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Factor V Leiden Mutation and the Risks for Thromboembolic Disease: A Clinical Perspective

Daniel T. Price, MD; and Paul M. Ridker, MD
[+] Article, Author, and Disclosure Information

From Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Requests for Reprints: Paul M. Ridker, MD, Division of Cardiovascular Diseases, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Current Author Addresses: Dr. Price: Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;127(10):895-903. doi:10.7326/0003-4819-127-10-199711150-00007
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Background: A single point mutation in the gene coding for coagulation factor V results in a form of factor Va that is resistant to degradation by activated protein C and leads to a relative hypercoagulable state. This mutation, factor V Leiden, is found in 4% to 6% of the U.S. population.

Purpose: To review clinical data on factor V Leiden mutation, with emphasis on prevalence of and risks for thromboembolism and implications for screening and management.

Data Sources: A MEDLINE search of the English-language literature published between 1993 and April 1997 and an extensive bibliography review.

Study Selection: Case-control and prospective cohort studies were reviewed if clinical features of thromboembolic disease associated with factor V Leiden mutation or resistance to activated protein C were presented. Original research articles were reviewed if they addressed the identification of the laboratory abnormality of activated protein C or factor V Leiden mutation. Case reports and case series were reviewed when no analytic data were available.

Data Extraction: Review of the identified articles.

Data Synthesis: Factor V Leiden mutation is associated with three- to sixfold increases in risks for primary and recurrent venous thromboembolism, especially in patients without transient risk factors, such as surgery or trauma. Risks for venous thromboembolism in genetically affected persons are substantially higher among patients with coexistent predispositions for thrombosis, such as advanced age, use of oral contraceptives, hyperhomocystinemia, and deficiencies of protein C and protein S. Factor V Leiden mutation does not seem to increase risks for arterial thrombosis. Whether patients with the mutation would benefit from more intense or prolonged anticoagulation is unknown.

Conclusions: The presence of factor V Leiden mutation predisposes patients to venous thromboembolism, but screening for this disorder is of uncertain utility. Decisions about whether to screen for the mutation will depend on the results of clinical trials designed to evaluate the benefit-to-risk ratio of long-term anticoagulation in the secondary prevention of venous thromboembolism in patients with resistance to activated protein C.


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Figure 1.
The pathways that generate factor Xa and thrombin and the natural anticoagulant mechanisms that regulate activity of these enzymes.

After generation, factor Xa binds to factor Va on activated platelets, mediating conversion of prothrombin to thrombin; the latter, in turn, acts on fibrinogen to form a fibrin clot. Activated protein C functions as a potent anticoagulant by inactivating factors VIIIa and Va. Factor V Leiden mutation results in a form of coagulation factor V that, when activated to factor Va, is relatively resistant to degradation by activated protein C. This defect, known as resistance to activated protein C, is the most common inherited predisposition to thrombosis currently known. Reproduced with permission from Millenson MM, Bauer KA. Pathogenesis of venous thromboembolism. In: Hull R, Pineo GF, eds. Disorders of Thrombosis. Philadelphia: WB Saunders; 1996:175-90.

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Figure 2.
Relation between ratio of resistance to activated protein C and carrier state for factor V Leiden mutation.

A = adenine; G = guanine.

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Figure 3.
Thrombosis-free survival in persons with familial thrombophilia, A = adenine; G = guanine.

Adapted from Zoller B, Svensson PJ, He X, Dahlback B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest. 1994; 94:2521-4.

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Figure 4.
Adjusted relative risks for future venous thromboembolism among apparently healthy men with factor V Leiden mutation.

Secondary venous thromboembolism includes events associated with cancer, surgery, or trauma. Adapted from Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995; 332:912-7.

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Figure 5.
Interrelations of factor V Leiden mutation and 1) hyperhomocystinemia [left] and 2) oral contraceptive use (right) on risks for venous thromboembolism.

+ = present; −= absent. Adapted from Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risks of future venous thromboembolism. Circulation. 1997; 95:1777-82; and from Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994; 344:1453-7.

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