Hemolytic Anemia PDF

Haemolytic anaemia  Haemolysis means shortening of the normal red cell lifespan  To compensate,  Bone marrow may increase its output of red cells 6- 8 fold by  increasing the proportion of red cells production  expanding the volume of active marrow,  and releasing reticulocytes premature...

Haemolytic anaemia  Haemolysis means shortening of the normal red cell lifespan  To compensate,  Bone marrow may increase its output of red cells 6- 8 fold by  increasing the proportion of red cells production  expanding the volume of active marrow,  and releasing reticulocytes prematurely.  Anaemia only occurs if the rate of destruction exceeds this increased production rate.  Red cell destruction haemoglobin breakdown in the liver causing a modest rise in unconjugated bilirubin in the blood and mild jaundice.  Increased reabsorption of urobilinogen from the gut results in an increase in urinary urobilinogen  Red cell destruction releases LDH into the serum  Extravascular haemolysis  Physiological red cell destruction occurs in the reticuloendothelial cells in the liver or spleen, so avoiding free haemoglobin in the plasma.  In most haemolytic states, haemolysis is predominantly extravascular. Intravascular haemolysis  Less commonly, red cell lysis occurs within the blood stream due to:  membrane damage by complement (ABO transfusion reactions, paroxysmal nocturnal haemoglobinuria),  infections (malaria, Clostridium perfringens),  mechanical trauma (heart valves, )  or oxidative damage (e.g. drugs such as dapsone and maloprim).  When intravascular red cell destruction occurs, free haemoglobin is released into the plasma. Red cell membrane defects  Hereditary spherocytosis  Hereditary elliptocytosis Red cell enzymopathies The mature red cell must produce energy via ATP to maintain a normal internal environment and cell volume whilst protecting itself from the oxidative stress presented by oxygen carriage. Glucose-6-phosphate dehydrogenase deficiency The enzyme glucose-6-phosphate dehydrogenase (G6PD) is pivotal Deficiencies result in the most common human enzymopathy, affecting 10% of the world’s population. A geographical distribution which parallels the malaria because heterozygotes are protected from malarial parasitisation. Pyruvate kinase deficiency o This is the second most common red cell enzyme defect. o It results in deficiency of ATP production and a chronic hemolytic anemia. o It is inherited as an autosomal recessive trait. o The extent of anemia is variable o Enzyme activity is only 5–20% of normal. o Transfusion support may be necessary. Autoimmune haemolytic anaemia o This results from increased red cell destruction due to red cell autoantibodies. o The antibodies may be IgG or M, or more rarely IgE or A. o If an antibody strongly fixes complement it will cause intravascular haemolysis o But if complement activation is weak the haemolysis will be extravascular. o Antibody-coated red cells lose membrane to macrophages in the spleen and hence spherocytes are present in the blood.. The optimum temperature at which the antibody is active (thermal specificity) is used to classify immune haemolysis: Warm antibodies  Bind best at 37°C and account for 80% of cases.  The majority are IgG Cold antibodies  Bind best at 4°C but can bind up to 37°C in some cases.  They account for the other 20% of cases  They are usually IgM and bind complement.  Warm autoimmune haemolysis  The incidence of warm autoimmune haemolysis is approximately 1/100 000 population per year  It occurs at all ages but is more common in middle age in females.  Unknown cause in up to 50% of cases.  The remainder are secondary to a wide variety of other conditions. Investigations  CBC, RETICS, LFTs  The diagnosis is confirmed by the direct Coombs or antiglobulin test o The patient’s red cells are mixed with Coombs reagent, which contains antibodies against human IgG/M/complement. o If the red cells have been coated by antibody in vivo, the Coombs reagent will induce their agglutination o Around 10% of all warm autoimmune haemolytic anaemias are Coombs test-negative. Management  If the haemolysis is secondary to an underlying cause this must be treated and any implicated drugs stopped.  Patients treated initially with prednisolone 1 mg/kg orally.  A response is seen in 70–80% of cases may take up to 3 weeks.  A rise in Hg will be matched by a fall in bilirubin, LDH and reticulocyte levels.  Once the Hg has normalised and the reticulocytosis resolved, the corticosteroid dose reduced slowly over about 10 weeks(tapering).  Corticosteroids work by decreasing macrophage destruction of Antibody coated red cells and reducing antibody production.  Transfusion support may be required for Life threatening problems, such as heart failure or rapid falls in haemoglobin.  If the haemolysis fails to respond to corticosteroids or can only be stabilised by large doses, then splenectomy should be considered.  This removes a main site of red cell destruction and antibody production, with a good response in 50–60% of cases.  If splenectomy is not appropriate alternative immunosuppressive therapy with azathioprine or cyclophosphamide may be considered.  This is least suitable for young patients, in whom long-term immunosuppression carries a risk of secondary neoplasms.  The anti-CD20 (B cell) monoclonal antibody, rituximab, has shown some success in difficult cases. Cold agglutinin disease  This is due to antibodies, usually IgM, which bind to the red cells at low temperatures and cause them to agglutinate.  It may cause intravascular haemolysis if complement fixation occurs.  Treatment is directed at any underlying lymphoma  But if the disease is idiopathic, patients must keep extremities warm, especially in winter  Some patients respond to corticosteroid therapy and blood transfusion  All patients should receive folic acid supplementation. Paroxysmal nocturnal haemoglobinuria  (PNH) is a rare acquired, life threatening disease of the blood Characterized by  destruction of red blood cells ,  blood clots in unusual sites,&  impaired bone marrow function,  aplastic anemia and myelodysplastic syndrom  results in intravascular haemolysis and anaemia because of increased sensitivity of red cells to lysis by complement.  Episodes of intravascular haemolysis result in haemoglobinuria, in early morning urine, has a characteristic red–brown colour. Management  Is supportive with transfusion and treatment of thrombosis.  Recently, the anti-complement C5 monoclonal antibody eculizumab was shown to be effective in reducing haemolysis Haemoglobinopathies  These diseases are caused by mutations affecting the genes encoding the globin chains of the haemoglobin molecule.  Normal haemoglobin is comprised of HbA-αα/ββ)  Alpha globin chains are produced throughout life, including in the fetus, so severe mutations may cause intrauterine death. o Fetal haemoglobin (HbF-αα/γγ) has two gamma chains, while the predominant adult haemoglobin (HbA-αα/ββ) has two beta chains. o Thus, disorders affecting the beta chain do not present until after 6 months of age. o A constant small amount of haemoglobin A2 (HbA2-αα/δδ, usually less than 2%) is made from birth. o The haemoglobinopathies can be classified into qualitative or quantitative abnormalities Sickle-cell anaemia  SCD results from a single glutamic acid to valine substitution at position 6 of the beta globin polypeptide chain.  It is inherited as an autosomal recessive trait.  Homozygotes only produce abnormal beta chains that make haemoglobin S (HbS, termed SS), and this results in the clinical syndrome of sickle-cell disease.  Heterozygotes produce a mixture of normal and abnormal beta chains that make normal HbA and HbS (termed AS), and this results in the clinically asymptomatic sickle-cell trait  With a few minor exceptions, people with only one gene for hemoglobin S (Hb S) are phenotypically normal (sickle trait).  People who inherit two Hb S genes from their parents have sickle cell disease. Clinical features  Sickling is precipitated by hypoxia, acidosis, dehydration and infection.  Irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation.  This results in a number of acute syndromes, termed ‘crises’, and chronic organ damage  Painful vaso-occlusive crisis.  This is the most common crisis  Plugging of small vessels in the bone produces acute severe bone pain.  This affects areas of active marrow: the hands and feet in children (so-called dactylitis) or the femora, humeri, ribs, pelvis and vertebrae in adults.  Patients usually have a systemic response with tachycardia, sweating and a fever.  Sickle chest syndrome.  This may follow a vaso-occlusive crisis and is the most common cause of death in adult.  Bone marrow infarction results in fat emboli to the lungs, which cause further sickling and infarction, leading to ventilatory failure if not treated. Sequestration crisis. (formation of a piece of dead tissue that has detected from the surrounding healthy tissue)  Thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. In children, the spleen is the most common site.  Massive splenic enlargement may result in severe anaemia, circulatory collapse and death.  Recurrent sickling in the spleen In childhood results in infarction and adults may have no functional spleen. In adults, the liver may undergo sequestration with severe pain due to capsular stretching.  Aplastic crisis. Infection with human parvovirus B19 results in a severe but self- limiting red cell aplasia. This produces a very low haemoglobin, which may cause heart failure  Priapism (obstruction of venous outflow from the corporal bodies as a consequence of the interaction of sickled erythrocyte with endothelial cells ,leukocyte, and platelets, leading to vascular obstruction)is a disorder means a prolonged rigid erection of the penis  It is a complication seen in affected men  Treated by oxygenation, analgesic,IV fluid and transfusion and most important step aspiration Investigations:  Patients with SCD have a compensated anaemia, usually around 60–80 g/L.  The blood film shows sickle cells, target cells and features of hyposplenism.  A ↑Retics.  Hb electrophoresis to determineThe presence HbS  The definitive diagnosis requires haemoglobin electrophoresis to demonstrate the absence of HbA, 2–20% HbF and the predominance of HbS.  Both parents of the affected individual will have sickle-cell trait. Management  All patients with sickle-cell disease should receive prophylaxis with daily folic acid penicillin V to protect against pneumococcal infection, which may be lethal in the presence of hyposplenism.  These patients should be vaccinated against pneumococcus, meningococcus, Haemophilus influenzae B, hepatitis B and seasonal influenza.  Vaso-occlusive crises are managed by aggressive rehydration, oxygen therapy, adequate analgesia (which often requires opiates) and antibiotics.  Transfusion  A high HbF level inhibits polymerisation of HbS and reduces sickling.  Patients with sickle-cell disease and high HbF levels have a mild clinical course with few crises.  Some agents are able to increase synthesis of HbF and this has been used to reduce the frequency of severe crises.  The oral cytotoxic agent hydroxycarbamide has been shown to have clinical benefit with acceptable side effects in children and adults who have recurrent severe crises.  Relatively few allogeneic stem cell transplants from HLA- matched siblings have been performed but this procedure appears to be potentially curative DEFINITION: Thalassemias are group of autosomal recessive herediatery hemoglobin disorders charactarized by reduction or absence of the synthesis of beta or alpha chain of the hemoglobin According to the chain deffect , we can classify thalasemia into: (α) Alpha Thalassemia Or (β) Beta Thalassemia What causes thalassemia?  Hemoglobin consists of four protein chains, two alpha globin chains and two beta globin chains.  Each chain — both alpha and beta — contains genetic information, or genes, passed down from your parents.  Think of these genes as the “code” or programming that controls each chain and (as a result) your hemoglobin.  If any of these genes are defective or missing, you’ll have thalassemia..  Alpha globin protein chains consist of four genes, two from each parent.  Beta globin protein chains consist of two genes, one from each parent. The thalassemia you have depends on whether your alpha or beta chain contains the genetic defect. The extent of the defect will determine how severe your condition is. 1) Talassemia minor or Microcythemia or Thalassemia trait  Indicate asymptomatic condition of heterozygot carrier of the genetic anomaly 2) Thalassemia intermedia: Indicate clinical picture of less severity, less signs and symptoms and mild to moderate anamia. Transfusion therapy is not generaly needed 3) Thalassemia major or (Mediterranean Anemia) or (Cooleys Anemia) Indicate unagressive & fatal anemia , if not properly treated, due to presence of mutaion in both allels of the chromosome 11  One defective or missing alpha gene means that you won’t experience symptoms. Another name for this condition is alpha thalassemia minima.  Two defective or missing alpha genes means that if you experience symptoms, they’ll likely be mild. Another name is alpha thalassemia minor.  Three defective or missing alpha genes means that you’ll experience moderate to severe symptoms. Another name for this condition is Hemoglobin H disease.  Four defective or missing alpha genes usually results in death. In those rare instances when a newborn survives, they’ll likely need lifelong blood transfusions. Another name for this condition is hydrops fetalis with Hemoglobin Barts. I -Alpha-thalassaemia  Reduced or absent alpha-chain synthesis is common in Southeast Asia.  There are two alpha gene loci on chromosome 16 and therefore each individual carries four alpha gene alleles. If one is deleted, there is no clinical effect. If two are deleted, there may be a mild hypochromic anaemia..  If three are deleted, the patient has haemoglobin H disease If all four are deleted, the baby is stillborn (hydrops fetalis).  Haemoglobin H is a beta-chain tetramer, formed from the excess of beta chains, which is functionally useless, so that patients depend on their low levels of HbA for oxygen transport. Treatment of haemoglobin H disease is similar to that of beta-thalassaemia of intermediate severity, involving folic acid supplementation, transfusion if required and avoidance of iron therapy II- Beta-thalassaemia  Failure to synthesise beta chains (beta-thalassaemia) is the most common type of thalassaemia,  most prevalent in the Mediterranean area.  Heterozygotes have thalassaemia minor, acondition in which there is usually mild microcytic anaemia and little or no clinical disability,  may be detected only when iron therapy for a mild microcytic anaemia fails.  Homozygotes(thalassaemia major) either are unable to synthesise haemoglobin A or, produce very little; after the first 4–6 months of life,  They develop profound transfusion-dependent hypochromic anaemia.  The diagnostic features are summarised in Box. CLINICAL ASPECTS Classical presentation ANEMIA, JAUNDICE OF V.DEGREE FAILURE TO THRIFE BONE MALFORMATION (MAINLY SKULL ) HEPATOSPLENOMEGALIY HEMOSIDEROSIS RECURRENT INFECTION HEART FAILURE o Mild to moderate symptoms Beta thalassemia intermedia may cause mild anemia symptoms, or it may cause the following symptoms associated with more moderate disease:  Growth problems.  Delayed puberty.  Bone abnormalities, such as osteoporosis.  An enlarged spleen (the organ that plays a part in fighting infection). o Severe symptoms Missing three alpha genes (Hemoglobin H disease) often causes anemia symptoms at birth and leads to severe lifelong anemia. Beta thalassemia major (Cooley’s anemia) often leads to severe anemia symptoms noticeable by age 2. Symptoms of severe anemia include those associated with mild to moderate disease, Additional symptoms may include:  Poor appetite.  Pale or yellowish skin (jaundice).  Urine that’s dark or tea-colored.  Irregular bone structure in your face.  Diagnosis and Tests  Moderate and severe thalassemia are often diagnosed in childhood Because symptoms usually appear within the first two years of your child’s life.  A complete blood count (CBC) that includes measures of hemoglobin and the quantity (and size) of red blood cells. People with thalassemia have fewer healthy red blood cells and less hemoglobin than normal. They may also have smaller-than-normal red blood cells.  A reticulocyte count (a measure of young red blood cells) may indicate that your bone marrow isn’t producing enough RBCs. Studies of iron will indicate whether the cause of your anemia is an iron deficiency or thalassemia.  Hemoglobin electrophoresis is used to diagnose beta thalassemia. Genetic testing is used to diagnose alpha thalassemia.  MANAGEMENT Blood Transfusion Hb above 9g/dl, improve growth, and decrease the typical cranio-fascial deformity. According the WHO reccomendation, Hb should maintaned around (9.5g|dl). RBC concentrate. Splenectomy Indcation: Hypersplenism. >10 years old. Pressure symptoms. Trauma. 1. Desferrioxamine (Desferal):.1 To be given s.c. regularlly in adequate doses. 40-50 mg per kg daily for 5-6 days a week. 2. Deferiprone (L1): Used in compination with DFX or alone, in some patients. 3. BMT Some selected lucky patients completely cured after bone marrow transplantation, and SCT. Criteria to be considered for BMT ; Non splenectomised pt. No signs or symptoms of organic hemosidrosis. HLA-compatible. prevention Strategy of preventione: 1.Health Education. 2.Screening of the population. 3.Genetic counselling 4.Prenatal diagnosis.  CONCLUSION Thalassemia , is a hereditiry disease, caratterized by chronic anemia of grave form which is now well known by its clinical characters. Thank you for your attendance