Platelets and Thrombosis in Myeloproliferative Diseases

Abstract

The myeloproliferative disorders have been the "poor cousins" in the family of hematological malignancies for some time. Recently this field has advanced considerably with the description of a mutation in the JAK2 kinase detectable in the majority of patients and the publication of two landmark clinical trials-ECLAP and MRC PT1. But although both ECLAP and MRC PT1 inform clinical management and allude to the complexities of thrombosis we still lack fundamental knowledge, and our understanding of thrombosis in these conditions has not paralleled advances in the field of thrombosis and vascular biology. The predominant clinical complications of essential thrombocythemia and polycythemia vera are thrombotic and hemorrhagic; these significantly impact upon prognosis and quality of life. Here the current status of our knowledge is reviewed with specific emphasis upon the role of the platelet in the pathogenesis of thrombosis as well as the impact of recent data from ECLAP and MRC PT1.

Thrombocytosis and Thrombosis

“…Unfortunately, notwithstanding a number of platelet functional abnormalities or defects of membrane and granuli proteins have been described in CMPD, no consistent correlation with cardiovascular events in either PV or ET has been demonstrated. 5,31 However, increased formation of neutrophil-platelet aggregates, associated with enhanced expression of activation markers CD11b and CD62P, has been reported in patients with ET and PV, 37 and possibly correlated with patient history of microvascular or major thrombotic events; interestingly, in vitro formation of leukocyte-platelet aggregates was reduced in patients who had been treated with aspirin and/or HU. 37 A specific issue is represented by the occurrence of thrombocytosis following splenectomy in PMF.…”

“…Also, the role of inherited or acquired thrombophilia conditions is unclear; the Italian guidelines for ET management recommended routine screening in ET patients with either personal or familial history of thrombosis, 40 while indications from the British guidelines were the opposite. 31 On the other hand, recent data indicate that a novel, powerful risk factor for thrombosis in both PV 41 and ET 42 is represented by leukocytosis. Particularly in ET, presence of leukocytosis allowed to identify a subgroup of "low-risk" patients who actually had a hazard ratio for thrombosis 3.1-fold greater than conventional "low-risk" category and similar to "high-risk" patients.…”

“…As for thrombocytosis per se, no obvious correlation with risk of major cardiovascular events has been demonstrated in a number of studies, although clinical improvement of microcirculatory disturbances and/ or improved platelet function after control of thrombocytosis have been reported. 30,31 In the PVSG study, platelet count closest to thrombotic event did not predict for its occurrence. Also, in the ECLAP prospective study, which enrolled 1638 PV patients with a median follow-up of 2.8 years and registered 226 thrombotic events, platelet count was not associated with thrombosis; major thrombosis occurred in 8.3% and 9.3% of patients whose baseline platelet count was greater, or lower, than 400 × 10 9 /L, respectively.…”

“…1 Reduction of platelet count proved effective in normalizing the von Willebrand multimer profile in plasma and in reducing bleeding tendency. 1,30,31 Risk Factors for Thrombosis Due to the considerations above, it is not surprising that thrombocytosis is not considered among the criteria for thrombosis risk assessment in CMPD ( Table 2). Indeed, established risk factors for thrombosis in both ET and PV are older age (>60 years) and previous thrombosis history, and the presence of either of these define a "high-risk" category of candidates for myelosuppressive therapy.…”

“…Reported figures ranged from 12% to 39% in PV and from 11% to 25% in ET; the retrospective, uncontrolled nature of the studies, together with the relatively small number of patients included and variable follow-up, may explain the wide range of values described. 30,31 In childhood ET, thrombosis probably occurs at a rate similar to adults, affecting one-third of children at diagnosis and one-fifth during follow-up. 8 Epidemiologic inference from two prospective studies, the ECLAP and the MCR-PT1, indicated that the cumulative rate of cardiovascular events ranged from 2.5% to 5.0% and from 1.9% to 3% per patient-year in PV and ET, respectively, depending on the low-or high-risk patient category.…”