Hemolytic anemia occurs when the bone marrow is unable to increase production to make up for the premature destruction of red blood cells and the abnormal breakdown of red blood cells either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications such as gallstones and pulmonary hypertension.

1. Classification of Hemolytic anemias I. Red cell abnormality (Intracorpuscular factors) A. Hereditary 1. Membrane defect (spherocytosis, elliptocytosis) 2. Metabolic defect (Glucoze-6-Phosphate-Dehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK) deficiency) 3. Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle cell anemia ) B. Acquired 1. Membrane abnormality-paroxysmal nocturnal hemoglobinuria (PNH)

2. HEMOLYTIC ANEMIAS Hemolytic anemias = reduced red-cell life span

3. 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

4. Mechanisms of hemolysis: - intravascular - extravascular

5. 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)

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

7. 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

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

9. 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

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

11. Autoimmune hemolytic anemia caused by warm-reactive 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, Waldenstr Ö m’s macroglobulinemia) - miscellaneous (thyroid disease, malignancy )

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

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

14. 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

15. 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 =CD55 and a membrane inhibitor of reactive lysis =CD59) - red cells are more sensitive to the lytic effect of complement - intravascular hemolysis 2. Symptoms - passage of dark brown urine in the morning

16. 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 (CD59, CD55) 4. Treatment : - washed RBC transfusion - iron therapy - allogenic bone marrow transplantation

17. 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