Classification of Hemolytic anemias I Red cell abnormality

Classification of Hemolytic anemias I. Red cell abnormality (Intracorpuscular factors) A. Hereditary 1. Membrane defect (spherocytosis, elliptocytosis) 2. Metabolic defect (Glucoze-6 -Phosphate-Dehydrogenaze (G 6 PD) deficiency, Pyruvate kinase (PK) deficiency) 3. Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia ) B. Acquired 1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH)

HEMOLYTIC ANEMIAS Hemolytic anemias = reduced red-cell life span

II. Extracorpuscular factors A. Immune hemolytic anemias 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible blood B. Nonimmune hemolytic anemias 1. Chemicals 2. Bacterial infections, parasitic infections (malaria), venons 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves 4. Hypersplenism

Mechanisms of hemolysis: - intravascular - extravascular

Inravascular hemolysis (1): - red cells destruction occurs in vascular space - clinical states associated with Intravascular hemolysis: acute hemolytic transfusion reactions severe and extensive burns paroxysmal nocturnal hemoglobinuria severe microangiopathic hemolysis physical trauma bacterial infections and parasitic infections (sepsis)

Inravascular hemolysis (2): - laboratory signs of intravascular hemolysis: indirect hyperbilirubinemia erythroid hyperplasia hemoglobinemia methemoalbuminemia hemoglobinuria absence or reduced of free serum haptoglobin hemosiderynuria

Extravascular hemolysis : - red cells destruction occurs in reticuloendothelial system - clinical states associated with extravascular hemolysis : autoimmune hemolysis delayed hemolytic transfusion reactions hemoglobinopathies hereditary spherocytosis hypersplenism hemolysis with liver disease - laboratory signs of extravascular hemolysis: indirect hyperbilirubinemia increased excretion of bilirubin by bile erythroid hyperplasia hemosiderosis

Hemolytic anemia - clinical features: - pallor - jaundice - splenomegaly

Laboratory features: 1. Laboratory features - normocytic/macrocytic, hyperchromic anemia - reticulocytosis - increased serum iron - antiglobulin Coombs’ test is positive 2. Blood smear - anisopoikilocytosis, spherocytes - erythroblasts - schistocytes 3. Bone marrow smear - erythroid hyperplasia

Diagnosis of hemolytic syndrome: 1. Anemia 2. Reticulocytosis 3. Indirect hyperbilirubinemia

Autoimmune hemolytic anemia caused by warmreactive antibodies: I. Primary II. Secondary 1. acute - viral infections - drugs ( -Methyldopa, Penicillin, Quinine, Quinidine) 2. chronic - rheumatoid arthritis, systemic lupus erythematosus - lymphoproliferative disorders (chronic lymphocytic leukemia, lymphomas, WaldenstrÖm’s macroglobulinemia) - miscellaneous (thyroid disease, malignancy )

Autoimmune hemolytic anemia caused by coldreactive antibodies: I. Primary cold agglutinin disease II. Secondary hemolysis: - mycoplasma infections - viral infections - lymphoproliferative disorders III. Paroxysmal cold hemoglobinuria

Autoimmune hemolytic anemia - diagnosis - positive Coombs’ test Treatment: - steroids - splenectomy - immunosupressive agents - transfusion

Hereditary microspherocytosis 1. Pathophysiology - red cell membrane protein defects (spectrin deficiency) resulting cytoskeleton instability 2. Familly history 3. Clinical features - splenomegaly 4. Laboratory features - hemolytic anemia - blood smear-microspherocytes - abnormal osmotic fragility test - positive autohemolysis test - prevention of increased autohemolysis by including glucose in incubation medium 5. Treatment - splenectomy

Paroxysmal nocturnal hemoglobinuria 1. Pathogenesis - an acquired clonal disease, arising from a somatic mutation in a single abnormal stem cell - glycosyl-phosphatidyl- inositol (GPI) anchor abnormality - deficiency of the GPI anchored membrane proteins (decay-accelerating factor =CD 55 and a membrane inhibitor of reactive lysis =CD 59) - red cells are more sensitive to the lytic effect of complement - intravascular hemolysis 2. Symptoms - passage of dark brown urine in the morning

3. PNH –laboratory features: - pancytopenia - chronic urinary iron loss - serum iron concentration decreased - hemoglobinuria - hemosiderinuria - positive Ham’s test (acid hemolysis test) - positive sugar-water test - specific immunophenotype of erytrocytes (CD 59, CD 55) 4. Treatment: - washed RBC transfusion - iron therapy - allogenic bone marrow transplantation

SICKLE CELL ANEMIA Definition: chronic hemolytic anemia occuring almost exclusively in blacks and characterized by sickle-shaped red cells(RBCs) caused by homozygous inheritance of Hemoglobin S

SICKLE CELL ANEMIA-pathogenesis - In Hb S, valine is substituted for glutamic acid in the sixth amino acid of the ß chain. - Deoxy-Hb S is much less soluble than deoxy Hb A; it forms a gelatinous network of fibrous polymersthat cause RBCs to sickle at sites of low p. O 2. - Hemolysis-because sickle RBCs are too fragile to withstand the mechanical trauma of circulation - Occlusion in microvascular circulation caused by distorted, inflexible RBCs adhering to vascular endothelium

SICKLE CELL ANEMIA-incidence - Homozygous - about 0, 3% of blacks in the USA (have sickle cell anemia) - Hetezygotes-8 -13% of blacks, (are not anemic, but the sickling trait=sicklemia can be demonstrated in vitro)

SICKLE CELL ANEMIA-clinical features IN HOMOZYGOTES 1. Clinical complications due to severe hemolytic anaemia - slowed growth and development in children - bilirubins stones - aplastic crisis - congestive heart failure from chronic anemias and cardiac overload compensation 2. Consequences of vaso-occlusion of the microcirculations (tissue ischemia and infarction) - infarction of spleen, brain, marrow, kidney, lung, aseptic necrosis, central nervous system and ophtalmic vascular lesions

SICKLE CELL ANEMIA-laboratory findinges 1. Anemia-normocytic or slightly macrocytic 2. Leukocytosis(chronic neutrophilia) 3. Thrombocytosis-usually mild<1000 G/l 4. Reticulocytosis 5. Peripheral smear: sickle shaped red cells, polychromatophilia, Howell-Jolly bodies 6. Hb -electrophoresis

SICKLE CELL ANEMIA-therapy Preventive measures: prevention or remedy of: infections(penicillin prophylaxis and pneumococcal vaccination), fever, dehydratation, acidosis, hypoxemia, cold exposure Blood transfusions for very severe anemia New approaches to therapy; 1. Activation of Hb F synthesis -5 -azacytidine 2. Antisickling agents acting on hemoglobin or membrane 3. Bone marrow transplantation