VTE risk and family history: provocative findings

In this issue of Blood, Couturaud and colleagues take us one step closer to identifying a root cause for unprovoked venous thromboembolism (VTE) by comparing the VTE risk in first-degree relatives of patients who had experienced unprovoked venous thrombosis to the corresponding risk in first-degree relatives of patients whose thrombotic event was provoked by an environmental factor such as surgery.¹ 

VTE is a disease with many causes, and many environmental factors such as cancer, surgery, and estrogen use have been independently associated with an increased risk of venous thrombosis.²  Although the genetic contribution to VTE risk is illustrated by families deficient in endogenous anticoagulant proteins such as protein C, protein S, and antithrombin,^3,4  our incomplete understanding of this disease is highlighted by the fact that many patients with apparently unprovoked VTE have no identifiable thrombophilia (inherited or acquired).

It is not surprising that Couturaud et al¹  found that first-degree relatives of VTE patients are themselves at increased risk to experience venous thrombosis. However, the observations that unprovoked (vs provoked) VTE and younger age at the time of first VTE are both associated with a higher risk of venous thrombosis in a first-degree relative have some important implications. One hypothesis that emerges from the findings of Couturaud et al is that patients with unprovoked VTE and a first-degree relative who had unprovoked VTE at a young age may be at higher risk for recurrent VTE than are otherwise similar patients. If confirmed in a prospective study, this sort of association could have implications for the recommended duration of anticoagulant therapy. Second, as the authors point out, the knowledge gained from this study may lead clinicians to recommend that patients with a first-degree relative who has experienced VTE avoid estrogen-containing contraceptive strategies and use aggressive VTE prophylaxis after surgery or hospitalization. Whether these common-sense suggestions should differ according to whether the first-degree relative’s clot was provoked or occurred at an older age is not clear, but the finding that a family history of VTE, even if provoked, increases risk is important.

Since the only familial thrombophilia testing routinely performed in the Couturaud study was for factor V Leiden and prothrombin 20210A gene variants, some of the increased risk observed among these first-degree relatives of VTE patients is likely attributable to known, inherited thrombophilias such as deficiency of protein C, protein S, or antithrombin. However, because these congenital deficiencies are quite rare, even within VTE patient cohorts, the associations described in the study by Couturaud et al strongly suggest that additional as yet unidentified genetic or epigenetic factors contribute to the development of VTE. Like many pathologic conditions, venous thrombosis is almost always the result of more than one contributing factor. The study by Couturaud and colleagues suggests that the search for additional inherited thrombophilic variations in the human genome should continue.