Acquired Aplastic Anemias
What is it?
Aplastic anemia is a rare and serious disease characterized by the inability of the bone marrow to produce sufficient numbers of blood cells. In the presence of bone marrow aplasia, there is a simultaneous reduction in red blood cells, white blood cells and platelets.
It should be specified that it is not an oncologic disease, but is a bone marrow and blood cell disease characterized by lack of cell production by the marrow. In the definition of this disease, the term "aplasia" indicates in fact the inability of the marrow - the organ responsible for producing red blood cells, white blood cells and platelets to be released into the bloodstream - to adequately produce blood cells. Most patients develop "pancytopenia", i. e. all three series (red blood cells, white blood cells and platelets) are decreased and the marrow is "empty": aplastic anemia is therefore a syndrome of bone marrow failure.
Causes and risk factors
The three main causes of an "empty marrow" are:
- direct damage to the marrow: drugs, such as chemotherapies, and radiation can cause a transient, dose-dependent lowering of the count, which recovers spontaneously; some, on the other hand, due to exposure to toxic molecules (such as benzene) can develop early marrow failure.
- constitutional syndromes: bone marrow failure derives from mutations - generally hereditary - of the DNA of the germ cell; Fanconi anemia, dyskeratosis congenita, or GATA2 disease, etc. belong to this group. Constitutional syndromes classically occur in childhood, and may be associated with physical abnormalities.
- immune-mediated aplastic anemia (almost all cases of sporadic aplastic anemia, especially if severe and acute, appear to be immune-mediated), i.e. there is an altered response of the immune system that leads to marrow damage and thus to pancytopenia.
Factors that may temporarily, or permanently, damage the bone marrow and impair blood cell production include: radiation and chemotherapy, toxic chemicals, drugs, autoimmune diseases, viral infections, pregnancy, unknown factors.
Which are the symptoms?
Aplastic anemia should be suspected in patients who have pancytopenia (depression of white blood cell, red blood cell, and platelet counts) and hypocellular (i.e., empty) bone marrow.
Typical symptoms include fatigue and ease of bruising or bleeding; infections may be present, but there is generally no long-standing history of illness. The disease may occur suddenly or progress slowly over weeks or months. There is a well-known distribution with respect to age of onset with one peak in mid to late childhood and another in the elderly age: it can develop at any age, but is more common in adolescents and young adults (20-25 years old) and in people over 50 years old.
It affects men and women equally. The estimated annual incidence of aplastic anemia is approximately 2 cases per million in Europe and North America, with a 2-3 times higher incidence in East Asia.
The disease has two forms: acquired and present at birth (congenital).
Congenital forms (20%) usually represent the terminal stage in the evolution of a genetic disease (e.g., Fanconi anemia or dyskeratosis congenita). Acquired form of the disease is the most common and is estimated to account for 80% of bone marrow aplasias.
The acquired form can be divided according to the origin of the disease into:
- idiopathic bone marrow aplasia (when causes are unknown, 80% of cases)
- secondary bone marrow aplasia (when causes are known, 20%)
In ~10% of patients, a history of nonviral hepatitis may precede the onset of aplastic anemia; an uncommon association with eosinophilic fasciitis has also been reported. With rare exceptions, such as chloramphenicol, antiepileptic drugs, and the emerging link to immunotherapies, it may be difficult to establish a causal relationship with drugs or toxins.
How is it diagnosed?
Diagnosis is based on exclusion of other disorders that may cause pancytopenia.
The followimh is made for diagnosis making:
- investigations on peripheral blood – sample collection
- bone marrow blood investigations
· bone marrow biopsy
The diagnosis of aplastic anemia is confirmed according to the "Camitta criteria":
- bone marrow biopsy cellularity <25%.
- 2 of 3 of the following criteria:
hemoglobin <10 g /dL,
reticulocytes <50 × 109 / l
platelets <50 × 109 / l
- neutrophilic leukocytes (ANC) <1.5 × 109 / l
How is it treated?
In the treatment of aplastic anemia, two levels should be distinguished: the supportive therapy (aimed not to cure the disease but to manage symptoms and avoid complications) and the treatment with curative purpose.
Treatments with curative purposes:
- Bone Marrow Transplantation. Stem cell transplantation is the treatment of replacing diseased bone marrow with healthy bone marrow from a donor to restore normal blood cell production. This is the option of choice for young patients who have family donor with identical HLA (molecules that determine donor-recipient compatibility) and can, therefore, quickly access the transplant option. Transplantation is limited by complications such as transplant rejection and graft versus host disease (GVHD), as well as the availability of suitable donors. Where there is no available HLA matched sibling, a search for a donor in the IBMDR registry is initiated. Young age is a favorable factor for unrelated HLA-matched transplantation. Further possibilities - to be considered in the absence of response to pharmacological therapy alone (see below) and the non-availability of family or registry donors with full compatibility - are the transplantation of cord blood units or transplantation from family donors with 50% compatibility.
- Immunosuppression. Since aplastic anemia is a pathology based on an immune-mediated mechanism, the use of immunosuppression strategies (drugs that suppress/inhibit/eliminate the patient's immune system inducing a reorganization of the same) has shown satisfactory results. For people who cannot undergo a bone marrow transplant and for those who have bone marrow aplasia caused by an autoimmune disease, the therapy involves the use of drugs suppressing the immune system, the so-called immunosuppressive drugs, such as cyclosporine and antithymocyte globulin. These drugs block the activity of immune cells that are destroying the bone marrow and cause it to resume generating new blood cells. Immunosuppressive therapy is less complicated than transplantation and is available to all patients. However, since it does not replace the affected marrow or immune system, late recurrences of the disease may occur. ATG+cyclosporine combination is now a recognized standard in the immunosuppressive therapy of aplastic anemia. Another growth factor - eltrombopag, a synthetic thrombopoietin mimetic - proved to be useful in refractory aplastic anemia.
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