Hemolytic Anemias PDF

Hemolytic Anemias ILOs At the end of this session, the student will be able to: ▪ Define hemolytic anemias. ▪ Explain the underlying pathophysiologic intrinsic and extrinsic defects in red blood cell that presented with hemolytic anemia. ▪ Describe the types, clinical...

Hemolytic Anemias ILOs At the end of this session, the student will be able to: ▪ Define hemolytic anemias. ▪ Explain the underlying pathophysiologic intrinsic and extrinsic defects in red blood cell that presented with hemolytic anemia. ▪ Describe the types, clinical picture, and diagnostic approach to thalassemia and Sickle cell anemia. ▪ Discuss the treatment options of thalassemia and Sickle cell anemia. ▪ Mention the characteristics of Autoimmune Hemolytic Anemia. ▪ Outline the main management for Autoimmune Hemolytic Anemia.. o The hemolytic anemias are a group of disorders in which red blood cell survival is reduced, either episodically or continuously. o The bone marrow has the ability to increase erythroid production up to eightfold in response to reduced red cell survival, o So anemia will be present only when red cell survival is extremely short or the ability of the bone marrow to compensate is impaired. o Hemolytic disorders are generally classified according to whether the defect is intrinsic to the red cell or due to some external factor. ❖ Causes Intrinsic defects have been described in all components of the red blood cell (most of these disorders are hereditary) including: 1. The membrane 2. Enzyme systems 3. Hemoglobin External factors are: 1. Immune-mediated 2. Infections of red blood cells 3. Microangiopathic hemolytic anemia (MAHA) Certain laboratory features are common to all hemolytic anemias. o Decreased Haptoglobin, a normal plasma protein that binds and clears free hemoglobin released into plasma. o When intravascular hemolysis occurs, transient hemoglobinemia ensues. o Hemoglobin is filtered through the renal glomerulus and is usually reabsorbed by tubular cells. o Hemoglobinuria will be present only when the capacity for reabsorption of hemoglobin by renal tubular cells is exceeded. o In the absence of hemoglobinuria, evidence for prior intravascular hemolysis is the presence of hemosiderin in shed renal tubular cells (positive urine hemosiderin). o Hemolysis increases the indirect bilirubin, and the total bilirubin may rise to 4 mg/dL or more. o Serum LDH levels are strikingly elevated in cases of microangiopathic hemolysis (thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome) and may be elevated in other hemolytic anemias. The Thalassemia Essentials of Diagnosis: o Positive family history. o Lifelong personal history of microcytic anemia. o Microcytosis disproportionate to the degree of anemia. o Normal or elevated red blood cell count. o Abnormal red blood cell morphology with microcytes, hypochromia, acanthocytes, and target cells. o In beta-thalassemia, elevated levels of hemoglobin A2 and F. The thalassemia variants: 1. Alpha-thalassemia trait 2. Hemoglobin H disease  3. Beta-thalassemia minor 4. Beta-thalassemia intermedia 5. Beta-thalassemia major o The thalassemias are hereditary disorders characterized by reduction in the synthesis of globin chains (alpha or beta). o Reduced globin chain synthesis causes reduced hemoglobin synthesis and a hypochromic microcytic anemia because of defective hemoglobinization of red blood cells. o Thalassemias can be considered among the hyperproliferative HA, the anemias related to abnormal hemoglobin, and the hypoproliferative anemias, since all of these factors play a role in pathogenesis. o The hallmark laboratory features are small (low MCV) and pale (low mean corpuscular hemoglobin [MCH]) red blood cells, anemia, and a normal to elevated red blood cell count (ie, a large number of the small and pale red blood cells are being produced). o Normal adult hemoglobin is primarily hemoglobin A, which represents approximately 98% of circulating hemoglobin. o Hemoglobin A is formed from a tetramer of two alpha-globin chains and two beta- globin chains and is designated alpha2 beta2. o The tetramer alpha2gamma2 forms hemoglobin F, which is the major hemoglobin of fetal life but which composes less than 1% of normal adult hemoglobin. Alpha-thalassemia results from decreased production of alpha-polypeptide chains due to a deletion of one or more alpha genes. Beta-thalassemia results from decreased production of beta-polypeptide chains due to either mutations or deletions in the beta globin gene, leading to impaired production of hemoglobin (Hb) A. In beta-thalassemia, clinical phenotypes are classified into 3 groups based on the degree to which beta globin production is impaired: Minor (or trait) Intermedia Major The thalassemias are described as: Thalassemia trait: there are laboratory features without significant clinical impact. Thalassemia intermedia: is an occasional red blood cell transfusion requirement or other moderate clinical impact. Thalassemia major: when the disorder is life-threatening and the patient is transfusion- dependent. Most patients with thalassemia major die of the consequences of iron overload from red blood cell transfusions. Clinical Findings - alpha-thalassemia o When three alpha-globin genes are present, the patient is hematologically normal (silent carrier). o When two alpha-globin genes are present, the patient is said to have alpha- thalassemia trait, a form of thalassemia minor. o When only one alpha globin gene is present, the patient has hemoglobin H disease. This is a chronic hemolytic anemia of variable severity (thalassemia minor or intermedia). o When all four alpha-globin genes are deleted, no normal hemoglobin is produced and the affected fetus is stillborn (hydrops fetalis) o Physical examination might reveal pallor & splenomegaly. o Affected individuals usually do not need transfusions. o They may be required during periods of hemolytic exacerbation caused by infection or other stressors or during periods of erythropoietic shutdown caused by certain viruses (“aplastic crisis”). Clinical Findings - Beta-thalassemia o Patients homozygous for beta-thalassemia have beta-thalassemia major (Cooley anemia). o Affected children are normal at birth, but after 6 months, when hemoglobin synthesis switches from hemoglobin F to hemoglobin A, severe anemia develops that requires transfusion. o The clinical course is modified significantly by transfusion therapy, but transfusional iron overload (hemosiderosis) results in a clinical picture similar to hemochromatosis, with heart failure, cardiac arrhythmias, cirrhosis, endocrinopathies, and pseudoxanthoma elasticum (calcification and fragmentation of the elastic fibers of the skin, retina, and cardiovascular system), usually after more than 100 units of red blood cells have been transfused. o Stunted growth o Bony deformities (abnormal facial structure, pathologic bone fractures) o Hepatosplenomegaly o Jaundice o Thrombophilia Laboratory Findings 1. Alpha-thalassemia trait 2. Hemoglobin H disease 3. Beta-thalassemia minor 4. Beta-thalassemia intermedia 5. Beta-thalassemia major Thalassemia -Treatment 1. Patients with mild thalassemia (alpha-thalassemia trait or beta-thalassemia minor) require no treatment and should be identified so that they will not be subjected to repeated evaluations and treatment for iron deficiency. 2. Patients with hemoglobin H disease should take folic acid supplementation (1 mg/day orally) and avoid iron therapy and oxidative drugs such as sulfonamides. 3. Patients with severe thalassemia are maintained on a regular transfusion schedule (in part to suppress endogenous erythropoiesis and therefore bone marrow expansion) and receive folic acid supplementation. 4. Splenectomy is performed if hypersplenism causes a marked increase in the transfusion requirement or refractory symptoms. 5. Patients with regular transfusion requirements should be treated with iron chelation (oral or parenteral) in order to prevent or delay life-limiting organ damage from iron overload. 6. Luspatercept, has been FDA approved for transfusion-dependent beta-thalassemia. It is a TGF-beta ligand trap that promotes erythroid maturation and reduces transfusion needs. 7. Allogeneic stem cell transplantation is the treatment of choice for beta-thalassemia major and the only available cure. 8. Autologous gene therapy is showing promise for thalassemia major. Sickle Cell Anemia (SCA) General Considerations o Autosomal recessive disorder in which an abnormal hemoglobin leads to chronic hemolytic anemia. o A single DNA base change leads to an amino acid substitution of valine for glutamate in the sixth position on the beta-globin chain. o The abnormal beta chain is designated betas and the tetramer of alpha-2betas-2 is designated hemoglobin SS. o Hemoglobin S is unstable and polymerizes in the setting of various stressors, including hypoxemia and acidosis, leading to the formation of sickled red blood cells. Sickle Cell Trait o Heterozygous hemoglobin genotype AS. o Hematologically normal, with no anemia and normal red blood cells on peripheral blood smear. o Hemoglobin electrophoresis will reveal ~40% of Hb is hemoglobin S. o People with sickle cell trait may be at increased risk for venous thromboembolism. o Chronic sickling of red blood cells in the acidotic renal medulla results in microscopic and gross hematuria, hyposthenuria (poor urine concentrating ability), and possibly chronic kidney disease. o No treatment is necessary but genetic counseling is recommended. Sickle-Thalassemia o Patients with homozygous sickle cell anemia and alpha-thalassemia have less vigorous hemolysis and run higher hemoglobins than SS patients due to reduced red blood cell sickling related to a lower hemoglobin concentration within the red blood cell and higher hemoglobin F levels. o The MCV is low, and the red cells are hypochromic. Sickle cell anemia General Considerations o Sickled cells result in hemolysis and the release of ATP, which is converted to adenosine. o Adenosine binds to its receptor (A2B), resulting in the production of 2,3- biphosphoglycerate and the induction of more sickling, and to its receptor (A2A) on natural killer cells, resulting in pulmonary inflammation. o The free hemoglobin from hemolysis scavenges nitric oxide causing endothelial dysfunction, vascular injury, and pulmonary hypertension. o The rate of sickling is influenced by the intracellular concentration of hemoglobin S and by the presence of other hemoglobins within the cell. o Hemoglobin F cannot participate in polymer formation, and its presence markedly retards sickling. o Factors that increase sickling are red blood cell dehydration and factors that lead to formation of deoxyhemoglobin S (eg, acidosis and hypoxemia), either systemic or local in tissues. o Hemolytic crises may be related to splenic sequestration of sickled cells (primarily in childhood before the spleen has been infarcted as a result of repeated sickling) or with coexistent disorders such as G6PD deficiency. Clinical Findings Symptoms and Signs: o Chronic hemolytic anemia produces jaundice, pigment (calcium bilirubinate) gallstones, splenomegaly (early in life), and poorly healing skin ulcers over the lower tibia. o Life-threatening severe anemia can occur during hemolytic or aplastic crises, the latter generally associated with viral or other infection caused by immuno-incompetence from hyposplenism or by folic acid deficiency causing reduced erythropoiesis. o Acute vaso-occlusion: Acute painful episodes from clusters of sickled red cells may occur spontaneously or be provoked by infection, dehydration, or hypoxia. o Common sites of acute painful episodes include the spine and long bones. o Episodes last hours to days and may produce low-grade fever. o May cause strokes due to sagittal sinus venous thrombosis. o Episodes are not associated with increased hemolysis. o Repeated episodes of vascular occlusion especially affect the heart, lungs, and liver. o The acute chest syndrome is characterized by acute chest pain, hypoxemia, and pulmonary infiltrates on a chest radiograph and must be distinguished from an infectious pneumonia. o Ischemic necrosis of bones (avascular necrosis) may occur, rendering the bone susceptible to osteomyelitis due to salmonellae and (somewhat less commonly) staphylococci. o Delayed puberty. o An increased incidence of infection is related to hyposplenism as well as to defects in the alternate complement pathway. o On examination, patients are often chronically ill and jaundiced. o There is often hepatomegaly, but the spleen is not palpable in adult life. o The heart may be enlarged with a hyperdynamic precordium and systolic murmurs and, in some cases, a pronounced increase in P2. o Non-healing cutaneous ulcers of the lower leg and retinopathy may be present. Laboratory Findings o Chronic hemolytic anemia is present. o The hematocrit is usually 20–30%. o The peripheral blood smear: sickled cells comprising 5–50% of red cells. o Reticulocytosis (10–25%), nucleated red blood cells, and hallmarks of hyposplenism such as Howell-Jolly bodies and target cells. o Leucocytosis is characteristically present (12–15×109/L), and reactive thrombocytosis may occur. o Indirect bilirubin levels are high. o The diagnosis of sickle cell anemia is confirmed by hemoglobin electrophoresis. o Hemoglobin S will usually comprise 85–98% of Hb. o In homozygous S disease, no hemoglobin A will be present. o Hemoglobin F levels are sometimes increased, and high hemoglobin F levels (15– 20%) are associated with a more benign clinical course. o Patients with S-beta+-thalassemia and SS alpha-thalassemia also have a more benign clinical course than straight sickle cell anemia (SS). SICKLE CELL ANEMIA (SCA) Essentials of Diagnosis 1. Recurrent pain episodes. 2. Positive family history and lifelong history of hemolytic anemia. 3. Irreversibly sickled cells on peripheral blood smear. 4. Hemoglobin S is the major hemoglobin seen on electrophoresis. AUTOIMMUNE HEMOLYTIC ANEMIA Essentials of Diagnosis: 1. Acquired hemolytic anemia caused by IgG autoantibody. 2. Spherocytes and reticulocytosis on peripheral blood smear. 3. Positive antiglobulin (Coomb’s) test. 4. Autoimmune Hemolytic Anemia o Approximately one-half of all cases of autoimmune hemolytic anemia are idiopathic. o The disorder may also be seen in association with systemic lupus erythematosus, other rheumatic disorders, chronic lymphocytic leukemia (CLL), or lymphomas. o It must be distinguished from drug-induced hemolytic anemia. Autoimmune hemolytic anemia is an acquired disorder in which an IgG Autoantibody is formed that binds to a red blood cell membrane protein. The antibody recognized by macrophages present in the spleen and RES. The interaction between splenic macrophages and the antibody-coated red blood cell results in removal of red blood cell membrane and the formation of a spherocyte then lysis of cells. Drug-induced hemolytic anemia: When a drug coats the red blood cell membrane, the autoantibody is directed against the membrane-drug complex. Clinical Findings o Autoimmune hemolytic anemia typically produces an anemia of rapid onset that may be life-threatening. o Patients C/O fatigue and dyspnea and may present with angina pectoris or heart failure. o On examination, jaundice and splenomegaly are usually present. o Death from cardiovascular collapse can occur in the setting of rapid hemolysis. Laboratory Findings o The anemia is of variable degree, may be very severe. o Hematocrit of less than 10%. o Reticulocytosis o Spherocytes on the peripheral blood smear. o In severe hemolysis, the stressed bone marrow may also release nucleated red blood cells. o The serum indirect bilirubin is increased and the haptoglobin is low. o The antiglobulin (Coombs) test forms the basis for diagnosis. Treatment o Prednisone: 1–2 mg/kg/day orally in divided doses. o Patients with DAT-negative and DAT-positive autoimmune hemolysis respond equally well to corticosteroids. o Transfused red blood cells will survive similarly to the patient’s own red blood cells. o Because of difficulty in performing the cross-match, possible “incompatible” blood may need to be given. o Immunosuppressive agents: cyclophosphamide, vincristine, azathioprine, mycophenolate mofetil, alemtuzumab (an anti-CD52 antibody), or cyclosporine. o Plasmapheresis: in rapid hemolysis, to remove autoantibodies. o High-dose intravenous immune globulin (1 g/kg daily for 2 days) may be effective in controlling hemolysis. o Splenectomy: if prednisone is ineffective or if the disease recurs on tapering the dose. o Rituximab: For refractory cases to prednisone and splenectomy A monoclonal antibody against the B cell antigen CD20 Dose is 375 mg/m2 intravenously weekly for 4 weeks. o Treatment of an associated lymphoproliferative disorder will also treat the hemolytic anemia.