coombs test on incubated RBCs. 19  Immunohemolytic Anemias 1. Warm Antibody Type  Primary (idiopathic) > 60%  Secondary: a. B-cell lymphoid neoplasms (e.g., CLL) b. SLE c. drugs (e.g., α-methyldopa, penicillin, quinidine) 2. Cold Antibody Type  Acute: a. Mycoplasma infection b. infectious mononucleosis  Chronic: a. idiopathic 20 b. B-cell lymphoid neoplasms (e.g., lymphoplasmacytic lymphoma) Warm Antibody Immunohemolytic Anemias The most common form Characterized by the presence of IgG (rarely, IgA) Antibodies are active at 37°C Hemolysis due to: – opsonization of the RBCs by IgG and subsequent phagocytosis by splenic macrophages – Spherocytosis: in idiopathic immune hemolytic anemia Clinical features: – chronic mild anemia with moderate splenomegaly – require no treatment 21  Cold Antibody Immunohemolytic Anemias Characterized by the presence of IgM antibodies Antibodies are active below 30°C Mainly occur in distal body parts (e.g., hands, toes) Fixation with complement causes intravascular hemolysis Also extravascular hemolysis mainly by Kupffer cells Clinical features: Acute: mild transient anemia Chronic: anemia, associated with Raynaud phenomenon 22  Hemolytic Disease of Newborn (HDN) HDN ABO system: – ABO hemolytic disease of the newborn Rhesus system: – rhesus D hemolytic disease of the newborn (called Rh disease) is the commonest form of severe HDN. – rhesus c hemolytic disease of the newborn – is the third most common form of severe HDN Kell system: – anti-Kell hemolytic disease of the newborn anti-K 1 antibodies - is the second most common form anti-K 2 ,anti-K 3 and anti-K 4 antibodies - rare 23  Hemolytic Disease of Newborn (HDN) HDN Mainly Rh incompatibility Babies affected by HDN are usually in a mother's second or higher pregnancy, after she has become sensitized with a first baby. IgG produced by the mother pass through placenta and destroy fetal RBC HDN due to Rh incompatibility is about three times more likely in Caucasian babies than African- American babies. 24  Hemolytic Disease of Newborn (HDN) HDN Features: – anemia – neonatal jaundice, may cause kernicterus. – fetal death from heart failure hydrops fetalis – reticulocytosis – high erythroblasts in the fetal blood – so HDN also called erythroblastosis fetalis 25  HDN: Diagnosis history and laboratory findings: Blood tests (newborn): – Biochemistry tests: hyperbillirubinemia – Peripheral blood smear: reticulocytes Erythroblasts – Positive direct Coombs test Blood tests (mother): – Positive indirect Coombs test – presence of Rh positive antibodies in the mother's blood 26  Anemia Classification (according to mechanism of production) II. Increased Rate of Destruction (Hemolytic Anemias) A. Intrinsic (intracorpuscular) abnormalities of RBCs: 1. Hereditary a. Disorders of RBC membrane cytoskeleton (e.g., spherocytosis, elliptocytosis) b. RBC enzyme deficiencies 1) Glycolytic enzymes: pyruvate kinase, hexokinase 2) Enzymes of hexose monophosphate shunt: glucose-6-phosphate dehydrogenase, glutathione synthetase c. Disorders of hemoglobin synthesis 1) Deficient globin synthesis: thalassemia syndromes 2) Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia 2. Acquired a. Membrane defect: paroxysmal nocturnal hemoglobinuria B. Extrinsic (extracorpuscular) abnormalities: 1. Antibody mediated a. Isohemagglutinins: transfusion reactions, erythroblastosis fetalis (Rh disease of the newborn) b. Autoantibodies: idiopathic (primary), drug-associated, SLE 2. Mechanical trauma to RBCs a. Microangiopathic hemolytic anemias: thrombotic thrombocy-topenic purpura, DIC 27 3. Infections: malaria  Hemolytic Anemias: Mechanical Trauma to RBC Causes: 1. Cardiac valve prostheses: more severe with mechanical valves than with bioprosthetic 2. Microangiopathic hemolytic anemia: – RBCs squeeze through abnormally narrowed vessels Causes of microangiopathic hemolytic anemia: – disseminated intravascular coagulation (DIC) DIC – Malignant HTN, SLE, TTP 28 – hemolytic-uremic syndrome, syndrome disseminated cancer  Mechanical Trauma to RBC: morphology Injured RBCs: – schistocytes – burr cells – helmet cells – triangle cells 29 Burr cell 30