Click here to view next page of this article

Essential Thrombocythemia

Classification of the chronic myeloid disorders (CMD) is based on certain molecular, cytogenetic, morphologic, and clinical characteristics. In the context of a CMD, the demonstration of the bcr/abl genetic translocation between chromosomes 9 and 22 mandates a diagnosis of chronic myelocytic leukemia (CML). In the absence of a clonal increase in red cell mass (RCM) defines PV. Accurate diagnosis is not always easy in the remaining subgroups.

Clonal studies based on X chromosome-associated genes or their products have consistently shown a stem cell origin for the clonal process in both MDS and CMPD. It is generally believed that the primary clonogenic event governs disease expression. Alternatively, clonal generation at either hierarchically different stem cell levels may underlie the phenotypic diversity.

In general, serum thrombopoietin (TPO) levels are inversely correlated with platelet and megakaryocyte mass. In patients with ET, however, serum TPO levels are usually elevated or normal despite an increased megakaryocyte mass. The discrepancy has been attributed to ineffective TPO clearance because of markedly reduced TPO-receptor (c-Mpl) expression.

During evaluation of thrombocytosis, both reactive and a variety of clonal causes need to be entertained (table 1). A persistent and otherwise unexplained elevation in platelet count, in a non-splenectomized patient with normal serum ferritin and C-reactive protein levels, suggests clonal thrombocytosis. A bone marrow examination with cytogenetic studies.

Clinical aspects

Population-based epidemiologic studies suggest that ET may be the most frequent among the CMPD with an estimated incidence of 2.5/100,000. Median age at diagnosis is approximately 60 years and there is a slight preponderance of females. Approximately 25% of patients with ET are asymptomatic at presentation. The rest may present with vasomotor symptoms (headaches, transient neurologic or ocular symptoms, distal paraesthesias, and erythromelalgia), thrombosis, or bleeding. Thrombotic events include strokes, transient ischemic attacks, retinal artery or venous occlusions, coronary artery ischemia, pulmonary embolism, hepatic or portal vein thrombosis, deep vein thrombosis, and digital ischemia.

Leukemic conversions occur in less than 5 percent of all patients with ET. Treatment with certain agents may increase the risk of acute leukemia. In contrast, specific therapy may or may not modify the risk of fibrotic transformation that occurs in less than 5 percent of patients with ET. Spontaneous early-term abortions occur in up to 45 percent of the pregnancies.

Prognostic factors

Age and a history of previous thrombosis are the most powerful predictors of recurrent thrombosis in ET. The ratio of thrombotic events to the total number of person-years of observation was 1.7 for patients younger than age 40 years, 15.1 for those older than 60 years, and 31.4 for those with a previous history of thrombosis. Neither the degree of thrombocytosis nor the presence of platelet function abnormalities has been correlated with thrombotic risk.

Treatment

The most frequent symptoms in ET are vasomotor and are easily managed with low-dose ASA (75-100 mg/day). Bleeding complications are less frequent and may be prevented by the avoidance of NSAIDs. On the other hand, approximately 20 percent of the patients present with major thrombotic events and another 15 percent may experience recurrent thrombosis.

In a randomized study, the use of HU, compared to no treatment, has been shown to reduce the risk of thrombosis, in high-risk patients (table 2), from 24 percent to less than 4 percent. Therefore, current evidence supports the use of HU in high-risk patients with ET.

Thrombotic events in low-risk patients with ET are too infrequent to justify the long-term use of potentially harmful agents. The risk may be higher, however, in the presence of cardiovascular risk factors and/or extreme uncontrolled thrombocytosis.

To date, there is no randomized study that directly implicates HU as being more leukemogenic than any other therapeutic strategy, either in ET. On the other hand, there are several non-randomized studies that have either supported or refuted a significant increase in leukemic conversion associated with the long-term use of HU.

Alternative platelet-lowering agents in essential thrombocythemia

Anagrelide is an oral imidazole quinazoline derivative that has a species-specific platelet lowering effect in humans (table 3). The platelet inhibitory activity of anagrelide is seen only at higher than therapeutic doses used for controlling thrombocytosis and should not be a concern during the treatment of patients with ET.