IN THE NAME OF GOD

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

ETIOLOGIC CLASSIFICATION 1.Acquired 2.Inherited

Acquired Aplastic Anemia Acquired aplastic anemia can occur in any age group and is usuallythe consequence of an autoimmune attakagainsthematopoieticstem cells

These inherited disorders can masqueradeas acquired aplastic anemia rarely respond toimmunosuppressive therapies management usually consists ofsupportive care or bone marrow transplantation in severe cases

Aplastic anemia most commonly presents between the ages of15 and 25 There is a second smaller peak in incidence afterage 60

Etiologic Aplastic Anemia 1.Idiopathic 2.Toxin and benzene 3.Drugs 4.Viruses 5.Pregnancy 6.Radiation

Although aplastic anemia has beencausally associated with many agents including drugs benzeneexposure insecticides and viruses No etiologic agent can be identifiedin most cases A

Benzene Howeverrigorous epidemiologic study supporting an association between environmental toxins andaplastic anemia are lacking

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

Classification of most commonly drugs causing Aplastic Anemia Nonsteroidal analgestic Phenylbutazone,indomethacin,ibuprofen,sulindac piroxicam diclofenac Anticonvulsant: Hydantoin carbamazepine phenacemid Antibiotic Sulfonamides chloramphenicol Antiprotozoal Quinacrine chloroquine Antithyroid Methimazol propylthiouracil Gold

Most cases of druginducedaplastic anemia lead to an idiosyncratic immuneresponse directed against hematopoietic stem cells and are managedsimilarly to those with idiopathic aplastic anemia

Notableexceptions include patients who receive high doses of cytotoxicchemotherapy drugs: cytotoxicchemotherapy drugs antimetabolites antimitotics individuals who have thiopurine methyltransferase deficiency (TPMT)

Viruses Viral infection sespecially in chronicallyill patients often lead to transient cytopenias but frank aplasticanemia is uncommon

COMMON VIRUS 1. Epstein-Barr virus 2. Human immunodeficiency virus 3.B19 parvovirus 4.Herpesviruses 5.Non-A, non-B, non-C, non-D, non-E, and non-G hepatitis virus

severe anemia that occurs in sickle cell anemia patients who are acutely infected withB19 parvovirus

Seronegative hepatitis precedes thediagnosis of aplastic anemia in 3 to 5% of cases and is recognizedas hepatitis-associated aplastic anemia

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

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

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

PATHOPHYSIOLOGY Autoimmunity Stem Cell Clonality

cytotoxic T lymphocytes were found to mediate the destruction ofhematopoietic stem cells in aplastic anemia

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

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

1.complete blood count 2.reticulocyte count 3.bone marrow aspirate and biopsy 4.Cytogenetic study 5.Flowcytometry

BM AspirationBM Biopsy

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

A hypocellular bone marrow is required for the diagnosis ofaplastic anemia

Classification Acquired aplastic anemia is classified as: 1.non severeAA 2. severeAA 3.very severeAA based onthe degree of peripheral blood pancytopenia

Classification of Aplastic Anemia severe aplastic anemia 1.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 anemia 1.Bone marrow cellularity <25% 2.Peripheral blood cytopenias do not fulfill criteria for SAA

SUPPORTIVE CARE Patients with symptomatic anemia and/or thrombocytopeniaassociated with wet purpura or bleeding require immediate bloodtransfusions

All transfusions in patients with suspected aplastic anemia should be irradiated to prevent transfusion-associatedgraft versus host disease

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

Blood donationfrom family members should be avoided to prevent alloimmunization that could also complicate future BMT

Antibiotic Overwhelming sepsis caused by bacteria or fungus (especiallyAspergillus) is the most frequent cause of death from aplasticanemia

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

Patientswith febrile neutropenia should be treated promptly with broadspectrum Antibiotics In patients with persistent fever after the initiationof antibacterial antibioticsAspergillus coverage should be added

Prophylaxis for Pneumocystis carinii pneumonia should begiven to all patients for at least 6 months after: 1. immunosuppressivetherapy 2.BMT 3. high-dose cyclophosphamide therapy

Growth Factors Hematopoietic growth factor deficiencysuch as Erythropoietin granulocyte colony-stimulating factor thrombopoietin granulocytemonocytecolony-stimulating factor is not responsible for the bonemarrow failure in aplastic anemia

Patients with moresignificant cytopeniassuch as symptomatic anemia may benefit from a trial of : immunosuppressive therapy with anti thymocyteglobulin and cyclosporine (ATG/CSA) CSA alone

Bone Marrow Transplantation Allogeneic BMT from an HLA-matched sibling donor is the treatmentof choice at most centers for young patients with SAA

Immunosuppressive Therapy Immunosuppressive 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