American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing
2001; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês
10.1097/00125817-200103000-00009
ISSN1530-0366
AutoresWayne W. Grody, John H. Griffin, Annette K. Taylor, Bruce R. Korf, John A. Heit,
Tópico(s)Cardiovascular Issues in Pregnancy
ResumoSUMMARY OF ISSUES AND RECOMMENDATIONSIssue 1: Which methodology should be used: Factor V Leiden DNA testing or functional activated protein C (APC) resistance testing?Recommendation 1When appropriate clinical care requires testing for the factor V Leiden allele, either direct DNA-based genotyping or a factor V Leiden-specific functional assay is recommended. Patients who test positive by a functional assay should then be further studied with the DNA test for confirmation and to distinguish heterozygotes from homozygotes. Patients on heparin therapy or with known lupus anticoagulant should proceed directly to molecular testing if the modified functional assay is not used. When relatives of individuals known to have factor V Leiden are tested, the DNA method is recommended.Issue 2: Who should be tested?Recommendation 2Opinions and practices regarding factor V Leiden testing vary. Some physicians advocate testing of all patients with venous thrombosis except when active malignancy is present. Others exclude testing in patients over age 60 in the absence of a family history of thrombosis or a previous thrombotic event.There is growing consensus that testing should be performed in at least the following circumstances (these are the same general recommendations for testing for any thrombophilia):Age 50, except when active malignancy is present.Relatives of individuals known to have factor V Leiden. Knowledge that they have factor V Leiden may influence management of pregnancy and may be a factor in decision-making regarding oral contraceptive use.Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption, intrauterine fetal growth retardation, or stillbirth. Knowledge of factor V Leiden carrier status may influence management of future pregnancies.Random screening of the general population for factor V Leiden is not recommended.Routine testing is not recommended for patients with a personal or family history of arterial thrombotic disorders (e.g., acute coronary syndromes or stroke) except for the special situation of myocardial infarction in young female smokers. Testing may be worthwhile for young patients (<50 years of age) who develop acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease.Neither prenatal testing nor routine newborn screening is recommended.Issue 3: Should testing be offered to individuals with environmental risk factors?Recommendation 3Factor V Leiden testing is recommended in women with venous thromboembolism during pregnancy or oral contraceptive use. In contrast to general screening before administration of oral contraceptives, targeted testing of women with a personal or family history of venous thrombosis is advisable. Routine screening for factor V Leiden in asymptomatic women contemplating or using oral contraceptives is not recommended, except for those with a personal history of thromboembolism or other medical risk factors. Those women with a family history of thromboembolism, APC resistance, or documented factor V Leiden mutation should be counseled about their risks and options and considered for testing depending on the overall clinical situation. Women with a history of recurrent late-trimester fetal loss should also be considered for testing. Whether or not the woman smokes would not alter these recommendations. Screening of asymptomatic individuals with other recognized environmental risk factors such as surgery, trauma, paralysis, and malignancy is not necessary or recommended, since all such individuals should receive appropriate medical prophylaxis for thrombosis regardless of carrier status.Issue 4: Should patients found to be positive for factor V Leiden or APC resistance be tested for any of the other heritable thrombophilic risk factors?Recommendation 4Patients testing positive for factor V Leiden or APC resistance should be considered for molecular genetic testing for the most common other thrombophilias with overlapping phenotype for which testing is easy and readily available. At present, only the prothrombin 20210A variant fits these criteria. It is present in 1–2% of the general population, its involvement in venous thromboembolism is well-established, and the DNA test is as simple as that for factor V Leiden (with which it can even be multiplexed). Protein S, protein C, and antithrombin III deficiencies are too genetically heterogeneous for routine molecular genetic testing, but testing by functional coagulation assays may be considered, especially if there is a strong family history of venous thrombosis. Hyperhomocysteinemia should be considered and tested (in most cases by measuring plasma homocysteine levels) as another potential risk factor in those found to be positive for factor V Leiden. Patients with classic homocystinuria are at extremely elevated risk of thromboembolism and should probably be tested for other available thrombophilic risk factors.Issue 5: Should testing for other heritable thrombophilic factors be performed simultaneously with factor V Leiden testing?Recommendation 5Physicians ordering factor V Leiden on a venous thrombosis patient for any of the indications recommended here should also consider the utility of functional, biochemical, and molecular screening for other heritable thrombophilic factors, especially prothrombin 20210A and plasma homocysteine levels.Issue 6: Are there any other factor V mutations in addition to factor V Leiden which should be tested?Recommendation 6The factor V Leiden (R506Q) mutation is currently the only molecular analysis of the factor V gene indicated in the routine workup of thrombotic risk.Issue 7: What are the recommended methodologies and quality assurance standards for performing these tests?Recommendation 7The factor V Leiden mutation test should be performed using any of the accepted technical approaches as long as they have been properly validated by the laboratory, while adhering to current ACMG/CAP quality assurance guidelines for molecular genetic testing.Issue 8: What are the appropriate pre- and postanalytic procedures to be followed in factor V Leiden testing?Recommendation 8Formal informed consent should not be required for factor V Leiden testing, but individuals being tested should be made aware that this is a genetic test, that test results have implications about risk in other family members, and that there may be attendant issues of confidentiality and possible insurance discrimination. The laboratory's report should state explicitly the relative risk implications for factor V Leiden heterozygotes and homozygotes, the risk that other relatives may have the mutation, and the recommendation, if indicated, for testing for other inherited hypercoagulabilities.It is important for individuals testing positive for factor V Leiden to understand the risk implications and genetic implications of their result. Patients should be counseled about these implications by their physician or genetic counselor.BACKGROUNDNormal hemostasis requires a delicate balance between the natural procoagulant and anticoagulant systems. Both of these systems are subject to disruption by either inherited or acquired (including both intrinsic and environmental) defects. Inherited defects associated with clinical bleeding disorders (e.g., hemophilia A and B and von Willebrand disease) have been known and studied for centuries. In contrast, inherited defects causing thrombosis have been recognized more recently. These heritable thrombophilias (hypercoagulabilities) include factor V Leiden (R506Q mutation), the prothrombin 20210A mutation, antithrombin III deficiency, and deficiencies of protein C and protein S.The incidence of venous thrombosis is about 1 per 1,000 person-years1.Silverstein M.D. Heit J.A. Mohr D.N. Petterson T.M. O'Fallon W.M. Melton L.J. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based cohort study.1:STN:280:DyaK1c7otVGiug%3D%3D10.1001/archinte.158.6.585Arch Intern Med. 1998; 158: 585-593Google Scholar and leads to 50,000 deaths annually in this country.2.Heit J.A. Silverstin M.D. Lohse C.M. Petterson T.M. O'Fallon W.M. Melton L.J. Hooper C. Evatt B. The factor V R506Q and prothrombin 20210G→A mutations as independent risk factors for venous thromboembolism: a population-based case-control study.Thromb Haemost. 1999; 1229a: 387Google Scholar It is a multifactorial disorder, involving one or a combination of genetic risk factors and acquired or environmental conditions such as pregnancy, oral contraceptive use, estrogen therapy, malignancy, stroke with extremity paresis, trauma, surgery, or immobility.3.Heit J.A. Silverstein M.D. Mohr D.N. Petterson T.M. O'Fallon W.M. Melton L.J. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study.1:STN:280:DC%2BD3c7pvFGnsw%3D%3D10.1001/archinte.160.6.809Arch Intern Med. 2000; 160: 809-815Google Scholar The risk increases with the number of genetic and/or environmental conditions present, though venous thromboembolism can occur in the absence of known risk factors. Known genetic causes are present in approximately 25% of unselected venous thrombosis cases and up to 63% of familial cases.4.Bertina R.M. Factor V. Leiden and other coagulation factor mutations affecting thrombotic risk.1:CAS:528:DyaK2sXmtVyiuro%3D9299960Clin Chem. 1997; 43: 1678-1683Google ScholarFactor V R506Q (Leiden), causing activated protein C (APC) resistance, was discovered in 1994 and is the most common genetic risk factor for venous thrombosis. It is present in 5% of Caucasian Americans, 20% of idiopathic first venous thrombosis cases, and 60% of venous thrombosis cases in pregnant women. Knowledge of the presence of factor V Leiden in patients and relatives can influence management and prevention of venous thrombosis in some cases. Factor V Leiden has also been associated with increased risk of recurrent pregnancy loss and placental infarction.The procoagulant systemThe normal function of the procoagulant system is to target a hemostatic plug containing platelets and fibrin into a breach within the inside lining of “injured” blood vessels. The procoagulant system has been characterized as a “cascade” of amplifying enzymatic reactions leading to the final serine protease, thrombin. The procoagulant system is triggered by exposure of the coagulation activator, tissue factor, to circulating blood. Tissue factor normally is sequestered from the circulation within the wall of blood vessels and only exposed to blood after vessel wall injury. Exposed (or expressed) tissue factor binds circulating factor VIIa, and in the presence of anionic phospholipid and divalent cations (e.g., calcium), forms a factor X-ase complex. This factor X-ase complex either directly cleaves (“activates”) factor X to Xa, or activates factor IX to IXa, by limited proteolysis. Factor IXa binds factor VIIIa to form a second factor X-ase complex, which activates factor X to Xa. Factor Xa binds factor Va to form the prothrombinase complex, which activates prothrombin to thrombin. Thrombin produces a hemostatic plug by cleaving fibrinogen to form fibrin monomers, by activation of platelets, and by activating factor XIII to XIIIa which crosslinks strands of fibrin monomers to form a stable hemostatic plug. In a feedback amplification loop, thrombin also increases its own production by activating factors V, VIII, and XI. Together factors Va and VIIIa can potentially increase the rate of thrombin generation by one million-fold and provide major control points for the regulation of thrombin generation.The anticoagulant systemThe function of the natural anticoagulant system is to confine a normal hemostatic plug to the site of vessel wall injury and to prevent the beneficial thrombus from propagating to form a pathologic thrombus, which occludes the lumen of the vessel or embolizes to occlude distant vessels. The recognized anticoagulant components of this system include antithrombin III, protein C, and protein S. The anticoagulant system is activated in parallel with the procoagulant system. Protein C is a circulating vitamin K-dependent zymogen, which is activated to APC, the active enzyme, by the thrombin-thrombomodulin complex. APC functions as a natural anticoagulant by inactivating (via proteolysis) procoagulant factors Va and VIIIa in the presence of protein S. Antithrombin III is a ser ine p rotease in hibitor (SERPIN) and acts as a pseudosubstrate to irreversibly inhibit thrombin by covalently binding the thrombin enzymatic active site. The rate of thrombin inhibition by antithrombin III is increased markedly by glycosaminoglycans (e.g., heparin). Familial reductions in plasma antithrombin III, protein C, or protein S activity due to either reduced plasma protein levels (i.e., altered protein expression), or normal levels of a dysfunctional protein (i.e., altered protein structure), are strongly associated with deep vein thrombosis and pulmonary embolism (venous thromboembolism), and validate the important role of these proteins in the natural anticoagulant system. Altogether, however, the prevalence of these previously recognized familial thrombophilias among venous thromboembolism patients ranges from 5 to 20%, depending on cohort selection.5.Heijboer H. Brandjes D.P.M. Buller H.R. Sturk A. ten Cate J.W. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis.1:STN:280:DyaK3M%2Fkt1yrsw%3D%3D10.1056/NEJM199011293232202N Engl J Med. 1990; 323: 1512-1516Google ScholarActivated protein C resistance and the factor V Leiden mutationThe report of three unrelated probands and their families with idiopathic recurrent venous thromboembolism whose plasma was resistant to the anticoagulant effect of exogenously added APC6.Dahlback B. Carlsson M. Svensson P.J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.1:CAS:528:DyaK3sXhsVCrtbs%3D10.1073/pnas.90.3.1004Proc Natl Acad Sci USA. 1993; 90: 1004-1008Google Scholar has provided exciting new insights into the etiology of venous thromboembolism. Early epidemiologic data suggested that an abnormally low anticoagulant response to APC, termed “activated protein C resistance (APC-R),” was familial, with an autosomal dominant or semidominant inheritance pattern.7.Svensson P.R. Dahlback B. Resistance to activated protein C as a basis of venous thrombosis.1:STN:280:DyaK2c7jsVWisA%3D%3D10.1056/NEJM199402243300801N Engl J Med. 1994; 330: 517-522Google Scholar Factor Va isolated from APC-R patient plasma was resistant to inactivation by APC.8.Sun X. Evatt B. Griffin J.H. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia.1:STN:280:DyaK2c3ltVyqsw%3D%3D8193349Blood. 1994; 83: 3120-3125Google Scholar Subsequent work identified a single point mutation (G to A) at nucleotide 1691 of the factor V gene, which results in substitution of a glutamine for arginine at residue 506 (R506Q), one of three APC cleavage sites (R306, R506, R679).9.Bertina R.M. Koeleman B.P.C. Koster T. Rosendaal F.R. Dirven R.J. de Ronde H. van der Velden P.A. Reitsma P.H. Mutations in blood coagulation factor V associated with resistance to activated protein C.Nature. 1994; 343: 1535-1536Google Scholar, 10.Voorberg J. Roelse J. Koopman R. Buller H. Berends F. ten Cate J. Mertens K. van Mourik J. Association of idiopathic venous thromboembolism with a single point-mutation at Arg506 of factor V.1:CAS:528:DyaK2MXjvVWlsg%3D%3D10.1016/S0140-6736(94)92939-4Lancet. 1994; 343: 1535-1536Google Scholar, 11.Greengard J.S. Sun X. Xu X. Fernandez J.A. Griffin J.H. Evatt B. Activated protein C resistance caused by Arg506Gln mutation in Factor Va.1:STN:280:DyaK2c3jvFWnuw%3D%3D10.1016/S0140-6736(94)92497-XLancet. 1994; 343: 1361-1362Google Scholar, 12.Zoller B. Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis.1:STN:280:DyaK2c3ns1Krsw%3D%3D10.1016/S0140-6736(94)92940-8Lancet. 1994; 343: 1536-1538Google Scholar, 13.Kalafatis M. Rand M.D. Mann K.G. The mechanism of inactivation of human factor V and human factor Va by activated protein C.1:CAS:528:DyaK2MXitVSktbw%3D7989361J Biol Chem. 1994; 269: 31869-31880Google Scholar This mutation is known as factor V Leiden. Initial APC cleavage at the R506 position is required for optimal exposure and subsequent rapid inactivation of factor V by APC cleavage at positions R306 and R679.14.Kalafatis M. Bertina R. Rand M.D. Mann K.G. Characterization of the molecular defect in factor V-R506Q.1:CAS:528:DyaK2MXjvVyrtb8%3D10.1074/jbc.270.8.4053J Biol Chem. 1995; 270: 4053-4057Google Scholar,15.Heeb M.J. Kojima Y. Greengard J. Griffin J.H. Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V.1:CAS:528:DyaK2MXmtlOmtrg%3D7780127Blood. 1995; 85: 3405-3411Google Scholar Depending on the APC resistance functional assay used and the cut-off values for defining an abnormal result, the factor V Leiden mutation may account for 85–95% of patients with APC resistance. Recent studies show that APC-R with normal factor V R506 genotype is a risk factor for venous thrombosis.16.De Visser M.C. Rosendaal F.R. Bertina R.M. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis.1:CAS:528:DyaK1MXht1Cjur4%3D9949170Blood. 1999; 93: 1271-1276Google Scholar,17.Rodeghiero F. Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism.1:CAS:528:DyaK1MXivVCmu7g%3D10.7326/0003-4819-130-8-199904200-00004Ann Intern Med. 1999; 130: 643-650Google ScholarAPC resistance is the most common recognized abnormality of coagulation among patients with venous thromboembolism. The factor V Leiden mutation is carried in heterozygous form by about 5% of the Caucasian population; it is rarer in Hispanic-Americans, rarer still in African-Americans, and virtually absent in Africans and Asians.18.Ridker P.M. Miletich J.P. Hennekens C.H. Buring J.E. Ethnic distribution of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening.10.1001/jama.1997.03540400055031JAMA. 1997; 227: 1305-1307Google Scholar,19.Gregg J.P. Yamane A. Grody W.W. The prevalence of the factor V Leiden mutation in four distinct American ethnic populations.1:STN:280:DyaK1c%2Fns1WktQ%3D%3D10.1002/(SICI)1096-8628(19971219)73:3 3.0.CO;2-JAm J Med Genet. 1997; 73: 334-336Google Scholar It is believed to produce a relative risk of venous thrombosis of about 7-fold in the heterozygous state and about 80-fold in the homozygous state. It is the most common hereditary thrombophilia and is found in roughly 11–20% of individuals of all ages presenting with their first episode of venous thrombosis.20.Koster T. Rosendaal F.R. de Ronde H. Briet E. Vandenbroucke J.P. Bertina R.M. Venous thrombosis due to poor anticoagulant response to activated protein C.1:STN:280:DyaK2c%2Fns12htQ%3D%3D10.1016/S0140-6736(05)80081-9Lancet. 1993; 342: 1503Google Scholar,21.Ridker P.M. Hennekens C.H. Lindpaintner K. Stampfer M.J. Eisenberg P.R. Miletich J.P. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently health men.1:CAS:528:DyaK2MXls1Kktb8%3D10.1056/NEJM199504063321403N Engl J Med. 1995; 332: 912-917Google Scholar When venous thrombosis patients are selected to be under 50 years old and/or to have recurrent thrombosis, up to 40% have the factor V Leiden genotype. Because only a single mutation is involved, testing by any number of simple and inexpensive molecular genetic methods is possible.CHARGE TO THE WORKING GROUPGiven the high allele frequency of the factor V Leiden mutation and some of the other inherited thrombophilia defects, questions regarding criteria for testing and the possibility of population screening have been raised. The issues are quite complex and were referred to a specially appointed working group of the ACMG for deliberation. It should be noted at the outset that the group's proposed recommendations as presented here were based on the best scientific evidence available at the time. However, the heritable thrombophilia field is changing rapidly as more clinical studies to further define the genetic risks are completed and additional interacting factors are identified, making the attempt to develop recommendations something of a moving target. As such, these recommendations should be understood as being subject to change as new knowledge accrues.ISSUES AND RECOMMENDATIONS1. Which methodology should be used: Factor V Leiden DNA testing or functional APC resistance testing?APC resistance due to factor V Leiden can be diagnosed by functional analysis of the intrinsic or extrinsic coagulation pathway or by direct molecular genetic testing for the R506Q mutation in the factor V gene. The coagulation assay for APC resistance is based on a functional analysis of the anticoagulant effect on patient plasma of exogenously added APC. As an anticoagulant, APC normally decreases the rate of thrombin generation in plasma. Available APC resistance assays test for the APC anticoagulant effect via either prolongation of clotting time (e.g., activated partial thromboplastin time [aPTT], prothrombin time [PT], etc.), or by direct measurement of thrombin generation using a chromogenic substrate. The traditional functional test, based on the partial thromboplastin time (aPTT), casts a wider net, since not all cases of clinical APC resistance are due to the factor V Leiden mutation. However, it lacks specificity for factor V Leiden and is subject to perturbation by acute phase reactants, pregnancy, oral contraceptives, the acquired lupus anticoagulant syndrome (antiphospholipid antibody), and yet undefined factors.22.Shapiro S.S. The lupus anticoagulant/antiphospholipid syndrome.1:CAS:528:DyaK28XitlSntbs%3D10.1146/annurev.med.47.1.533Annu Rev Med. 1996; 47: 533-553Google Scholar In addition, it cannot be used in patients receiving heparin or warfarin sodium anticoagulant therapy, and it is much less efficient at distinguishing factor V Leiden heterozygotes from homozygotes due to extensive overlap in the assay values. Making this distinction is clinically important since homozygotes have about a 10-fold higher risk of thrombotic events than heterozygotes. A recent modification of the functional assay, involving dilution of patient plasma into factor V-deficient plasma, provides quite reliable differentiation of heterozygotes and homozygotes and little or no interference by the other clinical factors, but narrows the specificity to that of the mutation assay, so that cases of APC resistance due to other causes will be missed.8.Sun X. Evatt B. Griffin J.H. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia.1:STN:280:DyaK2c3ltVyqsw%3D%3D8193349Blood. 1994; 83: 3120-3125Google Scholar,23.Trossaert M. Conard J. Horellou M.H. Samama M.M. Ireland H. Bayston T.A. Lane D.A. Modified APC resistance assay for patients on oral anticoagulant.1:STN:280:DyaK2M%2FovFCqug%3D%3D10.1016/S0140-6736(94)90494-4Lancet. 1994; 344: 1709Google Scholar,24.Legnani C. Palareti G. Biagi R. Coccheri S. Bernardi F. Rosendaal F.R. Reitsma P.H. de Ronde H. Bertina R.M. Activated protein C resistance: a comparison between two clotting assays and their relationship to the presence of the factor V Leiden mutation.1:CAS:528:DyaK28Xkt1Whs7g%3D10.1046/j.1365-2141.1996.d01-1709.xBr J Haematol. 1996; 93: 694-699Google Scholar Despite this drawback, the modified assay has been adopted widely; therefore, any consideration of the relative merits of molecular versus coagulation testing must take this into account.Other points of comparison between the tests are cost and convenience of specimen handling. Currently, the cost for the DNA test is higher than that for the functional test (though this is likely to change with the advent of new automated DNA technologies). The DNA test requires blood at room temperature, while the APC resistance test requires citrated frozen plasma, which must be prepared using centrifugation.Recommendation 1When appropriate clinical care requires testing for the factor V Leiden allele, either direct DNA-based genotyping or a factor V Leiden-specific functional assay is recommended. Patients who test positive by a functional assay should then be further studied with the DNA test for confirmation and to distinguish heterozygotes from homozygotes. Patients on heparin therapy or with known lupus anticoagulant should proceed directly to molecular testing if the modified functional assay is not used. When relatives of individuals known to have factor V Leiden are tested, the DNA method is recommended.2. Who should be tested?Although factor V Leiden is detected in an appreciable percentage of patients, opinions differ as to the usefulness of identifying the mutation and the clinical criteria for testing. Testing would clearly be helpful if it identified individuals with increased recurrence risk who could then be considered for long-term antithrombotic therapy. In general, for patients with a first, objectively documented venous thromboembolism, the risk of recurrence is highest during the first 6–12 months after the event, with a cumulative recurrence rate of about 30% by 8–10 years.25.Prandoni P. Lensing A.W.A. Cogo A. Cuppini S. Villalta S. Carta M. Cattelan A.M. Polistena P. Bernardi E. Prins M. The long-term clinical course of acute deep venous thrombosis.1:STN:280:DyaK283ksFSktw%3D%3D10.7326/0003-4819-125-1-199607010-00001Ann Intern Med. 1996; 125: 1-7Google Scholar,26.Heit J.A. Mohr D.N. Silverstein M.D. Petterson T.M. O'Fallon W.M. Melton L.J. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.1:STN:280:DC%2BD3c7pvFGgtA%3D%3D10.1001/archinte.160.6.761Arch Intern Med. 2000; 160: 761-768Google Scholar Patients with persistent risk factors for venous thromboembolism (e.g., cancer, stroke with extremity paresis, obesity) and patients with idiopathic venous thromboembolism are at highest risk for recurrence.27.Kearon C. Gent M. Hirsh J. Weitz J. Kovacs M.J. Anderson D.R. Turpie A.G. Green D. Ginsberg J.S. Wells P. MacKinnon B. Julian J.A. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.1:CAS:528:DyaK1MXit1aitb0%3D10.1056/NEJM199903253401201N Engl J Med. 1999; 340: 901-907Google Scholar,28.the Duration of Anticoagulation Trial Study Group The duration of oral anticoagulation therapy after a second episode of venous thromboembolism.1:CAS:528:DyaK2sXhsVektrc%3D10.1056/NEJM199702063360601N Engl J Med. 1997; 336: 393-398Google Scholar It is not yet clear whether factor V Leiden heterozygosity increases risk of recurrent venous thrombosis. A few studies21.Ridker P.M. Hennekens C.H. Lindpaintner K. Stampfer M.J. Eisenberg P.R. Miletich J.P. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently health men.1:CAS:528:DyaK2MXls1Kktb8%3D10.1056/NEJM199504063321403N Engl J Med. 1995; 332: 912-917Google Scholar,29.Simioni P. Prandoni P. Lensing A.W.A. Scudeller A. Sardella C. Prins M.H. Villalta S. Dazzi F. Girolami A. The risk of recurrent thromboembolism in patients with an Arg506-Gln mutation in the gene for Factor V (Factor V Leiden).1:CAS:528:DyaK2sXhsVekt74%3D10.1056/NEJM199702063360602N Engl J Med. 1997; 336: 399-403Google Scholar found increases in recurrence risk of 4- to 5-fold and 2-fold, respectively, but other studies found no increase.30.Rintelen C. Pabinger I. Knobl P. Lechner K. Mannhalter C. Probability of recurrence of thrombosis in patients with and without factor V Leiden.1:CAS:528:DyaK28Xhs1Cqtro%3D10.1055/s-0038-1650249Thromb Haemost. 1996; 75: 229-232Google Scholar,31.Eichinger S. Pbinger I. Stumpflen A. Hirschl M. Bialonczyk C. Schneider B. Mannhalter C. Minar E. Lechner K. Kyrle P.A. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden.1:CAS:528:DyaK2sXislOjs7w%3D10.1055/s-0038-1656023Thromb Haemost. 1997; 77: 624-628Google Scholar Currently, identification of factor V Leiden heterozygosity does not change the therapeutic approach to venous thrombosis or subsequent prophylaxis in most patients. For patients with recurrent venous thromboembolism, some clinicians recommend lifelong anticoagulation therapy, regardless of whether a genetic risk factor is present,32.Hyers T.M. Agnelli G. Hull R.D. Weg J.G. Morris T.A. Samama M. Tapson V.F. Antithrombotic therapy for venous thromboembolism.10.1378/chest.114.5_Supplement.561SChest. 1998; 114: 531S-560SGoogle Scholar while other clinicians would test patients to assist in decision-making about indefinite anticoagulant therapy and genetic counseling of patients and their families.Despite the reservations listed above, there are several arguments in favor of testing for factor V Leiden. In some circumstances, knowledge of the factor V Leiden status strongly influences patient management. Testing will identify factor V Leide
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