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Aplast anemia.pptx

  1. 1. APLAST ANEMIA Dr Mohammad Yaqoob Bahar, MD, PGY2 Internal Medicine
  2. 2. ANEMIA • Anemia: • Hb <13.6 g/dL in males • Hb <12 g/dL in females • Or • Hematocrit below 41% in males • Hematocrit below 36% in females • Hematocrit levels are less useful than hemoglobin levels in assessing anemia because they are calculated rather than measured directly
  3. 3. APPROACH TO ANEMIA • Hemoglobin • Hematocrit • red cell indices: • MCV: mean cell volume in femtoliters • MCH: mean cell hemoglobin in picograms per cell • MCHC: mean concentration of hemoglobin per volume of red cells in grams per liter
  4. 4. • Reticulocyte count • Peripheral Blood Smear • Bone marrow biopsy
  5. 5. CLASSIFICATION OF ANEMIA 1. Marrow production defects (hypoproliferation) 1. low reticulocyte production index together 2. little or no change in red cell morphology (a normocytic, normochromic anemia) 2. red cell maturation defects (ineffective erythropoiesis) 1. slight to moderately elevated reticulocyte production index 2. either macrocytic 3. Or microcytic 3. decreased red cell survival (blood loss/hemolysis).
  6. 6. RPI<2.5% RPI<2.5% RPI > 2.5% RPI < 2.5% RPI: Reticulocyte production index 1. Blood loss 2. Intravascular hemolysis
  7. 7. • Definiation • Epidemiology and Etiology • Pathophysiology • Clinical features • Diagnosis and Lab Exam • Differential Diagnosis • Treatment
  8. 8. DEFINIATION •Pancytopenia with hypocelluar bone marrow •Men = women •age distribution is biphasic •the major peak in the teens and twenties •a second rise in older adults
  9. 9. ETIOLOGY • Most cases: Idiopathic • Radiation • Chemmicals • Drugs • Infections • Immunologic diseases • Hepatitis • Pregnancy • PNH • Constitutional Syndromes (mostly Genetic)
  10. 10. RADIATION • Marrow aplasia • DNA damage • Nuclear accidents • employees of hospitals, laboratories, and industry (food sterilization, metal radiography, etc.), • Innocents exposed to stolen, misplaced, or misused sources
  11. 11. DRUGS AND CHEMMICALS • Toxins: • benzene, • Toluene • insecticides • Medications: • Chloramphenicol • gold salts • Sulfonamides • Phenytoin • Carbamazepine • Quinacrine • Tolbutamide • Heavy metals • Cholorquine • CA inhibitors (acetazolamide) • D- Pencillamines
  12. 12. INFECTIONS •Rarely follow infectious mononucleosis (EBV virus) •Parvo virus •CMV •Echo virus •…
  13. 13. IMMUNOLOGIC •SLE: Pancytopenia with hypocellular bone marrow •transfusion-associated graft-versus-host disease (GVHD) •Thymoma •Idiopathic
  14. 14. HEPATITIS • Post-hepatitis marrow failure accounts for ∼5% of etiologies in most series • Patients are usually young men who have recovered from a bout of liver inflammation 1–2 months earlier • the subsequent pancytopenia is very severe • The hepatitis is seronegative (non-A, nonB, non-C) • immune-mediated
  15. 15. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA • Mutation of PIG-A gene mutation in hematopoietic stem cells • Coombs ⊝ hemolytic anemia, pancytopenia, venous thrombosis (eg, BuddChiari syndrome) • episodic hemoglobinuria resulting in reddish-brown urine • flow cytometry tests demonstrates deficiencies of CD55 and CD59 • Eculizumab is a humanized monoclonal antibody against complement protein C5 given every 2 weeks
  16. 16. CONGENITAL • Fanconi anemia • congenital developmental anomalies • progressive pancytopenia • an increased risk of malignancy • short stature, café au lait spots • anomalies involving the thumb, radius, and genitourinary tract • DNA Repairs defects • 17 different genetic defects
  17. 17. CONGENITAL • Diamond Blackfon and Shwachman-Diamond syndrome • are ribosomopathies • early in life with neutropenia, pancreatic insufficiency, and malabsorption • Telemeopathies: defects in telomere length maintenance • Dyskeratosis congenitalis
  18. 18. PATHOPHYSIOLOGY Suppersion or injury to hematopoeitc stem cell Hypoplastic bone marrow Fails to produce mature blood cells pancytopenia
  19. 19. • Direct hematopoietic stem cell injury: radiation, chemotherapy, toxins, or pharmacologic agents. • SLE: suppression of the hematopoietic stem cell by an IgG autoantibody • The most common pathogenesis of aplastic anemia appears to be autoimmune suppression of hematopoiesis by a T-cell-mediated cellular mechanism, so-called idiopathic aplastic anemia.
  20. 20. PATHOPHYSIOLOGY CONT… • defects in maintenance of the hematopoietic stem cell telomere length (eg, dyskeratosis congenita) or in DNA repair pathways (eg, Fanconi anemia) have been identified and are likely linked to both the initiation of bone marrow failure and the propensity to later progress to myelodysplasia, PNH, or AML. • Complex detrimental immune responses to viruses can also cause aplastic anemia
  21. 21. SYMPTOMS • can appear abruptly or insidiously • Bleeding is the most common early symptom; • a complaint of days to weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual flow, and sometimes petechiae will have been noticed. • With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in catastrophic intracranial or retinal hemorrhage
  22. 22. • Symptoms of anemia: frequent, including lassitude, weakness, shortness of breath, and a pounding sensation in the ears. • Infection is an unusual first symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, anorectal infection, or frank sepsis occurs early • Systemic complaints and weight loss should point to other etiologies of pancytopenia • Prior medical drug use, chemical exposure, and preceding viral illnesses must often be elicited with directed questioning
  23. 23. PHYSICAL EXAM • Petechiae and ecchymoses are typical,retinal hemorrhages may be present. • Pallor of the skin and mucous membranes is common. • Infection on presentation is unusual but may occur if the patient has been symptomatic for a few weeks. • Lymphadenopathy and splenomegaly are highly atypical of aplastic anemia.
  24. 24. • Café au lait spots and short stature suggest Fanconi anemia; • peculiar nails and leukoplakia suggest dyskeratosis congenita; • early graying (and use of hair dyes to mask it!) suggests a telomerase defect
  25. 25. •hepatosplenomegaly, lymphadenopathy, or bone tenderness should not be present, and their presence should lead to questioning the diagnosis
  26. 26. LAB FINDINGS • Hallmark is pancytopenia (but at first only one on 2 cell lines may be reduced) • Anemia may be severe • always associated with reticulocytopenia • Red blood cell morphology is unremarkable (Normocytic) , but there may be mild macrocytosis (increased MCV) • Neutrophils and platelets are reduced in number, and no immature or abnormal forms are seen on the blood smear
  27. 27. LAB FINDINGS • presence of immature myeloid forms suggests leukemia or MDS; • nucleated red blood cells (RBCs) suggest marrow fibrosis or tumor invasion; • abnormal platelets suggest either peripheral destruction or MDS
  28. 28. BONE MARROW BIOPSY • bone marrow aspirate and the bone marrow biopsy appear hypocellular • biopsy (which should be >1 cm in length) is superior for determination of cellularity and shows mainly fat under the microscope, • with hematopoietic cells occupying <25% of the marrow space • Residual hematopoietic cells should have normal morphology
  30. 30. DIFFERENTIAL DIAGNOSIS • Aplastic anemia must be differentiated from other causes of pancytopenia
  31. 31. DIFFERENTIAL DIAGNOSIS • Hypocellular forms of myelodysplasia or acute leukemia: • presence of cellular morphologic abnormalities • increased percentage of blasts • abnormal karyotype in bone marrow cells typical of MDS or acute leukemia. • Hairy cell leukemia has been misdiagnosed as aplastic anemia: • presence of splenomegaly • abnormal “hairy” lymphoid cells in a hypocellular bone marrow biopsy.
  32. 32. DIFFERENTIAL DIAGNOSIS • Pancytopenia with a normocellular bone marrow may be due to systemic lupus erythematosus, disseminated infection, hypersplenism, nutritional (eg, vitamin B12 or folate) deficiency, or myelodysplasia. • Isolated thrombocytopenia may occur early as aplastic anemia develops and may be confused with immune thrombocytopenia
  33. 33. SEVERE APLASTIC ANEMIA •presence of two of three parameters: •absolute neutrophil count <500/μL, •platelet count <20,000/μL •corrected reticulocyte count <1% (or absolute reticulocyte count <60,000/μL)
  34. 34. TREATMENT • stem cell transplant • Immunosuppression:allow recovery of the patient’s residual bone marrow function • Glucocorticoids are not of value as primary therapy • Suspect exposures to drugs or chemicals should be discontinued
  35. 35. STEM CELL TRANSPLANT • first choice for the younger patient with a fully histocompatible sibling donor • may also benefit from allogeneic bone marrow transplantation using an unrelated donor • In transplant candidates, transfusion of blood from family members should be avoided so as to prevent sensitization to histocompatibility antigens • allogeneic transplant from fully matched siblings, long-term survival rates for children are ∼90%. • Transplant morbidity and mortality are increased among adults, due to the higher risk of chronic GVHD and infections
  36. 36. IMMUNOSUPPRESION • adults over age 40 years • those without HLA matched hematopoietic stem cell donors • Anti-thymocyte Globulin (ATG) plus cyclosporine • equine ATG 40 mg/kg/day intravenously for 4 days in combination with cyclosporine, 6 mg/kg orally twice daily • Equine ATG is superior to rabbit ATG, resulting in a higher response rate and better survival
  37. 37. IMMUNOSUPPRESION • ATG should be used in combination with corticosteroids (prednisone or methylprednisolone 1–2 mg/kg/day orally for 1 week, followed by a taper over 2 weeks) to avoid ATG infusion reactions and serum sickness • Responses usually occur in 1–3 months and are usually only partial, but the blood counts rise high enough to give patients a safe and transfusion-free life. • The full benefit of immunosuppression is generally assessed at 4 months post-equine ATG. • Cyclosporine and eltrombopag are maintained at full doses for 6 months and then stopped in responding patients
  38. 38. IMMUNOSUPPRESION • Relapse (recurrent pancytopenia) is frequent, often occurring as cyclosporine is tapered or discontinued • Overall survival is equivalent with transplantation and immunosuppression • older patients do better with immunoauppresion (ATG and cyclosporine) whereas transplant is preferred in children and if neutropenia is profound
  39. 39. ELTROMBOPAG • Hematopoietic growth factors (HGFs) such as erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are not effective in aplastic anemia • Endogenous levels are high • Eltrombopag (a thrombopoietin mimetic) is now being added to ATG plus cyclosporine with tri-lineage hematologic responses as high as 90%
  40. 40. ANDROGENS • Androgens (such as fluoxymesterone 10–20 mg/day orally in divided doses or danazol 200 mg orally twice daily) have been widely used in the past, with a low response rate, and may be considered in mild cases
  41. 41. SUPPORTIVE CARE • First and most important, infection in the presence of severe neutropenia must be aggressively treated by prompt institution of parenteral, broad-spectrum antibiotics • Therapy is empirical and must not await results of culture • foci of infection such as oropharyngeal or anorectal abscesses, pneumonia, sinusitis, and typhlitis (necrotizing colitis) should be sought on physical examination and with radiographic studies • Indewelling plastic catheters: Vancomycin
  42. 42. SUPPORTIVE CARE • Persistent or recrudescent fever implies fungal disease: Candida and Aspergillus are common, especially after several courses of antibacterial antibiotics • Granulocyte transfusions can be effective when bacterial or fungal infection is progressive or refractory to antibiotics. • Hand washing, the single best method of preventing the spread of infection
  43. 43. SUPPORTIVE CARE • platelet and erythrocyte numbers can be maintained by transfusion • goal is to maintain the platelet count >10,000/μL • Menstruation should be suppressed either by oral estrogens or nasal follicle-stimulating hormone/luteinizing hormone antagonists. • Aspirin and other nonsteroidal anti-inflammatory agents must be avoided in the presence of thrombocytopenia
  44. 44. SUPPORTIVE CARE • RBCs should be transfused • hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac or pulmonary disease); • a regimen of 2 units every 2 weeks will replace normal losses in a patient without a functioning bone marrow. • In chronic anemia, the iron chelators deferoxamine and deferasirox should be added at approximately the fiftieth transfusion to avoid secondary hemochromatosis
  45. 45. PROGNOSIS • severe aplastic anemia have a rapidly fatal illness if left untreated • major prognostic determinant is the blood count • Allogeneic bone marrow transplant from an HLA-matched sibling donor produces survival rates of over 80% in recipients under 20 years old and of about 65–70% in those 20 to 50 years old
  46. 46. • Equine ATG-cyclosporine immunosuppressive treatment leads to a response in approximately 70% of patients (including those with hepatitis virus–associated aplastic anemia) and in up to 90% of patients with the addition of eltrombopag • Up to one-third of patients will relapse with aplastic anemia after ATG-based therapy • Factors that predict response to ATG-cyclosporine therapy are patient’s age, reticulocyte count, lymphocyte count, and age- adjusted telomere length of leukocytes at the time of diagnosis
  47. 47. WHEN TO ADMIT • Treatment of neutropenic infection • The administration of ATG • Allogeneic bone marrow transplantation
  48. 48. Thanks