Aplastic Anemia
BASIC INFORMATION
Aplastic anemia is a bone marrow failure resulting from a variety of causes and characterized by stem cell destruction or suppression leading to pancytopenia. The term “aplastic anemia” is reserved for pancytopenias with diminished production of all cell lineages in the bone marrow, and is associated with reduced cellularity, and lack of an apparent cause for the aplasia. Aplasia following chemotherapy, or other medications that interfere with cellular division, is excluded from this category.
SYNONYMS
Refractory anemia
Hypoplastic anemia
EPIDEMIOLOGY & DEMOGRAPHICS
• There is no predominant age or sex for the acquired form.
• The annual incidence of aplastic anemia in the U.S. is 3 to 9 cases/1 million persons.
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Skin pallor, ecchymosis, petechiae, retinal hemorrhage
• Possible fever, mouth and tongue ulceration, pharyngitis
• Possible short stature or skeletal and nail anomalies in the congenital form
• Possible audible systolic ejection murmur with profound anemia
ETIOLOGY
A number of medications, whose inherent mechanism of action is not expected to compromise bone marrow function, can cause aplastic anemia. The causal relationship has been demonstrated convincingly for only a few substances. These are chloramphenicol, phenytoin, gold preparations, and probably the sulfonamides. Recently, infections have also been identified as an initiating cause of aplastic anemia. Thus, cases of aplastic anemia following non-A, non-B, non-C hepatitis, or acute mononucleosis, have been described.
• In most patients with acquired aplastic anemia, bone marrow failure results from immunologically mediated, active destruction of blood-forming cells by lymphocytes.
• Common etiologic factors in aplastic anemia:
• Skin pallor, ecchymosis, petechiae, retinal hemorrhage
• Possible fever, mouth and tongue ulceration, pharyngitis
• Possible short stature or skeletal and nail anomalies in the congenital form
• Possible audible systolic ejection murmur with profound anemia
ETIOLOGY
A number of medications, whose inherent mechanism of action is not expected to compromise bone marrow function, can cause aplastic anemia. The causal relationship has been demonstrated convincingly for only a few substances. These are chloramphenicol, phenytoin, gold preparations, and probably the sulfonamides. Recently, infections have also been identified as an initiating cause of aplastic anemia. Thus, cases of aplastic anemia following non-A, non-B, non-C hepatitis, or acute mononucleosis, have been described.
• In most patients with acquired aplastic anemia, bone marrow failure results from immunologically mediated, active destruction of blood-forming cells by lymphocytes.
• Common etiologic factors in aplastic anemia:
WORKUP
• Diagnostic workup consists primarily of bone marrow aspiration and biopsy and laboratory evaluation (CBC and examination of blood film).
• Bone marrow examination generally reveals paucity or absence of eryth-ropoietic and myelopoietic precursor cells; patients with pure red cell aplasia demonstrate only absence of RBC precursors in the marrow.
LABORATORY TESTS
Laboratory findings are characterized by profound pancytopenia. Erythrocyte indices are normal or macrocytic, the reticulocyte count is close to zero. The diagnosis is confirmed by bone marrowanalysis. The most difficult differential diagnosis is hypoplastic myelodysplastic syndrome (MDS). This differentiation can be made by a careful morphologic analysis. A complicating factor is that aplastic anemia can develop into MDS and therefore, a mixed clinical picture may be encountered.
• CBC reveals pancytopenia. Macrocytosis and toxic granulation of neutrophils may also be present. Isolated cytopenias may occur in the early stages.
• Reticulocyte count reveals reticulocytopenia.
• Additional initial laboratory evaluation should include Ham test to exclude paroxysmal nocturnal hemoglobinuria (PNH) and testing for hepatitis C.
IMAGING STUDIES
• Chest x-ray examination
• Abdominal sonogram or CT scan to evaluate for splenomegaly
• Radiography of hand and forearm in patients with constitutional anemia
• CT scan of thymus region if thymoma-associated RBC aplasia is suspected
TREATMENT
NONPHARMACOLOGIC THERAPY
• Discontinuation of any offending drugs or agents
• Evaluation for bone marrow transplantation
ACUTE GENERAL Rx
• Aggressive treatment of neutropenic fevers with parenteral broadspectrum antibiotics
• Platelet and RBC transfusions prn; however, avoidance of transfusions in patients who are candidates for bone marrow transplantation
• Immunosuppressive therapy with antithymocyte globulin (ATG) and/or cyclosporine (CSP); ATG in combination with prednisone (1 to 2 mg/kg/day initially) to avoid complications of serum sickness
• Transplantation of allogeneic marrow or peripheral blood stem cell transplantation from a histocompatible sibling usually cures the underlying bone marrow failure
• In patients with severe aplastic anemia who are not candidates for allogenic bone marrow, use of high-dose cyclophosphamide therapy without bone marrow transplantation represents a third option for initial treatment of aplastic anemia. Survival at 2 yr has been reported at 84%; however, the study was small and uncontrolled.
CHRONIC Rx
• Long-term patient monitoring with physical examination and routine laboratory evaluation to screen for relapse
• ATG with CSP restore hematopoiesis in approximately two-thirds of patients; however, recovery of blood cell count is often incomplete, recurrent pancytopenia requires retreatment. In some patients, myelodysplasia is a late complication of immunosuppressive therapy.
• Patients refractory to immunosuppression have a poor long-term outlook and should consider unrelated stem cell transplantation.
• There is little justification for either a therapeutic trial of corticosteroids as primary treatment or for their long-term use to prevent bleeding.
DISPOSITION
• Patients with severe aplastic anemia who have marrow transplants before the onset of transfusion-induced sensitization have an excellent probability of long-term survival and normal life; age is a significant factor; the incidence of graft vs. host disease increases with age and is >90% in patients >30 yr of age.
• Following bone marrow transplantation from an HLA-identical sibling, >70% of patients are long-term survivors and can be considered cured.
• Response to immunosuppression in aplastic anemia is independent of age, but treatment is associated with increased mortality in older patients.
• Overall 5-yr survival rate for aplastic anemia is now 70% to 90%.
• Diagnostic workup consists primarily of bone marrow aspiration and biopsy and laboratory evaluation (CBC and examination of blood film).
• Bone marrow examination generally reveals paucity or absence of eryth-ropoietic and myelopoietic precursor cells; patients with pure red cell aplasia demonstrate only absence of RBC precursors in the marrow.
LABORATORY TESTS
Laboratory findings are characterized by profound pancytopenia. Erythrocyte indices are normal or macrocytic, the reticulocyte count is close to zero. The diagnosis is confirmed by bone marrowanalysis. The most difficult differential diagnosis is hypoplastic myelodysplastic syndrome (MDS). This differentiation can be made by a careful morphologic analysis. A complicating factor is that aplastic anemia can develop into MDS and therefore, a mixed clinical picture may be encountered.
• CBC reveals pancytopenia. Macrocytosis and toxic granulation of neutrophils may also be present. Isolated cytopenias may occur in the early stages.
• Reticulocyte count reveals reticulocytopenia.
• Additional initial laboratory evaluation should include Ham test to exclude paroxysmal nocturnal hemoglobinuria (PNH) and testing for hepatitis C.
IMAGING STUDIES
• Chest x-ray examination
• Abdominal sonogram or CT scan to evaluate for splenomegaly
• Radiography of hand and forearm in patients with constitutional anemia
• CT scan of thymus region if thymoma-associated RBC aplasia is suspected
TREATMENT
NONPHARMACOLOGIC THERAPY
• Discontinuation of any offending drugs or agents
• Evaluation for bone marrow transplantation
ACUTE GENERAL Rx
• Aggressive treatment of neutropenic fevers with parenteral broadspectrum antibiotics
• Platelet and RBC transfusions prn; however, avoidance of transfusions in patients who are candidates for bone marrow transplantation
• Immunosuppressive therapy with antithymocyte globulin (ATG) and/or cyclosporine (CSP); ATG in combination with prednisone (1 to 2 mg/kg/day initially) to avoid complications of serum sickness
• Transplantation of allogeneic marrow or peripheral blood stem cell transplantation from a histocompatible sibling usually cures the underlying bone marrow failure
• In patients with severe aplastic anemia who are not candidates for allogenic bone marrow, use of high-dose cyclophosphamide therapy without bone marrow transplantation represents a third option for initial treatment of aplastic anemia. Survival at 2 yr has been reported at 84%; however, the study was small and uncontrolled.
CHRONIC Rx
• Long-term patient monitoring with physical examination and routine laboratory evaluation to screen for relapse
• ATG with CSP restore hematopoiesis in approximately two-thirds of patients; however, recovery of blood cell count is often incomplete, recurrent pancytopenia requires retreatment. In some patients, myelodysplasia is a late complication of immunosuppressive therapy.
• Patients refractory to immunosuppression have a poor long-term outlook and should consider unrelated stem cell transplantation.
• There is little justification for either a therapeutic trial of corticosteroids as primary treatment or for their long-term use to prevent bleeding.
DISPOSITION
• Patients with severe aplastic anemia who have marrow transplants before the onset of transfusion-induced sensitization have an excellent probability of long-term survival and normal life; age is a significant factor; the incidence of graft vs. host disease increases with age and is >90% in patients >30 yr of age.
• Following bone marrow transplantation from an HLA-identical sibling, >70% of patients are long-term survivors and can be considered cured.
• Response to immunosuppression in aplastic anemia is independent of age, but treatment is associated with increased mortality in older patients.
• Overall 5-yr survival rate for aplastic anemia is now 70% to 90%.
Toxins (e.g., benzene, insecticides)
Drugs (e.g., Felbatol, cimetidine, busulfan and other myelosuppressive drugs, gold salts, chloramphenicol, sulfonamides, trimethadione, quinacrine, phenylbutazone)
Ionizing irradiation
Infections (e.g., hepatitis C, HIV)
Idiopathic
Inherited (Fanconi’s anemia)
Other: immunologic, pregnancy
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
• Bone marrow infiltration from lymphoma, carcinoma, myelofibrosis
• Severe infection
• Hypoplastic acute lymphoblastic leukemia in children
• Hypoplastic myelodysplastic syndrome or hypoplastic acute myeloid leukemia in adults
• Hypersplenism
• Hairy cell leukemia
Drugs (e.g., Felbatol, cimetidine, busulfan and other myelosuppressive drugs, gold salts, chloramphenicol, sulfonamides, trimethadione, quinacrine, phenylbutazone)
Ionizing irradiation
Infections (e.g., hepatitis C, HIV)
Idiopathic
Inherited (Fanconi’s anemia)
Other: immunologic, pregnancy
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
• Bone marrow infiltration from lymphoma, carcinoma, myelofibrosis
• Severe infection
• Hypoplastic acute lymphoblastic leukemia in children
• Hypoplastic myelodysplastic syndrome or hypoplastic acute myeloid leukemia in adults
• Hypersplenism
• Hairy cell leukemia
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