Common Risk Factors Add to Inherited Thrombophilia to Predict Venous Thromboembolism Risk in Families.

Alexia Robin,David Trégouët,Dominique Brunet,Geoffroy Venton,Manal Ibrahim,Marie-Christine Alessi,Marie-Christine Barthet,Noemie Resseguier,Noemie Saut,Pierre Morange,Pierre Suchon

doi:10.1055/s-0039-1677807

Abstract

The clinical venous thromboembolism (VTE) pattern often shows wide heterogeneity within relatives of a VTE-affected family, although they carry the same thrombophilia defect. It is then mandatory to develop additional tools for assessing VTE risk in families with thrombophilia. This study aims to assess whether common environmental and genetic risk factors for VTE contribute to explain this heterogeneity. A total of 2,214 relatives from 651 families with known inherited thrombophilia were recruited at the referral center for thrombophilia in Marseilles, France, from 1986 to 2013. A thrombophilia screening was systematically performed in all included relatives. According to the severity of the thrombophilia defect, individuals were split into three groups: no familial defect, mild thrombophilia, and severe thrombophilia. In addition, common genetic factors (ABO blood group and 11 polymorphisms selected on the basis of their association with VTE in the general population) were genotyped. Furthermore, body mass index and smoking were collected. VTE incidence was 1.74, 3.64, and 6.40 per 1,000 person-years in individuals with no familial defect, mild thrombophilia, and severe thrombophilia, respectively. Five common risk factors were associated with VTE in this population: obesity, smoking, ABO blood group, and F11 _rs2036914 and FGG _rs2066865 polymorphisms. These common factors were then included into a three-level risk score. The score was highly efficient for assessing VTE risk in mild thrombophilia patients by identifying two groups with different VTE risk; individuals with low score had the same risk as individuals with no familial defect whereas individuals with high score had the same risk as individuals with severe thrombophilia. An overall score including the five items plus the thrombophilia status was built and displayed an area under the receiver operating characteristic curve of 0.702 for discriminating VTE and non-VTE relatives. In conclusion, integrating common environmental and genetic risk factors improved VTE risk assessment in relatives from families with thrombophilia.

Highlights

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third cause of cardiovascular death.[1]
In clinical practice, when an inherited disorder is suspected a thrombophilia testing consisting of the search for the five following defects is performed: antithrombin (AT), protein C (PC) and protein S (PS) deficiencies, factor V Leiden (FVL), and the G20210A prothrombin mutation (PTM).[5]
Five common genetic and environmental factors were associated with VTE in families with thrombophilia: F11_rs2036914, FGG_rs2066865, ABO blood group, obesity, and smoking status

Summary

Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third cause of cardiovascular death.[1]. In clinical practice, when an inherited disorder is suspected a thrombophilia testing consisting of the search for the five following defects is performed: antithrombin (AT), protein C (PC) and protein S (PS) deficiencies, factor V Leiden (FVL), and the G20210A prothrombin mutation (PTM).[5] When a defect is diagnosed in a patient with a personal history of VTE, testing of family members is often performed to aid decision-making regarding future VTE prophylaxis in at-risk situations. The prevention strategy is mostly based on the result of the thrombophilia testing probably leading to an overprevention in particular in mild thrombophilia carriers (i.e., heterozygosity for FVL or PTM). Relatives with a negative thrombophilia testing are often falsely considered at low risk

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