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

Treatment depends on the cause and nature of the breakdown. 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) 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: 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 de-compensation.

Acquired haemolytic anaemia: immune Classification: Acquired haemolytic anaemia: immune Immune (direct antiglobulin test often positive): Warm antibody autoimmune haemolytic anaemia: antibody (usually IgG) binds most avidly at core body temperature. Associated with underlying diseases such as: SLE Lymphoma Chronic lymphocytic leukaemia.3 Cold antibody autoimmune haemolytic anaemia: antibody binds RBC at temperature below body temperature. (often IgM, but may be IgG). Can be idiopathic, or associated with infection or malignancy. Drug-induced immune haemolytic anaemia. Alloimmune haemolytic anaemia: haemolytic disease of the newborn or transfusion reaction.

Non-immune (direct antiglobulin test negative): Classification: Acquired haemolytic anaemia: non-immune Non-immune (direct antiglobulin test negative): Infection: malaria, babesiosis, bartonellosis Bacterial toxins: Clostridium perfringens infection. Drug-induced (by non-immune mechanism). HELP syndrome (haemolysis, elevated liver enzymes, low platelet count) in pregnancy; Mechanical prosthetic heart valve March haemolysis. Membrane disorder (acquired): Paroxysmal nocturnal haemoglobinuria. Liver disease. Thermal injury. Osmotic lysis. Hypersplenism.

Red cell membrane disorders: Hereditary spherocytosis Elliptocytosis Classification: Congenital haemolytic anaemia Red cell enzyme defects: Glucose-6-phosphate dehydrogenase deficiency Pyruvate kinase deficiency Haemoglobinopathies: Sickle cell anaemia Thalassaemia Red cell membrane disorders: Hereditary spherocytosis Elliptocytosis Pyropoikilocytosis

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.

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 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 thrombotic thrombocytopenic purpura. Signs of underlying disorder, e.g. malar rash in patients with SLE.

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.

Common features(HA) General – jaundice, pallor Other sign- splenomegaly, bossing of skull Hb.- N to severely reduced MCV,MCH- usually increased RC- increased Bilirubin – increased(unconjugated) LDH- increased Heptoglobin- reduced to absent

Investigation Tests of increased red cell breakdown Serum bilirubin – indirect/unconjugate ↑ Urine urobilinogen ↑ Faecal stercobilinogen ↑ S. heptaoglobin ↓/ absent Plasma LDH ↑ Evidence of intravascular hemolysis - hemoglobinaemia, hemoglobinuria, methaemoglobinaemia, haemosiderinuria

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 Intravascular haemolysis Haemoglobinemia. Methaemoglobinaemia. Hemoglobinuria. Genetic: Red cell morphology: Spherocytes Elliptocytes Schistocytes Screen for sickle cell 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: Thrombotic thrombocytopenic purpura. Haemolytic uraemic syndrome,

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. Transfusions may be essential for patients with angina or a severely compromised cardiopulmonary status. It is best to administer packed red blood cells slowly to avoid cardiac stress. Iron therapy This is indicated for patients with severe intravascular hemolysis in which persistent haemoglobinuria has caused substantial iron loss

HEMOLYTIC ANEMIA Corticosteroids are indicated in autoimmune hemolytic anemia (AIHA). Increasing evidence supports the use of rituximab in AIHA, particularly warm antibody AIHA Intravenous immunoglobulin G (IVIG) has been used for patients with AIHA, but only a few patients have responded to this treatment, and the responses have been transient. Erythropoietin (EPO) has been used to try to reduce transfusion requirements, with variable outcomes. EPO has reduced transfusion requirements include: Children with CRF AIHA with reticulocytopenia  A patient with sickle cell disease undergoing hemodialysis for renal failure. Infants with hereditary spherocytosis 

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.

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