Abstract
Factor V Leiden is a genetic mutation that confers resistance to the action of activated protein C and thus predisposes to venous thromboembolism. It’s inherited as an autosomal dominant trait and is prevalent amongst Caucasians with a carrier rate of 4%. Deep venous thrombosis and pulmonary embolism are the most common clinical manifestations of FVL related VTE although it can also affect other sites. Genetic testing for FVL is used for diagnostic as well as predictive purposes. Diagnosis of FVL is based on protein assays and
DNA analysis technology. Familial genetic testing for FVL is generally not recommended except in instances where a strong family history of early age VTE exists. Clinical management of VTE associated to FVL is done as per the standard guidelines for management of VTE. FVL has only modest effects on the recurrence rate of VTE regardless of the duration of the initial or long term oral anticoagulant therapy.
Factor V Leiden
The aim of this paper is to describe the pathophysiology, clinical presentation and epidemiology of Factor V Leiden (FVL). Details pertaining to the point of mutation as well as how it is inherited will also be provided. Last but not least, the diagnostic processes, medical management, prognosis of the disease and the recommendations for familial genetic testing will be discussed.
Clinical presentation, pathophysiology and epidemiology of Factor V Leiden.
The blood coagulation process is controlled by anticoagulant proteins present either on the surface of endothelial cells or in plasma. A key plasma protein in the natural anticoagulation process is the vitamin K-dependent protein C. Its activated by the thrombin-thrombomodulin complex on the surface of endothelial cells following which it exerts selective proteolytic degradation action on factors Va and VIIIa. Its effects are potentiated by Protein S which acts as its co-factor. The latter is also a vitamin-K dependent plasma protein which exists in two forms, one, as a free protein which is also its active form and two bound to complement binding protein (C4BP). Factor Va encoded by the Leiden mutation has an altered Protein C cleavage site which makes it resistant to proteolytic degradation by APC while retaining its physiological pro-coagulation properties. The cofactor activity of C4BP is also lost because it depends on Factor V (Tuq et al., 2011).
The net effect of the aforementioned changes therefore include the stabilization of prothrombinase complex, an increase in the production of thrombin and the feedback activation of both Factors V and VIII and hence a predisposition to venous thromboembolism (VTE). The most common clinical presentation of VTE related to FVL are deep venous thrombosis and pulmonary embolism although thrombi formation can occur in other sites such as the brain (Kovac et al., 2011). The prevalence of FVL mutation varies greatly in ethnic groups. However, it’s common amongst Caucasians (Jews, Indians, Europeans and Arabs) with an estimated carrier rate of 4%. The latter estimates are increased in certain European countries up to 10 to 15%. Amongst persons with either a family or personal history of thrombosis, the estimated carrier frequency ranges from 20-60% (Cohn et al., 2010).
Genetics of FVL
The Leiden gene mutation occurs due to changes at position 506 of the Factor Va proteic molecule whereby arginine is replaced with glutamine. The Leiden gene mutation is inherited in an autosomal dominant fashion. The risk for VTE is increased 18 times for homozygotes and fivefold for heterozygotes. In essence therefore, FVL is the most common genetic cause for APC resistance accounting for up to 95% of reported cases and subsequently VTE. The high incidence of FVL amongst Caucasians is thought to be due to natural selection whereby it conferred resistance to hemophilia (Kovac et al., 2011).
Recommendations for familial genetic testing for FVL
The benefits of genetic testing for relatives to thrombophilic carriers remains uncertain mainly because VTE is a multifactorial disease that results from the interaction of a number of risk factors some of which are yet to be elucidated upon (Ho, Hankey & Eikelboom, 2010). Further, the risk for VTE in first-degree relatives of patients with VTE is only increased two to three fold. In addition, FVL mutation has not been associated with a highly increased risk for VTE in the absence of a previous episode of VTE or a first-degree family history of the disease. Therefore, it is recommended that screening for FVL mutation should be carried out only if a strong family history of VTE at a relatively early age for instance, less than fifty years exists (Blikenberg et al., 2010).
Diagnosis and clinical management of FVL related VTE
Review of literature reveals that testing for FVL is done for two major reasons, diagnostic and predictive. Diagnostic FVL testing is recommended for all patients with a previous history of or following a VTE. Predictive testing on the other hand is aimed at evaluating the risk of thrombosis in an otherwise healthy client for instance before the prescription of oral contraceptives (Blikenberg et al., 2010; Hindorff, 2009). As far as diagnostic FVL testing in a thrombophillic patient is concerned, the first step in the diagnostic process should establish whether the patient in question has any of the common causes of the disease. The second step should entail the collection and analysis of assays to characterize the defect. To avoid misinterpreting the results, it is imperative that the influence of variables such as the time of testing, age, pregnancy status and the stage of an inflammatory response on the patient coagulation status be considered (Margetic, 2010). Protein-based FVL detection assays include antibody -mediated sensor detection and the conventional functional APC resistance coagulation test. DNA-based FVL detection assays include DNA hybridization, denaturing gradient gel electrophoresis, PCR assays, ligase-based assays, and single-stranded conformational PCR analysis amongst others (Oh &.Smith, 2011).
Generally, there is no real consensus on the management of VTE associated with FVL. However, the management of a first VTE episode follows standard guidelines (Kujovich, 2010). Basically it entails the administration of a combination of a parenteral anticoagulant such as low molecular weight heparin or unfractionated heparin and vitamin K antagonist warfarrin. Parenteral anticoagulation therapy is given overlapping with warfarrin for a minimum of five days following which it is discontinued provided the International Normalized Ratio (INR) has remained between 2 to3 within the preceding twenty four hours. Warfarrin therapy is then continued for a period ranging from 3 to 6 months (Bauer, 2010). Decisions pertaining to the optimal duration of warfarrin therapy are normally based on individualized assessments of the risks for recurrence of VTE and anti-coagulant related bleeding. This is so because study findings have shown that the FVL mutation has a modest effect (OR of 1.5) on the recurrence of VTE following the treatment of the first episode. Long term anticoagulant therapy is not recommended for asymptomatic patients heterozygotic for FVL. Prophylactic long-term anticoagulation may however be considered in patients perceived to be at a high clinical risk for VTE (Kujovich, 2010).
Prognosis of VTE associated with FVL
As previously mentioned, FVL has relatively modest effects on the recurrence of VTE after the initial treatment. Generally, unprovoked VTE has an estimated 10% annual recurrence rate in the first two years following the cessation of warfarrin therapy. This rate drops to 3% in the subsequent years such that at the fourth year, the cumulative recurrence rate is approximately 25%. Findings of clinical trials have shown that neither the prolongation of the period of oral anticoagulant therapy beyond three months or the initial three month therapy reduces the risk for recurrence of VTE (Bauer, 2010).
Conclusion
In conclusion therefore, FVL mutation is a genetic variation inherited in a dominant autosomal manner that has a net effect of conferring resistance to activated Protein C (APC). Subsequently, it predisposes its carriers to VTE. The most common manifestations of FVL linked VTE are DVT and PE although thrombi have been reported to occur in other sites. The incidence of the FVL mutation is most common amongst Caucasians and is virtually absent amongst people of Asian and African descent. Diagnosis of FVL is based on protein assays and DNA analysis. Clinical management of a first episode of unprovoked VTE associated with FVL is done as per standard guidelines. Decisions on the duration of oral anticoagulation therapy are based on the merit of individual cases. FVL does not significantly increase the risk of recurrence of VTE after the initial therapy. Familial testing for the FVL mutation is only recommended in cases whereby there is a strong family history of VTE with the disease occurring at a relatively young age.
References
Blikenberg, O., Kristoffersen, A., Sandberg, S., Steen, V.M., & Houge, G. (2010, March 24).
Usefulness of factor V Leiden mutation testing in clinical practice. European Journal of Human Genetics, 18(8), 862-866. doi: 10.1038/ejhg.2010.33
Cohn, D.M., Repping, S., Buller, H.R., Meijers, J.C., & Middeldorp, S. (2010). Increased sperm count may account for high population frequency of factor V Leiden. Journal of
Thrombosis and Hemostasis, 8(3), 513-516. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
Hindorff, L.A., Burke, W., Laberge, A., Rice, K.M., Lumley, T., Leppig, K., Rosendaal, F.R.,
Larson,E.B., & Psaty, B.M. (2009). Motivating factors for physician ordering of Factor V
Leiden genetic testing. Arch Intern Medicine, 169(1), 68-74. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
Ho, W.K., Hankey, G.J., & Eikelboom, J.W. (2011). Should adult patients be routinely tested for heritable thrombophilia after an episode of venous thromboembolism? [Abstract]. The
Medical Journal of Australia, 195(3), 139-142. Abstract. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
Kovac, M., Mitic, G., Mikovic,Z., Antonijevic, N., Djordjevic, V., Mikovic, D., Mandic, V.,Rakicevic, L., & Radojkovic, D. (2010). Type and location of venous thromboembolism in carriers of Factor V Leiden or prothrombin G20210A mutation versus patients with no mutation. Clinical and Applied Thrombosis/Hemostasis, 16(1), 66-70. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/
Kujovich, J.L. (2010). Factor V Leiden thrombophilia [Abstract]. Genetics in Medicine, 13(1), 1-16. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
Margetic, S. (2010). Diagnostic algorithm for thrombophilia screening [Abstract]. Clinical chemistry and
laboratory medicine, 48 (1), 27-39. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
Oh, H., & Smith, S.L. (2010). Evolving methods for single nucleotide polymorphism detection:
Factor V Leiden mutation detection [Abstract]. Journal of Clinical Laboratory, 25(4), 259-288.. doi: 10.1002/jcla.20470
Tuq, E., Aydin, H., Kaplan, E., & Doqruer, D. (2011). Frequency of genetic mutations associated with thromboembolism in the Western Black Sea Region. Internal Medicine, 50(1), 17-21. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
