Thrombosis and hemorrhage are frequent complications in patients with essential thrombocythemia and have a major impact upon disease prognosis and quality of life. The mechanisms underlying these complications are not well understood. Congenital and acquired thrombophilias have been proposed as contributing factors. These studies have been limited by the number of candidate genes available, and by the lack of replication in subsequent independent studies.

We have performed association studies with candidate genes in 75 Caucasian individuals diagnosed with ET, of which 39 suffered at least one thrombotic event either in large blood vessels (N=17) or in the microcirculation (N=20), or in both (N=2), and 21 developed excessive bleeding complications. Cases ranged in age from 11 to 81 and those who had experienced a thrombotic event had a mean age approximately 8 years older than those who had not (p < 0.10). We also studied 200 Caucasian controls from the same geographic area.

The list of candidate variants studied included a total of 17 genetic polymorphisms in genes that encode for the platelet receptors ITGA2, GP1BA, ITGB3 and GP6, for the coagulation factors F2, F5, F7, and F13 and for critical proteins involved in normal hemostasis and fibrinolysis such as MTHFR, THBD, FGA, PLAT and PECAM1. These gene variants were selected based on their biological significance as well as their minor allele frequency.

The differences in genotype distributions and allele frequencies between the case and control groups and between cases affected by thrombosis or hemorrhage and unaffected cases were assessed using chi-square analysis. Logistic regression analysis models were used to estimate genotype-specific odds ratios (OR) and construct 95% confidence intervals (CI) for each studied variant, adjusted for factors such as age, platelet count and sex that might confound the genotype-disease status association. The frequency of the rarer C allele at the F7 promoter polymorphism - 32T>C (rs561241) was significantly higher in ET cases (24.3%) vs. controls (11.7%) p < 0.005, and the frequency of the rarer A allele at the ITGA2 at position 1648G>A was significantly higher in ET cases (45.0%) vs. controls (38.3%) p < 0.05, after adjustment for 17 hypothesis tests. No variants significantly discriminated between cases with and without thrombosis or hemorrhage. However, for the F7-32 polymorphism, the odds of being a C-allele carrier were suggestively lower for cases who had experienced a thrombotic event relative to cases who had not, after adjustment for age, platelet count and sex effects (OR = 0.33, 95% CI: 0.12, 0.90; p < 0.05 unadjusted).

Although it is not clear why the F7-32C allele is more frequent in patients with ET, it appears to exhibit a protective effect against thrombosis within this cohort. Further studies in the factor F7 gene are underway to elucidate the significance of this association.

Disclosure: No relevant conflicts of interest to declare.

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