Aplastic Anemia

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Aplastic anemia is peripheral blood pancytopenia and a hypocellular marrow in which normal marrow is replaced by fat cells. Abnormal cells are not found in aplastic anemia.

It is a rare condition; with 2-5/million cases per year. Incidence is higher in East, male to female incidence is equal. It is the disease of young adults, 2nd peak occurs in 4th -5th decade of life.
Paul Ehrlich (1854-1915) described the first case of aplastic anaemia in a pregnant woman who died of marrow failure in 1888. The term “aplastic anaemia” was first used by Anatole Chauffard in 1904.

Diagnosis of Pancytopenia

Pancytopenia is suspected from signs and symptoms and diagnosis is made by checking full blood count.
Red cell life span is 120 days while platelet life span is 6 days. Granulocyte life span is less than 24 hours. Constant marrow activity is needed to replace dead cells.

Aetiology

Inherited (20%)

Fanconi Anaemia
Dyskeratosis congenita
Shwachman-Diamond syndrome
Diamond-Blackfan anaemia.

Acquired (80%)

Idiopathic
Drug induced
Viral (hepatitis, EBV)
Ionising radiation
Toxins (pesticides, benzene, arsenic)
Pregnancy
Leukaemic

Inherited marrow failure

Inherited marrow failure is an important diagnosis to make. Detailed history and examination plays fundamental role.

Nail dystrophy, skin pigmentation and leukoplakia may suggest dyskeratosis. Short stature, metaphyseal dysarthrosis, pancreatic exocrine deficiency or family history of cytopenia is present in Shwachman-Diamond syndrome.
Gene mutations analysis may prove helpful.

Pathogenesis

Disease may be a consequence of a primary defect or damage to haematopoietic stem cell. Possible immunological attack on stem cells may play a role. HLA-D2 is overrepresented in patients, suggesting a role for antigen recognition. Defective microenvironment is present (i.e. marrow stromal defect)

Clinical Features

Anaemia; tiredness & fatigue, palpitations, shortness of breath
Low white count; recurrent infections, flu-like illness.
Low platelets; easy bruising and bleeding.

Investigations

Full Blood Count
Reticulocyte count
Blood film
B12/folate levels
Liver function tests
Virology
Bone marrow aspirate & trephine
PNH screen.

Bone marrow aspirate in aplastic anaemia
Bone marrow aspirate is hypocellular. Abnormal cytogenetics is found in 12% patients. Trisomy 6, 8, or 15 are most common. Monosomy 7 may have poor outcome, suggesting possible hypoplastic myelodysplastic syndrome.

Paroxysmal nocturnal haemoglobinuria (PNH) screening
Historically, test was Ham’s test; which showed red cell lysis by complement activation in acidified serum. Currently test for absent proteins on cell surface, CD55 (DAF) and CD59 (MIRL), is used.

Clinical Course

Clinical course 1

Stable aplastic anemia
Pancytopenia remains stable over months to years.
Greater the degree of pancytopenia the worse the prognosis.

Clinical course 2

Progressive or fluctuating aplasia.
Initially small degrees of pancytopenia or single lineage cytopenia.
Progressive sometimes following viral infections.
Occasionally single cytopenia e.g. thrombocytopenia becomes true aplastic anaemia.

Clinical course 3

Unstable Aplasia.
Improvement in counts may be associated with abnormal clones.
PNH clone in up to 20% of long term aplastic anaemia.
Often only detected by lab tests and not clinically significant.

Severe Aplastic Anaemia

Granulocytes <0.5 x 10^9/l
Platelets <20 x 10^9/l
Reticulocytes <1%
Marrow trephine markedly hypocellular <25% normal

Treatment of Aplastic Anemia

Treatment is mostly supportive with blood products. Prophylactic antibiotics are also given along with growth factor support. Androgens may play a role. Immunosuppressive therapy with antilymphocyte globulin & cyclosporin is also used. Allogeneic stem cell transplantation is the ultimate solution.

Immunosuppressive therapy is indicated for patients greater than 40 years of age, patients with no HLA matched sibling donors. Anti-Thymocyte Globulin(ATG) or anti-lymphocyte globulin (ALG), cyclosporin, methylprednisolone are used. Best results are for combination therapy. Response is slow, requiring 4-12 weeks to see early improvement.

Response rates are 60-70%. Relapses are common and continued supportive care is needed. Up to 50% of relapsed patients will respond to 2nd course of immunosuppressive therapy.

HLA identical sibling bone marrow transplant
Age should be less than 40 years. Conditioning with cyclophosphamide & antithymocyte globulin, with cyclosporin and methotrexate is done. Long term overall survival is 80-90% in such patients. Chronic graft versus host disease (GVHD) remains a problem for 25-40% of patients.

New Approaches to Transplantation

Fludarabine based regimens
Umbilical cord blood transplants

Further Reading

Postgraduate Haematology, by Hoffbrand & Lewis Fifth Edition
Making Therapeutic decisions in adults with Aplastic Anaemia; Judith Marsh. ASH education program Book 2006.

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The writer enjoys medical education and has special interest in community medicine.