Essential Thrombocythemia and Polycythemia Vera

 

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This issue of Seminars in Thrombosis and Hemostasis reviews myeloproliferative diseases with thrombocythemia, most notably polycythemia vera (PV) and essential thrombocythemia (ET). The diagnosis and differential diagnosis of these conditions is difficult, and several consensus groups have attempted to provide guidelines to overcome some of these problems. Equally problematic is the treatment of these patients. The most common complications of these disorders are thromboembolic events, not only microvascular but also macrovascular. Some patients experience bleedings, whereas others have both bleedings and thromboses. Antithrombotic medications reduce the risk of thromboembolism, but do not address the underlying condition that leads to the thrombocythemia. Unfortunately, some of the drugs presently used are associated with an increased risk for malignancies, especially leukemias, so that patient selection is extremely important. Many of these problems and difficulties are addressed in the following contributions.

In the first article, Johansson describes the epidemiology of PV and ET. The prevalence of PV is ~30 to 35 cases/100,000 of the general population, with no difference in gender; however, the risk increases with age. European-born Jews appear to have a higher incidence. At present, mortality seems to be similar to that of the healthy population. The prevalence of ET also approximates 30/100,000, with a 2-fold higher incidence in females. The life expectancy is not different from that of the general healthy population.

Michiels and collaborators review the clinical presentation, laboratory features, and pathobiology of platelet-mediated microvascular disorders (especially PV and ET). The most commonly encountered clinical features entail serious arterial microvascular disturbances with potentially devastating sequelae. Some patients present with a hemorrhagic diathesis, whereas others may have both bleedings and thromboses. There are many features that PV and ET have in common, and this makes the differential diagnosis difficult at times. The authors elaborate the differences, however, and make valuable recommendations that should help clarify many of the problems. The authors also review the management options for these patients. This comprehensive review highlights the features of these diseases and should help the clinician make the correct treatment choices.

Briére discusses the diagnosis and management options for patients who present with the Budd-Chiari syndrome in conjunction with thrombocythemias of various origins. Myeloproliferative disorders can be the cause of the syndrome in many patients, although several have prothrombotic conditions. In view of the heterogeneity of the myeloproliferative disorders, at present it is difficult to derive a standardized treatment option for patients with the Budd-Chiari syndrome.

Thiele and Kvasnicka emphasize the importance of making bone marrow examinations an integral part of the diagnostic workup of these disorders. Bone marrow findings, as illustrated by excellent examples, greatly improve the accurate diagnosis and differential diagnosis of the many myeloproliferative disorders. It is especially important that the bone marrow findings allow for a clear differentiation between true and false ET.

Schwarz and colleagues report on the establishment of guidelines, approved by the Czech Hematological Society, for the diagnosis and treatment of myeloproliferative disorders with thrombocythemia. Guidelines have been proposed previously by the World Health Organization, the Rotterdam Thrombocythemia Group, and the European Clinical and Pathological Study Group. Although the guidelines are similar in principle, there are differences between the recommendations; some do not entail bone marrow examination, which appears to be crucial for the establishment of the correct diagnosis. The authors elaborate on the differences, examine them thoroughly, point out the strengths and weaknesses of the guidelines, and then present the guidelines that were developed by Czech clinicians and scientists.

Mossuz, on behalf of a multicenter study group for myeloproliferative disorders in France, addresses the diagnostic criteria for ET and PV from a laboratory perspective, incorporating assays of erythropoietin into the diagnostic workup. Erythropoietin levels are low in sera of most patients with PV, but are mostly normal in patients suffering from ET. The assays are readily available, appear to be reliable and accurate, and are reasonably priced. Low levels of erythropoietin in ET patients seem to predict thromboembolic complications. The authors explain why the determination of erythropoietin levels greatly aids in the diagnosis and differential diagnosis of these two disease entities.

In the next article, Landolfi and coworkers review the role of aspirin in the treatment of patients with thrombocythemia. Because arterial vascular occlusions present the most serious complications of these diseases, and given that these occlusions are caused by platelet activation in vivo, it is reasonable to use antiaggregating agents, especially aspirin, for their treatment. The authors review the studies that have been conducted with aspirin to date, list indications and contraindications by risk stratification, and delineate which patients should and should not receive aspirin.

Birgegard reviews the treatment of myeloproliferative disorders with anagrelide. This compound is especially effective in patients with ET, but there are several side effects that need to be recognized. These complications are the main reason for the high dropout rate of patients in some of the studies. The use of anagrelide is still a matter of debate, but some physicians prefer anagrelide to several other agents that are used in the treatment of these disorders because of their potentially increased leukemic risks. The author reviews the pertinent literature and clearly delineates the advantages and disadvantages of anagrelide.

Lengfelder and colleagues discuss the diagnosis and management of patients with PV. Recent discoveries have made the diagnosis somewhat easier, but there are still obstacles that prevent a diagnosis from being made beyond any doubt; these obstacles are described by the authors. The main choice of treatment for PV is still phlebotomy, but other options have become available. The authors summarize all potential treatment modalities and provide the reader with a good understanding of the present status of the management of patients with PV.

Finazzi explores the risk stratification, staging, and treatment of PV, focusing on the experience gained by a group of Italian investigators. Given that thromboembolic complications are the most prominent risks for PV patients, treatment with aspirin was shown to reduce the risk markedly. However, aspirin does not address the underlying cause of the thrombocythemia that characterizes PV. Many of the drugs that are presently used to treat the cause have serious side effects; some are associated with a transformation to cancers, especially leukemias. The author makes recommendations on how to select the proper patient for the safest management options.

Harrison describes the management of patients with ET. These patients have a priori a better prognosis than those with PV, but thromboembolic events also present the greatest risks. Antiplatelet agents, especially aspirin in low doses, reduce the risk markedly, but again do not address the underlying problem of thrombocythemia. Hydroxyurea or anagrelide are being used to eliminate the cause. The author reviews the options, indications, and contraindications of these agents, based on results from the largest trial so far conducted on these patients, the Medical Research Council Primary Thrombocythemia 1 study from the United Kingdom.

Gordeuk and Prchal report on Chuvash polycythemia. This disease is due to a mutation in the Hippel-Lindau gene. The disease was first described in a specific region of Russia. This gene mutation leads to an enhanced transcription of erythropoietin and thus to a polycythemia that is the prominent presenting clinical manifestation. Patients have both a bleeding and a thrombosing tendency and, in general, have a shortened life expectancy. Although similar mutations in the gene are associated with an increased risk of malignancies, these are uncommon in patients with Chuvash polycythemia. This article provides an interesting review of a relatively rare and newly discovered form of polycythemia.

In the last article, Akkerman describes the role of thrombopoietin (TPO) in platelet function. In megakaryocytes and hematopoietic stem cells, TPO receptors (through a complex set of mechanisms) regulate proliferation, maturation, and antiapoptosis. These receptors and mechanisms for signal transduction are also found in platelets, but here they control aggregation and secretion. TPO increases the sensitivity of platelets to stimulation by agonists so that lower stimulator concentrations are required to achieve the actions. The author describes these mechanisms in detail.

Thanks and appreciation is expressed to all authors who so expertly contributed to this informative issue. Gratitude is also due to the guest editors, especially Professor Michiels, for the great effort made to assemble this issue.