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Factor V Leiden and the Risk for Venous Thromboembolism in the Adult Danish Population

Klaus Juul, MD; Anne Tybjærg-Hansen, MD, DMSc; Peter Schnohr, MD; and Børge G. Nordestgaard, MD, DMSc
[+] Article, Author, and Disclosure Information

From Herlev University Hospital, Herlev, Denmark; Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, and The Copenhagen City Heart Study, Bispebjerg University Hospital, Copenhagen, Denmark.

Acknowledgments: The authors thank Hanne Damm for technical assistance and the participants of the Copenhagen City Heart Study for their willingness to participate.

Grant Support: By grants from the Danish Heart Foundation, the Danish Medical Research Council, Chief Physician Johan Boserup and Lise Boserup's Fund, Lykfeldt's Fund, Dagmar Marshall's Fund, Wedelborg's Fund, Lily Benthine Lund's Fund, the Beckett Fund, and P. Carl Petersen's Fund.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; e-mail, brno@herlevhosp.kbhamt.dk.

Current Author Addresses: Drs. Juul and Nordestgaard: Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.

Dr. Tybjærg-Hansen: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 3, DK-2100 Copenhagen, Denmark.

Dr. Schnohr: The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen, Denmark.

Author Contributions: Conception and design: K. Juul, A. Tybjærg-Hansen, P. Schnohr, B.G. Nordestgaard.

Analysis and interpretation of the data: K. Juul, A. Tybjærg-Hansen, B.G. Nordestgaard.

Drafting of the article: K. Juul.

Critical revision of the article for important intellectual content: K. Juul, A. Tybjærg-Hansen, B.G. Nordestgaard.

Final approval of the article: K. Juul, A. Tybjærg-Hansen, B.G. Nordestgaard.

Statistical expertise: K. Juul, A. Tybjærg-Hansen, B.G. Nordestgaard.

Obtaining of funding: K. Juul, A. Tybjærg-Hansen, B.G. Nordestgaard.

Collection and assembly of data: K. Juul, A. Tybjærg-Hansen, P. Schnohr, B.G. Nordestgaard.

Ann Intern Med. 2004;140(5):330-337. doi:10.7326/0003-4819-140-5-200403020-00008
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In this adult Danish population cohort, 8534 persons were noncarriers of factor V Leiden, 699 were heterozygotes, and 20 were homozygotes. This genotype distribution did not differ from that predicted by the Hardy–Weinberg equilibrium (P= 0.16). Baseline characteristics did not differ with respect to factor V Leiden genotype (Table 1).

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Grahic Jump Location
Figure 1.
Cumulative incidence of venous thromboembolism (deep venous thrombosis and pulmonary embolism combined) according to factor V Leiden genotype.P

For heterozygotes compared with noncarriers, homozygotes compared with noncarriers, and homozygotes compared with heterozygotes, log-rank < 0.001.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Absolute 10-year risk for venous thromboembolism (deep venous thrombosis and pulmonary embolism combined) according to age, smoking, body mass index, and factor V Leiden genotype.
Grahic Jump Location




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Submit a Comment/Letter
Factor V Leiden: a difference in cohort and case-control studies?
Posted on April 7, 2004
Jan P Vandenbroucke
Deptartment of Clinical Epidemiology, Leiden University Medical Center
Conflict of Interest: None Declared

In a Danish cohort study, following 9523 individuals from 1976, venous thrombosis risk was increased 3-fold among carriers of factor V Leiden (216 persons developed venous thrombosis; 43 carriers)[1]. This relative risk was substantially lower than the 7-fold risk that we reported from a case-control study of 474 patients and 474 controls (92 and 14 carriers)[2]. The Danish authors ascribe the difference to "ascertainment bias" and a preponderance of risk factors among cases. This is a misapprehension of case-control studies: persons who develop disease always have more risk factors, in whatever study design [3]. As an example the Danish authors cite that in our study 66% of young women with venous thrombosis used oral contraceptives, while they found no users among their patients. This does not mean that something is wrong with case ascertainment in a case-control study, and certainly not that oral contraceptives play no role in venous thrombosis in Danish adults. Rather, this is a consequence of the Danish study base which consisted of an aging cohort of mainly middle aged and older persons. The one-time addition of 500 younger persons is of little help, given the low incidence of venous thrombosis. In contrast, we included cases from age 15 onwards as they occurred in the general population. Thus, a difference in relative risk of factor V Leiden may first of all reflect an age difference of the study base. Moreover, the inclusion of persons with a previous venous thrombosis, of persons with cancer and with a primary diagnosis of pulmonary embolism in the Danish study will all tend to lower the relative risk, as these conditions are less associated with factor V Leiden.

Both estimates might be correct: ours for a first venous thrombosis of the legs in the general population free of cancer, and the Danish for all venous thromboembolism in a cohort of middle-aged and elderly persons. However, the Danish figures may well suffer from diagnostic misclassification: the study was initially prospective, but case detection was by routine administrative registries. Cases were verified afterwards, and had occurred over 23 years in many different hospitals and medical practices. Since the Danish case ascertainment amounts to a retrospective chart review - spanning two decades - a large degree of diagnostic uncertainty is likely. In contrast, in our case-control study cases were enrolled concurrently over a short period of time and only included when diagnosed by appropriate and recent instrumentation.

Jan P Vandenbroucke, MD, PhD Frits R Rosendaal, MD, PhD Department of Clinical Epidemiology and Thrombosis and Haemostasis Research Center, Leiden University Medical Center PO Box 9600 2300 RC Leiden The Netherlands

1. Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140:330-337.

2. 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.

3. Rosendaal FR. Bridging case-control studies and randomized trials. Curr Control Trials Cardiovasc Med. 2001;2(3):109-110. Epub 2001 May 31.

Conflict of Interest:

None declared

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Summary for Patients

Blood Clots in People with Factor V Leiden Mutation

The summary below is from the full report titled “Factor V Leiden and the Risk for Venous Thromboembolism in the Adult Danish Population.” It is in the 2 March 2004 issue of Annals of Internal Medicine (volume 140, pages 330-337). The authors are K. Juul, A. Tybjærg-Hansen, P. Schnohr, and B.G. Nordestgaard.


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