in the name of god definition aplastic anemia is a clinical syndromemanifested as a deficiency: red...
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IN THE NAME OF GOD
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Definition
• Aplastic anemia is a clinical syndromemanifested as a deficiency:
• red cells, neutrophils monocytes and platelets in the blood
• fatty replacement of the marrow with a near absence of hematopoietic precursor cells
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ETIOLOGIC CLASSIFICATION
1. Acquired2. Inherited
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Acquired Aplastic AnemiaAcquired aplastic anemia can occur in any age
group and is usuallythe consequence of an autoimmune attakagainsthematopoieticstem cells
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• These inherited disorders can masqueradeas acquired aplastic anemia
• rarely respond toimmunosuppressive therapies
• management usually consists ofsupportive care or bone marrow transplantation in severe cases
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• Aplastic anemia most commonly presents between the ages of15 and 25
• There is a second smaller peak in incidence afterage 60
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Etiologic Aplastic Anemia1. Idiopathic2. Toxin and benzene3. Drugs4. Viruses5. Pregnancy6. Radiation
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• Although aplastic anemia has beencausally associated with many agents including drugs benzeneexposure insecticides and viruses
• No etiologic agent can be identifiedin most cases
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Benzene• Howeverrigorous epidemiologic study
supporting an association between environmental toxins andaplastic anemia are lacking
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RADIATION• Ionizing radiation is directly toxic to bone
marrow stem/progenitorcells• high doses (> 1.5 Gy to the whole body) can
lead tosevere pancytopenia within 2 to 4 weeks after exposure
• the LDsohas been estimated at about 4.5 Gy and a dose of lOGy or greateris thought to have 100% mortality
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Classification of most commonly drugs causing Aplastic Anemia
Nonsteroidal analgestic• Phenylbutazone,indomethacin,ibuprofen,sulindac piroxicam diclofenacAnticonvulsant:• Hydantoin carbamazepine phenacemidAntibiotic• Sulfonamides chloramphenicolAntiprotozoal• Quinacrine chloroquineAntithyroid• Methimazol propylthiouracil
Gold
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• Most cases of druginducedaplastic anemia lead to an idiosyncratic immuneresponse directed against hematopoietic stem cells and are managedsimilarly to those with idiopathic aplastic anemia
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• Notableexceptions include patients who receive high doses of cytotoxicchemotherapy drugs:
• cytotoxicchemotherapy drugs• antimetabolites• antimitotics• individuals who have thiopurine
methyltransferase deficiency (TPMT)
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Viruses• Viral infection sespecially in chronicallyill
patients often lead to transient cytopenias but frank aplasticanemia is uncommon
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COMMON VIRUS
1. Epstein-Barr virus2. Human immunodeficiency virus3. B19 parvovirus4. Herpesviruses5. Non-A, non-B, non-C, non-D, non-E, and
non-G hepatitis virus
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• severe anemia that occurs in sickle cell anemia patients who are acutely infected withB19 parvovirus
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• Seronegative hepatitis precedes thediagnosis of aplastic anemia in 3 to 5% of cases and is recognizedas hepatitis-associated aplastic anemia
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• In most cases the hepatitis resolves spontaneously
• however when severe aplastic anemia follows it is often fatal and presents within a few months after the onset of hepatitis
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Pregnancy
• Pregnancy-associated aplastic anemia is a rare entity
• despitenumerous case reports the association is not well understood
• The onset of aplastic anemia can occur during pregnancy or shortly after delivery
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• In contrast to idiopathic aplastic anemia, pregnancyassociatedaplastic anemia is often associated with spontaneousremissions
• in patients with severe disease therapyshould be initiated promptly since maternal and fetal mortalityare not uncommon
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PATHOPHYSIOLOGY
• Autoimmunity• Stem Cell• Clonality
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• cytotoxic T lymphocytes were found to mediate the destruction ofhematopoietic stem cells in aplastic anemia
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Stem Cells
• reduction in the number of hematopoietic stem/progenitor cellsis a universal laboratory finding in aplastic anemia
• C034 + cells assayable hematopoietic and long-term culture-initiatingcells are strikingly reduced in aplastic anemia
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CLINICAL FEATURES
• Clinical manifestations are proportional to theperipheral blood cytopenias and include:
• dyspnea on exertion fatigue• easy bruising petechia epistaxis gingival
bleeding heavy menses headache• fever
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1. complete blood count2. reticulocyte count3. bone marrow aspirate and biopsy4. Cytogenetic study5. Flowcytometry
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BM Aspiration BM Biopsy
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• Patientsyounger than 40 years of age should be screened for Fanconi anemia
• using the clastogenic agents diepoxybutane and mitomycin Cthat test for increased chromosomal breakage
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• A hypocellular bone marrow is required for the diagnosis ofaplastic anemia
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Classification
Acquired aplastic anemia is classified as:1. non severeAA2. severeAA3. very severeAA• based onthe degree of peripheral blood
pancytopenia
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Classification of Aplastic Anemia
• severe aplastic anemia1. Bone marrow cellularity <25%2. Two of three peripheral blood criteria:• Absolute neutrophil count <500/mm3• Platelet count <20,OOO/mm3• Reticulocyte count <60,OOO/mm3 or < 1% corrected reticulocyte count
• Very severe aplastic anemia (VSAA)• Same as SAAwith absolute neutrophil count <200/mm3
• Nonsevere (moderate) aplastic anemia1. Bone marrow cellularity <25%2. Peripheral blood cytopenias do not fulfill criteria for SAA
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SUPPORTIVE CARE
• Patients with symptomatic anemia and/or thrombocytopeniaassociated with wet purpura or bleeding require immediate bloodtransfusions
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• All transfusions in patients with suspected aplastic anemia should be irradiated to prevent transfusion-associatedgraft versus host disease
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If the patient is a potential BMTcandidate and is cytomegalovirus negative theCMVstatusis unknown
• CMV transmission should be avoided by :1. Either leukoreduction 2. or the use of CMV-negative products
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• Blood donationfrom family members should be avoided to prevent alloimmunization
that could also complicate future BMT
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Antibiotic
• Overwhelming sepsis caused by bacteria or fungus (especiallyAspergillus)
• is the most frequent cause of death from aplasticanemia
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• In most circumstances prophylactic antibiotics are unnecessary
• for patients with absolute neutrophil counts thatare consistently <200 prophylaxis with oral antibiotics such as a:
• quinolone • triazole antifungal is reasonable
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• Patientswith febrile neutropenia should be treated promptly with broadspectrum
Antibiotics• In patients with persistent fever after the
initiationof antibacterial antibioticsAspergillus coverage should be added
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Prophylaxis for Pneumocystis carinii pneumonia should begiven to all patients for at least 6 months after:
1. immunosuppressivetherapy2. BMT3. high-dose cyclophosphamide therapy
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Growth FactorsHematopoietic growth factor deficiencysuch as • Erythropoietin• granulocyte• colony-stimulating factor• thrombopoietin• granulocytemonocytecolony-stimulating factor is not responsible for the bonemarrow failure in
aplastic anemia
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• Patients with moresignificant cytopeniassuch as symptomatic anemia may benefit from a trial of :
• immunosuppressive therapy with anti thymocyteglobulin and cyclosporine (ATG/CSA)
• CSA alone
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Bone Marrow Transplantation
• Allogeneic BMT from an HLA-matched sibling donor is the treatmentof choice at most centers for young patients with SAA
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Immunosuppressive TherapyImmunosuppressive therapy with
• Immunosuppressive therapy with ATG/CSA is used in patientswho are not candidates for bone marrow transplantation
• becauseof older age or lack of a matched sibling donor
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