of 37/37
HEMOLYTIC ANEMIA Dr.ETEMADFAR Pediatric hematologist LOGO [email protected] om

Hemolytic anemia

  • View

  • Download

Embed Size (px)

Text of Hemolytic anemia

  1. 1. HEMOLYTIC ANEMIA Dr.ETEMADFAR Pediatric hematologist LOGO
  2. 2. Introduction Autoimmune hemolytic anemia (AIHA) is an immunologic disorder in which antibodies are produced that target RBCs shortening of red cell survival due to the products of an immune response All require antigen-antibody reactions
  3. 3. Classification of Immune Hemolytic Anemia
  4. 4. Characteristics of Erythrocyte Autoantibodies Warm AIHA caused by IgG autoantibodies that are optimally reactive at 37 C CAD is typified by IgM autoantibodies that are optimally reactive at 4C PCH is a form of cold-reacting AIHA caused by IgG autoantibodies mixed-type AIHA with both IgG warm and IgM cold autoantibodies
  5. 5. Warm-Reactive Autoantibodies maximally reactive at 37C typically react with a patients own RBCs IgG1 is the most common subclass IgG1 and IgG3 activate C1 more readily, bind strongly to FcRI, FcRII, and FcRIII, and increase RBC destruction in comparison with IgG2 and IgG4 subtypes
  6. 6. Cold-Reactive Autoantibodies primarily associated with CAD and PCH PCH is the most common form in children Both are bind RBCs optimally at temperatures below 37C and usually below 31C Cold agglutinins are IgM autoantibodies that primarily cause extravascular hemolysis but can mediate intravascular hemolysis as well PCH is IgG mediated and causes intravascular hemolysis
  7. 7. pathogenesis of a cold-reactive autoantibody bind host RBCs and activate complement complement fixation by these antibodies occurs at 20C to 25C Complement fixation cause RBC destruction via opsonization by macrophages
  8. 8. Cold Agglutinin Disease acute and often a result of Mycoplasma pneumoniae infection Other viruses:EBV,varicella and adenovirus CAD typically occurs in the second or third week of illness jaundice and pallor due to rapid onset of hemolysis The hemolysis is self-limiting, and the degree of anemia is typically mild to moderate
  9. 9. Cold Agglutinin Disease (cont.) cold autoantibody is an IgM with anti-I specificity associated with M. pneumoniae and anti-i specificity associated with EBV high (256) cold agglutinin titers with postinfectious CAD Treatment of postinfectious CAD is supportive and includes keeping the patient warm and using a blood warmer if the degree of anemia warrants RBC transfusion
  10. 10. Cold Agglutinin Disease (cont.) chronic form of CAD is seen in elderly patients associated with lymphoma, chronic lymphocytic anemia hemoglobinuria from intravascular hemolysis and acrocyanosis of the ears, nose, fingers, and toes from autoagglutination of RBCs in the skin capillaries, particularly in cold weathe are seen Autoagglutination can be enhanced by cooling the blood to 4C and is reversed by warming to 37C Higher(1000) cold agglutinin titers
  11. 11. Paroxysmal Cold Hemoglobinuria PCH occurs primarily in children as an acute transient condition following an upper respiratory or viral infection detected by the Donath-Landsteiner test PCH is the second most common form of AIHA in children
  12. 12. Clinical manifestation of PCH In children, PCH classically presents within several weeks after a viral infection sudden onset of hemoglobinuria, accompanied by fever, pallor, and jaundice headache, abdominal pain, nausea, vomiting, or diarrhea Hepatomegaly and splenomegaly were reported in up to 25% of cases
  13. 13. LABORATORY FINDING OF PCH Reticulocytosis is characteristic, reticulocytopenia can be observed PBS demonstrates RBC agglutination, polychromasia nucleated RBCs, and spherocytes DAT is negative Donath-Landsteiner test is positive LDH,BUN,Cr, unconjugated bilirubin, haptoglobin
  14. 14. PRIMARY AIHA incidence of about 1 per 75,000 to median age of diagnosis of 3.8 years typically after a recent infection Warm-reactive antibodies are IgG class and account for the majority of AIHA cases in children IgM-mediated CAD is uncommon in children and mostly affects adults and elderly persons PCH primarily presents in children, with the median age at diagnosis being 5 years
  15. 15. PRIMARY AIHA Clinical course: 1) Warm Ab:acute illness or intermittent remissions and relapses 2) Cold Ab:severe but acute self-limited illness requiring short-term supportive care with transfusion improved mortality rate from 18% to 4% result of improvement in supportive care
  16. 16. In a largest cohort study of 265 pediatric patients with AIHA: 37% were diagnosed with Evans syndrome 4% had died 6% had no response or were in partial remission 90% were in complete remission while either receiving or not receiving therapy
  17. 17. Treatment of Acute AIHA transfusion Corticosteroid IVIG Plasma exchange ACUTE AIHA TREATMENT
  18. 18. Transfusion Therapy Mild anemia & no symptom:observation only Modrate to sever anemia or symptomatic: transfusion therapy very severe anemia with hemoglobin levels6 : RBC transfusion should be instituted as soon as possible in warm, idiopathic AIHA, antibody is against blood group antigens that are present on most RBCs. no truly matched RBC units are possible, but transfusion can be safely performed
  19. 19. Corticosteroid Therapy Mechanism to improve hemolysis in warm AIHA : 1-decrease in serum antibody concentration 2-decreasing sequestration in the spleen Dosage:1-2 mg/kg q 6 h for 1-3 day Then 2 mg/kg/day for children 1 mg/kg/day for adolescent:2-4 week Then taper slowly in 3-12 mouth overall clinical response is approximately 80%
  20. 20. Intravenous Immunoglobulin Dose of 0.5-1 mg/kg/day 5 day overall clinical response is approximately 40% not considered first-line treatment for AIHA in children may be considered in a patient who is not responding to steroids
  21. 21. Therapeutic Plasma Exchange TPE in warm AIHA is considered a category III intervention TPE can significantly reduce antibody titers, in CAD(Ig M) may be considered as a temporizing measure in a severely ill child who has a suboptimal response to RBC transfusion and may not have had time to respond to corticosteroid therapy
  22. 22. Treatment of Chronic or Refractory AIHA Splenectomy and rituximab are the only second- line treatments with proven short-term efficacy 1) Rituximab : monoclonal antibody specific for the CD20 antigen complement-mediated cytotoxicity inhibition of B-cell proliferation induction of apoptosis 375 mg/m2 weekly for 1 to 6 weeks More than 90% of patients have a complete response that lasted 7 to 28 months at least 1.5 gm/dL increase in Hb at a median of 12 days from the time the first dose of rituximab
  23. 23. Treatment of Chronic or Refractory AIHA(cont) 2)splenectomy: complete and partial response in approximately two thirds of patients 50% of patients will remain in remission for years mortality and morbidity of laparoscopic splenectomy for hematologic indications was 0.6% and 18% prior to surgery immunize with the polyvalent polysaccharide vaccines against Streptococcus pneumoniae and Neisseria meningitides H. influenzae penicillin prophylaxis twice a day for at least several years after surgery
  24. 24. Alternative Immunotherapeutic Agents indicated in patients who do not respond to corticosteroids, rituximab, and splenectomy or who have contraindications to those therapies Cyclophosphamide, cyclosporine, azathioprine 6- mercaptopurine and Campath-1H have been used to treat refractory AIHA treatment should be continued for up to 6 months before it is considered to have failed
  25. 25. 9 adult patient with severe refractory AIHA treted with cyclophosphamide 50 mg/kg/day for 4 days : Six patients achieved complete remission with normal hemoglobin three patients had partial remissions,as a hemoglobin level of at least 10 gm/dL without transfusion support Patients became RBC transfusionindependent after a median of 19 days High-dose cyclophosphamide was well tolerated common adverse effects included nausea, vomiting, and transient myelosuppression
  26. 26. T-lymphocyte function inhibitor Cyclosporine, 6-mercaptopurine, and Cell-Cept interfere with autoantibody synthesis cyclosporine has improved the course of AIHA it is not routinely used because of the adverse effects 6-MP in 7 pediatric patients with AIHA was reported (five cases of primary AIHA and two cases of secondary AIHA) all responded Cell-cept use in 3 adult all responded (Hb10) Campath-1H monoclonal antibodies improve refractory disease but do not induce a prolonged remission
  27. 27. Hematopoietic Stem Cell Transplantation 36 patients with severe refractory autoimmune cytopenia, two underwent allogeneic HSCT and five patients autologous HSCT: two allogeneic HSCT achieved continuous remission five autologous HSCT, one died of treatment-related causes, one died of progressive disease, two had no response, and one had a transient response this treatment option should be reserved for patients with severe life-threatening disease for whom all other therapies have failed
  28. 28. Treatment Cold-Reactive AIHA In children, CAD typically occurs after an infection In mild, compensated anemia not require treatment or transfusions If transfusion is indicated, a blood warmer need In severe cases of cold, IgM-mediated AIHA, plasmapheresis can remove autoantibodies treatment of PCH is also supportive with transfusion
  29. 29. Therapy for Autoimmune Hemolytic Anemias
  30. 30. SECONDARY AUTOIMMUNE HEMOLYTIC ANEMIA 24% to 63% of all pediatric AIHA case 1) Evans Syndrome: combination of ITP, AIHA, and/or autoimmune neutropenia, or immune pancytopenia Autoantibodies are directed at specific antigens on RBCs, plt, or neutrophils but are not cross-reactive 13% to 73% of published pediatric AIHA cases Evans is a chronic disorder, by frequent exacerbations and remissions Neutropenia occurs in up to 55% of patients at presentation
  31. 31. management of Evans syndrome : treat symptomatic cytopenias including moderate to severe anemia, thrombocytopenia with bleeding, or prolonged and/or severe neutropenia (ANC 500/L) first-line therapy is corticosteroids with or without IVIG steroids are useful in the acute setting, most patients will require adjuvant or alternative therapy to sustain a remission IVIG as a single agent has not been reported for treatment Rituximab,an anti-CD20 monoclonal antibody, is an effective second-line
  32. 32. management of Evans syndrome(cont.) Splenectomy can achieve improvement of cytopenias, but the response is often transient and relapse occurs in most cases 1 to 2 months later splenectomy should be reserved for patients who do not respond to other second-line therapies Cyclophosphamide has induced remission Alemtuzumab (Campath-1H) is an IgG monoclonal AB directed the CD52 antigen on T and B lymphocyte in the European Group study, of 22 patients who underwent HSCT for refractory autoimmune cytopenias, 11 had Evans syndrome two autologous 9 allogeneic - in autologous: one no response ,one relaps - in allogeneic HSCT five continuous remission, one relapse, and three died of treatment-related causes
  33. 33. Acute Lymphoproliferative Syndrome ALPS, an inherited disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway excess of T-cell receptor +CD3+CD4CD8 T (double-negative T [DNT]) lymphocytes that accumulate in the lymph nodes, spleen, and peripheral blood results in chronic lymphoproliferation, autoimmune disease, increased risk of malignancy
  34. 34. Acute Lymphoproliferative Syndrome (cont.) clinical presentation : chronic lymphadenopathy, splenomegaly, multilineage cytopenias resulting from sequestration and autoimmune destruction, and an increased risk of B-cell lymphoma 60% to 70% have heterozygous germline mutations in FAS, autosomal-dominant fashion 10% of FAS mutations are acquired and no genetic defect in 30%
  35. 35. Treatment of ALPS High-dose pulse therapy with intravenous methylprednisolone (5 to 10 mg/kg) IVIG in combination with corticosteroids low-dose GCSF (1 to 2 g/kg) 2-3 times weekly for patients with isolated chronic neutropenia and associated infections CellCept and sirolimus : 80% responses for their cytopenias
  36. 36. Other couse of secondary AIHA Immunodeficiency: CVID, AIDS,WAS Systemic Disorders: SLE, Sjgren, scleroderma Malignancy: acute leukemia,lymphoma,MDS Infections: EBV, CMV, M.pneumonia,varicella Drug: Piperacillin, cefotetan, ceftriaxone
  37. 37. LOGO