Dr. M. A Sofi MD; FRCP (London); FRCEdin; FRCSEdin HEMOLYTIC ANEMIA Dr. M. A Sofi MD; FRCP (London); FRCEdin; FRCSEdin

HEMOLYTIC ANEMIA Hemolysis is the premature destruction of erythrocytes. A hemolytic anemia will develop if bone marrow activity cannot compensate for the erythrocyte loss. The severity of the anemia depends on whether the onset of hemolysis is gradual or abrupt and on the extent of erythrocyte destruction. Mild hemolysis can be asymptomatic while the anemia in severe hemolysis can be life threatening and cause angina and cardiopulmonary decompensation.

HEMOLYTIC ANEMIA Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human 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.

HEMOLYTIC ANEMIA Hemolytic anemia involves: Abnormal and accelerated destruction of red cells. Increased breakdown of hemoglobin, which may result in: Increased bilirubin level (mainly indirect-reacting) with jaundice Increased fecal and urinary urobilinogen Hemoglobinemia, methemalbuminemia, hemoglobinuria and hemosiderinuria Bone marrow compensatory reaction: Erythroid hyperplasia with accelerated production of red cells, reticulocytosis, and slight macrocytosis. Expansion of bone marrow in infants and children with severe chronic hemolysis - changes in bone visible on X- ray The balance between red cell destruction and marrow compensation determines the severity of anemias.

HEMOLYTIC ANEMIA Pathogenesis Normal red cells have a lifespan of about 120 days. The lifespan may be very short in haemolytic anaemia (eg as short as five days in sickle cell anemia). Hemolysis may occur by two mechanisms: Intravascular: Complement fixation Trauma Extravascular: most common: Red cells are removed from the circulation by the mononuclear-phagocytic system either because they are intrinsically defective or because of the presence of bound immunoglobulins to their surfaces.

Causes extravascular hemolysis in the adult Intrinsic red blood cell defects Enzyme deficiencies (e.g., G6PD or pyruvate kinase deficiencies) Hemoglobinopathies (e.g., sickle cell disease, thalassemias, unstable hemoglobins) Membrane defects (e.g., hereditary spherocytosis, elliptocytosis) Extrinsic red blood cell defects Liver disease Hypersplenism Infections (e.g., bartonella, babesia, malaria)Oxidant agents (eg, dapsone, nitrites, aniline dyes) Other agents (e.g., lead, copper, snake and spider bites) Large granular lymphocyte leukemia Autoimmune hemolytic anemia (warm- or cold- reacting, drugs) Intravenous immune globulin infusion

Causes intravascular hemolysis in the adult Microangiopathic hemolytic anemia (e.g., TTP, HUS, aortic stenosis, prosthetic valve leak) Transfusion reactions (e.g., ABO incompatibility) Infection (e.g., clostridial sepsis, severe malaria) Paroxysmal cold hemoglobinuria; cold agglutinin disease Paroxysmal nocturnal hemoglobinuria Following intravenous infusion of Rho(D) immune globulin Following intravenous infusion with hypotonic solutions Snake bites Exposure to compounds with high oxidant potential (e.g., copper poisoning, Wilson disease)

HEMOLYTIC ANEMIA: Etiology Intrinsic causes: Red cell membrane abnormalities: Hereditary spherocytosis, Elliptocytosis. Hemoglobin abnormalities: Sickle cell anemia, Thalassemia. Congenital dyserythropoietic anemia Enzyme defects: Glucose-6-phosphate dehydrogenase (G6PD), Pyruvate kinase deficiency

HEMOLYTIC ANEMIA: Etiology Extrinsic causes Acquired hemolytic anemia may be caused by immune- mediated causes, drugs and other miscellaneous causes. Immune-mediated causes could include transient factors as in Mycoplasma pneumoniae infection (cold agglutinin disease) Permanent factors as in autoimmune diseases like autoimmune hemolytic anemi (itself more common in diseases such as systemic lupus erythematosus, Rheumatoid arthritis, Hodgkin's lymphoma Chronic lymphocytic leukemia.

HEMOLYTIC ANEMIA: Etiology Extrinsic: Paroxysmal nocturnal hemoglobinuria (PNH), is a rare, acquired, potentially life-threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia. Any of the causes of hypersplenism (increased activity of the spleen), such as portal hypertension Acquired hemolytic anemia in burns and as a result of infections. Lead poisoning causes non- immune hemolytic anemia. Runners can suffer hemolytic anemia due to "footstrike hemolysis", destruction of red blood cells in feet at foot impact. Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients, and severe hemolytic anemia occurs in 3%

HEMOLYTIC ANEMIA: Peripheral blood smear with sickled cells Thalassemia marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.

HEMOLYTIC ANEMIA The direct antiglobulin (Coombs) test is used to determine whether RBC-binding antibody (IgG) or complement (C3) is present on RBC membranes. The patient's RBCs are incubated with antibodies to human IgG and C3. If IgG or C3 is bound to RBC membranes, agglutination occurs–a positive result. The indirect antiglobulin (Coombs) test is used to detect IgG antibodies against RBCs in a patient's serum. The patient's serum is incubated with reagent RBCs; then Coombs serum (antibodies to human IgG, or human anti-IgG) is added. If agglutination occurs, IgG antibodies (autoantibodies or alloantibodies) against RBCs are present.

HEMOLYTIC ANEMIA Epidemiology Risk factors are variable and depend on the underlying cause. Sickle cell disorders mainly affect Africans and Arabs. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has several variants, divided into five classes according to the level of enzyme activity. These have typical geographic spread. Common locations are the Middle East and the Mediterranean. Autoimmune haemolytic anaemia is slightly more common in females than in males. Most often, it presents in middle-aged and older individuals.

HEMOLYTIC ANEMIA Symptoms Symptoms are due to both anemia and the underlying disorder. Patients with minimal long- standing haemolytic anemia can be asymptomatic. Severe anemia, especially of sudden onset, may cause tachycardia, dyspnoea, angina and weakness. Gallstones may cause abdominal pain. Bilirubin stones can develop in patients with persistent haemolysis. Haemoglobinuria can occur in patients with intravascular haemolysis. Medication history: Some medications, e.g. penicillin, quinine and L- dopa, may cause immune haemolysis. Oxidant drugs, e.g. nalidixic acid, (and also fava beans and infections) can trigger haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

HEMOLYTIC ANEMIA Signs Signs of anemia: general pallor. Tachycardia, tachypnoea and hypotension. Mild jaundice may occur due to haemolysis. Splenomegaly: occurs with some causes, e.g. hereditary spherocytosis. Leg ulcers may occur in some causes of haemolytic anemia, e.g. sickle cell anaemia. Right upper abdominal quadrant tenderness may indicate gallbladder disease. Bleeding and petechiae indicate thrombocytopenia due to Evans' syndrome or thrombotic thrombocytopenic purpura if neurological signs are also present. Signs of underlying disorder, e.g. malar rash in patients with SLE.

HEMOLYTIC ANEMIA Investigations: Complete blood cell count Peripheral blood smear Serum lactate dehydrogenase (LDH) study Serum haptoglobin Indirect bilirubin Platelet count is normal in most hemoltic anemias Thrombocytopenia: SLE, Microangiopathic haemolytic anaemia,TTP, HUS, DIC. High MCH and MCHC: suggest spherocytosis. Coombs' test: Immune-mediated haemolytic anaemia (antibody-mediated destruction of RBCs). Cold agglutinins: Mycoplasma infections and a Infectious mononucleosis. PNH. Ultrasound to estimate spleen size. CXR and ECG: may be needed to assess cardiopulmonary status.

HEMOLYTIC ANEMIA Assess presence of haemolysis Red cell destruction: Reduced haemoglobin. Spherocytes, fragmented red cells, nucleated red cells or other abnormal red cells. Increased serum unconjugated bilirubin, Increased LDH and Reduced or absent haptoglobin. Increased urinary urobilinogen, haemosiderinuria. Increased red cell production: Increased reticulocytosis: may also be due to blood loss or a bone marrow response to iron, vitamin B12 or folate deficiencies. Increased red cell MCV (due to reticulocytosis; but there are many other causes, e.g. vitamin B12 and folate deficiency

HEMOLYTIC ANEMIA Determine haemolysis is intravascular Increased plasma haemoglobin. Methaemoglobinaemia. Hemoglobinuria. Identify the cause Genetic: Red cell morphology: Spherocytes (suggest congenital spherocytosis or autoimmune haemolytic anaemia), Elliptocytes, schistocytes Screen for sickle cell: sickling under reduced conditions. Hemoglobin electrophoresis. Red cell enzyme assays. Acquired: Antibodies: IgG warm antibodies IgM cold antibodies The direct antiglobulin test is positive in autoimmune haemolytic anaemia. Red cell morphology: e.g. haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura.

HEMOLYTIC ANEMIA MECHANISM DISORDER Disorders Extrinsic to the RBC Reticuloendothelial hyperactivity Hypersplenism Immunologic abnormalities Autoimmune hemolytic anemias: Cold antibody Paroxysmal cold hemoglobinuria Warm antibody Infectious organisms Babesia sp Bartonella bacilliformis Plasmodium falciparum P. malariae P. vivax Toxin production by infectious organisms Clostridium perfringens α- and β-Hemolytic streptococci Meningococci Mechanical trauma March hemoglobinuria Skeletal trauma Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome Valvular heart disorders

HEMOLYTIC ANEMIA MECHANISM DISORDER Toxins Compounds with oxidant potential (e.g., dapsone, phenazopyridine) Copper (Wilson disease) Lead Insect venom Snake venom Intrinsic RBC abnormalities Congenital RBC membrane disorders Hereditary elliptocytosis Hereditary spherocytosis Acquired RBC membrane disorders Hypophosphatemia Paroxysmal nocturnal hemoglobinuria Stomatocytosis Disorders of RBC metabolism Embden-Meyerhof pathway defects (eg, pyruvate kinase deficiency) Hexose monophosphate shunt defects (eg, G6PD deficiency) Disorders of Hb synthesis Hb C disease Hb S-C disease Hb E disease Sickle cell disease Thalassemias

HEMOLYTIC ANEMIA General measures Administer folic acid because active haemolysis may cause folate deficiency.  Discontinue medications that may have precipitated or aggravated haemolysis. Transfusion therapy Avoid transfusions unless absolutely necessary, but they may be essential.  In autoimmune haemolytic anemia, type-matching and cross-matching may be difficult. Use the least incompatible blood if transfusions are indicated. The risk of acute hemolysis of transfused blood is high, but the degree depends on the rate of infusion. Iron therapy This is indicated for patients with severe intravascular hemolysis in which persistent haemoglobinuria has caused substantial iron loss

HEMOLYTIC ANEMIA Splenectomy This may be the first choice of treatment in some types of haemolytic anaemia such as hereditary spherocytosis.  In other cases it is recommended when other measures have failed.  Splenectomy is usually not recommended in haemolytic disorders such as cold agglutinin haemolytic anaemia. Complications: Anemia may lead to high- output cardiac failure. Jaundice creates problems associated with increased unconjugated bilirubin. In patients with intravascular haemolysis, iron deficiency due to chronic haemoglobinuria can exacerbate anemia and weakness.