Part 2: Essential Thrombocythemia and Polycythemia Vera

This issue of Seminars in Thrombosis and Hemostasis extends the discussion on myeloproliferative disorders (MPDs) from the previous issue, focusing on diagnosis, staging, and management of these patients.

The first article by Michiels and coworkers primarily entails aspects of diagnosis of essential thrombocythemia (ET), polycythemia vera (PV), and other related disorders. New insights into the diagnostic and differential diagnostic features, especially the discovery of the Janus kinase 2 (JAK2) mutation, have improved these difficulties with diagnosis. Previous classifications by the Polycythemia Vera Study Group and the World Health Organization now need refinement, and the authors attempt to update these aspects. Still, problems remain, and new clinical trials promise further advancements in the pathophysiology of these disorders and their management.

Villeval and associates focus on the JAK2 mutation and its impact on diagnosis and management of MPDs. They especially examine the issue why and how this unique mutation can explain the diversity of the syndrome and the various clinical presentations. Although this discovery has aided accurate diagnosis greatly, it remains to be seen how it will impact management of these patients.

Thiele and coworkers describe the effect of anagrelide on megakaryopoiesis and platelet function by examining extensively bone marrows of patients with ET. Anagrelide affects megakaryopoiesis by blocking maturation at lower ploidy stages and by reducing stimulation of myelofibrosis. In contrast, hydroxyurea causes dysplastic changes of megakaryopoiesis, thus raising concern about its leukemogenic potential.

Kvasnicka and Thiele next demonstrate that bone marrow examinations enhance the diagnostic reliability for MPDs and also enable recognition of evolving myelofibrotic transformation. Generally, patients with ET have a normal life expectancy, except in the elderly. This is also the case for patients with PV and chronic idiopathic myelofibrosis.

Griesshammer reviews the risk factors for thromboembolic complications and bleedings in patients with ET. Elevated platelet counts, previous thromboembolic episodes, age, cardiovascular risk factors, hereditary thrombophilia, clonality, and JAK2 mutation increase risk of thrombosis. Based on these criteria, ET can be stratified in low-, intermediate-, and high-risk patients. Such stratification impacts management of the patients.

Bellucci and Michiels closely review the role of JAK2 mutation on bone marrow function. This mutation leads to a trilinear hematopoietic myeloproliferation and is thus related to ET, PV, and related diseases. The impact of this mutation on disease progression and developing complications is described extensively.

Petrides updates the present knowledge of the mechanism of action of anagrelide, a compound designed to reduce platelet counts in patients with ET. Much has been learned about the mechanism of action of this drug, its metabolism, and its therapeutic efficacy. One of the actions of anagrelide involves interference with signal transduction by the thrombopoietin receptor. Clinical trials have compared anagrelide with hydroxyurea, both alone and in combination with aspirin. Combinations appear to increase the bleeding tendency. This article provides an updated understanding of this important drug.

Quintás-Cardama and colleagues review the status of therapy of the Philadelphia chromosome-negative MPDs with pegylated interferon-α (PEG-IFN-α). Recombinant human IFN-α is another cytoreductive agent that has been used to treat these patients. However, side effects have led to high patient dropout rates, and this has been a major drawback for the drug. PEG-IFN-α has a different pharmacokinetic profile and is better tolerated by patients. The authors summarize the data so far available with this new compound.

Kiladjian and coworkers describe the long-term use of hydroxyurea and pipobroman in the treatment of patients with PV and ET. The data presented are based on three French studies that have observed patients for more than 10 years. The leukemogenic potential of hydroxyurea is still of some concern for its long-term use. The study shows that the leukemogenic effects of hydroxyurea and pipobroman are higher than anticipated, and the authors strongly advocate randomized clinical trials with nonleukemogenic compounds, such as IFN-α and anagrelide.

The management of pregnant patients with ET and PV is reviewed by Griesshammer and coworkers. About 300 case reports can be found in the literature; most describe high rates of stillbirth and major maternal complications. Low-dose aspirin appears to be useful in these patients, and low molecular weight heparins and IFN-α can also be considered. The authors recommend the use of a registry that has been established in Europe. They also offer an algorithm for managing MPD patients before, during, and after pregnancy.

Gisslinger updates diagnosis and management of patients with ET. These patients are at high risk for thromboembolic complications and also at risk for bleedings. An exact diagnosis is mandatory and the risk for morbidity has to be calculated for each individual patient. When cytoreductive drugs are used, the benefits should outweigh the potential side effects. Elderly patients may be treated with hydroxyurea; younger ones may be treated with anagrelide or IFN-α. Caution should be exercised when combining anagrelide with aspirin because this may lead to bleeding problems.

In the last article, Silver discusses the treatment of PV. In PV, erythropoiesis and megakaryopoiesis are greatly accelerated, leading primarily to thromboembolic complications in the micro- and macrovasculature. Phlebotomy is still the mainstay of treatment. Alkylating agents and radioactive phosphorus should be used with caution, but may be employed in older patients. In addition, hydroxyurea and IFN-α have been used. The optimal treatment is still not agreed upon and the discovery of the JAK2 mutation may lead to new and safer treatment modalities.

Thanks and appreciation is expressed to all authors for their excellent and thought-provoking contributions. Drs. Griesshammer and Michiels are commended for the assembly of this issue. The two issues of the journal should provide the readers with an up-to-date status of diagnosis and treatment options on myeloproliferative disorders.