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. Acquired2. Inherited

Acquired Aplastic AnemiaAcquired 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 Anemia1. Idiopathic2. Toxin and benzene3. Drugs4. Viruses5. Pregnancy6. Radiation

• Although aplastic anemia has beencausally associated with many agents including drugs benzeneexposure insecticides and viruses

• No etiologic agent can be identifiedin most cases

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 diclofenacAnticonvulsant:• Hydantoin carbamazepine phenacemidAntibiotic• Sulfonamides chloramphenicolAntiprotozoal• Quinacrine chloroquineAntithyroid• 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 virus2. Human immunodeficiency virus3. B19 parvovirus4. Herpesviruses5. 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 count2. reticulocyte count3. bone marrow aspirate and biopsy4. Cytogenetic study5. Flowcytometry

BM Aspiration BM 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 severeAA2. severeAA3. very severeAA• based onthe degree of peripheral blood

pancytopenia

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

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. immunosuppressivetherapy2. BMT3. high-dose cyclophosphamide therapy

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

• 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 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