Thromboembolism - Factor V Leiden and Prothrombin Gene Mutation

4/23/2003

Question: How valuable are Factor-V Leiden and prothrombin gene mutation as indicators or markers for  hypercoagulable state and risk of venous thromboembolism?

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Unique Identifier:12529095

Authors: Crowther MA. Kelton JG.

Institution: St. Joseph's Hospital and McMaster University Medical Centre, Room L208, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Title: Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system.[summary for patients in Ann Intern Med. 2003 Jan 21;138(2):I10; PMID: 12529114]. [Review] [76 refs]

Source: Annals of Internal Medicine. 138(2):128-34, 2003 Jan 21.

Abstract: Congenital causes of venous thrombosis have gained increasing prominence with the description of the factor V Leiden mutation and the prothrombin gene mutation. More recently, the description of the association between increased levels of coagulation factors and venous thrombosis and the finding that patients with thrombophilia can harbor more than one prothrombotic state have further increased the clinical relevance of the congenital thrombophilic states. In this qualitative review, we summarize current knowledge of the congenital prothrombotic states and propose a simple classification system that divides the states into two broad groups: those associated with reduced levels of the inhibitors of the coagulation cascade and those associated with increased levels or function of the coagulation factors. The first group is less common than the second, but it is associated with a much higher risk for venous thrombosis. This review provides clinicians with an evidence-based, practical guide to the congenital prothrombotic states. [References: 76]

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Unique Identifier:11958494

Authors: Eckman MH. Singh SK. Erban JK. Kao G.

Institution: Division of General Internal Medicine, Center for Clinical Effectiveness, University of Cincinnati, OH 45267-0535, USA. mark.eckman@uc.edu

Title: Testing for factor V Leiden in patients with pulmonary or venous thromboembolism: a cost-effectiveness analysis.

Source: Medical Decision Making. 22(2):108-24, 2002 Mar-Apr.

Abstract: BACKGROUND: Survivors of venous thromboembolism who have the factor V Leiden mutation have an increased risk of recurrent venous thromboembolism (VTE), but the cost-effectiveness of testing for factor VLeiden has not been assessed. METHODS: We used a Markov state transition decision model to evaluate the cost-effectiveness of factor V Leiden testing and treatment strategies in survivors of VTE using a societal perspective for costs, effectiveness-measured in quality-adjusted life years, and incremental cost-effectiveness. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles. Cost estimates were derived from Medicare reimbursement and other sources. The analysis examined 3 hypothetical cohorts of 35-year-old women having suffered their 1st episode of VTE. Interventions included oral anticoagulant therapy for 6 months versus testing. Patients found to have the factor V Leiden mutation were then treated with either 3 years or lifelong oral anticoagulant therapy. RESULTS: Total costs for testing followed by 3 years of treatment were $9,676, whereas those for no testing were $10,392 and those for testing followed by lifelong therapy were $13,179. Testing followed by 3 years of treatment increased quality-adjusted life expectancy by roughly 0.15 years. In sensitivity analyses using a more plausible constant risk model of recurrent VTE, testing followed by lifelong anticoagulation was the favored strategy. However, the marginal cost-effectiveness ratio was highly dependent on the rate of recurrent VTE, the risk of major hemorrhage, prevalence offactor V Leiden, patient age, and the efficacy of anticoagulation therapy. CONCLUSIONS: Testing followed by lifelong anticoagulation is unlikely to be a cost-effective strategy in patient populations with a very low prevalence of factor V Leiden; for those with a lower risk for recurrent VTE, such as patients with a clear precipitant; or for patients with risk factors for bleeding while receiving anticoagulant therapy. The only patients for whom testing followed by lifelong anticoagulant therapy may be a reasonable strategy are those with no obvious precipitant for VTE (i.e., idiopathic VTE) who are at low risk for bleeding complications from oral anticoagulant therapy. These results highlight the need for further clinical investigation and the development of multivariable models predicting the risk of recurrent VTE based on factor V Leiden status, idiopathic versus precipitated VTE, treatment, and the coinheritance of other common thrombophilias, such as the prothrombin gene mutation. CAS Registry/EC Number 0 (Anticoagulants). 9001-24-5 (Factor V).

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Unique Identifier:11380448

Authors: De Stefano V. Martinelli I. Mannucci PM. Paciaroni K. Rossi E. Chiusolo P. Casorelli I. Leone G.

Institution: Department of Haematology, Catholic University, Rome, Italy. v.destefano@eudoramail.com

Title: The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation.

Source: British Journal of Haematology. 113(3):630-5, 2001 Jun.

Abstract: The G20210A mutation in the prothrombin gene is associated with an increased risk of a first venous thromboembolic episode; few data are available about the long-term risk for recurrent venous thromboembolism and it is not known whether or not carriers of the mutation should be recommended lifelong anticoagulant treatment after the first thrombosis. We investigated 624 patients, referred for previous objectively documented deep venous thrombosis of the legs or pulmonary embolism, to determine the risk of recurrent thromboembolism in heterozygous carriers of the G20210A mutation in the prothrombin gene after the first episode of venous thromboembolism. After exclusion of other inherited (anti-thrombin, protein C, protein S deficiency and factor V Leiden) or acquired (anti-phospholipid antibody syndrome) causes of thrombophilia, 52 heterozygous carriers of the prothrombin mutation were compared with 283 patients with normal genotype. The relative risk for recurrent venous thromboembolism was calculated between groups using a Cox's proportional hazard model. The patients with the prothrombin mutation had a risk for spontaneous recurrent venous thromboembolism similar to that of patients with normal genotype (hazard ratio 1.3; 95% CI, 0.7-2.3). The circumstances of the first event (spontaneous or secondary) did not produce any substantial variation in the risk for recurrence. In conclusion, the carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype. CAS Registry/EC Number 0 (Anticoagulants). 9001-26-7 (Prothrombin).

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Unique Identifier:11167765

Authors: Martinelli I. Bucciarelli P. Margaglione M. De Stefano V. Castaman G. Mannucci PM.

Institution: Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, IRCCS Maggiore Hospital, University of Milan, Italy. martin@polic.cilea.it

Title: The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both.

Source: British Journal of Haematology. 111(4):1223-9, 2000 Dec.

Abstract: Factor V Leiden and the G20210A mutation in the prothrombin gene are the most frequent abnormalities associated with venous thromboembolism. It is unknown whether the risks due to the presence of either mutation are of the same magnitude. We compared the prevalence and incidence rate of venous thromboembolism in relatives with either mutation or both. The finding of different rates might influence the strategies for primary prevention of thrombosis in carriers of these mutations. The study population included 1076 relatives of probands with the prothrombin gene mutation, factor V Leiden or both who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were non-carriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations and 2.5% in non-carriers. Annual incidences of thrombosis were 0.13% [95% confidence interval (CI) 0.06-0.24], 0.19% (0.13-0.25), 0.42% (0.15-0.83) and 0.066% (0.03-0.11), respectively, and the relative risk of thrombosis was two times higher in carriers of the prothrombin gene mutation, three times higher in those with factor V Leiden and six times higher in double carriers than in non-carriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation is slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it is two or three times higher. These findings suggest that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations. CAS Registry/EC Number 0 (factor V Leiden). 9001-24-5 (Factor V). 9001-26-7 (Prothrombin).

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Unique Identifier:11095555

Authors: Kohlmeier RE. Cho CG. Bux RC. Guerra L. Rulon JJ. Selby DM. Gulley ML.

Institution: Department of Pathology, University of Texas Health Science Center and Audie L. Murphy Veteran's Hospital, San Antonio 78284-7750, USA.

Title: Prothrombin gene mutation uncommon in pulmonary embolism.

Source: Southern Medical Journal. 93(11):1073-7, 2000 Nov.

Abstract: BACKGROUND: Venous thrombosis followed by pulmonary embolism is one of the most common causes of sudden death among middle-aged adults. Several inherited polymorphisms are associated with heightened risk of venous thrombosis, including mutation at position 20210 of the prothrombin gene and mutation at codon 506 of the factor V gene. METHODS: We studied mutation prevalence in 67 individuals who died of pulmonary embolism and were autopsied in a medical examiner's facility over a 5-year period. Mutations were identified by polymerase chain reaction followed by allele-specific endonuclease digestion. RESULTS: Traditional risk factors for pulmonary embolism (eg, immobility, oral contraceptive use, cancer) were identified in 75%. Heterozygous mutation of the prothrombin gene was found in 3/67 (4%), and heterozygous mutation of the factor V gene was identified in 3/66 (4%). No homozygotes or compound heterozygotes were identified. The prevalence of mutation was not significantly different from that of the general population. CONCLUSIONS: Individuals who die suddenly from pulmonary embolism are not often affected by prothrombin or factor V gene mutations. Therefore, medical examiners need not routinely test for these mutations in individuals who die of pulmonary embolism. CAS Registry/EC Number 0 (factor V Leiden). 9001-24-5 (Factor V). 9001-26-7 (Prothrombin).