Myeloproliferative Disorders

Polycythemia vera is one of a group of conditions referred to as the myeloproliferative disorders. These include essential thrombocytosis (ET) and agnogenic myeloid metaplasia with myelofibrosis (AMM/MF), also known as idiopathic myelo-fibrosis. All these disorders are characterized by the overproduction of one or more cell types. In PV the clinical picture is dominated by the increased production of RBCs. In ET the clinical picture is dominated by increased numbers of platelets, which may reach values as high as 2 x 106^L. With AMM/MF the clinical picture is dominated by various cytopenias associated with marrow fibrosis and splenomegaly. Splenomegaly, in this case, likely represents extramedullary hematopoiesis.

Many features of these diseases overlap. In PV, the spent phase may resemble myelofibrosis. Some patients with ET will eventually manifest an increased RBC mass. The occasional overlapping and thus confusing nature of these disorders has been partially explained by the recent demonstration of a very high frequency of a point mutation in a signaling molecule on the EPO signaling pathway (Kralovics et al., 2005). In several reports, almost two thirds to three quarters of patients with PV had this mutation in JAK2, with lower frequencies seen in patients with ET and AMM/MF. The mutation results in a constitutively activated pathway and the overproduction of bone marrow cellular elements.

It can be anticipated that this will become a useful molecular test in the differential diagnosis of these disorders and will almost certainly become a target for drug development.

In ET the peripheral smear reveals increased numbers of platelets of various sizes. Platelet counts may be high, in excess of 1 or 2 x 106^L. There may be an associated leukocytosis, and Hb level is typically normal. The decision to treat such patients is not always easy. Generally, patients with platelet count approaching 1 x 106^L are treated, even with no associated symptoms or signs. Asymptomatic young women with ET require special consideration; watchful waiting is probably sufficient, although hydroxyurea plus aspirin is the most effective approach for patients who require treatment.

Patients with AMM/MF tend to run an indolent course. Usually, over time, the spleen continues to enlarge, and peripheral RBC destruction increases. There also may be varying degrees of thrombocytopenia caused by impaired bone marrow production and increased splenic sequestration. In all the myeloproliferative disorders, platelet function may be abnormal. Treatment of AMM/MF is largely symptomatic. The anemia can be treated with transfusions, or epoetin therapy can be attempted, although no good clinical trials support these approaches. In advanced cases of myeloid metaplasia, the spleen may grow to such a size that it may require removal to stabilize peripheral blood counts. Proper management of all the myeloproliferative disorders is associated with extended survival.

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