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(Circulation. 1995;92:2800-2802.)
© 1995 American Heart Association, Inc.

Articles

Factor V Leiden and Risks of Recurrent Idiopathic Venous Thromboembolism

Paul M. Ridker, MD; Joseph P. Miletich, MD; Meir J. Stampfer, MD; Samuel Z. Goldhaber, MD; Klaus Lindpaintner, MD; Charles H. Hennekens, MD

From the Divisions of Preventive Medicine (P.M.R., C.H.H.) and Cardiovascular Disease (P.M.R., S.Z.G., K.L.) and the Channing Laboratory (M.J.S.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School; the Department of Ambulatory Care and Prevention (C.H.H.), Harvard Medical School; and the Departments of Nutrition (M.J.S.) and Epidemiology (M.J.S., C.H.H.), Harvard School of Public Health, Boston, Mass; and the Division of Laboratory Medicine (J.P.M.), Washington University School of Medicine, St Louis, Mo.

	Abstract

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Background Whether Leiden mutation in the gene coding for coagulation factor V is associated with recurrent idiopathic venous thromboembolism (VTE) is unknown, but such data are necessary to evaluate the merits of genetic screening in secondary prevention of thromboembolic disease.

Methods and Results Among 14 916 apparently healthy men who provided DNA samples and were followed in the Physicians' Health Study through August 1994, 77 suffered an idiopathic VTE. These 77 men were followed for an additional average period of 68.3 months, during which time 11 (14.3%) suffered a recurrent idiopathic VTE. Factor V Leiden status was assessed in these men, and incidence rates of recurrence were calculated by genotype. All recurrent events occurred after cessation of anticoagulation. Seven recurrences occurred among 63 genetically unaffected subjects (11.1%; incidence rate, 1.82 per 100 person-years), while four occurred among those 14 heterozygous for factor V Leiden (28.6%; incidence rate, 7.46 per 100 person-years). Thus, factor V Leiden was associated with a fourfold to fivefold increase in risk of recurrent VTE (crude relative risk, 4.1; P=.04; age- and smoking-adjusted relative risk, 4.7; P=.047). There was no difference in mean time between index and recurrent events by genotype. Among heterozygous men, 76% of recurrent events were attributable to mutation.

Conclusions In prospective evaluation of 77 men with a history of idiopathic VTE, factor V Leiden was associated with a fourfold to fivefold increased risk of recurrent thrombosis. These data raise the possibility that patients with VTE affected by factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared with those without mutation.

Key Words: coagulation • genes • embolism

	Introduction

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A mutation in the gene coding for coagulation factor V appears to be the underlying cause of most cases of resistance to activated protein C, a recently described abnormality of hemostasis associated with pathological thrombus formation.^{1 2 3 4 5 6} This mutation, factor V Leiden, is present in 4% to 6% of the general population.^{7 8 9} Our data and others indicate that heterozygosity for factor V Leiden is associated with threefold to sevenfold elevations of risk for venous thrombosis, particularly events not related to cancer or surgery.^{7 8 9} Rates of thromboembolism among genetically affected women taking oral contraceptives are increased,¹⁰ as are risks among those homozygous for the mutation.^{11 12} Data are also available indicating that the risk of thrombosis associated with factor V Leiden appears to be limited to the venous system, with no increase in rates of arterial thrombosis, at least in the coronary and cerebral circulations.⁹

From a clinical perspective, screening programs for factor V Leiden to identify individuals at high risk for a first thrombosis are unlikely to be effective, since mutation is common in the general population and the occurrence of first venous thrombosis is rare. On the other hand, if factor V Leiden increases rates of recurrent thromboembolism, then it may be reasonable to screen patients who have survived a first event, since the risk of recurrence is substantial in this group. This approach to secondary prevention would be particularly useful if more aggressive or prolonged anticoagulation regimens are of greater net benefit among genetically affected patients who have already survived a first thrombotic event.

Among 14 916 apparently healthy men participating in the Physicians' Health Study, the presence of factor V Leiden was associated with an approximately threefold increase in risk of first idiopathic venous thrombosis.⁹ Here, we report whether factor V Leiden predicts risk of recurrence among 77 study participants who suffered a first idiopathic venous thromboembolism (VTE).

	Methods

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Detailed descriptions of the Physicians' Health Study (PHS) and methods to assess factor V Leiden have been reported.^{9 13} In brief, the PHS is a prospective cohort of 22 071 US male physicians 40 to 84 years old at study entry who were randomized in a double-blind, placebo-controlled, 2x2 factorial design to low-dose aspirin, ß-carotene, both, or neither and then were followed for the occurrence of vascular diseases and cancer. At enrollment, participants were asked to provide whole-blood samples. Of the 22 071 subjects, 14 916 provided baseline specimens (68%).

Participants in the PHS complete questionnaires annually concerning risk factors and disease outcomes. For any self-report of either deep venous thrombosis (DVT) or pulmonary embolism (PE), hospital records, death certificates, and autopsy reports are requested and reviewed by an end-points committee of physicians who use standardized criteria to confirm or reject the diagnosis of each reported event. A diagnosis of DVT was confirmed when there was documentation of either a positive venographic study or ultrasound study. Reported cases of DVT documented by impedance plethysmography or Doppler examination but not by ultrasonography were not considered confirmed. The diagnosis of PE was confirmed when a positive angiogram or ventilation-perfusion scan showed at least two segmental defects without ventilation defects. DVTs neither associated with cancer nor occurring after surgery were considered idiopathic. For the purposes of this analysis, a recurrent idiopathic VTE was defined as a second DVT or PE occurring 3 months after the initial event in which there was no evidence of temporal association with either cancer or recent surgery.

For each patient with a confirmed first idiopathic VTE, whole blood collected and stored at baseline was thawed, had DNA extracted, and was assayed for presence or absence of factor V Leiden by use of a polymerase chain reaction–based assay system.⁹

Since the 77 men who suffered a first idiopathic VTE had different lengths of follow-up after their initial event, person-years of exposure were calculated for each participant. For individuals suffering a recurrent idiopathic VTE, exposure was calculated as the time between diagnoses of the first and second VTEs. For those who did not suffer a recurrent event, exposure was calculated as the time between diagnosis of the first VTE and August 1994. For those who did not suffer a recurrent event but who died before August 1994, exposure was calculated as the time between diagnosis of the first VTE and the date of death. No participants were lost to follow-up.

Incidence rates of recurrent idiopathic VTE for patients with and without factor V Leiden were computed as the number of recurrent events divided by total exposure time for each group. The relative risk of recurrent idiopathic VTE associated with mutation was computed as the ratio of the incidence rate among genetically affected men divided by the incidence rate among those unaffected. The attributable fractions among the total group and the genetically affected group were computed.¹⁴ Adjusted estimates of risk were computed by use of Poisson regression models that controlled for age and smoking habit. All probability values are two sided.

	Results

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Of the 77 study participants who survived a first idiopathic VTE, 14 (18.2%) were heterozygous for factor V Leiden, while 63 (81.8%) were homozygous for the wild-type allele. After their index event, these 77 were followed for an average period of 68.3 months, during which time 11 (14.3%) suffered recurrent idiopathic VTE. The overall incidence rate of recurrent idiopathic VTE was 2.51 per 100 person-years of observation.

Seven episodes of recurrent idiopathic VTE occurred among 63 genetically unaffected subjects (11.1%; incidence rate, 1.82 per 100 person-years), while four occurred among 14 subjects heterozygous for factor V Leiden (28.6%; incidence rate, 7.46 per 100 person-years). Accordingly, the incidence rate difference between genetically affected and unaffected men was 5.64 per 100 person-years of follow-up. Thus, in crude analysis, presence of factor V Leiden was associated with a fourfold increase in risk of recurrent idiopathic VTE (relative risk, 4.1; P=.04) (Table). Among genetically affected men, 76% of recurrent events were estimated to be attributable to presence of the mutation, whereas in the total cohort of 77, the corresponding figure was 28%.

View this table: [in this window] [in a new window]   Table 1. Incidence Rates1 and Crude and Adjusted Incidence Rate Ratios2 of Recurrent Idiopathic Venous Thrombosis Among a Cohort of 77 Men Followed Prospectively in the Physicians' Health Study, Based on the Presence or Absence of Heterozygosity for Factor V Leiden

We reviewed records of the 11 men who suffered recurrent idiopathic VTE to determine anticoagulation treatment after the first event. In each case, intravenous heparin was initially given for a period between 5 and 9 days, and an outpatient regimen of oral warfarin was prescribed, usually for a period of 3 months. All recurrent events occurred after cessation of therapy. Compared with the index event, 5 recurrent events were contralateral DVTs, 1 was an ipsilateral DVT, 2 were contralateral DVTs complicated by PE, and 3 were isolated PEs.

The time between index and recurrent events ranged from 10 to 96 months for the genetically unaffected men who suffered a second idiopathic VTE and from 21 to 101 months for the men heterozygous for factor V Leiden. There was no difference in mean time between the index and recurrent events by genotype (41.4 versus 46.5 months, P=.8).

In multivariate analyses controlling simultaneously for age at first VTE and smoking habit, the relative risk of recurrent VTE associated with factor V Leiden was 4.6 (relative risk, 0.047). No statistically significant associations were found between factor V Leiden and body mass index, exercise frequency, hypertension, or diabetes.

	Discussion

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In prospective follow-up of 77 men who survived an initial idiopathic VTE, factor V Leiden was associated with a statistically significant fourfold to fivefold increase in risk of a recurrent event. Specifically, during an average follow-up period of 68.3 months, almost 30% of carriers suffered recurrent idiopathic VTE compared with 11% of those without mutation. All recurrent events occurred after cessation of standard outpatient anticoagulation regimens. The increased risk of recurrent VTE associated with factor V Leiden is additive to the 3.5-fold increase in risk of first idiopathic VTE associated with heterozygosity for this mutation previously described for these men.⁹

These findings have important implications for the management of patients experiencing a first idiopathic DVT or PE. Based on studies of patients admitted to hospital with VTE,^{15 16 17 18} current treatment recommendations from the American College of Chest Physicians include intravenous heparinization for a period of 5 to 7 days followed by 3 months of oral antithrombotic therapy with warfarin, with the dosage adjusted to an international normalized ratio between 2.0 and 3.0.¹⁹ In large part, these data are based on the belief that 3 months of oral anticoagulation is sufficient to prevent recurrences and longer periods may increase risks of hemorrhage.²⁰ On the other hand, there are lower rates of recurrent VTE when oral anticoagulant therapy is given for 6 months rather than 6 weeks,²¹ suggesting that longer-term therapy may provide a better benefit-to-risk ratio for some patients, particularly those in whom the index event was not associated with a reversible risk factor.²²

Since patients heterozygous for factor V Leiden may have substantially increased risks of recurrent disease, their net clinical benefit may be greater with long-term anticoagulation, whereas genetically unaffected individuals may not require long-term therapy. In this regard, our finding that recurrent events may occur years after cessation of anticoagulation therapy is not unique. Indeed, in one study, 24% of patients with idiopathic VTE treated with warfarin for 3 months suffered a recurrent event within 2 years,²³ and recurrence rates in a trial of short- versus long-term anticoagulation ranged between 10% and 20% over a similar period.²¹ In addition, recurrence rates of 30% have been reported among older patients with a history of DVT.²⁴ Whether these patients were also disproportionately affected by mutation in the gene coding for coagulation factor V is unknown.

Although statistically significant, the present data are based on small numbers. Nonetheless, our finding that patients at high risk for recurrence can easily be identified on the basis of their genotype raises the possibility that secondary screening programs using factor V Leiden testing may have clinical utility. Before widespread secondary screening can be advocated, however, it is necessary to discern whether more prolonged or intense anticoagulation regimens will reduce these high rates of recurrent disease with an acceptable risk profile. Thus, these data support a need for randomized trials of long-term versus short-term anticoagulation with adjusted-dose warfarin in the secondary prevention of VTE among individuals heterozygous for factor V Leiden. Additional trials of low-molecular-weight heparin and oral direct thrombin inhibitors may also merit consideration in this high-risk population.

	Acknowledgments

 
Dr Ridker is the recipient of a Clinician Scientist Award from the American Heart Association, Dallas, Tex.

	Footnotes

 
Reprint requests to Dr Paul Ridker, Brigham and Women's Hospital, 900 Commonwealth Ave East, Boston, MA 02115.

Received August 23, 1995; revision received September 14, 1995; accepted September 15, 1995.

	References

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