Severe aplastic anemia is a rare hematological disorder characterized by pancytopenia due to bone marrow failure, whereby depletion of pluripotent stem cells is commonly mediated by an autoimmune response. Accordingly, immunosuppression and hematopoietic stem cell transplantation constitute treatment options, with only the latter being curative.
SAA patients don't generally share demographic features, but a medical history of seronegative hepatitis no longer than a year before presentation may be indicative of post-hepatitis SAA. Moreover, any reference to previous episodes of hematological disorders should be taken into account even though they may not have been related to clinical symptoms.
Pancytopenia as well as any combination of anemia, thrombocytopenia and neutropenia may also be diagnosed incidentally during routine analyses of blood samples. Single hematological disorders don't usually prompt a suspicion of SAA, those patients are often treated with standard therapies, e.g., dietary supplementation of iron, folate or vitamin B12, administration of corticosteroids.
As per definition, SAA may be diagnosed if a patient presents with bone marrow cellularity <25% (up to 50% in case less than a third of visible cells correspond to hematopoietic stem cells) and at least two of the following: neutropenia with <0.5×10^9/l, thrombocytopenia with <20×10^9/l and reticulocyte counts <20×10^9/l . Accordingly, diagnosis of SAA requires the analysis of bone marrow specimens and blood samples.
In SAA patients, complete blood count and reticulocyte count usually reveal pancytopenia and decreased levels of reticulocytes; lymphopenia is rare. The mean corpuscular volume is often augmented. Mild anemia and macrocytosis may indicate SAA in patients otherwise possibly diagnosed with immune thrombocytopenic purpura. It may be recommendable to repeat laboratory analyses of blood samples to rule out temporary anomalies due to medication or environmental factors.
In order to evaluate the condition of the bone marrow, both aspirates and biopsy specimens should be analyzed . Hypocellularity and prominent fat spaces are the hallmarks of SAA, and besides overall reduced hematopoiesis and lack of myeloid progenitor cells, dyserythropoiesis may also be observed. In contrast, excess blasts, striking dysplasia or hemophagocytosis are not characteristic of SAA. Upon cytogenetic analysis, bone marrow cells of most SAA patients do not show any chromosomal aberrations. In only 10% of samples, monosomy or trisomy may be detected . These are not necessarily incompatible with a good response to immunosuppressive treatment.
SAA patients require supportive care and causative treatment. Contrary to MAA, watchful waiting is not an option in SAA .
Immediate medical attention should be provided to compensate for the effects of pancytopenia. Patients suffering from anemia, thrombocytopenia and a bleeding diathesis should receive transfusions of the respective blood products. Additional measures should be taken to avoid trauma and further hemorrhages. Antimicrobials may be administered both prophylactically and therapeutically to prevent or manage bacterial infections. Broad spectrum antibiotics are indicated to this end; underdosing and early termination of drug therapy should strictly be avoided. SAA patients are also at high risks of fungal infections, but prophylactic use of antimycotics has so far only been recommended for VSAA patients . As a general measure to prevent infection, patients should be advised to avoid contact with garbage and compost, and possibly with animals and plants.
With regards to causative therapy, immunosuppression by means of the combined administration of antithymocyte globulin and cyclosporin A is the approach of choice. In most patients, hematopoiesis can be restored this way . Some patients only show partial responses to immunosuppressive therapy and may later be considered for HSCT. Indeed, experts recommend to refer every SAA patient for HSCT if a matched sibling donor is available  . In case of partial or non-responders to immunosuppressive treatment and in the absence of a matched sibling donor, HSCT by an unrelated matched donor should be offered. Of note, the prophylactic measures described above should be maintained during the first months after initiation of immunosuppressive therapy or HSCT.
Survival rates of AA patients have constantly been increasing. To date, 68% of AA patients who receive immunosuppressive treatment are alive ten years after the initial diagnosis and this also applies to 73% of individuals who were treated with HSCT . In the 1990s, the 3-months-survival was 73% . Old age continues to be an unfavorable prognostic factor. Furthermore, disease severity negatively correlates with survival and patients diagnosed with MAA generally have a better prognosis than those suffering from SAA.
If left untreated or if the patient does not respond to therapy, they are at risk of life-threatening hemorrhages or develop severe immunodeficiency, recurrent infections and eventually lethal sepsis open link. Clonal disease due to aggressive immunosuppression and complications of HSCT are the main risks associated with available treatment options.
Congenital AA is a very rare condition, with the most common underlying disease being Fanconi anemia. Fanconi anemia is inherited with an autosomal recessive trait and results from mutations of genes encoding for the so-called Fanconi anemia complementation group proteins. Accordingly, these genes have been designated FANC genes. The respective gene products are involved in recognition and repair of DNA damage . Furthermore, congenital AA has occasionally been related to Shwachman-Diamond syndrome or Diamond-Blackfan syndrome .
More commonly, SAA is acquired. In recent years, acquired SAA has increasingly been recognized as an autoimmune disease characterized by T cell-mediated destruction of hematopoietic stem cells. According to current knowledge, autoreactive, cytotoxic CD8+ T cells play a key role in AA pathogenesis . These cells trigger a type 1 autoimmune response dominated by cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which may induce expression of Fas receptor and subsequent apoptosis of CD34+ stem cells and which impair proliferation of progenitor cells . Still, little is known about the trigger of this autoimmune reaction. Historically, AA has been related to numerous infectious, non-infectious diseases, exposure to physical and chemical noxious agents. AA may follow an episode of seronegative hepatitis, or may be associated with eosinophilic fasciitis or pregnancy .
The overall incidence of AA is two cases per million per year in the western world ., with this number comprising MAA, SAA as well as VSAA. Interestingly, incidence rates in Asia are more than twice as high. This observation implies higher exposure to etiologic agents in the respective geographic regions, which led to the suspicion of infectious pathogens to act as triggers of the autoimmune response underlying the disease . Despite its low incidence, SAA is still the most common condition prompting HSCT besides myeloid and lymphoid malignancies.
AA may affect patients of both genders and all age groups, but about half of all cases are diagnosed in individuals aged less than 30 years . Adults aged 30 to 60 years are least frequently affected and incidence rises again among the elderly. With regards to the severe form of the disease, a trend towards an increase of incidence with age has been reported recently . In that same study, a male predominance has been observed. Similar results have been obtained in other retrospective studies .
The autoimmune response underlying acquired SAA is triggered by an as-of-yet unknown stimulus, possibly by bacterial or viral pathogens or non-infectious agents. This stimulus is directly followed by clonal expansion of cytotoxic T cells that mediate the destruction of hematopoietic stem cells by means of distinct downstream events:
Families affected by congenital SAA may benefit from genetic counselling. With respect to acquired SAA, specific measures cannot be recommended due to remaining knowledge gaps regarding the disease etiology.
Aplastic anemia (AA) is a rare, potentially life-threatening hematological disorder provoked by bone marrow failure and extensive disturbances of hematopoiesis. Patients may suffer from congenital or acquired AA, and this distinction implies a heterogenous etiology for this condition: Congenital AA results from genetic defects, acquired AA is nowadays considered an autoimmune disease.
Furthermore, AA cases may be classified according to the severity of the disease. Here, moderate aplastic anemia (MAA), severe aplastic anemia (SAA) and very severe aplastic anemia (VSAA) are distinguished. As has been indicated above, the clinical hallmark of AA is pancytopenia and accordingly, peripheral blood cell counts reflect the severity of hematopoietic defects .:
For SAA to be diagnosed, at least two of the aforementioned cell count criteria should be fulfilled. Furthermore, bone marrow hypocellularity with cell counts reduced to <25% of physiological values are required.
Hematopoietic stem cell transplantation (HSCT) is curative in both congenital and acquired SAA, but the limited availability of matched donors as well as the high risk of complications restrict its application. Considerable shares of patients suffering from acquired SAA respond to immunosuppressive therapy . - a fact that prompted research efforts as to the autoimmune nature of AA -, but myeloproliferative disorders like myelodysplasia and acute myelocytic leukemia may be induced by such treatment. The risk of clonal disease after immunosuppressive therapy has been estimated to be about 3% .
Human blood consists of many different types of cells, mainly of erythrocytes (also called red blood cells, they carry oxygen), leukocytes (also known as white blood cells, they constitute essential parts of the immune system) and platelets (required for coagulation). All these cells originate from hematopoietic stem cells in the bone marrow which differentiate from progenitor cells and other developmental stages until finally turning into mature blood cells. Thus, disturbances of blood cell formation at a very early stage, namely at the level of hematopoietic stem cells, results in reduced cell counts of all blood cells. This condition is termed pancytopenia. It is the hallmark of aplastic anemia, whereby "aplastic" refers to the disease affecting the formation of blood cells in the bone marrow and "anemia" describes the shortage of red blood cells, which commonly manifests first. If cell counts of erythrocytes, leukocytes and platelets are severely reduced, the patient may be diagnosed with severe aplastic anemia (SAA).
Symptoms associated with SAA are those of anemia, leukocytopenia and thrombocytopenia, i.e., lack of the respective populations of blood cells. Anemia most frequently causes fatigue, headaches and dizziness; thrombocytopenia provokes a tendency to bleed. Patients may note themselves prone to hematomas and observe small bleedings in the skin. Leukocytopenia renders the patient susceptible to infections, but typically manifests at later stages. Patients may tend to contract stomatitis, gingivitis, upper respiratory infection or pneumonia, among others.
If a patient is diagnosed with SAA, they will receive supportive care to compensate for pancytopenia. This may comprise transfusion of blood products and prophylactic and therapeutic use of antimicrobials. Eventually, causative treatment is required. Immunosuppressive therapy is effective in the majority of patients and is preferred if siblings who may donate stem cells are not available. Otherwise, the patient is referred to for stem cell transplantation. Ideally, these cells are donated by a suitable sibling, but they may also be donated by a non-related person.