A Simple Genetic Thrombosis Score Of Five Single Nucleotide Polymorphisms Is Associated With Risk Of First Venous Thrombosis In Pregnant Women

Venous thrombosis (VT), a major cause of maternal morbidity and mortality, is increased 4- to 5- fold during pregnancy. A thrombosis score comprising 5 single nucleotide polymorphisms (SNPs) [rs6025 (Factor V Leiden), rs1799963 (Prothrombin 20210 G>A), rs8176719 (ABO 261G>deletion), rs2066865 (FGG 10034 C>T) and rs2036914 (F11 10364T>C)] was previously shown to be associated with VT events in the general population. We asked whether this thrombosis score could predict VT in pregnant and postpartum women in a case-control study on the etiology of thrombosis.

We studied women during pregnancy and up to three months postpartum (55 controls, 144 cases) selected from over 5000 female cases and controls of the MEGA (the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis) study. The thrombosis score was calculated for each individual as a sum of risk alleles weighted by the log of the published odds ratio (de Haan et al, Blood 2012). The VT risk per unit of thrombosis score was calculated as a continuous variable in a logistic regression model that adjusted for age, smoking history and family history of VT. The thrombosis scores ranged from 0 to 1.8 in female participants in MEGA with genotypes for the 5 SNPs (n=3,464).

In pregnant and postpartum women, the odds ratio per unit increase in thrombosis score was 10.7 (95%CI 3.2 to 36.2). When the thrombosis score was evaluated in a sub study of pregnant and postpartum women who do not carry factor V Leiden—an important contributant to the risk score— the remaining 4-SNP thrombosis score was also associated with VT: the odds ratio per unit increase in thrombosis score was 10.6 (95%CI 2.3-48.3).The American College of Obstetricians and Gynecologists recommends thromboprophylaxis during pregnancy and postpartum periods in women who are compound carriers of both factor V Leiden and prothrombin 20210 G>A; these compound carriers who do not carry other risk variants would have a thrombosis score of 1.02. Compared with women in the bottom quintile of thrombosis scores, women with thrombosis scores equal to or greater than 1.02 had an odds ratio for VT of 12.3 (95%CI 1.5 to 99.9). About 2% of female controls in MEGA had thrombosis scores equal to or greater than 1.02.

A 5-SNP thrombosis score that combines the VT risk of 5 genetic variants is associated with VT in pregnant women.

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