Thrombosis is the most frequent complication in essential thrombocythemia (ET) that impairs quality of life and contributes to mortality and morbidity of patients. The molecular basis of thrombosis in ET remains unclear. Polymorphisms (SNPs) in coagulation factors (FII-G20210A, FV-Leiden) and the V617F mutation of JAK2 gene (JAK2-V617F) have previously been shown to associate with thrombosis in ET. Since thrombosis occurs frequently in JAK2-V617F negative ET and FII-G20210A and FV-Leiden polymorphisms occur only in up to 5% of patients, we examined the hypothesis that other genetic factors contribute to the thrombotic risk in ET. In addition to FII-G20210A and FV-Leiden we studied thirteen candidate SNPs of genes involved in coagulation (F7, F13A1, VWF, THSD1, ATIII), platelet aggregation (P2Y12, GPIIIA, GPIIB, FCGR2A) and endothelial function (NOS3, ADRA2B) previously implicated in thrombosis in non-MPD patients. We studied 94 patients with the diagnosis of ET retrospectively observed for clinical variables such as venous and arterial thrombosis, stroke, myocardial infarction, deep vein thrombosis (DVT), bleeding, angina pectoris, superficial venous thrombosis (SVT), and pulmonary embolism. SNP genotyping was performed using allele-specific PCR and sequencing. We examined the association of individual SNPs with the presence or absence of clinical variables (adjusted for age, sex, and BMI). In our ET cohort, JAK2-V617F showed significant correlation with the presence of DVT (OR 10.08; 95%CI 1.15–88.49; P=0.01). Both FII-G20210A and FV-Leiden were rare in this cohort (2% and 4%, respectively) and thus did not show any significant associations. Homozygosity for the 298Asp variant of NOS3 gene (encoding the endothelial nitric oxide synthase) showed significant correlation with stroke (OR 46.75, 95%CI 1.38–147, P=0.014). Similarly, homozygosity for the 131Arg variant of Fc receptor gamma 2A (FCGR2A) involved in platelet GPVI signaling correlated with the presence of SVT (OR 9.46, 95%CI 1.48–60.82, P=0.014). Our results indicate that genetic factors other than JAK2-V617F, FII-G20210A and FV-Leiden contribute to thrombotic risk in ET. Furthermore, the nitric oxide and the platelet GPVI signaling pathways are likely to play an important role in the pathogenesis of thrombosis in ET.

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