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15 November 1997 | Volume 127 Issue 10 | Pages 895-903
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.
In 1993, investigators in Sweden and the Netherlands described a novel defect in the hemostatic pathway, referred to as resistance to activated protein C [5-7]. A single adenine-for-guanine point mutation in the gene coding for coagulation factor V leads to the replacement of arginine by glutamine at position 506. This site is one of the three cleavage sites on factor V for the natural anticoagulant activated protein C. This mutation, which is known as factor V Leiden, makes the activated form of factor V (Va) relatively resistant to degradation by activated protein C. This, in turn, leads to the laboratory abnormality of resistance to activated protein C (Figure 1). Factor V Leiden mutation is responsible for most cases of resistance to activated protein C [8-13]. REVIEW
Factor V Leiden Mutation and the Risks for Thromboembolic Disease: A Clinical Perspective
Thrombophilia is an increased propensity to form thrombosis in the arterial or venous circulation [1, 2]. When patients have thromboembolic disease at a young age, have recurrent thromboembolism, or have a strong family history of thromboembolism, physicians often begin a laboratory workup for thrombophilia. The evaluation usually includes a search for inherited disorders of hemostasis by measurement of antithrombin III, protein C, and protein S levels, as well as qualitative and quantitative assays for fibrinogen [1-4]. Acquired abnormalities, such as lupus anticoagulant and antiphospholipid antibody, are also often included in the assessment [1, 2]. In most cases, however, no defect is identified.
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Clinical studies indicate that factor V Leiden mutation is associated with increased risks for primary [7, 9, 14, 15] and recurrent [16, 17] venous thromboembolism, for venous thrombosis during use of oral contraceptives [18-21] and pregnancy [21-23], and for thrombosis in the presence of other genetic and acquired abnormalities of anticoagulation [24-29]. On the basis of these observations, screening programs for factor V Leiden mutation have been proposed [21, 30, 31]. However, when deciding whether to evaluate a patient for factor V Leiden mutation, one must consider the prevalence of the mutation, the absolute and relative risks imparted by the mutation, the characteristics of available tests, and the benefit-to-risk ratios of any therapeutic intervention based on a positive test finding.
Methods
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Data Synthesis
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Although a definitive genetic diagnosis of factor V Leiden mutation status can be made by using techniques based on polymerase chain reaction [9-12], relatively simple plasma testing for resistance to activated protein C is available. The plasma-based test is performed by measuring the activated partial thromboplastin time in the presence and absence of activated protein C; results are expressed as a ratio of these values, normalized to pooled plasma [5, 32]. A reduced ratio correlates well with heterozygosity or homozygosity for factor V Leiden mutation (Figure 2).
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Many factors influence these values, and standard assays for resistance to activated protein C are less reliable when a patient is receiving anticoagulant therapy [32-35] or has lupus anticoagulant [35]. Protein S deficiency does not appreciably alter results [34]. Assay methods that use factor V-deficient plasma overcome these limitations and are now available as commercial kits that can be performed in most laboratories [33-37]. Genetic confirmation for the presence or absence of factor V Leiden mutation is generally recommended for persons with a positive result on plasma-based testing for resistance to activated protein C.
Prevalence
Unlike previously described inherited defects of hemostasis, factor V Leiden mutation is common. The carrier frequency of factor V Leiden mutation in healthy control populations ranges from 3% to 7% in Europe and the United States and may be as high as 15% in some selected groups [7, 15, 38, 39].
In the largest population study to date, the prevalence of factor V Leiden mutation was determined in a cohort of 4047 U.S. men and women [39]. In this cross-sectional study, the overall carrier frequency for the mutation was 3.71% (95% CI, 3.14% to 4.33%) and the allele frequency was 1.89% (CI, 1.61% to 2.21%). The observed distribution of genotypes was consistent with that predicted by the Hardy-Weinberg equilibrium. Prevalence of factor V Leiden mutation was highest in white persons (5.27% [CI, 4.42% to 6.22%]) and was significantly less prevalent in other ethnic groups (2.21% in Hispanic Americans, 1.23% in African Americans, 0.45% in Asian Americans, and 1.25% in Native Americans) (P < 0.001) [39]. Other reports also show that the mutation is not distributed equally among ethnic groups [38, 40-42]: It is notably uncommon in Asian and African populations, a fact that may explain the decreased risk for venous thromboembolism in these groups [43, 44].
Factor V Leiden Mutation and Risk for Venous Thromboembolism
The relation between factor V Leiden mutation and venous thromboembolism was first recognized in families severely affected by recurrent thrombosis [5, 6]. Of 14 families with thrombophilia, 9 (64%) had resistance to activated protein C; the disorder was inherited in a manner consistent with an autosomal dominant trait [5, 6]. Affected persons in these families have reduced thrombosis-free survival (Figure 3) [13]. In another selected series of unexplained juvenile or recurrent thrombosis, the prevalence of resistance to activated protein C was 52% to 64% [45]. Familial thrombosis and juvenile thrombosis are relatively rare, and it was initially uncertain whether factor V Leiden mutation was also an important risk factor for venous thrombosis in the general population.
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The significance of resistance to activated protein C as a risk factor for venous thromboembolism in the general population was shown in the Leiden Thrombophilia Study, a population-based case–control study of 301 patients younger than 70 years of age who had a first episode of deep venous thrombosis not related to a malignant condition [7]. Resistance to activated protein C was detected in 21% of patients with deep venous thrombosis compared with 5% of age- and sex-matched controls; this yielded an almost sevenfold (matched odds ratio, 6.6 [CI, 3.6 to 12.0]) increase in risk for deep venous thrombosis in persons with resistance to activated protein C. Subsequent analysis showed that 80% of these persons with resistance to activated protein C were heterozygous or homozygous for factor V Leiden mutation [9]. Other studies support the high correlation between resistance to activated protein C and factor V Leiden mutation [10-13]. In referral populations of patients with venous thromboembolism, factor V Leiden mutation is the most common identifiable risk factor (prevalence, 11% to 37%) [6, 7, 12, 14, 15].
The association between factor V Leiden mutation and the risk for venous thromboembolism was confirmed in a large prospective study of apparently healthy men participating in the Physicians' Health Study [15]. Among 14 916 men who had no history of cardiovascular disease or cancer, 121 cases of venous thromboembolism accrued during a mean follow-up period of 8.6 years. The prevalence of the mutation was 11.6% among men with venous thromboembolism compared with 6.0% among those who remained healthy during follow-up (relative risk, 2.7 [CI, 1.3 to 5.6]; P = 0.008). In patients whose events were considered idiopathic, the risk imparted by the mutation was higher (relative risk, 3.5 [CI, 1.5 to 8.4]; P = 0.004). No association was seen between factor V Leiden mutation and thromboembolism associated with surgery, trauma, or cancer (secondary events) (relative risk, 1.7 [CI, 0.6 to 5.3]; P = 0.3). The effects of the mutation seemed greatest among men older than 60 years of age; in this subgroup, the adjusted relative risk was 4.0 (CI, 1.6 to 9.7; P = 0.003) for any type of venous thrombosis and 7.0 (CI, 2.6 to 19.1; P < 0.001) for primary venous thrombosis (Figure 4).
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Patients homozygous for factor V Leiden mutation seem to be at even higher risk. In the Leiden Thrombophilia Study, the risk for venous thromboembolism among patients homozygous for factor V Leiden mutation was increased 80-fold (CI, 22-fold to 289-fold) [7, 14]. Furthermore, homozygous patients who were presented with initial thromboembolism at a younger age (median age, 31 years) than did those who were heterozygous (median age, 44 years) or unaffected (median age, 46 years) by the mutation [14].
In cross-sectional and retrospective studies, the age at first thromboembolic event has been reported to be slightly less in patients heterozygous for factor V Leiden mutation than in persons without the mutation [5, 7, 9, 14, 45]. However, reports of increased thromboembolic risk among young carriers of factor V Leiden mutation probably reflect an increased prevalence of trauma, use of oral contraceptives, and pregnancy in this group compared with older persons. In studies not confounded by the presence of these acquired risk factors, risks associated with factor V Leiden mutation increase with age. In the Physicians' Health Study, for example, the incidence of thromboembolism among heterozygous male carriers of factor V Leiden mutation increased with age at a rate significantly greater than that in unaffected men (P for trend across age groups = 0.008) [46]. In particular, for men 70 years of age or older, the incidence of venous thromboembolism in genetically affected men was significantly greater than that in unaffected men (7.83 compared with 1.86 events per 1000 person-years; P = 0.028) [46].
Interaction with Concomitant Inherited Defects of Hemostasis
Factor V Leiden mutation enhances the risk for thrombosis in patients with other thrombophilic states, such as protein C and protein S deficiencies or hyperhomocystinemia [24-29]. In a study of 113 patients with symptomatic protein C deficiency, the prevalence of the factor V Leiden mutation was 14% [24]. In a study of seven families with both protein S deficiency and factor V Leiden mutation, 72% of members with both defects had a thrombotic event compared with 19% of those with only protein S deficiency and 19% of those with only factor V Leiden mutation [26].
Factor V Leiden mutation also seems to enhance the thrombotic risk associated with both inherited and acquired forms of hyperhomocystinemia [28, 29]. In one study of 11 patients with homozygous familial homocystinuria, the 6 who demonstrated clinically apparent thrombosis were heterozygous or homozygous for factor V Leiden mutation [28]. Factor V Leiden also seems to modulate the thrombotic risk associated with moderately elevated homocysteine levels because of less severe genetic defects or inadequate intake of vitamin B6, vitamin B (12), or folate. In a prospective study of men evaluated for moderate hyperhomocystinemia and factor V Leiden mutation, those with both disorders had a 10-fold increase in risk for any form of venous thromboembolism (relative risk, 9.65; P = 0.009) and a 20-fold increase in the risk for idiopathic venous thromboembolism (relative risk, 21.8; P = 0.0004) compared with men who had neither abnormality (Figure 5, left). In this study, the risk for developing idiopathic thromboembolism in doubly affected persons was significantly greater than the risk associated with either condition alone [29]; this observation may help explain why some [47-50] but not all [51, 52] previous studies of hyperhomocystinemia found positive associations with venous thromboembolism.
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Use of Oral Contraceptives and Postmenopausal Estrogen Replacement
Oral contraceptives increase the risk for venous thromboembolism [53]. A recent World Health Organization case–control study of 1143 women with venous thromboembolism [54] showed that the relative risk among persons using oral contraceptives compared with persons who did not use oral contraceptives was 4.15 (CI, 3.09 to 5.57) in Europe and 3.25 (CI, 2.59 to 4.08) in developing countries.
As with other inherited thrombophilic states [55], use of oral contraceptives seems to augment the increased risk for venous thromboembolism associated with factor V Leiden mutation [18-21]. In a comparison between 155 consecutive premenopausal woman who presented with deep venous thrombosis not related to a malignant condition and a control sample of 169 premenopausal woman without history of venous thromboembolism, the risk for thromboembolic events was increased fourfold with oral contraceptive use alone (relative risk, 3.8 [CI, 2.4 to 6.0]) and increased eightfold with factor V Leiden mutation alone (relative risk, 7.9 [CI, 3.2 to 19.4]). However, the risk for thromboembolic events was increased more than 30-fold in women with factor V Leiden mutation who also used oral contraceptives (relative risk, 34.7 [CI, 7.8 to 154]) (Figure 5, right) [18].
Oral contraceptives with a third-generation progestogen result in a significantly greater risk for venous thromboembolism both in persons who carry factor V Leiden mutation and normal persons than in persons who used contraceptives that contained a second-generation progestogen [19, 56]. This observation suggests that estrogen content may not be solely responsible for the thrombotic risk seen in users of oral contraceptives.
Increased risks for thromboembolism associated with oral contraceptive use and factor V Leiden mutation are supported by other, smaller studies [19-21]. Persons who are homozygous for factor V Leiden may be at especially high risk in this setting [20]. It has also been suggested that oral contraception may cause resistance to activated protein C independent of the factor V mutation [57-59]. The clinical effect of acquired resistance to activated protein C is uncertain.
The use of estrogen as hormone replacement therapy in postmenopausal women has not traditionally been considered a major risk factor for venous thromboembolism [60-63]. However, recent studies have challenged this view [64-66]. Specifically, two case–control studies from the United Kingdom [64] and the United States [65] showed that the relative risk for idiopathic thromboembolism was approximately 3.5 in users of oral estrogen replacement compared with nonusers (relative risk in the British study, 3.5 [CI, 1.8 to 7.0]; relative risk in the U.S. study, 3.6 [CI, 1.6 to 7.8]). In addition, a large prospective cohort study [66] demonstrated that in 123 cases of primary pulmonary embolism, the risk was significantly higher in current users of postmenopausal hormones than in nonusers (adjusted relative risk, 2.1 [CI, 1.2 to 3.8]).
No studies have examined the potential interaction between factor V Leiden mutation and hormone replacement therapy. However, compared with women using oral contraceptives, those receiving replacement therapy tend to be older and thus have a higher absolute risk for idiopathic thromboembolism. Thus, the absolute increase in risk associated with factor V Leiden mutation may be greater among persons using hormone replacement therapy than among those using oral contraceptives.
Risk for Venous Thromboembolism during Pregnancy
Pregnancy and the puerperium predispose women to venous thromboembolism, which is a major cause of maternal death [67, 68]. The cause of the increased risk is uncertain but may be related to pregnancy-induced changes in hemostasis [69-71]. In this regard, associations between venous thromboembolism during pregnancy and factor V Leiden mutation have been reported [21-23]. In small case series, 40% to 59% of women with pregnancy-related venous thromboembolism had resistance to activated protein C or factor V Leiden mutation. In one study [22], carriers of the mutation seemed more prone to develop thrombosis during the first pregnancy. In another study of 50 patients with second-trimester pregnancy loss [72], the prevalence of resistance to activated protein C was 20%, significantly higher than the prevalence in women who only had a history of first-trimester miscarriage (5.7%; P < 0.02) and the prevalence in controls (4.3%; P < 0.02). Finally, studies have shown that resistance to activated protein C can be acquired during pregnancy [23, 73]. All of these observations require confirmation in larger controlled studies.
Risk for Recurrent Venous Thromboembolism
An important clinical problem for patients with a first episode of thromboembolism is the high risk for recurrence. In a recent long-term follow-up study of 355 patients with a first episode of symptomatic venous thrombosis, the incidence of recurrent disease was 30.3% after 8 years (CI, 23.6% to 37.0%) [74]. The presence of factor V Leiden mutation may be associated with an increased rate of recurrence [16, 17]. One prospective study followed 77 men who survived an initial episode of idiopathic venous thromboembolism for an average of 68.3 months [16]. Persons with factor V Leiden mutation were four times more likely to have a recurrent event (relative risk, 4.1; P = 0.04), such that 76% of recurrences were attributable to mutation. All recurrences occurred after cessation of standard anti-coagulant therapy.
Another prospective trial of 251 patients with a first episode of deep venous thrombosis reported that 16.3% carried factor V Leiden mutation [17]. All patients were followed for as long as 8 years (mean duration of follow-up, 3.9 years), during which time those with factor V Leiden mutation had a higher risk for recurrent thromboembolism than did those without the mutation (39.7% compared with 18.3%; hazard ratio, 2.4 [CI, 1.3 to 4.5]; P < 0.01).
A smaller retrospective study compared 21 patients who had factor V Leiden mutation (5 homozygotes and 16 heterozygotes) with age- and sex-matched controls who had venous thromboembolism without mutation [75]. All 5 homozygotes had had recurrent events before the study period compared with 9 of 16 heterozygotes and 9 of 21 persons without mutation. During the observation period, homozygotes had a rate of recurrence of 9.5% per patient per year. Patients who were heterozygous for the mutation did not have a significantly higher rate of recurrence than did those without the mutation (4.8% per patient per year compared with 5% per patient per year); follow-up in this study was limited.
Risk for Arterial Thromboembolism
Arterial thromboembolism, predominantly myocardial infarction and stroke, is the leading cause of illness and death in the United States. After two case reports of early myocardial infarction in patients homozygous for factor V Leiden mutation [76] and other case reports suggesting an association with stroke [77-79], several investigators hypothesized that this mutation might be an important risk factor for arterial thrombotic events. In the largest study to address this issue, however, no significant difference in the prevalence of the factor V mutation was found between men with myocardial infarction (6.1%; P >0.2) or cerebrovascular disease (4.3% percent; P >0.2) and men without cardiovascular disease (6%) [15]. Furthermore, most population-based and case–control studies confirm that factor V Leiden mutation is not a risk factor for myocardial infarction [80-83] or cerebrovascular disease [84-86].
Screening for Factor V Leiden Mutation
Venous thromboembolism is associated with more than 300 000 hospitalizations annually in the United States, and pulmonary embolism is directly responsible for 50 000 to 100 000 deaths each year [87-89]. However, despite strong associations between factor V Leiden mutation and risks for thromboembolism, decisions on whether to screen for this inherited defect are complex and vary in different clinical settings.
For example, the lifetime risk for venous thromboembolism among unselected persons is lower than the population prevalence of the factor V Leiden mutation. Thus, screening programs for primary prevention are likely to be inefficient. In fact, if persons found to carry the mutation are subsequently advised to use long-term anticoagulant therapy, screening intended for primary prevention could result in a net clinical hazard because the lifetime risks of anticoagulation are substantial.
In contrast, screening for factor V Leiden mutation may prove effective among patients who have had a first episode of venous thromboembolism and are at substantial risk for recurrence. In this group, however, the risks for recurrent thromboembolic disease associated with the factor V Leiden mutation seem to be limited to events without a short-term risk factor [16]. Thus, it is unlikely that screening before surgery is warranted, particularly because adequate thromboprophylaxis in the postoperative period reduces risks in all patients regardless of factor V Leiden status [90]. Moreover, no data from randomized trials are available to show that long-term prophylaxis will prevent recurrent thromboses among patients identified as carrying the factor V Leiden mutation. Clinical trials designed to evaluate the benefit-to-risk ratio of factor V Leiden mutation screening and subsequent long-term anticoagulation are therefore needed. Such trials will need to consider that differential rates of mutation occur in various patient groups [39, 40] and that thrombosis associated with factor V Leiden mutation is not limited to young patients [47].
Among pregnant women, maternal death from pulmonary embolism is rare, occurring in 1 to 5 of every 100 000 deliveries [68, 91]. If half of these events occurred among the 5% of women who carry factor V Leiden mutation, then the frequency of puerperal death from pulmonary embolism among women with the mutation ranges from 1 in 2000 to 1 in 15 000 [92]. However, it has also been estimated that the risks for severe complications associated with anticoagulation during and after pregnancy might also affect approximately 1 in 2000 women [92]. Thus, in this higher-risk group, screening for factor V Leiden mutation also has uncertain utility.
Among young women using oral contraceptives, the risk for venous thrombosis is increased, particularly among those with factor V Leiden mutation [18, 20]. In this age group, however, the absolute risk is sufficiently low that even large differences in relative risks may be of limited importance. For example, the estimated incidence of venous thromboembolism in young women is 2 per 10 000 person-years, and the incidence of fatal pulmonary embolism is 6 per 100 000 person-years [92]. Assuming that all fatal events are attributable to factor V Leiden mutation, almost half a million women would require screening to identify the 20 000 to 25 000 women who carry the mutation and would be denied oral contraception in order to avoid one death per year [92]. In this setting, the costs of such a program are formidable and the possibility of a net medical hazard must again be considered, particularly if women denied oral contraception do not obtain an alternative and equally effective form of birth control.
Thus, until clinical trials showing efficacy of longterm therapy are undertaken, screening for the factor V Leiden mutation is likely to remain clinically important for persons with a family or personal history of thrombophilia. In this group, knowledge of factor V Leiden mutation status may be particularly useful if the affected person or family member is found to be homozygous [14]. It is important to recognize, however, that the identification of those who should avoid oral contraception and those who will require gestational or puerperal anticoagulation can often be achieved by a complete family and personal history in which previous thromboembolic events are carefully emphasized [93].
Dr. Ridker: Division of Cardiovascular Diseases, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
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References
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1. Schafer AI, The hypercoagulable states. Ann Intern Med. 1985; 102:814-28.
2. Nachman RL, Silverstein R. Hypercoagulable states. Ann Intern Med. 1993; 119:819-27.
3. Heijboer H, Brandjes DP, Buller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deepvein thrombosis. N Engl J Med. 1990; 323:1512-6.
4. Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis Cell. 1993; 72:477-80.
5. Dahlback B, Carlsson M, Svensson PJ. 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. Proc Natl Acad Sci U S A. 1993; 90:1004-8.
6. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med. 1994; 330:517-22.
7. Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet. 1993; 342:1503-6.
8. Dahlback B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A. 1994; 91:1396-400.
9. Bertina RM, Koeleman B, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994; 369:64-7.
10. Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis Lancet. 1994; 343:1536-8.
11. Sun X, Evatt B, Griffin JH. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Blood. 1994; 83:3120-5.
12. Voorberg J, Roelse J, Koopman R, Buller H, Berends F, ten Cate JW, et al. Association of idiopathic venous thromboembolism with single pointmutation at Arg506 of factor V. Lancet. 1994; 343:1535-6.
13. 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.
14. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995; 85:1504-8.
15. 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.
16. Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and recurrent idiopathic venous thromboembolism. Circulation. 1995; 92:2800-2.
17. Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH, et al. The risk of recurrent venous thromboembolism in patients with an Arg506
Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med. 1997; 336:399-403.
18. 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.
19. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet. 1995; 346:1593-6.
20. Rintelen C, Mannhalter C, Ireland H, Lane DA, Knobl P, Lechner K, et al. Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. Br J Haematol. 1996; 93:487-90.
21. Hellgren M, Svensson P, Dahlback B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol. 1995; 173:210-3.
22. Bokarewa MI, Bremme K, Blomback M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol. 1996; 92:473-8.
23. Hirsch DR, Mikkola KM, Marks PW, Fox EA, Dorfman DM, Ewenstein BM, et al. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J. 1996; 131:1145-8.
24. Gandrille S, Greengard JS, Alhenc-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, et al. Incidence of activated protein C resistance caused by the ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. The French Network on the behalf of INSERM. Blood. 1995; 86:219-24.
25. Koeleman BP, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood. 1994; 84:1031-5.
26. Zoller B, Berntsdotter A, Garcia de Frutos P, Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood. 1995; 85:3518-23.
27. Koeleman BP, van Rumpt D, Hamulyak K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families? Thromb Haemost. 1995; 74:580-3.
28. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, et al. Coexistence of hereditary homocystinuria and factor V Leiden-effect on thrombosis. N Engl J Med. 1996; 334:763-8.
29. 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.
30. Dahlback B. Are we ready for factor V Leiden screening? Lancet. 1996; 347:1346-7.
31. Rosendaal FR. Oral contraceptives and screening for factor V Leiden [Letter]. Thromb Haemost. 1996; 75:524-5.
32. de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost. 1994; 72:880-6.
33. Tosetto A, Rodeghiero F. Diagnosis of APC resistance in patients on oral anticoagulant therapy [Letter]. Thromb Haemost. 1995; 73:732-3.
34. Cadroy Y, Sie P, Alhenc-Gelas M, Aiach M. Evaluation of APC resistance in the plasma of patients with Q506 mutation of factor V (factor V Leiden) and treated with oral anticoagulants [Letter]. Thromb Haemost. 1995; 73:734-5.
35. Halbmeyer WM, Haushofer A, Schon R, Fischer M. Influence of lupus anticoagulant in a commercially available kit for APC-resistance [Letter]. Thromb Haemost. 1994; 72:643-51.
36. Gilmore G, Thom J, Baker RI. Diagnosis of APC resistance in patients on standard or low molecular weight heparin [Letter]. Thromb Haemost. 1996; 75:372-3.
37. Le DT, Griffin JH, Greengard JS, Mujumdar V, Rapaport SI. Use of a generally applicable tissue factor-dependent factor V assay to detect activated protein C-resistant factor Va in patients receiving warfarin and in patients with a lupus anticoagulant. Blood. 1995; 85:1704-11.
38. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995; 346:1133-4.
39. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA. 1997; 277:1305-7.
40. Mannucci PM, Duca F, Peyvandi F, Tagliabue I, Merati G, Martinelli I. et al. Frequency of factor V Arg506 Gln in Italians [Letter]. Thromb Haemost. 1996; 75:694.
41. Chan LC, Bourke C, Lam CK, Liu HW, Brookes S, Jenkins V, et al. Lack of activated protein C resistance in healthy Hong Kong Chinese blood donors-correlation with absence of Arg506-Gln mutation of factor V gene [Letter]. Thromb Haemost. 1996; 75:522-3.
42. Fujimura H, Kambayash J, Monden M, Kato H, Miyata T. Coagulation factor V Leiden mutation may have a racial background [Letter]. Thromb Haemost. 1995; 74:1381-2.
43. Burkitt DP. Varicose veins, deep vein thrombosis, and haemorrhoids: epidemiology and suggested aetiology. BMJ. 1972; 2:556-61.
44. Nathwani AC, Tuddenham EG. Epidemiology of coagulation disorders. Baillieres Clin Haemotol. 1992; 5:383-439.
45. Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in the majority of thrombophilic patients. Blood. 1993; 82:1989-93.
46. Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer MJ, Hennekens CH. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med. 1997; 126:528-31.
47. den Heijer M, Blom HJ, Gerrits WB, Rosendaal FR, Haak HL, Wijermans PW, et al. Is hyperhomocysteinaemia a risk factor for recurrent thrombosis? Lancet. 1995; 345:882-5.
48. den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996; 334:759-62.
49. Falcon CR. Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb. 1994; 14:1080-3.
50. Bienvenu T, Ankri A, Chadefaux B, Kamoun P. [Plasma homocysteine assay in the exploration of thrombosis in young subjects.] Presse Med. 1991; 20:985-8.
51. Brattstrom L, Tengborn L, Lagerstedt C, Israelsson B, Hultberg B. Plasma homocysteine in venous thromboembolism. Haemostasis. 1991; 21:51-7.
52. Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol. 1995; 15:1321-3.
53. Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. Br Med J (Clin Res Ed). 1986; 292:526.
54. Venous thromboembolic disease and combined oral contraceptives: results of the international multicentre case–control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995; 346:1575-82.
55. Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural Inhibitors. Thromb Haemost. 1994; 71:548-52.
56. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995; 346:1582-8.
57. Bokarewa MI, Falk G, Sten-Linder M, Egberg N, Blomback M, Bremme K. Thrombotic risk factors and oral contraception. J Lab Clin Med. 1995; 126:294-8.
58. Henkens CM, Bom VJ, Seinen AJ, van der Meer J. Sensitivity to activated protein C: influence of oral contraceptives and sex. Thromb Haemost. 1995; 73:402-4.
59. Olivary O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, et al. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol. 1995; 91:465-70.
60. Surgically confirmed gallbladder disease, venous thromboembolism, and breast tumors in relation to postmenopausal estrogen therapy. A report from the Boston Combined Surveillance Program, Boston University Medical Center. N Engl J Med. 1974; 290:15-9.
61. Petitti DB, Wingerd J, Pellegrin F, Ramcharan S. Risk of vascular disease in women. Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA. 1979; 242:1150-4.
62. Natchigall LE, Natchigall RH, Natchigall RD, Beckman EM. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol. 1979; 54:74-9.
63. Devor M, Barrett-Connor E, Renvall M, Feigal D Jr. Ramsdell J. Estrogen replacement therapy and risk of venous thrombosis. Am J Med. 1992; 92:275-82.
64. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348:977-80.
65. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996; 348:981-3.
66. Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, et al. Prospective study of exogenous hormones and risk of pulmonary embolism. Lancet. 1996; 348:983-7.
67. Sachs BP, Brown DA, Driscoll SG, Schulman E, Acker D, Ransil BJ, et al. Maternal mortality in Massachusetts. Trends and prevention. N Engl J Med. 1987; 316:667-72.
68. Sipes SL, Weiner CP. Venous thromboembolic disease in pregnancy. Semin Perinatol. 1990; 14:103-18.
69. Stirling Y, Woolf L, North WR, Seghatchian MJ, Meade TW. Haemostasis of normal pregnancy. Thromb Haemost. 1984; 52:176-82.
70. Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood. 1986; 68:881-5.
71. Friederich PW, Sanson B, Simoni P, Zanardi S, Huisman MV, Kindt I, et al. Frequency of pregnancy-related venous thrombembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann Intern Med. 1996; 125:955-60.
72. Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haemotol. 1996; 92:489-90.
73. Cumming AM, Tait RC, Fildes S, Yoong A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol. 1995; 90:725-7.
74. Prandoni P, Lensing AW, Cogo A, Cuppini S, Villata S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125:1-7.
75. Rintelen C, Pabinger I, Knobl P, Lechner K, Mannhalter C. Probability of recurrence of thrombosis in patients with and without factor V Leiden. Thromb Haemost. 1996; 75:229-32.
76. Holm J, Zoller B, Svensson P, Berntorp E, Erhardt L, Dahlback B. Myocardial infarction associated with homozygous resistance to activated protein C [Letter]. Lancet. 1994; 344:952-3.
77. Halbmayer WM, Haushofer A, Schon R, Fischer M. The prevalence of poor anticoagulant response to activated protein C (APC resistance) among patients suffering from stroke or venous thrombosis and among healthy subjects. Blood Coagul Fibrinolysis. 1994; 5:51-7.
78. Simioni P, de Ronde H, Prandoni P, Saladini M, Bertina RM, Girolami A. Ischemic stroke in young patients with activated protein C resistance. A report of three cases belonging to three different kindreds. Stroke. 1995; 26:885-90.
79. Albucher JF, Guiraud-Chaumeil B, Choller F, Cadroy Y, Sie P. Frequency of resistance to activated protein C due to factor V mutation in young patients with ischemic stroke [Letter]. Stroke. 1996; 27:766-7.
80. Emmerich J, Poirier O, Evans A, Marques-Vidal P, Arveiler D, Luc G, et al. Myocardial infarction, Arg 506 to Gln factor V mutation, and activated protein C resistance [Letter]. Lancet. 1995; 345:321.
81. Samani NJ, Lodwick D, Martin D, Kimber P. Resistance to activated protein C and risk of premature myocardial infarction [Letter]. Lancet. 1995; 344:1709-10.
82. Demarmels Biasiutti F, Merlo C, Furlan M, Sulzer I, Binder BR, Lammle B. No association of APC resistance with myocardial infarction. Blood Coagul Fibrinolysis. 1995; 6:456-9.[Medline]
83. Prohaska W, Mannebach H, Schmidt M, Gleichmann U, Kleesiek K. Evidence against heterozygous coagulation factor V 1691 GA mutation with resistance to activated protein C being a risk factor for coronary artery disease and myocardial infarction. J Mol Med. 1995; 73:521-4.
84. Press RD, Liu XY, Beamer N, Coull BM. Ischemic stroke in the elderly. Role of common factor V mutation causing resistance to activated protein C. Stroke. 1996; 27:44-8.
85. Zuber M, Toulon P, Mas JL. Resistance to activated protein C in cerebral thromboembolism: a case control study. Cerebrovascular Disease. 1995; 5:189.
86. Cushman M, Bhushan F, Bovill E, Tracy R. Plasma resistance to activated protein C in venous and arterial thrombosis [Letter]. Thromb Haemost. 1994; 72:647.
87. Prevention of venous thrombosis and pulmonary embolism. NIH Consensus Development. JAMA. 1986; 256:744-9.
88. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT study. Arch Intern Med. 1991; 151:933-8.[Abstract]
89. Kniffin WD Jr, Baron JA, Barrett J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med. 1994; 154:861-6.[Abstract]
90. Crowther MA, Hayward CP, Hamid C, Johnston M, Gent M, Levine M, et al. Activated protein C resistance is not associated with postoperative deep vein thrombosis in patients undergoing hip or knee surgery [Abstract]. Blood. 1995; 86(Suppl 1):616a.
91. Treffers PE, Huidekoper BL, Weenink GH, Kloosterman GJ. Epidemiological observations of thromboembolic disease during pregnancy and in the puerperium, in 56,022 women. Int J Gynaecol Obstet. 1983; 21:327-31.
92. Vandenbroucke JP, van der Meer FJ, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ. 1996; 313:1127-30.
93. Lee RV. Thromboembolic disease and pregnancy: are all women equal? [Editorial] Ann Intern Med. 1996; 125:1001-3.
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