Patients diagnosed with thromboembolic disease at a young age, or those who have a family history or recurrent episodes of the disease, typically undergo a battery of laboratory studies to identify inherited disorders of hemostasis. This work-up generally consists of measuring serum levels of antithrombin III, protein C and protein S, as well as performing qualitative and quantitative assays for fibrinogen. An unusual mutation in the hemostatic pathway, discovered in 1993, has had a profound effect on the way in which thromboembolic disease can be diagnosed and ultimately treated. This defect is referred to as resistance to activated protein C. A single gene mutation in the coding for coagulation factor V, known as factor V Leiden, makes the activated form of factor V (Va) relatively resistant to degradation by activated protein C. Price and Ridker reviewed the literature on factor V Leiden to identify the prevalence and risks of thromboembolism associated with this mutation and suggest methods for diagnosis and treatment.

Factor V Leiden mutation is rather common, affecting 3 to 7 percent of the population in Europe and the United States. It most commonly affects whites and is significantly less prevalent in other ethnic groups, most notably Asian and black populations. Patients who are homozygous for the mutation present with the disease at a younger age than those who are heterozygous for the mutation. In addition, the risks associated with this mutation appear to increase with age. The presence of factor V Leiden is associated with increased risk for primary and recurrent venous thromboembolism and for venous thromboembolism with use of oral contraceptives and during pregnancy. However, it does not appear to affect the incidence of arterial thromboembolism.

Definitive diagnosis of the mutation requires the use of techniques based on polymerase chain reaction, although resistance to activated protein C may also be identified using relatively simple plasma testing. These tests are less reliable if the patient is taking anticoagulant therapy or has lupus anticoagulant. The presence of protein S deficiency does not appreciably alter the results of plasma testing. Newer assay methods that use factor V-deficient plasma appear to be more reliable and are now available commercially. Positive results of plasma testing are usually followed by genetic confirmation of the mutation.

The authors conclude that the issues associated with screening for factor V Leiden are complex. Screening protocols for primary prevention are likely to be inefficient because the lifetime risk for venous thromboembolism in the general population is low. In fact, prescribing long-term anticoagulant therapy to affected persons may be hazardous. Among groups at higher risk, such as pregnant women and young women using oral contraceptives, the effectiveness of screening is also uncertain because of the hazards of anticoagulant therapy and the extremely low risk rates that would require massive screening programs to prevent possibly only one death per year. Screening does appear to be appropriate in persons with a family or personal history of venous thrombotic episodes, especially if the person is found to be homozygous.

editor's note: The frequency of factor V Leiden mutation as a cause of venous thromboembolic disease needs to be recognized. Patients with venous thromboses must be screened for the presence of this mutation. The efficacy of management with anticoagulant therapy requires further study.—r.s.