Haemolytic Anaemias Lecture Notes PDF

Haematology ”“Haemolytic Anaemias University Of Fallujah College Of Medicine Lecture : L12 Stage : 5th Lecturer : Assistant Professor: Mohammed Ismael Dawood Department: Medicine Date: 31/10/2024 Basic Learning Objectives: 1. Definit...

Haematology ”“Haemolytic Anaemias University Of Fallujah College Of Medicine Lecture : L12 Stage : 5th Lecturer : Assistant Professor: Mohammed Ismael Dawood Department: Medicine Date: 31/10/2024 Basic Learning Objectives: 1. Definition of haemolytic anaemia. 2. Pathogenesis & clinical consequences of haemolytic anaemia. 3. Red cell membrane defects. 4. Red cell enzymopathy. 5. Acquired hemolytic anaemi  Haemolytic anaemia  Normal red cells have a lifespan of 120 days.  Increased red cell destruction (haemolysis) leads to:  Increased LDH.  A modest increase in unconjugated bilirubin and mild jaundice.  Compensatory bone marrow activity results in increased reticulocytes and immature granulocytes in peripheral blood; blood films may also show the reason for haemolysis (e.g. spherocytosis).  The erythroid hyperplasia may also cause folate deficiency, leading to megaloblastosis.  When destruction exceeds production, haemolytic anaemia results.  Extravascular haemolysis:  Occurs in the reticulo-endothelial cells of the liver and spleen, so avoiding free Hb in the plasma.  In most haemolytic states, haemolysis is predominantly extravascular.  Intravascular haemolysis:  Releases free Hb into the plasma, where it binds to haptoglobin (an α2 globulin produced by the liver), resulting in a fall in haptoglobin levels.  Once haptoglobins are saturated, free Hb is oxidised to form methaemoglobin.  Excess free Hb may also be absorbed by renal tubular cells, where it is degraded and the iron stored as haemosiderin.  When the tubular cells are subsequently sloughed into the urine, they give rise to haemosiderinuria.  Red cell membrane defects Hereditary spherocytosis:  This is usually inherited as an autosomal dominant condition and has an incidence of 1: 5000.  The most common abnormalities are deficiencies of the red cell membrane proteins, beta spectrin or ankyrin.  The cells lose their normal elasticity and undergo destruction when they pass through the spleen.  The severity of spontaneous haemolysis varies.  Most cases feature an asymptomatic compensated chronic haemolytic state with spherocytes on the blood film and a reticulocytosis.  Pigment gallstones occur in up to 50% of patients and may cause cholecystitis.  The clinical course may be complicated by crises:  Haemolytic crisis: occurs uncommonly, usually with infection.  Megaloblastic crisis: follows the development of folate deficiency.  Aplastic crisis: occurs in association with parvovirus B19 infection; the virus directly invades red cell precursors and switches off red cell production.  Investigations:  Hb levels: variable, depending on the degree of compensation.  Blood film: shows spherocytes and reticulocytes.  Direct Coombs test: negative, excluding immune haemolysis.  Bilirubin and LDH: raised.  Screening of family members.  Management:  Folic acid prophylaxis (5 mg weekly) should be given for life.  Acute severe haemolytic crises require transfusion.  Splenectomy should be considered in moderate to severe cases but only after the age of 6 years because of the risk of sepsis.  Prior to splenectomy, patients should receive vaccination against pneumococcus, Haemophilus influenzae type B, meningococcus group C and influenza.  They should undergo regular immunisation against pneumococcus and influenza, and receive lifelong penicillin V. Hereditary elliptocytosis:  This is less common and generally milder than hereditary spherocytosis.  The blood film shows elliptocytic red cells and there is variable haemolysis.  Most cases are asymptomatic and do not require specific treatment; more severe cases are managed in a similar way to hereditary spherocytosis.  Red Cell Enzymopathy Glucose-6-phosphate dehydrogenase deficiency:  Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common inherited enzymopathy, affecting 10% of the world’s population.  G6PD is pivotal in the hexose monophosphate shunt and helps to protect the red cells against oxidative stress.  G6PD deficiency is an X-linked condition principally affecting males.  It results in acute intravascular haemolysis secondary to infection, drugs (e.g. antimalarials, sulphonamides, and nitrofurantoin) and ingestion of fava beans.  It can also cause chronic haemolysis and neonatal jaundice.  Management involves stopping any precipitant drugs. Transfusion may be required in severe cases.  Acquired haemolytic anaemia Autoimmune haemolytic anaemia:  This results from increased red cell destruction due to red cell autoantibodies.  If an antibody avidly fixes complement, it will result in intravascular haemolysis, but if complement activation is weak, the haemolysis will be extravascular.  Immune haemolysis is classified according to whether the antibodies bind best at 37°C (warm antibodies, 80% of cases) or 4°C (cold antibodies). Warm autoimmune haemolysis:  Warm autoimmune haemolysis occurs at all ages but is more common in middle age. Antibodies are usually IgG.  No underlying cause is identified in up to 50% of cases but known causes include: 1. Lymphoid neoplasms, e.g. lymphoma. 2. Solid tumours, e.g. lung, colon. 3. Connective tissue disease, e.g. systemic lupus erythematosus, rheumatoid arthritis. 4. Drugs, e.g. methyldopa.  Investigations:  There is evidence of haemolysis and spherocytes on the blood film.  The diagnosis is confirmed by the direct Coombs or antiglobulin test, in which red cells are mixed with Coombs reagent containing antibodies against human IgG/M/complement. If the red cells have been coated by antibody in vivo, agglutination occurs. The test will miss IgA and IgE antibodies.  Management:  Any underlying cause must be treated and any implicated drugs stopped.  Oral prednisolone (1 mg/kg) is the mainstay of treatment. It works by decreasing macrophage destruction of antibody-coated red cells and reducing antibody production.  Transfusion may be required for severe anaemia.  Splenectomy should be considered in refractory cases; this removes a main site of red cell destruction and antibody production.  Alternative immunosuppressive therapy (e.g. azathioprine, cyclophosphamide) may be required in some patients. Cold agglutinin disease:  This is due to antibodies (‘cold agglutinins’), usually IgM, which bind to the red cells at 4°C and cause them to agglutinate.  Agglutination may cause intravascular haemolysis if complement fixation occurs.  Causes include: 1. Lymphoma. 2. Infections, e.g. Mycoplasma pneumoniae, infectious mononucleosis. 3. Paroxysmal cold haemoglobinuria.  Cold antibodies optimally bind red cells at lower temperatures.  Red cell agglutination therefore occurs in small vessels in exposed areas, and patients may experience cold, painful and blue fingers and toes (acrocyanosis).  Management:  Any underlying cause must be treated.  All patients should receive folate supplements.  Patients must keep extremities warm, especially in winter.  Corticosteroid therapy and blood transfusion may be required in some patients.  Non-immune haemolytic anaemia Physical trauma:  Physical disruption of red cells may occur in a number of conditions and is characterised by the presence of red cell fragments on the blood film and markers of intravascular haemolysis.  Mechanical heart valves: High flow through incompetent valves results in shear stress damage.  March haemoglobinuria: Prolonged marching or marathon running can cause red cell damage in the capillaries in the feet.  Thermal injury: Severe burns cause thermal damage to red cells, characterised by fragmentation and the presence of microspherocytes in the blood.  Microangiopathic haemolytic anaemia: Fibrin deposition in capillaries can cause severe red cell disruption.  Causes include:  Malignant or pregnancy –induced hypertension.  Haemolytic uraemic syndrome.  TTP.  DIC. Infection:  Plasmodium falciparum malaria may be associated with intravascular haemolysis; when severe, this is termed blackwater fever due to the associated haemoglobinuria.  Clostridium perfringens septicaemia, usually in the context of ascending cholangitis, may cause severe intravascular haemolysis with marked spherocytosis due to bacterial production of a lecithinase which destroys the red cell membrane. Chemicals or drugs:  Dapsone and sulfasalazine cause haemolysis by oxidative denaturation of haemoglobin. Denatured haemoglobin forms Heinz bodies in the red cells, visible on supravital staining with brilliant cresyl blue.  Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives may all cause haemolysis. Paroxysmal nocturnal haemoglobinuria (PNH):  It is a rare acquired, non-malignant clonal expansion of haematopoietic stem cells deficient in GPI-anchor protein; it results in intravascular haemolysis and anaemia because of increased sensitivity of red cells to lysis by complement.  Episodes of intravascular haemolysis result in haemoglobinuria, most noticeable in early morning urine, which has a characteristic red–brown colour.  The disease is associated with an increased risk of venous thrombosis in unusual sites, such as the liver or abdomen.  PNH is also associated with hypoplastic bone marrow failure, aplastic anaemia and myelodysplastic syndrome.  Management:  Supportive with transfusion.  Treatment of thrombosis.  Recently, the anti-complement C5 monoclonal antibody eculizumab was shown to be effective in reducing haemolysis.