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

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

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 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. HEMOLYTIC ANEMIA

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 extravascular 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) Causes intravascular hemolysis in the adult

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 anemia (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: Etiology

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

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

Decreased RBC life span Increased haem(heme) catabolism – Increased serum unconjugated bilirubin – Increased endogenous CO production – Increased urobilinogen excretion Increased serum LDH Absence or decrease of serum haptoglobin* > 1 g /dl /week fall in blood Hb level Reduced glycosylated Hb Signs of intravascular hemolysis – Hemoglobinemia – Hemoglobinuria – Hemosiderinuria – Methemalbuminemia – Reduced serum hemopexin level Laboratory findings I- Increased RBC destruction

Laboratory findings II-Increased bone marrow activity and RBC production Blood – Reticulocytosis – Macrocytosis – Polychromatophilia – Erythroblastosis – Leukocytosis and thrombocytosis Bone marrow – Erythroid hyperplasia Ferrokinetic – Increased plasma iron turnover – Increased RBC iron turnover Biochemical – Increased RBC creatine – Increased activity of RBC enzymes eg: hexokinase, etc

Polychromasia Spherocyte : Elliptocytes: Stomatocytes: Acanthocytes: Echinocytes: Reticulocytes Her. Spherocytosis, immune hem. anemia, burns, chemical injury to RBC Hereditary ovalocytosis, Hereditary stomatocytosis, alcoholism Spur cell anemia with liver disease, abetalipoproteinemia Pyruvate kinase deficiency, uremia Morphologic abnormalities in hemolytic anemias

Investigations: Complete blood cell count Peripheral blood smear Serum lactate dehydrogenase (LDH) study Serum haptoglobin Indirect bilirubin Platelet count is normal in most hemolytic 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

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. HEMOLYTIC ANEMIA