Aplastic Anemia

Aplastic Anemia

—Deficiency or injury to the stem cells

—Hypocellular bone marrow
—Results in pancytopenia of the peripheral blood
—All cell lines affected

        Severity

—Moderate aplastic anemia

—Marrow cellularity <30%

—Absence of severe pancytopenia

—Depression of at least two of three blood elements below normal.

—Severe

oBone marrow cellularity <25% or marrow showing <50% normal with two of three peripheral blood count criteria:  

oANC <500

—Plt <20k

—Retic count <40k

—Very Severe

—All of above plus ANC less than 200.

Classification

—Inherited

—Fanconi’s anemia, dyskeratosis congenita, Shwachman-Diamond Syndrome, Reticular dysgenesis, Amegakaryocytic thrombocytopenia, familial aplastic anemia, preleukemia (monosomy 7) and nonhematologic disease (Down, Dubowitz, Seckel)

—Acquired

—Irradiation

—drugs and chemicals: cytotoxic agents, benzene, idiosyncratic reaction, chloramphenicol, NSAIDS, antiepileptics, Gold

—viruses: EBV, Hepatitis virus (non-A,non-B, non-C, non-G), Parvovirus (transient aplastic crisis or pure red cell aplasia), HIV

—Immune diseases: eosinophilic fasciitis, hyperimmunoglobulinemia, thymoma and thymic carcinoma, GvHD in immunodeficiency

—PNH

—Pregnancy

—Idiopathic 

Differential Diagnosis

—Pancytopenia with hypocellular bone marrow

—Acquired aplastic anemia  - Inherited aplastic anemia

—Hypoplastic MDS  - Hypoplastic AML

—Pancytopenia with cellular bone marrow

—Primary bone marrow diseases  -MDS

—PNH  - Myelofibrosis

—Myelophthisis  - Bone marrow lymphoma

—Hairy cell leukemia  - SLE, Sjogren’s disease

—Hypersplenism  - Vitamin B12 and folate deficiency

—Overwhelming infection  - Alcoholism

—Brucellosis  - Ehrlichiosis

—Sarcoidosis  - tuberculosis

—Hypocellular bone marrow with or without cytopenia

—Q fever  - Legionaires disease

—Mycobacteria  - Tuberculosis

—Hypothyroidism  - Anorexia nervosa

Etiology

   —Radiation—Chemicals—Drugs—Infections—Immunological  diseases—Pregnancy—Paroxysmal nocturnal hemoglobinuria—Constitutional disorders

Drugs causing aplastic anemia

—Cytotoxic drugs like alkylating agents, antimitotics

—Benzene

—Low probability : chloramphenicol,insecticides,antiprotozoals,  NSAIDS, anticonvulsants,heavy metals,

Pathogenesis

—Genetic predisposition found in HLA-DR2. 

-This correlates to response to immunosuppressants.

—Drug Injury

—Immune mediated injury

—Immune-mediated T-cell destruction of marrow

—Removal of lymphocytes from aplastic bone marrow improved colony number in tissue culture and addition of lymphocytes to normal marrow inhibited hematopoiesis in vitro.

Presenting Symptoms

       —Related to anemia—Fatigue, Shortness of breath—Related to neutrapenia—Infections—Related to thrombocytopenia—Bleeding (mucous membranes)

Diagnosis

—Blood macrocytic picture with thrombocytopenia and low granulocytes

—Reticulocytes are reduced or few

—No immature cell

—Bone marrow:-

—Ancillary studies: - chromosomal breakage study,flow cytometry, serological studies to exclude viral infections, MRI  spine

Bone marrow in aplastic Anemia

—Marrow is profoundly hypocellular with decrease in all elements.

—Residual hematopoietic cells are morphologically normal.

—Malignant infiltrates and fibrosis is absent.

—Hematopoiesis is non-megaloblastic.

Treatment 

—Supportive—Blood product transfusion & antibiotics—1/3 refractory to platelets—Bleeding deaths uncommon

Definitive Treatment

—Bone marrow transplantation

—Immunosuppression —no difference in long-term survival

Definitive Treatment

—Immunosuppression —Older patients—No sibling donors—Antithymocyte globulin (ATG) +/- cyclosporine—Response rate = 70%
—Long term survival = 65-90% 

—Marrow Transplantation

—Genotypically identical sibling donor marrow

—Cures aplastic anemia

—Death can occur as a result of complications of the procedure

—Long-term survival with younger pts 65%