Long-term consequences of venous thromboembolism in women

Background: Venous thromboembolism (VTE) is the third most common cardiovascular disease with a high recurrence rate. There is a risk of chronic complications affecting healthrelated quality-of life (QoL). Aim: To evaluate long-term consequences of VTE in women and to study and to explore the risk factors for recurrent event, arterial cardiovascular disease (CVD), mortality, postthrombotic syndrome (PTS) and QoL. Methods: We performed a cohort study inviting 1433 women with a previous episode of VTE (exposed) and 1402 women without VTE (unexposed). The cohort was derived from the ‘Thrombo Embolism Hormone Study’ (TEHS), a Swedish nation-wide case-control study on risk factors for VTE, recruiting women 2002 2009. During 2011 all women were followed up through a mailed questionnaire, including questions on life-style factors, recurrent VTE and inquiries according to the QoL instrument SF-36. To assess disease specific QoL, exposed women were also asked questions according to VEINES-Sym / VEINES-QoL. A modified Villalta scale was applied to evaluated PTS. Information on CVD and mortality was obtained through the Patient Register and the Cause of Death Register. Baseline data on life style factors, risk factors for VTE, including hormone treatment and family history of VTE and CVD were collected through a telephone interview within three months after the diagnosis of VTE for the exposed, or at time of inclusion in TEHS for unexposed. Blood samples for DNA-analyses were collected at time of inclusion in TEHS. Result: A total of 2117 women (1087 (75%) exposed and 1030 (73%) unexposed) accepted participation in the study. During a median follow-up of 5 years (range 0.1-9.1), 10 % of exposed women had a recurrent event. The risk of recurrence was highest among women with unprovoked VTE and obesity. Women with hormone-induced VTE had a lower risk of recurrence than women with unprovoked VTE but not as low as women with surgery/cast induced VTE. Women carrying the risk alleles of F5 rs6025/Factor V Leiden (FVL) and F11 rs2289252 had a significantly higher risk of recurrence compared to non-carriers (HR 1.7 (95% CI 1.1-2.6) and 1.8 (95% CI 1.1-3.0) respectively). In a subgroup analysis of women with unprovoked VTE the difference was even larger, with a cumulative recurrence rate of 21.9% (95% CI 13.7-34.0) versus 7.5 % (95% CI 3.4-16.0) for non-carriers at 5 years follow-up. The mortality rate for exposed women was 5.7 /1000 person years with the corresponding mortality rate for unexposed of 2.2 /1000 person years, generating a HR of 2.4 (95% CI 1.2-4.6). None of the exposed died from VTE. During follow-up 35 (3.2%, 95% CI 2.1-4.3) among the exposed and 14 (1.4%, 95% CI 0.7–2.1) among the unexposed had any CVD event. Women with unprovoked VTE and pulmonary embolism had the highest risk of both death and CVD. The prevalence of self-reported PTS among all exposed was 20 % (95% CI 18-22). Women with proximal deep vein thrombosis had the highest prevalence (30%, 95% CI 25-35). Women reporting PTS had significantly lower QoL compared to both unexposed women and exposed women without PTS. Other factors affecting QoL were obesity, physical inactivity and recurrent VTE. Conclusion: Among young and middle-aged women, the overall recurrence rate of VTE was low, indicating that the majority may not benefit from prolonged anticoagulation after a first episode of VTE. A combination of FVL and F11 rs2289252 may be useful to predict the risk of recurrence. PTS, the most common complication, was seriously affecting QoL. Women with prior VTE had a two-fold increased risk of both overall mortality and CVD compared to unexposed. Obesity was a shared risk factor for recurrent VTE, PTS and reduced QoL. LIST OF SCIENTIFIC PAPERS This thesis is based on the following papers, referred to in the text by their Roman numerals. I. Ljungqvist M, Sonnevi K, Bergendal A, Holmstrom M, Kieler H, Larfars G. Risk factors for recurrent venous thromboembolism in young and middle-aged women. Thrombosis research 2014;133(5):762-7. II. Bruzelius M, Ljungqvist M, Bottai, M, Bergendal A, Strawbridge R. J, Holmström M, Silveira A, Kieler H, Hamsten A, Lärfars G, Odeberg J. F 11 is associated with recurrent VTE in women. A prospective cohort study. Thrombosis and Haemostasis 2016;115(2):406-14. III. Ljungqvist M, Holmstrom M, Kieler H, Odeberg J, Larfars G. Cardiovascular disease and mortality after a first episode of venous thromboembolism in young and middle-aged women. Thrombosis Research 2016;138(2): 80-5. IV. Ljungqvist M, Holmstrom M, Kieler H, Larfars G. Long-term quality-of-life and post-thrombotic syndrome in women after a first episode of venous thromboembolism. Manuscript 2016. CONTENTS