Increased circulating procoagulant activity and thrombin generation in patients with myeloproliferative neoplasms

Microparticles (MPs) are membrane fragments ranging in size from 0.1 to 1 microm, and are considered as biomarkers reflecting prothrombotic state in many clinical diseases. The clinical course of myeloproliferative neoplasms (MPN) being frequently complicated by thrombotic events, we determined the MPs activity, i.e. circulating procoagulant activity (CPA), in polycythemia vera (PV) and essential thrombocythemia (ET) patients. To evaluate the influence of MPs on the coagulation, a thrombin generation test was realized in the absence and presence of thrombomodulin (TM). Compared with controls, patients had a higher CPA (24.0+/-9.0 vs 10.6+/-4.4 nM, p<0.001), which was associated with a lower inhibition of the thrombin generation in the presence of TM (20.1+/-9.5% vs 28.4+/-11.8%, p<0.001), compatible with a low sensitivity to TM. This sensitivity was influenced by the JAK2V617F mutational status, homozygous patients presenting the lowest inhibition rate of the thrombin generation. Filtration through a 0.22 microm membrane increased the sensitivity to TM in plasma, suggesting an influence of MPs in the "TM-resistance" observed in patients. Moreover, MPN patients receiving antiplatelet and/or cytoreductive therapies, our study suggests that CPA might be influenced by cytoreductive therapy. In conclusion, our data evidence in MPN patients the occurrence of an acquired "TM-resistance" partly determined by circulating microparticles. This TM-resistance might contribute to the hypercoagulable state observed in MPN patients, but the predictive value of the "TM-resistance" for thrombosis had not been evaluated.