Genetic Aspects of Venous Thromboembolism

Venous thromboembolism (VTE) refers to blood clots that develop in the deep veins of the arms or legs, referred to as deep vein thrombosis (DVT). Clots that break loose and travel to the lungs are referred to as pulmonary embolism (PE). VTE may be either "provoked," such as following a surgical procedure, a long flight or with prolonged immobilization; or "spontaneous," occurring without any obvious "trigger" associated with an increased risk for VTE. Many patients with "spontaneous" VTE have an inherited risk factor that increases their likelihood for developing a blood clot, also known as inherited thrombophilia (a group of inherited or acquired disorders that increase a person's risk of developing a blood clot in the veins or arteries).

The most common inherited or genetic risk factor for VTE is factor V Leiden. Factor V is a blood-clotting protein that is essential for normal hemostasis (blood clotting in response to an injury); patients who are missing factor V have an increased risk for bleeding. Factor V Leiden, which was first described at University Hospital in Leiden, The Netherlands, in 1994, is a "mutant" factor V that is resistant to being broken down by normal mechanisms. Factor V Leiden is associated with approximately a three-to 10-fold increased risk for VTE in persons who have inherited one copy of the mutation ("heterozygous"), and approximately an 80- fold risk in persons who have inherited two copies of the mutation ("homozygous"). As many as one in 20 Caucasian Americans are heterozygous for factor V Leiden; factor V Leiden is less common in African Americans.

Another common inherited risk factor for VTE is the prothrombin mutation ("G20210A"). Prothrombin, also called factor II, is another blood-clotting protein that is essential for normal hemostasis, and prothrombin gene G20210A is a specific mutation associated with an increased risk for VTE. Patients with this mutant prothrombin have a similar risk for VTE as patients with factor V Leiden. The prothrombin G20210A mutation is present in approximately one in 100 Caucasian Americans, and is less common in African Americans, similar to factor V Leiden.

Another group of inherited thrombophilias affects one of three proteins (antithrombin, protein C and protein S) involved in the regulation of blood clotting. A deficiency of any one of these proteins results in an increased risk for VTE. Although these disorders are less common than factor V Leiden or prothrombin gene G20210A, they generally result in a slightly greater risk for VTE (ranging from five-to 20-fold, depending on the specific disorder).

Although people with one (or more) inherited thrombophilias are at an increased risk for VTE compared to persons who do not have these inherited risk factors, it is important to recognize that, while these individuals have an increased relative risk for VTE, the absolute risk for VTE remains low. In other words, if the annual incidence for VTE is one in 1,000 individuals, a person who is heterozygous for factor V Leiden will have an annual incidence for VTE of approximately three to 10 in 1,000 individuals (reflecting a three-to 10-fold increased risk). Most people would still consider this to be a relatively low absolute risk for VTE.

Individuals without symptoms, but with a diagnosed thrombophilia, may find knowing their predisposition for VTE to be useful for certain clinical decisions. For example, women with factor V Leiden or another thrombophilia who have never had a VTE may elect to avoid using estrogen-containing oral contraceptives or hormone replacement therapy, since estrogens also increase the risk for VTE.

For individuals who have had a VTE and are on anticoagulant therapy, the identification of certain inherited thrombophilias may help determine how long a patient is kept on anticoagulation medicine. For example, a patient who is heterozygous for factor V Leiden may need to be treated for a standard course of anticoagulant therapy only after a VTE (for example, three to six months of anticoagulant therapy), whereas a patient with antithrombin-deficiency may be maintained on anticoagulant therapy with warfarin indefinitely. More research is needed on the optimal management of patients with VTE and thrombophilic disorders.

About the Author: Thomas L. Ortel, MD, PhD Dr. Ortel is an Associate Professor of Medicine and Pathology at Duke University Medical Center, Medical Director of the Hemostasis and Thrombosis Center at Duke. He is also Medical Director of the Clinical Coagulation Laboratory and the Platelet Antibody Laboratory at Duke, as well as the Duke Anticoagulation Clinic.