Differential diagnosis of aplastic anaemia includes disorders causing pancytopaenia (anaemia + leucopaenia + thrombocytopaenia). Disorders associated with pancytopaenia are listed in Table 3.9.
Clinically, patients with haematological malignancies usually have enlargement of lymph nodes, spleen or liver and in patients with metastatic carcinoma, primary tumour may be evident. Bone marrow examination shows the presence of abnormal cells.
Table 3.8: Grading of aplastic anaemia Severe aplastic anaemia (SAA)
(Camitta et al, 1976) Very severe aplastic anaemia
(VSAA) (Bacigalupo et al, 1988) Non-severe aplastic anaemia Peripheral blood
Hypersplenism is characterized by enlargement of spleen, peripheral blood cytopaenia, and normal or hypercellular bone marrow. Underlying cause of splenomegaly may be evident.
Pancytopaenia is a common feature of megaloblastic anaemia. Diagnosis however is readily evident from macrocytosis and hypersegmented neutrophils in peripheral blood and megaloblastic erythropoiesis in bone marrow.
Differentiation of hypoplastic anaemia from hypocellular MDS can be difficult.
Dysgranulocytic and dysmegakaryocytic features in peripheral blood and bone marrow, and abnormal cytogenetic analysis favour the latter condition. (Dyserythropoietic features are seen in MDS as well as aplastic anaemia). The distinction between hypocellular MDS and hypocellular AML rests on the percentage of blasts in bone marrow.
Diagnosis of PNH is based on demonstration of abnormal sensitivity of red cells to complement (Ham’s test) or flow cytometric analysis for CD55 or CD59 antigens.
For systemic lupus erythematosus, tests for anti-nuclear antibody and for anti-DNA antibody are done.
Gelatinous transformation of bone marrow (syn: serous degeneration, serous atrophy) is characterized by replacement of haematopoietic cells and fat cells in bone marrow by amorphous extracellular matrix. Its causes are (1) cachexia due to chronic debilitating illnesses like AIDS, cancer, tuberculosis, etc; (2) anorexia nervosa, and (3) acute infections with multiorgan failure. There is a variable cytopaenia in peripheral blood. Bone marrow examination shows deposition of pink, granular, amorphous matrix material replacing fat and haematopoietic tissue (Fig. 3.14). Matrix material is composed of acid mucopolysaccharides and stains positively with PAS and alcian blue (acid pH).
Haemophagocytosis syndrome (syn: haemophagocytic lymphohistiocytosis) is a potentially fatal disorder characterized by pancytopaenia, phagocytosis
2. Inherited bone marrow failure syndromes (Fanconi anaemia,
of haematopoietic cells and their progeny (Fig. 3.14), hepatosplenomegaly, and lymphadenopathy. Jaundice, hypofibrinogenaemia, and hypertriglyceridaemia are usual. The main histopathologic feature is lymphohistiocytic proliferation in spleen, liver, lymph nodes, and bone marrow. There is no specific laboratory test for diagnosis.
The syndrome may be acquired (secondary to cancer, infections, autoimmune disorders) or familial (autosomal recessive).
Treatment
There are two methods of treatment in severe aplastic anaemia—(1) allogeneic haematopoietic stem cell transplantation that attempts to achieve cure, and (2) immunosuppressive therapy to bring about remission. In patients with less severe aplastic anaemia, the major form of therapy is supportive in the hope of achieving spontaneous recovery.
Haematopoietic Stem Cell Transplantation (HSCT)
This is the ideal treatment in young patients (< 40 years) with severe and very severe aplastic anaemia if HLA-matched sibling donor is available. Patients more than 40 years of age are more likely to develop serious complications such as graft-versus-host disease and tolerate them poorly. Prospective candidates for haematopoietic stem cell transplantation should not be transfused with blood or blood products as far as possible (especially from family members if donor is a sibling) to avoid the risk of alloimmunisation and graft rejection.
Immunosuppressive Therapy
It is thought that a large number of cases of aplastic anaemia are caused by immunological mechanisms. Activated suppressor T cells have been shown to inhibit haematopoiesis.
Figure 3.14: (A) Gelatinous transformation of bone marrow showing replacement of marrow by pink amorphous material (B) Haemophagocytosis syndrome showing a macrophage with ingested neutrophil, nucleated red cells and mature red cell
A B
given to patients with severe aplastic anaemia who do not have HLA-matched sibling donor for HSCT and to all other patients of aplastic anaemia. About 30% of patients achieve complete remission while haematopoietic recovery is only partial in majority of patients. Late relapse occurs in some patients. Clonal haematopoietic disorders like paroxysmal nocturnal haemoglobinuria, myelodysplasia, or acute myeloid leukaemia can emerge after a few years.
Major side effect of HSCT is graft-vs-host disease, while main side effect of immunosuppressive therapy is development of PNH, AML, or myelodysplasia after a few years.
Androgens
Androgens stimulate erythropoiesis in bone marrow. They may be of some benefit in those patients who fail to show desired response to immunosuppressive therapy and who are not suitable for HSCT.
Supportive Measures
Packed red cells should be given when anaemia becomes symptomatic. Platelet transfusions are indicated in the presence of bleeding due to thrombocytopaenia and prophylactically when platelet count falls below 20,000/cmm. Usefulness of granulocyte transfusions is minimal and the chief form of treatment in neutropaenia with infection is antibiotics. Infections should be investigated particularly for opportunistic organisms and vigorously treated.
Prognosis
In the past majority of patients with severe aplastic anaemia used to die within 1 year of diagnosis. Now many patients undergoing marrow transplant can hope to achieve cure; however a proportion of these patients will develop serious complications such as graft-versus-host disease, infections, or graft rejection. Patients receiving immunosuppressive therapy can achieve complete or partial remission; long-term sequelae in these patients are recurrence or evolution of a clonal haematopoietic disorder such as PNH, MDS, or AML.
With supportive therapy, some patients with moderately severe aplastic anaemia can achieve spontaneous remission.
Approach to management of aplastic anaemia is shown in Figure 3.15.