Venous thromboembolism in women : an assessment of hormonal, genetic and other risk factors

Background: Venous thromboembolism (VTE) occurs in 1-2 in 1000 individuals per year. VTE is found in both sexes, but women have a higher incidence at younger ages, particularly during the childbearing years. Although several acquired and genetic risk factors for venous thrombosis have been identified, the modes and consequences of combinations of these risk factors are not fully understood.

Aim: The overall aim of this thesis was to clarify risk factors for VTE in women. Methods The ThromboEmbolismHormoneStudy (TEHS) is a nation-wide population-based case-control study that included 1470 cases and 1590 controls. All participants were recruited prospectively in Sweden from 2003 to 2009. Reports on acquired risk factors for thrombosis were collected through telephone interviews of the participants and genetic risk factors were identified by DNA analyses on blood samples.

Results: In Study I we found that risks associated with recognized acquired and genetic risk factors for VTE generally were of similar magnitude in pre-and postmenopausal women. The acquired, transient risk factors were stronger than the genetic factors and the combination of surgery and plaster cast yielded a 50-fold increased risk for VTE in both pre- and postmenopausal women.

In study II current use of combined hormonal contraception (CHC) was associated with a five-fold increased risk of VTE, adjusted odds ratio (ORadj)=5.3, 95% confidence interval (CI)=4.0-6.9. In adjusted analyses combinations with desogestrel had the highest risk (OR=11.4, 95% CI=6.0-22.0) followed by drospirenone, etonogestrel, norgestimate, levonorgestrel and norethisterone (OR=2.0, 95% CI=1.1-3.8). Current use of progestogen-only contraception (POC) was not associated with increased risks of VTE (ORadj=0.9, 95% CI=0.7-1.2). In stratified analyses (by dose) current users of “high dose” POC had an increased risk of VTE (ORadj=2.2, 95% CI=1.3-4.0).

In study III for the group of propionic acid derivatives, most women used ibuprofen (92%); of the women who used acetic acid derivatives, almost all used diclofenac (97%). In adjusted analyses overall use of NSAIDs was not associated with increased risks of VTE (ORadj=1.0, 95% CI=0.8–1.2). The adjusted OR was 0.9 for propionic acid derivatives (95% CI=0.72–1.10), 1.2 for acetic acid derivatives (95% CI=0.8–1.7) and 1.8 for coxibs (95% CI=0.7–4.3). For users of acetic acid derivatives and coxibs, the adjusted ORs increased by cumulative dose, suggesting a dose–effect relationship for these drugs.

Conclusion: Menopausal status has only a minor impact on the risk levels with regard to recognized risk factors for VTE. The risk of VTE associated with the use of CHC varies depending on the type of progestogen used, even after adjustment for individual factors such as smoking and body mass index (BMI). Except for high-dose preparations, POC seems to be a safer alternative to CHC, with no obvious increased risks for VTE. There is no apparent risk of VTE associated with the use of propionic acid derivatives in young and middle-aged women.

List of scientific papers

I. Bergendal A, Bremme K, Hedenmalm K, Lärfars G, Odeberg J, Persson I, Sundström A, Kieler H. Risk factors for venous thromboembolism in pre- and postmenopausal women. Thromb Res. 2012 Oct; 130(4): 596-601.
https://doi.org/10.1016/j.thromres.2012.05.024

II. Bergendal A, Persson I, Odeberg J, Sundström A, Holmström M, Schulman S, Björgell O, Kieler H. Hormonal contraception and the impact of progestogens, duration of use and hemostatic mutations on risks of venous thromboembolism: a case-control study. [Manuscript]

III. Bergendal A, Adami J, Bahmanyar S, Hedenmalm K, Lärfars G, Persson I, Sundström A, Kieler H. Non-steroidal anti-inflammatory drugs and venous thromboembolism in women. Pharmacoepidemiol Drug Saf. 2013 Mar 19.
https://doi.org/10.1002/pds.3436