Thrombophilia and Cardiovascular Risk Factors On the Absolute Risk of First and Recurrent Venous Thrombosis. Results From a Retrospective Family Cohort Study Involving 2097 Relatives.

Arterial and venous thromboembolism (VTE) share or seem to share cardiovascular risk factors such as older age, overweight and obesity, and possibly also hypertension, diabetes mellitus, dyslipidemia, and smoking. Little is known if subjects with common thrombophilia, (i.e. factor V Leiden, prothrombin G20210A or high factor VIII levels) are at higher risk of first or recurrent VTE due to cardiovascular risk factors. For subjects with rare thrombophilia (i.e. antithrombin, protein C or protein S deficiency), or non-carriers of thrombophilia no information is currently available whether contribution of cardiovascular risk factors increases the risk of first or recurrent VTE.

In a multi-center retrospective cohort study of families with thrombophilia, we performed a post-hoc analysis to identify if relatives with rare thrombophilia, common thrombophilia, and relatives without one of these thrombophilic defects were at increased risk of first or recurrent VTE due to cardiovascular risk factors. Known cardiovascular risk factors were recorded: hypertension, hyperlipidemia, the presence of diabetes mellitus, smoking habits and overweight/obesity defined by body mass index (BMI) ≥25-30 kg/m² or ≥30 kg/m², respectively. Observation time for first VTE started at the age of 15, and for recurrent VTE on the date when initial anticoagulant treatment was withdrawn. Observation time ended on the date of first VTE or recurrence, respectively, or at date of enrollment. First, the absolute risk of first VTE for cardiovascular risk factors was calculated for the whole cohort. Sensitivity analyses were performed to assess the effect of idiopathic or provoked classification of initial thrombotic event and type of event (deep vein thrombosis or pulmonary embolism). When a positive association was found, a further stratification was subsequently made to analyze whether relatives with rare, common, or no thrombophilia influenced these risks. A Cox-proportional hazards model was used to evaluate risks between groups for adjustments of age and sex.

Of a total of 2097 relatives, 55% were female, 180 (12%) had first VTE at a median age of 35 years and 52 (2%) had a recurrence at a median age of 40 years. Of relatives, 20% had hypertension, 13% dyslipidemia, 5% diabetes mellitus, 22% were previous smokers, 35% were overweight and 15% were obese. Point estimates of adjusted hazard ratios in relatives with hypertension, hyperlipidemia, diabetes mellitus or previous smokers, compared to their reference groups ranged between 0.9 and 1.1 and were not statistically significant. Relatives with VTE were heavier than relatives without VTE (mean BMI 27.0 vs 25.5 kg/m², P< 0.001); adjusted hazard ratio for each 1-point increase in BMI was 1.035 (95% CI, 1.010-1.066). Absolute risk of first VTE in normal weight, overweight or obese subjects was 0.16% (95% CI, 0.12-0.20), 0.20% (95% CI, 0.16-0.25), and 0.26% (95% CI, 0.19-0.36), respectively. Sensitivity analyses did not change these outcomes. Annual incidences of first VTE in non-carriers of thrombophilia, common thrombophilia carriers and rare thrombophilia carriers were 0.04%, 0.20% and 0.97%. In the non-carrier group, adjusted hazard ratios for first VTE in overweight or obese relatives were 6.1 (95% CI, 1.3-28.1) and 6.7 (95% CI, 1.2-37.6), compared to non-carriers of normal weight. In common thrombophilia carriers these risks were 1.7 (95% CI, 1.0-2.9) and 2.1 (95% CI, 1.2-3.8) fold increased. In rare thrombophilia carriers, overweight or obesity was not associated with an increased risk of first VTE (adjusted hazard ratios 0.8; 95% CI, 0.5-1.4 and 0.8; 95% CI, 0.4-1.7, respectively). For recurrence, overweight and obese relatives with common or rare thrombophilia seemed to have a slightly higher risk of recurrence than normal weight relatives, but the overall 10 year recurrence rate in both groups was similar.

Venous thrombotic risk increases with increasing BMI in non-carriers and common thrombophilia carriers. This effect is overruled in carriers of rare thrombophilia, where a deficiency itself irrespective of BMI apparently is sufficient to generate very high risk of thrombosis. Overweight and obesity seemed to increase the risk of recurrence in carriers of both common and rare thrombophilia. Other cardiovascular risk factors did not increase the risk of VTE in this thrombophilic family cohort.

No relevant conflicts of interest to declare.