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Severe Aplastic Anemia

SAA

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.

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Presentation

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.

Symptoms associated with SAA correspond to those of severe anemia, thrombocytopenia and - usually during later stages of the disease - neutropenia.

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.

Easy Bruising
  • These include fatigue, shortness of breath, fever, recurrent infections, easy bruising or unusual bleeding.[leukemiabmtprogram.org]
  • Platelets are responsible for normal blood clotting and low numbers can result in easy bruising and bleeding which can be deadly.[clinicaltrials.gov]
  • Some symptoms include tiredness, paleness, frequent infections, and easy bruising and bleeding. Aplastic anemia is diagnosed with blood and bone marrow tests. Treatment depends on the cause.[urmc.rochester.edu]
  • These are common symptoms for each: Low red blood cell count: Tiredness Shortness of breath Dizziness Pale skin Headaches Chest pain Irregular heartbeat Low white blood cell count: Infections Fever Low platelet count: Easy bruising and bleeding Nosebleeds[webmd.com]
Pneumonia
  • Although the patient had pneumonia on day 11, it was resolved promptly after engraftment on day 16.[ncbi.nlm.nih.gov]
  • After CBT, acute GVHD developed in 4 cases, CMV reactivation in 1, pneumonia in 1, and sepsis in 1. Four patients successfully engrafted, but 1 failed to engraft and had delayed autologous recovery.[ncbi.nlm.nih.gov]
  • Fungal pneumonias decreased from 30% to 3% ( P P .05). Aspergillus species were the most common fungal pathogens recovered in this patient population. Table 4.[cid.oxfordjournals.org]
  • The causes of the early deaths were sepsis (n 3), interstitial pneumonia (n 2), hemolysis of unknown cause (n 1) and accidental ingestion (n 1).[haematologica.org]
  • Prophylaxis for Pneumocystis jirovecii pneumonia should be given to all patients for at least six months after bone marrow transplantation but is not routinely given after ATG in Europe.[patient.info]
Dyspnea
  • A 16-yr-old male patient with hemochromatosis due to multiple packed red blood cell transfusions was referred to our emergency center for the treatment of severe aplastic anemia and dyspnea. He was diagnosed with aplastic anemia at 11-yr of age.[ncbi.nlm.nih.gov]
  • CASE A 60-year-old woman who complained of cough and dyspnea visited the Pulmonary Department in April 2000. Chest radiography and computed tomography (CT) showed a large mass in the anterior mediastinum, compatible with a thymoma ( Figure 1 ).[kjim.org]
  • Specific manifestations include the following: Anemia: May manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling Thrombocytopenia: May result in mucosal and gingival bleeding or petechial rashes Neutropenia: May manifest as overt[emedicine.medscape.com]
  • Aplastic anemia may present with the following signs and symptoms: Fatigue Dyspnea on exertion Easy bruising and bleeding (for example, epistaxis, gum bleeding, heavy menses, subconjunctival hemorrhages, melena, etcetera.)[cancertherapyadvisor.com]
  • Signs and symptoms of aplastic anemia may include the following: Pallor Headache Palpitations, dyspnea Fatigue Foot swelling Gingival bleeding, petechial rashes Overt and/or recurrent infections Oropharyngeal ulcerations A subset of patients with aplastic[emedicine.medscape.com]
Anemia
  • It has been associated with hematologic disorders, such as aplastic anemia. The clinical features and long-term outcomes of patients with eosinophilic fasciitis and associated aplastic anemia have been poorly described.[ncbi.nlm.nih.gov]
  • We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation[ncbi.nlm.nih.gov]
  • Mucormycosis with aplastic anemia is seen rarely. Only a few cases of cardiac mucormycosis with aplastic anemia have been reported in the literature.[ncbi.nlm.nih.gov]
  • The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant[ncbi.nlm.nih.gov]
  • Severe aplastic anemia is a well-recognized complication of fulminant non-A, non-B, and non-C hepatitis requiring orthotopic liver transplantation.[ncbi.nlm.nih.gov]
Fatigue
  • Patients typically have fatigue, infections, and increased or unusual bleeding. A bone marrow biopsy establishes the diagnosis. Treatment includes hematopoietic stem cell transplant or immunosuppressive therapy.[ncbi.nlm.nih.gov]
  • These include fatigue, shortness of breath, fever, recurrent infections, easy bruising or unusual bleeding.[leukemiabmtprogram.org]
  • It stops production of blood cells and causes fatigue, and can lead to infections and excessive bleeding. This condition can happen at any age, and often occurs suddenly.[mazecordblood.com]
  • As a result of the “empty” bone marrow, patients with SAA can be pale, and may experience fatigue (due to lower than normal red blood cells), infections (due to lower than normal white blood cells) and increased bruising and bleeding (due to lower than[bmt.umn.edu]
Fever
  • Dengue fever has rarely been reported as an etiology for aplastic anemia. An 8-year-old girl was admitted with fever, myalgia and petechiae. Dengue virus IgM antibodies were positive. She recovered completely, but her thrombocytopenia persisted.[ncbi.nlm.nih.gov]
  • The clinical spectrum of infections caused by non-typhoid Salmonella spp. includes gastroenteritis, enteric fever, bacteremia, and extraintestinal localized complications, especially in immunocompromised hosts.[ncbi.nlm.nih.gov]
  • Only fever reaction was observed as a complication of transfusion amongst the other complications such as acute lung damage, alloimmunisation, and graft-versus-host disease.[ncbi.nlm.nih.gov]
  • A rare association between dengue fever and AA has been reported. Dengue fever is a disease endemic to the western region of Saudi Arabia.[omicsonline.org]
  • About sixteen months after the operation, she was readmitted because of pancytopenia with cough and fever.[ncbi.nlm.nih.gov]
Weakness
  • You end up feeling weak, tired , and short of breath. Anemia comes in many forms. Iron-deficiency anemia is most common. Other types of the disease affect only small numbers of people.[webmd.com]
  • The most common symptom of all anemias is weakness.[everydayhealth.com]
  • When you are anemic, your body does not transport oxygen efficiently and this can make you tired and weak. RBCs carry oxygen using a protein called hemoglobin. Hemoglobin is necessary for efficient oxygen transport.[healthline.com]
  • Symptoms of chronic aplastic anemia include weakness and fatigue in the early stages, followed by shortness of breath, headache, fever, and pounding heart.[britannica.com]
Pain
  • She also complained of pain in the palatal area and the mandibular anterior region.[ncbi.nlm.nih.gov]
  • At age 13, abdominal pain was a sign of massive tumor. Extremely high levels of alpha-fetoprotein indicated the clinical diagnosis of hepatoblastoma that might be the first report as post-BMT malignancy.[ncbi.nlm.nih.gov]
  • Tell your health care provider right away if you have stomach area pain that may be a symptom of this type of blood clot New or worsened cataracts (a clouding of the lens in the eye).[us.promacta.com]
  • Sickle cells are stiff and sticky and tend to block blood flow in the vessels of the limbs and organs, causing pain and raising the risk for infection.[everydayhealth.com]
Loss of Appetite
  • Have a loss of appetite or lose weight. Have paler-than-normal skin. Have trouble breathing. Have rapid heartbeat. Have reduced ability to exercise or climb stairs. Low White Blood Cell Count A low white blood cell count is called neutropenia .[aamds.org]
Bleeding Gums
  • The intraoral examination identified bleeding gums; petechiae of the palate, tongue and cheek mucosa; and an atrophic, smooth and shining dorsal surface of the tongue.[ncbi.nlm.nih.gov]
  • Physical findings : Anemia with fatigue and pallor, bruising, petechiae (non-raised hemorrhage in the skin or in a membrane), and bleeding gums.[secure.ssa.gov]
  • Symptoms include: Bleeding gums Easy bruising Nose bleeds Rash, small pinpoint red marks on the skin (petechiae) Frequent or severe infections (less common) Mild cases of aplastic anemia that do not have symptoms may not require treatment.[medlineplus.gov]
  • Bleeding gums. Fevers. Sinus tenderness. Enlarged liver or spleen. Oral thrush (white patches on a red, moist, swollen surface, occurring anywhere in the mouth).[chw.org]
Periodontitis
  • This article describes the periodontal management of a patient with severe aplastic anemia.[ncbi.nlm.nih.gov]
Palpitations
  • Anaemia due to lack of red blood cells – weakness, tiredness, shortness of breath, light-headedness, palpitations.[leukaemiacare.org.uk]
  • Clinical manifestations are proportional to the peripheral-blood cytopenias and include: Patients with aplastic anaemia most commonly present with symptoms of anaemia (pallor, headache, palpitations, dyspneoa, fatigue, or ankle oedema) and thrombocytopenia[patient.info]
  • Specific manifestations include the following: Anemia: May manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling Thrombocytopenia: May result in mucosal and gingival bleeding or petechial rashes Neutropenia: May manifest as overt[emedicine.medscape.com]
  • Signs and symptoms of aplastic anemia may include the following: Pallor Headache Palpitations, dyspnea Fatigue Foot swelling Gingival bleeding, petechial rashes Overt and/or recurrent infections Oropharyngeal ulcerations A subset of patients with aplastic[emedicine.medscape.com]
Tachycardia
  • Symptoms for both types include: Chest pain Fast heartbeat, or tachycardia Headaches Trouble breathing Weakness and fatigue Treatment for sideroblastic anemia depends on the cause.[webmd.com]
  • Physical Examination Physical examination may show signs of anemia (eg, pallor, tachycardia) and of thrombocytopenia (eg, petechiae, purpura, ecchymoses). Overt signs of infection are usually not apparent at diagnosis.[emedicine.medscape.com]
Jaundice
  • Tell your health care provider right away if you have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice) unusual darkening of the urine unusual tiredness right upper stomach area (abdomen) pain[us.promacta.com]
  • Symptoms include chronic anemia, fatigue, yellow skin and eyes (jaundice), pale skin, and missing fingers and toes at birth. Some people never need treatment.[webmd.com]
  • If you have PNH, you have a higher risk of developing blood. which can cause symptoms such as severe leg, abdominal or chest pain, shortness of breath, jaundice or headache.[ohsu.edu]
  • […] inherited disorder even when no physical abnormalities are present. [ 5 ] In children and young adults, short stature, café au lait spots and skeletal anomalies suggest the possibility of a congenital form of aplastic anaemia. [ 6 ] A preceding history of jaundice[patient.info]
Arthralgia
  • Serum sickness, characterized by fever, skin rash, arthralgia, and serpentinous lesions on palms and soles, was observed in two patients (8%) and resolved with administration of prednisone.[scielo.br]
Tinnitus
  • Other symptoms may include a waxy pallor to the skin and mucous membranes, bleeding gums, a lack of energy during exercise, and tinnitus (ringing in the ears). Premenopausal women may have an increased menstrual flow and duration.[chealth.canoe.com]
Petechiae
  • An 8-year-old girl was admitted with fever, myalgia and petechiae. Dengue virus IgM antibodies were positive. She recovered completely, but her thrombocytopenia persisted. Six weeks later she became pancytopenic.[ncbi.nlm.nih.gov]
  • The intraoral examination identified bleeding gums; petechiae of the palate, tongue and cheek mucosa; and an atrophic, smooth and shining dorsal surface of the tongue.[ncbi.nlm.nih.gov]
  • Symptoms result from anemia, thrombocytopenia (petechiae, bleeding), or leukopenia (infections). Diagnosis requires demonstration of peripheral pancytopenia and a bone marrow biopsy revealing a hypocellular marrow.[msdmanuals.com]
  • Physical findings : Anemia with fatigue and pallor, bruising, petechiae (non-raised hemorrhage in the skin or in a membrane), and bleeding gums.[secure.ssa.gov]
Purpura
  • This initial indication was for adult patients with chronic immune thrombocytopenic purpura (ITP) following an insufficient response to corticosteroids, immunoglobulins, or splenectomy.[onclive.com]
  • Aplastic anemia and idiopathic thrombocytopenic purpura with antibody to platelet glycoprotein IIb/IIIa following resection of malignant thymoma. Acta Haematol 90:42–451993. 5. Dinol G, Saka B, Aktan M, Nalaci M, Keskin H.[kjim.org]
  • The patient received a transfusion of packed RBCs and platelets several times and was initially given intravenous Immunoglobulin (IVIG) plus folic acid, iron, and vitamin B 12 for presumed idiopathic thrombocytopenic purpura.[omicsonline.org]
  • This means a persistent hematocrit of 26% or less and reticulocyte (recently produced red blood cell) count of 4% or greater, or purpura (bleeding under the skin) and thrombocytopenia (reduced platelet count) of 40,000 platelets/cu.mm. or less despite[disabilitysecrets.com]
Headache
  • The most common adverse reactions were nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%).[onclive.com]
  • The most common side effects when PROMACTA is used to treat severe aplastic anemia are: nausea feeling tired cough diarrhea headache Laboratory tests may show abnormal changes to the cells in your bone marrow.[us.promacta.com]
  • Symptoms of chronic aplastic anemia include weakness and fatigue in the early stages, followed by shortness of breath, headache, fever, and pounding heart.[britannica.com]
Difficulty Concentrating
  • Symptoms of systemic mastocytosis include allergic skin reactions, difficulty concentrating and diarrhea. Doctors diagnose systemic mastocytosis by taking a small tissue sample called a biopsy.[ohsu.edu]

Workup

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 [1]. 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 [1]. 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 [16]. These are not necessarily incompatible with a good response to immunosuppressive treatment.

Cytopenia
  • His cytopenia and organ dysfunctions began to be gradually recovered since about 2002, following a 4-yr deferoxamine treatment. He showed completely normal ranges of peripheral blood cell counts, heart size, and liver function two years ago.[ncbi.nlm.nih.gov]
  • These cytopenias include agranulocytosis, PRCA and aplastic anemia. In fact, the overall long-term survival of patients with thymoma is poor once cytopenias occur.[kjim.org]
  • Alemtuzumab is currently approved to treat chronic lymphocytic leukemia and is also helpful in other conditions that require immunosuppression, such as rheumatoid arthritis and immune cytopenias.[clinicaltrials.gov]
  • Usually the type of treatment is dependent on age, but once the cytopenias (low blood counts) are severe or very severe, some kind of treatment must occur.[aamds.org]
  • […] alternative donor HCT may be a better treatment option than immunosupressive therapy for children and adolescents with SAA who lack an HLA-matched related donor [ 9 ] Using unrelated donor HCT for Diamond-Blackfan anemia at the onset of bi- or trilineage cytopenia[bethematchclinical.org]
Macrocytic Anemia
  • If it is much bigger than normal, then it is macrocytic anemia. Likewise, if the concentration of hemoglobin is much lower than normal, it is hypochromic anemia; if the concentration is much higher than normal, the RBCs are called hyperchromic.[labtestsonline.org]
  • Diamond-Blackfan anemia Diamond-Blackfan anemia (DBA) is characterized by a normochromic macrocytic anemia that can be isolated, or it can be associated with growth retardation or congenital malformation in the upper limbs, heart, and genitourinary systems[emedicine.medscape.com]
Macrocytosis
  • Although the anemia is often normocytic, mild macrocytosis can also be observed in association with stress erythropoiesis and elevated fetal hemoglobin levels.[emedicine.medscape.com]
Neutrophil Count Decreased
  • CsA was reduced, however, his neutrophil counts decreased, and CsA could not be discontinued. The patient was treated with rituximab monotherapy, and LPD resulted in complete remission.[ncbi.nlm.nih.gov]
Human Parvovirus B19
  • Human parvovirus B19 (PVB19) infection may cause mild pancytopenia characterized by transient and spontaneous recovery in healthy subjects.[ncbi.nlm.nih.gov]
  • Persistent infection with human parvovirus B19 (B19) is primarily associated with chronic bone marrow failure in immunocompromised patients, but occasionally this organism may also affect immunocompetent hosts.[ncbi.nlm.nih.gov]
  • Osaki M, Matsubara K, Iwasaki T, Kurata T, Nigami H, et al. (1999) Severe aplastic anemia associated with human parvovirus B19 infection in a patient without underlying disease. Ann Hematol 78: 83-86.[omicsonline.org]

Treatment

SAA patients require supportive care and causative treatment. Contrary to MAA, watchful waiting is not an option in SAA [17].

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 [18]. 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 [13]. 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 [19] [20]. 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.

Prognosis

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 [15]. In the 1990s, the 3-months-survival was 73% [11]. 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.

Etiology

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 [4]. Furthermore, congenital AA has occasionally been related to Shwachman-Diamond syndrome or Diamond-Blackfan syndrome [5].

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 [6]. 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 [7]. 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 [8].

Epidemiology

The overall incidence of AA is two cases per million per year in the western world [8]., 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 [9]. 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 [8]. 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 [10]. In that same study, a male predominance has been observed. Similar results have been obtained in other retrospective studies [11].

Sex distribution
Age distribution

Pathophysiology

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:

  • Proliferation of cytotoxic T cells is induced by interleukin-2 (IL-2), and while this process is usually subjected to control and suppression by regulatory T cells (T_reg), the vast majority of AA patients presents with depleted T_reg populations [12]. Proliferation of autoreactive T cells thus becomes self-containing since new clones continue to release IL-2. Of note, recovery of T_reg cell counts and function is considered an indicator of response to therapy. On the other hand, further impairment of immunoregulatory mechanisms by immunosuppressive therapy may favor the development of myeloproliferative disorders like myelodysplasia and acute myelocytic leukemia or paroxysmal nocturnal hemoglobinuria [13].
  • Cytotoxic T cells also release IFN-γ and TNF-α, and those cytokines induce the expression of cell death surface receptor Fas on CD34+ hematopoietic stem cells. In fact, the autoimmune reaction displayed by SAA patients is mainly directed against CD34+ stem cells [14]. Binding of Fas ligand to Fas receptor induces apoptosis. Accordingly, a good response to therapy is associated with a reduction of Fas expression by those cells.

Prevention

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.

Summary

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 [1].:

MAA SAA VSAA
neutrophils <1.0×10^9/l <0.5×10^9/l <0.2×10^9/l
platelets <50×10^9/l <20×10^9/l <20×10^9/l
reticulocytes <60×10^9/l <20×10^9/l <20×10^9/l

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 [2]. - 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% [3].

Patient Information

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.

References

Article

  1. Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009; 147(1):43-70.
  2. Yoshida N, Yagasaki H, Hama A, et al. Predicting response to immunosuppressive therapy in childhood aplastic anemia. Haematologica. 2011; 96(5):771-774.
  3. Baumann I, Fuhrer M, Behrendt S, et al. Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria. Histopathology. 2012; 61(1):10-17.
  4. Dong H, Nebert DW, Bruford EA, et al. Update of the human and mouse Fanconi anemia genes. Hum Genomics. 2015; 9:32.
  5. Kuijpers TW, Nannenberg E, Alders M, et al. Congenital aplastic anemia caused by mutations in the SBDS gene: a rare presentation of Shwachman-Diamond syndrome. Pediatrics. 2004; 114(3):e387-391.
  6. Giannakoulas NC, Karakantza M, Theodorou GL, et al. Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients. Br J Haematol. 2004; 124(1):97-105.
  7. Franzke A, Geffers R, Hunger JK, et al. Identification of novel regulators in T-cell differentiation of aplastic anemia patients. BMC Genomics. 2006; 7:263.
  8. Young NS, Scheinberg P, Calado RT. Aplastic anemia. Curr Opin Hematol. 2008; 15(3):162-168.
  9. Issaragrisil S, Kaufman DW, Anderson T, et al. The epidemiology of aplastic anemia in Thailand. Blood. 2006; 107(4):1299-1307.
  10. Biswajit H, Pratim PP, Kumar ST, et al. Aplastic anemia: a common hematological abnormality among peripheral pancytopenia. N Am J Med Sci. 2012; 4(9):384-388.
  11. Montané E, Ibáñez L, Vidal X, et al. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica. 2008; 93(4):518-523.
  12. Solomou EE, Rezvani K, Mielke S, et al. Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia. Blood. 2007; 110(5):1603-1606.
  13. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006; 108(8):2509-2519.
  14. Liu CY, Fu R, Wang HQ, et al. Fas/FasL in the immune pathogenesis of severe aplastic anemia. Genet Mol Res. 2014; 13(2):4083-4088.
  15. Locasciulli A, Oneto R, Bacigalupo A, et al. Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2007; 92(1):11-18.
  16. Gupta V, Brooker C, Tooze JA, et al. Clinical relevance of cytogenetic abnormalities at diagnosis of acquired aplastic anaemia in adults. Br J Haematol. 2006; 134(1):95-99.
  17. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012; 120(6):1185-1196.
  18. Höchsmann B, Moicean A, Risitano A, et al. Supportive care in severe and very severe aplastic anemia. Bone Marrow Transplant. 2013; 48(2):168-173.
  19. Führer M, Rampf U, Baumann I, et al. Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival. Blood. 2005; 106(6):2102-2104.
  20. Yoshida N, Yagasaki H, Hama A, et al. Predicting response to immunosuppressive therapy in childhood aplastic anemia. Haematologica. 2011; 96(5):771-774.

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Last updated: 2018-06-21 23:57