What is Aplastic Anemia?
Aplastic anemia is a bone marrow disease that causes pancytopenia, which is a reduction in all blood cells. In the presence of aplastic anemia there is therefore a simultaneous decrease in the number of red blood cells (anemia), white blood cells (leukopenia) and platelets (thrombocytopenia). This reduction follows the generalized decrease in the number of hematopoietic stem cells and their ability to generate mature blood elements.
We recognize three main mechanisms by which the bone marrow becomes insufficient:
- An intrinsic defect of the cells of the stem compartment;
- Immuno-mediated inhibition of hematopoietic proliferation and differentiation;
- Damage to the bone marrow microenvironment, secondary to immune diseases or infections, or exposure to particular physical or chemical agents
Treatment is based on the degree of cytopenia and can be divided into primary and supportive. Supportive therapy (eg transfusions or antibiotics) aims to correct the symptoms of aplastic anemia, without actually managing the underlying cause. The primary intervention may instead be based on bone marrow transplantation or on the administration of immunosuppressive drugs, typically an anti-lymphocyte serum in combination with ciclosporin.
Causes
Aplastic anemia has a varied etiology and includes both hereditary and acquired forms (idiopathic and secondary). Among the hereditary forms Fanconi anemia and congenital dyskeratosis are recalled, while among the acquired very often it is not possible to find a precise triggering factor ( idiopathic aplastic anemia ). To date, a multitude of synthetic substances have been identified whose myelotoxic potential can generate the disease in genetically predisposed subjects. Let's look at them in detail.
Drugs and myelotoxic substances
The risk of acquired aplastic anemia may increase with exposure to certain chemicals and / or with some medications . These factors can produce a dose-dependent or occasional toxic action (due to unpredictable effects and independent of the dose administered). The first category includes all the cytostatic substances that act directly on cell replication. Pesticides (organophosphates and carbamates) and organic solvents, such as benzene, toluene and trinitrotoluene, are implicated in the etiology.
Even accidental exposure or for therapeutic purposes to ionizing radiation can produce a medullary aplasia. Marie Curie, known for her studies in the field of radioactivity, died of aplastic anemia after having worked long without protection with radioactive materials; at that time, the damaging effects of ionizing radiation were still unknown.
Numerous drugs can sporadically induce the onset of aplastic anemia. These include: tolbutamide (antidiabetic), methylphenyldantoin (anticonvulsant), phenylbutazone (analgesic), chloramphenicol and quinacrine (antimicrobials). It is important to consider that these drugs are safe for most people and the likelihood of them causing the disease is extremely low.
Infections
Some viral agents can cause acquired aplastic anemia: Parvovirus (Parvovirus B19), Herpes virus (Epstein-Barr virus, cytomegalovirus ), Flavivirus (Hepatitis B virus, Hepatitis C virus, Dengue) and Retrovirus (HIV). Aplastic anemia occurs in about 2% of patients with severe viral hepatitis. The disease may also represent the outcome of an infection of Parvovirus B19, which causes infectious erythema or fifth disease, in children. This viral agent temporarily blocks the complete production of red blood cells (erythroblastopenia). In most cases, however, this effect goes unnoticed, as red blood cells live on average 120 days and the drop in production does not significantly affect the total number of circulating erythrocytes. However, in patients with associated conditions, such as sickle cell anemia, where the cellular life cycle is reduced, Parvovirus B19 infection can lead to a serious lack of red blood cells. HIV can directly infect hematopoietic progenitors and cause bone marrow hypoplasia.
Other risk factors
Aplastic anemia can be concomitant with other conditions, such as:
- Pregnancy (often resolves spontaneously after delivery);
- Autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis;
- Myelodysplastic syndromes;
- Paroxysmal nocturnal hemoglubinuria (PNH, chronic hemolytic anemia with thrombocytopenia and / or neutropenia).
Aplastic anemia may be associated with certain types of cancer and antineoplastic treatments (radiotherapy or chemotherapy).
Pathogenesis
Medical research has tried to understand how drugs, chemicals and viruses can cause aplastic anemia. The most commonly accepted explanation is that these agents are able to trigger an abnormal immune reaction in the body of some genetically predisposed people. The reaction is supported by activated cytotoxic T lymphocytes, which begin to release excess cytokines, in particular, interferon-γ and TNF-α; these substances can therefore trigger apoptosis of bone marrow stem cells.
The positive haematological response to treatment with drugs that suppress the immune system (immunosuppressive therapy) confirms the participation of an auto-immune component in aplastic anemia.
Symptoms
The symptoms of aplastic anemia depend on the severity of peripheral pancytopenia. Onset can be sudden (acute) or gradual, so it can progress over weeks or months.
The reduced number of erythrocytes (anemia), white blood cells (leukopenia) and platelets (thrombocytopenia) causes most of the signs and symptoms:
- Anemia : malaise, pallor and other associated symptoms, such as arrhythmias, dizziness, headache and chest pain.
- Thrombocytopenia : may be associated with bleeding symptoms, with petechiae, ecchymoses, epistaxis and gingival, conjunctival or other tissue bleeding.
- Leukopenia : increases the risk of infection. The reduction in the number of granulocytes commonly causes opportunistic infections of many bacterial and fungal species (such as oral candidiasis and pneumonia).
Aplastic anemia can also cause signs and symptoms that are not directly related to the low number of blood cells, such as nausea and skin rashes. Splenomegaly is absent, as are bone pains, typical of leukemia instead. The main causes of mortality from aplastic anemia include infections and bleeding.
Diagnosis
Patients with aplastic anemia present a picture of hypoplasia of the three major medullary proliferative chains (erythrocytes, white blood cells and platelets). The diagnosis of aplastic anemia includes history, blood count and bone marrow biopsy.
The first approach is to differentiate the condition from pure erythroid aplasia. In aplastic anemia, the patient has pancytopenia (ie anemia, leukopenia and thrombocytopenia) associated with the consequent decrease of all mature blood elements, which nevertheless remain within a certain range. In contrast, pure erythroid aplasia is characterized by the selective reduction or complete absence of red blood cell precursors.
The patient undergoes blood tests to find diagnostic clues, including a complete blood cell count, electrolyte and liver enzyme dosage, thyroid and kidney function tests, and iron, vitamin B12 and folic acid levels.
The diagnosis can be confirmed by bone marrow biopsy (or bone marrow aspiration). The sample thus taken is examined under a microscope to exclude other hematological diseases. In fact, the examination allows to evaluate the quantity and types of cells present and to identify any chromosomal anomalies. In the case of aplastic anemia, bone biopsy allows a precise quantification of cellular hypoplasia (reduced cellularity compared to normal values) and shows an increase in adipocytes, while chromosomal abnormalities are not typically found.
The following investigations can help establish the diagnosis of aplastic anemia:
- Bone marrow aspirate and biopsy: to exclude other causes of pancytopenia (ie significant neoplastic infiltration or myelofibrosis);
- History of recent iatrogenic exposures to cytotoxic chemotherapy: may cause transient bone marrow suppression;
- X-rays, computed tomography (CT) or ultrasound imaging tests: they can show an enlargement of lymph nodes (sign of lymphoma), kidneys and bones of the arms and hands (abnormal in Fanconi anemia);
- Chest X-ray: can be used to rule out infections;
- Liver tests: to check for liver disease;
- Microbiological analysis: to detect the presence of infections;
- Determination of vitamin B12 and folate levels: a deficiency of these vitamins can reduce the production of blood cells in the bone marrow;
- Flow cytometry and blood tests to establish the possible clinical picture of paroxysmal nocturnal hemoglobinuria (PNH);
- Antibody dosage: to measure immune competence.
Treatment
The goal of treatment is to correct the symptoms related to peripheral pancytopenia ( supportive therapy ) and to resume normal bone marrow activity ( primary therapy ).
Anemia and thrombocytopenia are managed with transfusions based on red blood cells and platelet concentrates, especially to prevent fatal bleeding in emergency situations. In case of infection, appropriate intravenous antibiotic therapy is prescribed.
Aplastic anemia with toxic etiology is transient, therefore reversible, but it is necessary to promptly suspend contact with the responsible chemical or pharmacological substance.
The primary treatment of aplastic anemia is to heal the disease and involves bone marrow transplantation or the use of immunosuppressants .
Allogeneic bone marrow transplantation (BMT) is considered the best treatment for children and young adults with aplastic anemia. The multipotent stem cells, taken from a compatible donor (eg HLA-identical sibling) and transferred to the patient, are in fact able to reconstitute the medullary proliferative lines. However, bone marrow transplantation is a procedure that presents many risks and side effects. In addition to the possible failure of the transplant, there is the possibility that the newly formed white blood cells can attack the rest of the body (a condition known as "graft versus host disease", that is, transplant disease against the host). For this reason, many doctors prefer to use immunosuppressive therapy as a first-line treatment for people over the age of 30-40 (as they could tolerate the procedure with difficulty). The outcome of bone marrow transplantation varies according to the age of the patient and depends on the availability of a compatible donor.
The pharmacological therapy of aplastic anemia involves the suppression of the immune system and often includes a short cycle of anti-lymphocyte globulins (ALG) or anti-thymocytes (ATG), combined with a treatment of several months with ciclosporin, to modulate the immune system. This therapeutic protocol induces responses in about 75% of cases. Corticosteroids may be needed to control ATG allergic reactions, while some hematopoiesis-stimulating drugs, including G-CSF (granulocyte colony stimulating factor), are often used in combination with immunosuppressive therapy to stimulate hematopoietic recovery.
Prognosis
The course of the disease is difficult to predict. The prognosis in the severe untreated disease is poor in most cases, while discontinuation of the toxic contact may be sufficient to resolve the milder cases. Fortunately, therapy can effectively control anemia, if started promptly, and treatment with immunosuppressive drugs or bone marrow transplantation guarantees an average 5-year survival for about 70% of patients. The survival rate after bone marrow transplantation is more favorable to young subjects under the age of 20 years.
Recurrences are common and the patient must undergo regular medical checks to determine if he is still in a state of remission. Relapse after treatment with ATG / cyclosporin can sometimes be controlled by repeating the therapeutic cycle.
Some patients with aplastic anemia develop paroxysmal nocturnal hemoglobinuria (PNH, chronic hemolytic anemia with thrombocytopenia and / or neutropenia). The onset of PNH could be interpreted as a mechanism to overcome the destruction of the bone marrow micro-environment mediated by the immune system.
Severe aplastic anemia can develop into myelodysplastic syndromes and leukemia.
