Published online before print April 11, 2002, doi: 10.1161/01.ATV.0000018301.91721.94
© 2002 American Heart Association, Inc.
Thrombosis |
Factor V Leiden, Hormone Replacement Therapy, and Risk of Venous Thromboembolic Events in Women With Coronary Disease
From the Department of Internal Medicine, Sections on Cardiology (D.M.H., D.A.M.), Medical Genetics (T.D.H.), and Hematology and Oncology (J.O.), and the Departments of Public Health Sciences (D.M.R.) and Biochemistry (D.B.), Wake Forest University School of Medicine, Winston-Salem, NC; the Department of Epidemiology and Biostatistics (E.V., J.A.S., D.G., S.B.H.), University of California, San Francisco; and the Department of Medicine (V.B.), University of Alabama at Birmingham.
Reprint requests to David M. Herrington, MD, MHS, Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail dherring{at}wfubmc.edu
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Abstract |
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Abstract— Oral contraceptive use in women with factor V Leiden is associated with increased rates of venous thromboembolic events (VTEs). However, the effects of hormone replacement therapy (HRT) in postmenopausal women with factor V Leiden are not known. A nested case-control study was conducted among women with established coronary disease enrolled in 2 randomized clinical trials of HRT, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) trial. The Leiden mutation was present in 8 (16.7%) of 48 cases with VTE compared with only 7 (6.3%) of 112 controls (odds ratio [OR]Leiden 3.3, 95% CI 1.1 to 9.8; P=0.03). In women without the factor V Leiden mutation, risk associated with HRT use was significantly increased (ORHRT 3.7, 95% CI 1.4 to 9.4; P<0.01). On the other hand, in women with the factor V Leiden mutation, the estimated risk associated with HRT was increased nearly 6-fold, although the CIs were wide and included unity (ORHRT 5.7, 95% CI 0.6 to 53.9; P=0.13). The OR for women with the Leiden mutation who were also assigned to HRT compared with wild-type women assigned to placebo was 14.1 (95% CI 2.7 to 72.4, P=0.0015). In women with the factor V Leiden mutation who were treated with HRT, the estimated absolute incidence of VTE was 15.4 of 1000 per year compared with 2.0 of 1000 per year in women without the mutation who were taking a placebo (P=0.0015). On the basis of these data, in women with coronary disease, the estimated number needed to screen for factor V Leiden to avoid an HRT-associated VTE during 5 years of treatment is 376. If factor V Leiden genotyping becomes less expensive, it could be cost effective to screen for the presence of the mutation before instituting HRT in women with coronary disease.
Key Words: cardiology • risk factors for stroke • genetics • thrombosis risk factors
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Introduction |
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In 1994, Bertina et al1 described a single point mutation in the gene coding for factor V. This mutation, referred to as the factor V Leiden mutation, renders factor Va relatively resistant to degradation by the natural anticoagulant, activated protein C (APC).2,3 The presence of this mutation or its functional consequence, APC resistance, is associated with an increased risk of venous thromboembolic events (VTEs).1,4–6 Risk for VTE appears to be even higher in women with APC resistance or the factor V Leiden mutation who are also pregnant7–11 or who use oral contraceptives.7,12–15 The effect of hormone replacement therapy (HRT) on the risk of VTE in women with APC resistance is not well established. One observational study found a multiplicative relationship between the effects of HRT and APC resistance on VTE risk,16 whereas a small randomized clinical trial of oral HRT in women with previously verified VTE failed to confirm such a relationship.17 Determining the relative and absolute impact of HRT and factor V Leiden on VTE risk is especially important for older women or for women with coronary disease, whose baseline risk of VTE is considerably higher than that of healthy premenopausal women.18,19
See page 879
To evaluate the association between factor V Leiden and VTE in women with coronary disease and its impact on the relationship between HRT and VTE in this population, we conducted a nested case-control study among participants of 2 multicenter randomized clinical trials of HRT in women with established coronary disease, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) trial.
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Methods |
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Study Populations
The details of the HERS20 and ERA21 trial designs and primary results22,23 have been previously reported. Participants were postmenopausal women aged <80 years with documented coronary artery disease. The participating clinical centers included 22 academic or community hospitals scattered throughout the continental United States. The exclusion criteria for both trials included a history of deep vein thrombosis (DVT) or pulmonary embolism (PE). In HERS, participants were randomly assigned to receive oral conjugated equine estrogen (0.625 mg daily) plus medroxyprogesterone acetate (2.5 mg daily) or placebo and were followed for an average of 4.1 years. In ERA, women were randomized to receive oral conjugated equine estrogen (0.625 mg daily), estrogen plus medroxyprogesterone acetate (2.5 mg daily), or placebo and were followed for 3.25 years.
Data Collection
At 4- to 6-month follow-up visits, women were queried about blood clots in the legs or lungs or any hospitalizations. A positive reply prompted retrieval of all pertinent medical records to verify the occurrence of a VTE. A diagnosis of DVT required confirmation by venography, impedance plethysmography, or ultrasound. A diagnosis of PE required confirmation by a segmental or larger ventilation/perfusion mismatch on a nuclear lung scan or an intraluminal filling defect by pulmonary angiography. VTEs were classified as idiopathic if they occurred in women without a preexisting diagnosis of cancer or the occurrence of an inpatient hospitalization or lower extremity or hip fracture within 3 months before the VTE. Events were adjudicated by individuals who were unaware of treatment assignment or factor V genotype.
In HERS, 47 (1.7%) of the women had a VTE (32 DVTs and 15 PEs). At the final follow-up visit, cases and 2 age- and clinic-matched controls were asked to provide an additional specimen of whole blood for factor V genotyping. For women who could not return for the final visit or who had died, consent was sought from them or their next of kin to use a previously collected Pap smear for extraction of DNA and genotyping. Consent was obtained, and factor V genotype was ascertained in 40 of 47 cases and 80 matched controls. Three of the remaining 7 cases declined participation, 3 did not have blood or a Pap smear available for analysis, and 1 matched control had a Pap smear that did not yield enough DNA for genotyping. In ERA, 8 (2.6%) of the women had a VTE (6 DVTs and 2 PEs). DNA for genotyping was available for all 8 cases. In view of the smaller number of VTE cases in ERA, 4 age- and clinic-matched controls were selected per case. For both cohorts, the study design and conduct were approved by the Wake Forest University Institutional Review Board.
Genotyping for the presence of the Leiden mutation (G1691A) in the factor V gene was performed on DNA extracted from anonymously labeled peripheral blood leukocytes or cells retrieved from Pap smears (Pap smear slides yielded 
200 ng DNA per slide). The genomic region containing the mutation site was amplified by polymerase chain reaction, and the presence of the Leiden mutation was inferred from the observed cleavage pattern with the restriction enzyme Mnl-I.1
Statistical Analyses
Baseline and on-study characteristics of the cases and controls were compared within each study and in the combined data; random effects models24 were used for continuous variables, and conditional logistic regression25 was used for binary variables, to take account of the matched case-control design. The association between factor V genotype and risk of VTE was examined by using conditional logistic regression models, again to take account of the matching and to adjust for treatment assignment. Odds ratios (ORs) generated by these models, accompanied by 95% CIs and nominal 2-tailed probability values, were used to approximate relative risks. In exploratory analyses, results from the 2 study cohorts were similar; therefore, the data from the 2 cohorts were combined. Similarly, preliminary analysis within the ERA cohort found no significant difference between the effects of unopposed estrogen and estrogen plus medroxyprogesterone acetate; thus, data from these 2 active treatment arms were combined. Additional models were also examined with adjustment for potential risk factors for VTE, including a previous diagnosis of cancer (excluding nonmelanoma skin cancer) or myocardial infarction (MI), inpatient hospitalization, or lower extremity or hip fracture within 90 days of the VTE, or use of aspirin or statins documented during the most recent clinic visit before the VTE. In these models, as well as in the initial comparison with cases, on-trial risk factors for controls were evaluated at the time in days since the randomization of VTE onset for the matched case. Tests for additive and multiplicative interaction were performed by using previously described methods.26
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Results |
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Characteristics of the VTE cases and controls from each clinical trial cohort are summarized in Table 1. In the pooled data, prior MI, cancer (other than nonmelanoma skin cancer), or hospitalization within 90 days were significantly associated with occurrence of VTE, and there was a nonsignificant trend toward increased risk among women with elevated triglycerides or a recent lower extremity or hip fracture and in women who did not use aspirin. In multivariate analyses, only hospitalization within 90 days and a history of MI remained significantly associated with VTE.
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The Leiden mutation was present in 8 (16.7%) of the 48 cases of VTE compared with only 7 (6.3%) of the 112 controls (Table 2). On the basis of these numbers, the estimated prevalence of factor V Leiden in the entire study population was 6.4%. After the age- and clinic-matched case-control design was taken into account and adjustments were made for treatment assignment, the risk of VTE was 3-fold greater in women with factor V Leiden compared with women without the mutation (ORLeiden 3.3, 95% CI 1.1 to 9.8; P=0.03). Similarly, the ORLeiden for a DVT was 3.2 (95% CI 1.0 to 10.3, P=0.05), and for a PE, it was 3.5 (95% CI 0.2 to 69.6, P=0.41). After additional adjustment for recent hospitalization and prior MI, the ORLeiden for VTE increased to 6.8 (95% CI 1.1 to 42.8, P=0.05). The number of cases was too small to support fully adjusted models with stable estimates for DVT or PE separately. Factor V Leiden was present in 5 (16%) of the 31 women with idiopathic VTE and 3 (18%) of the 17 women with nonidiopathic VTE.
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HRT use was associated with a >3-fold increase in the risk of VTE (OR 3.4, 95% CI 1.4 to 8.1; P=0.06). Adjustment for factor V Leiden status resulted in a slightly higher estimate of risk (ORHRT 3.9, 95% CI 1.6 to 9.6; P=0.004). After additional adjustment for recent hospitalization and prior MI, the risk associated with HRT use remained significant (ORHRT 4.8, 95% CI 1.3 to 17.5; P=0.02). Among women without factor V Leiden, the ORHRT was 4.5 (95% CI 1.2 to 16.9, P=0.02; Table 3). In contrast, among the fewer women with factor V Leiden, the OR for HRT suggested a >10-fold increase in risk compared with placebo; however, the CIs were wide and included unity (ORHRT 10.2, 95% CI 0.3 to 344; P=0.20). Compared with women without factor V Leiden taking placebo, women with factor V Leiden taking HRT had a 14-fold greater risk of VTE (ORHRT 14.1, 95% CI 2.7 to 72.4; P=0.002). Despite the suggestion of excess risk of HRT in women with factor V Leiden, formal tests for additive or multiplicative interaction were negative.
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Overall, 1.56% of the combined study cohort (n=3072) suffered a VTE. If it is assumed that the prevalence of factor V Leiden in the sample of controls was representative of all noncases, 2.08% of women with factor V Leiden had a VTE versus 1.49% of the women without factor V Leiden. If the variable length of follow-up among women in the 2 studies is taken into account, the overall incidence of VTE was 7.1 per 1000 women per year. In women without factor V Leiden who were assigned to placebo, the incidence of VTE was 2.0 (95% CI 0.8 to 3.2) events per 1000 women per year (Table 4). Treatment with HRT increased the estimated incidence to 5.8 events per 1000 women per year (95% CI 4.5 to 7.1). In factor V Leiden women treated with HRT, the incidence was further increased to 15.4 (95% CI 3.5 to 27.3) events per 1000 women per year. On the basis of these estimates, if women with coronary disease were screened for factor V Leiden before initiating HRT and if HRT was withheld from carriers of the mutation, the estimated number needed to screen to prevent 1 VTE during 5 years of therapy would be 376.
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Discussion |
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These data reveal significant increases in the risk of VTE in women with coronary disease who are carriers of the factor V Leiden mutation. The 6.4% prevalence of the mutation in this study population and the 3- to 6-fold relative increase in the risk of VTE in women with the mutation are consistent with earlier reports from studies of largely healthy normal subjects.27,28 However, because of the substantially higher baseline risk of VTE in this group of women with coronary disease, the absolute increase in risk associated with factor V Leiden (
0.5% per year) was much higher than that in healthier cohorts. Use of HRT in factor V Leiden–positive women further increased the risk to >1.5% per year. On the basis of these data, in women with coronary disease, 1 DVT might be prevented during a planned 5 years of treatment by withholding HRT from the expected 24 Leiden-positive women among 376 screened. For women who would use HRT for 10 years, the number needed to screen would be 188. The results of the present study are consistent with the results of previous studies demonstrating a multiplicative relationship between factor V Leiden or APC resistance and exogenous estrogen use and the risk of VTE.12,16 In a case-control study of idiopathic VTEs, Lowe et al16 observed a 13-fold increased risk in HRT users with APC resistance compared with women without APC resistance or HRT use; this risk was very similar to the 15-fold excess risk observed in the doubly exposed women in the present study.
The precise mechanism for the association between estrogen exposure and risk for VTE remains uncertain. Some,29–32 but not all, studies33 indicate that oral contraceptive use or pregnancy may result in an acquired form of APC resistance, similar to the functional defect associated with the factor V Leiden mutation. However, Douketis et al34 failed to find evidence of an effect of oral HRT on APC resistance. Currently available data are also inconsistent regarding the effects of HRT on thrombin generation or fibrinolytic potential.34
There are several limitations of the present study. The number of cases is small, thereby limiting precision in the estimates of the effects of factor V Leiden and the complexity of the models that could be used to adjust for other covariates. No information is available about concurrent thrombophilic states in the study participants. Some evidence suggests that factor V Leiden may be most important as a VTE risk factor in the presence of other thrombophilic conditions. Protein C deficiency,35 protein S deficiency,36 hyperhomocysteinemia,37 and the prothrombin G20210A genotype38 have all been reported to further increase the risk of VTE associated with factor V Leiden. The effects of HRT on the risk of VTE in women with or without heart disease who also have such thrombophilic conditions are not yet established. The estimates of the risk of VTE in the clinical trial participants reported in the present study may underestimate the risks in the general population, because women with a prior history of VTE or women with hypertriglyceridemia or advanced heart failure were excluded from participation. In addition, after it became clear that HRT was associated with an increased VTE risk in HERS, the protocol was changed so that HRT was withheld during acute hospitalizations, which may have further minimized the overall risk in this study population. Finally, the results of the present study may not apply to women of other ethnic backgrounds. The prevalence of the Leiden mutation is highest in northern Europeans and is almost nonexistent in most Asian populations.27
It is also important to emphasize that the observations in the present study are limited to women with established coronary disease. The joint effects of HRT and factor V Leiden in healthy women are not yet determined. In younger women with factor V Leiden, oral contraceptives increase risk by 0.2 per 1000 women per year.39 In the present study, in women with coronary disease and factor V Leiden, the increase in absolute risk associated with HRT use was >40-fold greater (8.3 per 1000 women per year). It is difficult to imagine many clinical settings in which the benefits of postmenopausal HRT would outweigh this increase in risk in women with existing coronary heart disease (CHD). This is especially true in light of the evidence that HRT is ineffective at slowing clinical22,40 or anatomic21,41 manifestations of atherosclerosis and may even be associated with an early increase in CHD events.22,42–44 Unfortunately, despite the higher absolute risk of VTE in women with CHD, the prevailing costs of $150 to $600 for a single clinical factor V Leiden determination makes screening impractical. Even if the low end of this range of cost is assumed, $50 000 would be spent on screening to prevent 1 VTE hospitalization. If clinical genotyping for factor V Leiden becomes less expensive, screening could become a cost-effective strategy in women with heart disease.45
In summary, in women with coronary disease, factor V Leiden and HRT use are independently associated with an increase in VTE risk. In women who have both risk factors, the absolute risk is 1.5% per year. If less expensive methods for factor V genotyping become more widely available, screening for factor V Leiden before initiating HRT might become a cost-effective strategy in women with coronary disease. However, even in women with coronary disease without factor V Leiden, the HRT-associated VTE risk must be carefully considered when HRT is used for approved noncoronary indications.
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Acknowledgments |
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This study was supported by grants U01 HL-45488 (Principal Investigator, D.M. Herrington) and M01 RR-07122 (General Clinical Research Center, Wake Forest University Baptist Medical Center) from the National Institutes of Health, Bethesda, Md, and a contract from Wyeth-Ayerst Research, Radnor, Pa. The authors thank Georgia Saylor for database construction and analyses, Karen Craver and Bridget Fitzgerald for the factor V Leiden genotyping, J.T. Tolentino for research assistance, and Karen Potvin Klein, MA, ELS, for her invaluable editorial assistance.
Received February 19, 2002; accepted April 2, 2002.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, Dehonde H, Van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994; 369: 64–66.[CrossRef][Medline] [Order article via Infotrieve]
2.
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: 1004–1008.
3. Zoller B, Dahlback B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet. 1994; 343: 1536–1538.[CrossRef][Medline] [Order article via Infotrieve]
4. 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: 1503–1506.[CrossRef][Medline] [Order article via Infotrieve]
5.
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: 1504–1508.
6.
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: 912–917.
7. Hirsch DR, Mikkola KM, Marks PW, Fox EA, Dorfman PM, Ewenstein BM, Goldhaber SZ. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J. 1996; 131: 1145–1148.[CrossRef][Medline] [Order article via Infotrieve]
8. Bokarewa MI, Bremme K, Blomback M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol. 1996; 92: 473–478.[CrossRef][Medline] [Order article via Infotrieve]
9. Hallak M, Senderowicz J, Cassel A, Shapira C, Aghai E, Auslender R, Abramovici H. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obstet Gynecol. 1997; 176: 889–893.[CrossRef][Medline] [Order article via Infotrieve]
10. Salomon O, Apter S, Shaham D, Hiller N, Bar-Ziv J, Itzchak Y, Gitel S, Rosenberg N, Strauss S, Kaufman N, Seligsohn U. Risk factors associated with postpartum ovarian vein thrombosis. Thromb Haemost. 1999; 82: 1015–1019.[Medline] [Order article via Infotrieve]
11. Middeldorp S, Libourel EJ, Hamulyak K, van der Meer FJ, Buller HR. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden. Br J Haematol. 2001; 113: 553–555.[CrossRef][Medline] [Order article via Infotrieve]
12. 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: 1453–1457.[CrossRef][Medline] [Order article via Infotrieve]
13. Bloemenkamp KWM, 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 progestogen. Lancet. 1995; 346: 1593–1596.[CrossRef][Medline] [Order article via Infotrieve]
14. Aslam S, Standen GR, Morse C, Scott GL. DVT following oral contraceptive therapy in association with homozygous factor V Leiden. Clin Lab Haematol. 1995; 17: 99–100.[Medline] [Order article via Infotrieve]
15. Rintelen C, Mannhalter C, Ireland H, Lane DA, Knobl P, Lechner K, Pabinger I. 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: 487–490.[CrossRef][Medline] [Order article via Infotrieve]
16. Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45–64 years: relationships to hormone replacement therapy. Thromb Haemost. 2000; 83: 530–535.[Medline] [Order article via Infotrieve]
17. Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy: results of the randomized, double-blind, placebo-controlled Estrogen in Venous Thromboembolism Trial (EVTET). Thromb Haemost. 2000; 84: 961–967.[Medline] [Order article via Infotrieve]
18. Vandenbroucke JP, Helmerhorst FM. Risk of venous thrombosis with hormone-replacement therapy. Lancet. 1996; 348: 972.[CrossRef][Medline] [Order article via Infotrieve]
19.
Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/Progestin Replacement Study. Ann Intern Med. 2000; 132: 689–696.
20. Grady D, Applegate W, Bush T, Furberg C, Riggs B, Hulley SB. Heart and Estrogen/Progestin Replacement Study (HERS): design, methods, and baseline characteristics. Control Clin Trials. 1998; 29: 314–335.
21. Herrington DM, Reboussin DM, Klein KP, Sharp PC, Shumaker SA, Snyder TE, Geisinger KR. The Estrogen Replacement and Atherosclerosis (ERA) study: study design and baseline characteristics of the cohort. Control Clin Trials. 2000; 21: 257–285.[CrossRef][Medline] [Order article via Infotrieve]
22.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998; 280: 605–613.
23.
Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000; 343: 522–529.
24. Jennrich RI, Liang K-Y. Unbalanced repeated-measures models with structured covariance matrices. Biometrics. 1986; 42: 805–820.[CrossRef][Medline] [Order article via Infotrieve]
25. McCullagh P, Nelder JA. Generalized Linear Models. New York, NY: John Wiley & Sons; 1989.
26. Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiology. 1992; 3: 452–456.[Medline] [Order article via Infotrieve]
27. Major DM, Sane DC, Herrington DM. Cardiovascular implications of the factor V Leiden mutation. Am Heart J. 2000; 140: 189–195.[CrossRef][Medline] [Order article via Infotrieve]
28.
Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997; 127: 895–903.
29. Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russo C. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol. 1995; 91: 465–470.[Medline] [Order article via Infotrieve]
30. Henkens CMA, van der Bom JG, van der Meer FJ. Lowered activated protein C-sensitivity ratio related to increased factor VIII-clotting activity. Thromb Haemost. 1995; 74: 1198–1199.[Medline] [Order article via Infotrieve]
31. Hellgren M, Svensson PJ, 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: 210–213.[CrossRef][Medline] [Order article via Infotrieve]
32. Cumming AM, Tait RC, Fildes S, Young A, Keeney S, Hay CR. Development of resistance to activated protein C during pregnancy. Br J Haematol. 1995; 90: 725–727.[Medline] [Order article via Infotrieve]
33. Osterud B, Asvang GB, Thijssen F. Resistance to activated protein C is reduced in women using oral contraceptives. Blood Coagul Fibrinolysis. 1994; 5: 853–854.[Medline] [Order article via Infotrieve]
34. Douketis JD, Gordon M, Johnston M, Julian JA, Adachi JR, Ginsberg JS. The effects of hormone replacement therapy on thrombin generation, fibrinolysis inhibition, and resistance to activated protein C: prospective cohort study and review of the literature. Thromb Res. 2000; 99: 25–34.[CrossRef][Medline] [Order article via Infotrieve]
35.
Gandrille S, Greengard JS, Alhenc-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, Griffin JH, Aiach M. 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: 219–224.
36. 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: 580–583.[Medline] [Order article via Infotrieve]
37.
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: 528–531.
38.
Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, Berliner S, Inbal A, Many A, Lubetsky A, Varon D, Martinowitz U, Seligsohn U. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol. 1999; 19: 511–518.
39.
Vandenbroucke JP, van der Meer FJ, Helmerhorst F, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ. 1996; 313: 1127–1130.
40.
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001; 345: 1243–1249.
41.
Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized, controlled trial. Arterioscler Thromb Vasc Biol. 2001; 21: 262–268.
42.
Heckbert SR, Kaplan RC, Weiss NS, Psaty BM, Lin D, Furberg CD, Starr JR, Anderson GD, LaCroix AZ. Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy. Arch Intern Med. 2001; 161: 1709–1713.
43.
Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses’ Health Study: a prospective, observational study. Ann Intern Med. 2001; 135: 1–8.
44. Lenfant C. Preliminary trends in the Women’s Health Initiative [press release]. Bethesda, Md: National Heart, Lung and Blood Institute; April 3, 2000.
45. Goldman L, Garber AM, Grover SA, Hlatky MA. Task Force 6: cost effectiveness of assessment and management of risk factors. J Am Coll Cardiol. 1996; 37: 964–1047.[CrossRef]
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 K. K. Koh and B.-K. Yoon Controversies regarding hormone therapy: Insights from inflammation and hemostasis Cardiovasc Res, April 1, 2006; 70(1): 22 - 30. [Abstract] [Full Text] [PDF]
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 C. Straczek, E. Oger, M. B. Yon de Jonage-Canonico, G. Plu-Bureau, J. Conard, G. Meyer, M. Alhenc-Gelas, H. Levesque, N. Trillot, M.-T. Barrellier, et al. Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women: Impact of the Route of Estrogen Administration Circulation, November 29, 2005; 112(22): 3495 - 3500. [Abstract] [Full Text] [PDF]
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R. K. Dubey, B. Imthurn, M. Barton, and E. K. Jackson Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen Cardiovasc Res, May 1, 2005; 66(2): 295 - 306. [Abstract] [Full Text] [PDF]
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 F. R. Rosendaal Venous Thrombosis: The Role of Genes, Environment, and Behavior Hematology, January 1, 2005; 2005(1): 1 - 12. [Abstract] [Full Text] [PDF]
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M. P. V. Gomes and S. R. Deitcher Risk of Venous Thromboembolic Disease Associated With Hormonal Contraceptives and Hormone Replacement Therapy: A Clinical Review Arch Intern Med, October 11, 2004; 164(18): 1965 - 1976. [Abstract] [Full Text] [PDF]
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 M. Cushman, L. H. Kuller, R. Prentice, R. J. Rodabough, B. M. Psaty, R. S. Stafford, S. Sidney, F. R. Rosendaal, and for the Women's Health Initiative Investigators Estrogen Plus Progestin and Risk of Venous Thrombosis JAMA, October 6, 2004; 292(13): 1573 - 1580. [Abstract] [Full Text] [PDF]
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 K. K. Koh and I. Sakuma Should Progestins Be Blamed for the Failure of Hormone Replacement Therapy to Reduce Cardiovascular Events in Randomized Controlled Trials? Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1171 - 1179. [Abstract] [Full Text] [PDF]
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S. E. Humphries, P. M. Ridker, and P. J. Talmud Genetic Testing for Cardiovascular Disease Susceptibility: A Useful Clinical Management Tool or Possible Misinformation? Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 628 - 636. [Abstract] [Full Text] [PDF]
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F. Iemolo, A. Martiniuk, D. A. Steinman, and J. D. Spence Sex Differences in Carotid Plaque and Stenosis Stroke, February 1, 2004; 35(2): 477 - 481. [Abstract] [Full Text] [PDF]
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 C. Duggan, K. Marriott, R. Edwards, and J. Cuzick Inherited and Acquired Risk Factors for Venous Thromboembolic Disease Among Women Taking Tamoxifen to Prevent Breast Cancer J. Clin. Oncol., October 1, 2003; 21(19): 3588 - 3593. [Abstract] [Full Text] [PDF]
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 A. P. Reiner, S. R. Heckbert, H. L. Vos, R. A. S. Ariens, R. N. Lemaitre, N. L. Smith, T. Lumley, T. D. Rea, L. A. Hindorff, G. D. Schellenbaum, et al. Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction Blood, July 1, 2003; 102(1): 25 - 30. [Abstract] [Full Text] [PDF]
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D. L. Ornstein and M. Cushman Factor V Leiden Circulation, April 22, 2003; 107 (15): e94 - e97. [Full Text] [PDF]
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 S. R Deitcher and M. P. Gomes Hypercoagulable state testing and malignancy screening following venous thromboembolic events Vascular Medicine, February 1, 2003; 8(1): 33 - 46. [Abstract] [PDF]
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D. M. Herrington Hormone Replacement Therapy and Heart Disease: Replacing Dogma With Data Circulation, January 7, 2003; 107(1): 2 - 4. [Full Text] [PDF]
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L. H. Kuller Hormone Replacement Therapy and Risk of Cardiovascular Disease: Implications of the Results of the Women's Health Initiative Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 11 - 16. [Abstract] [Full Text] [PDF]
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K. A. Bauer Hormone Replacement Therapy and the Factor V Leiden Mutation Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 879 - 880. [Full Text] [PDF]
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