Aplastic Anemia

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Diagnosis and reasoning

This young patient has presented with recurrent fever, worsening dyspnea, and new-onset easy bruising; examination reveals the presence of pallor and of multiple petechiae and ecchymotic patches. When these signs and symptoms are considered together, an alarming possibility becomes apparent: could these be manifestations of pancytopenia? An urgent complete blood count (CBC) and peripheral smear are an essential next step; the former confirms the presence of a pancytopenia, while the latter additionally reveals macrocytosis, anisopoikilocytosis and small platelets. When the above are considered along with her clinical presentation, the potential diagnoses include aplastic anemia (AA), myelodysplastic syndrome (MDS), and megaloblastic anemia due to vitamin B12 deficiency. Bone marrow (BM) examination is essential to differentiate between the above possibilities; this reveals a markedly hypocellular marrow (20% cellularity), with a profound reduction of all hematopoietic cells. Note that when the above result is considered along with the low absolute neutrophil count, platelet count, and reticulocyte count, the diagnostic criteria for severe AA are met. While the above diagnostic criteria are fairly precise, it is still preferable to exclude the other differential diagnoses. While it is difficult to differentiate hypocellular MDS from AA, the absence of dysplastic granulocytes and megakaryocytes and blast cells in BM, and normal cytogenetics excludes MDS. Furthermore, the absence of malignant infiltration rules out hematological malignancies.. In addition, note that this degree of BM hypoplasia due to vitamin B12 deficiency is exceedingly rare; the normal serum vitamin B12 levels completely exclude this possibility. AA can be congenital or acquired in origin; note however that most patients with congenital disease tend to present earlier in life; while Fanconi anemia can present in adult life, there are no other findings in the history or examination which would suggest this diagnosis. On the other hand, acquired AA is a definite possibility; while this is most often idiopathic in origin, the recent history of glandular fever raises the possibility of Epstein-Barr virus (EBV) as the etiological agent. However, this is made unlikely by the absence of the EBV genome in the nucleated cells. The specific management of patients newly diagnosed with AA consists of either allogeneic stem cell transplantation or immunosuppressive therapy. HLA typing is essential to find an HLA- identical sibling donor. When the patient is less than 40 years of age and bone marrow from an HLA- identical sibling donor is available (as in this case), allogeneic stem cell transplantation is the preferred mode of treatment. Until stem cell transplantation is performed, hematopoietic support is essential to maintain cell counts at safe levels. As this patient is about to undergo a bone marrow transplant, she should be transfused irradiated blood components as a precaution to prevent transfusion associated graft versus host disease. Recombinant erythropoietin is not routinely recommended, as it has no proven benefit in the management of patients with AA, and may even worsen the anemia, due to acquired pure red cell aplasia secondary to antibody formation against recombinant erythropoietin, and toxic reactions with other concomitantly used drugs. Note also that antibiotic prophylaxis is not recommended unless the patient’s absolute neutrophil count is consistently lower than 200/mm3.


Discussion

Aplastic anemia (AA) is a rare but serious disorder characterized by a decrease or a complete absence of hematopoietic precursor cells in the bone marrow, accompanied by peripheral blood cytopenias. AA can be classified as congenital or acquired, based on etiology; the disease can also be classified into non-severe, severe, and very severe forms, based on severity. Note that the latter classification takes peripheral blood criteria and the degree of bone marrow (BM) hypocellularity into account, as follows: Severe AA: - BM cellularity < 25% (or < 50% if hematopoietic cells are < 30%) - ≥ 2 of the following peripheral blood criteria: neutrophil count 0.5 ×10^9/L, platelet count 20 ×10^9/L, reticulocyte count < 20 ×10^9/L Very severe AA: - As above but with a peripheral blood neutrophil count < 0.2 ×10^9/L Nonsevere AA: - Hypocellular BM with peripheral blood cell counts not fulfilling the criteria for severe or very severe AA. Several studies point out that AA is 2 to 3 fold more common in Asia than in Europe, with annual incidences of 10 to 15 cases per million population, and 3 to 5 cases per million population in each region respectively. The male to female incidence approximately 1:1, although a slight male preponderance is seen in oriental countries. There are two distinct peaks in the age distribution of the disease, one among young adults, and another subsequent peak in the elderly. Another small spike is seen in childhood due to the inherited (congenital) form of the disease. Note that the vast majority (over 80%) of cases are due to the acquired form of the disease. Numerous defects at different stages of hematopoiesis including defects in the marrow stroma, defects in stem cells, inherent errors of hematopoietic cell function, and external injury to hematopoietic stem cells have been implicated in the pathophysiology of AA. However, following data from recent studies, the hypothesis that dysfunction of stem cells is the hallmark feature has gained wide acceptance.; here, it is speculated that activation of cytotoxic T cells and subsequent release of cytokines (particularly interferon-gamma) triggers apoptosis of stem cells. Etiology Fanconi anemia, dyskeratosis congenita, Diamond- Blackfan anemia, and Schwachman-Diamond syndrome are congenital causes of AA; in addition, certain specific human leukocyte antigens (HLA) have been identified in patients who have congenital AA. Approximately 50% to 75% of cases of acquired AA are idiopathic; the remainder are attributed to a variety of etiological factors including infections such as infectious mononucleosis, viral hepatitis and human immunodeficiency virus (HIV) infection; toxins such as benzene; drugs such as chloramphenicol and gold; autoimmune diseases; and rarely, pregnancy. In addition, paroxysmal nocturnal hemoglobinuria (PNH) coexists in a significant number of patients with AA. However, this is presumably due to the survival of a more adaptive stem cell line (the PNH cell line) rather than an etiological association. Signs and Symptoms The clinical features of AA are a direct result of the lack of hematopoietic precursor cells. Patients typically present with symptoms secondary to anemia, such as pallor, fatigue, headache, dizziness, shortness of breath and palpitations, and/or those due to thrombocytopenia, such as mucosal bleeding, petechial rashes and ecchymotic patches. Although rare, the medical literature is not completely devoid of cases in which patients present with recurrent or overt infections, due to severe neutropenia. In addition, patients with congenital AA may express characteristic phenotypic manifestations such as radial hypoplasia and generalised skin hyperpigmentation in Fanconi anemia, and nail dystrophy, oral leukoplakia and abnormal skin pigmentation in dyskeratosis congenita. Key investigations in these patients include a complete blood count, peripheral blood smear, bone marrow aspiration and trephine biopsy, and cytogenetic studies. The complete blood count typically demonstrates pancytopenia, with uniformly diminished neutrophil and platelet counts, along with anemia and reticulocytopenia. Lymphocyte counts are usually normal, and a macrocytosis is common. Peripheral smears typically confirm the presence of pancytopenia, and additionally may demonstrate anisopoikilocytosis, neutrophils with toxic granulation and small platelets. Note that the presence of abnormal cells such as dysplastic neutrophils, blast cells, abnormal platelets and hairy cells is generally considered suggestive of an alternate diagnosis. In addition, a BM aspiration and a trephine biopsy are necessary; these will demonstrate a hypocellular marrow with widespread fat cell infiltration and variable amounts of residual hemopoietic cells, without any evidence of dysplastic megakaryocytes or granulocytic cells. While diffuse hypocellularity is the general rule, occasionally patchy areas with normal or near-normal cellularity (known as “hot spots”) can be observed. Cytogenetic studies should also be performed on the BM to detect abnormal cytogenetic clones; if present, this may implie an alternate diagnosis, such as myelodysplastic syndrome (MDS). Note however that approximately 10% of classic AA cases may also have abnormal cytogenetic clones. Flow cytometry should also be performed to rule out the resence of a coexisting paroxysmal nocturnal hemoglobinuria (PNH) clone. In this test, external antibodies against CD55 and CD59 are used to detect red cells deficient with these angitens. The management of AA can be classified into specific management and supportive care. Specific management of a newly diagnosed patient with AA consists of either allogeneic stem cell transplantation or immunosuppressive therapy. An HLA-identical sibling was considered the sole compatible donor for allogeneic stem cell transplantation for years but with recent advances in immunology, transplantation from an HLA- matched unrelated donor has emerged as another possibility. Immunosuppressive therapy comprises a combination of Anti-thymocyte globulin (ATG) and cyclosporine. Prednisolone is best avoided, as it has no proven efficacy and may potentially trigger infection. Supportive care covers a wide range of clinical aspects including, transfusional support, treatment of infections, and provision of social and psychological support. Transfusional support with blood components is essential to maintain desirable cell counts; irradiated blood products are preferred in this regard to prevent development of alloantibodies to leukocytes present in transfused blood. Iron chelation with subcutaneous desferrioxamine is indicated in heavily transfused patients, to prevent iron overload. Hematopoietic growth factors (particularly, erythropoietin) are not routinely recommended, as the efficacy is unproven; however, a short course of Granulocyte colony-stimulating factor (G-CSF) may be considered in patients with life-threatening neutropenia, especially if severe systemic infections are present. Prompt and proper treatment of infections is essential, but prophylactic antibiotics should not be used indiscriminately in each and every patient; instead, individuals with absolute neutrophil counts consistently lower than 200/mm3 should be administered antibiotic prophylaxis. Vaccination should be deferred unless it is absolutely necessary, due to the risk of vaccine induced bone marrow suppression, and relapse of AA. However, following BM transplantation, similar to other patients who have undergone the procedure, routine vaccination is recommended. Patients should be followed up regularly in order to detect relapses, or emergence of other clonal disorders such as PNH and MDS. The clinical course of AA varies from the “seldom life-threatening” non-severe form, to the “if left untreated, essentially fatal” severe and very severe forms. It is estimated that the 2 year mortality rate in patients with severe or very severe AA who are treated with supportive care alone is approximately 80%. Recent advances in specific treatment modalities has resulted in longer survival rates. Studies reveal that the risk of succumbing to overwhelming bacterial and fungal infections (the most common cause of death in AA) following BM transplant or immunosuppression is significantly higher in elderly patients.


Take home messages

  1. Aplastic anemia (AA) is characterized by a decrease or a complete absence of hematopoietic precursor cells in the bone marrow, accompanied by peripheral blood cytopenias.
  2. AA is staged into severe, very severe and non-severe forms depending on peripheral blood criteria and the degree of bone marrow (BM) hypocellularity.
  3. Specific management of a newly diagnosed patient with AA consists of either allogeneic stem cell transplantation or immunosuppressive therapy.
  4. Prophylactic antibiotics are not routinely recommended in AA; however, patients with absolute neutrophil counts consistently lower than 0.2 x 109/L should receive antibiotic prophylaxis.

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