A. van Hylckama Vlieg

The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study

Objective To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands. Design Population based case-control study. Setting Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht). Participants Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls. Main outcome measures First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf’s method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model. Results Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives. Conclusions Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.

Estrogens, progestogens and thrombosis

Summary.  Hundreds of millions of women worldwide use either oral contraceptives or postmenopausal hormone replacement. The use of oral contraceptives leads to an increased risk of venous thrombosis, of myocardial infarction, of stroke and of peripheral artery disease, the risks of which are highest during the first year of use. Women with coagulation abnormalities have a higher risk of venous thrombosis when they use oral contraceptives (or postmenopausal hormones) than women without these abnormalities. The risk of venous thrombosis is also higher for preparations containing desogestrel or gestodene (third‐generation progestogens) than for those containing levonorgestrel (second‐generation progestogens). A previous thrombosis as well as obesity also increase the risk of oral contraceptive‐related thrombosis. Hormone replacement therapy increases the risk of venous thrombosis, and has no beneficial, and possibly even a detrimental, effect on the risk of arterial disease. The risk of arterial disease in oral contraceptive users and users of hormone replacement therapy is at most weakly affected by the presence of prothrombotic abnormalities.

High rate of unprovoked recurrent venous thrombosis is associated with high thrombin-generating potential in a prospective cohort study

Summary.  Objective: To determine the predictive value of measurement of parameters of thrombin generation for unprovoked recurrent venous thrombosis. Methods: Measurements were made of thrombin generation in a prospective cohort study of 188 patients with a first episode of venous thrombosis that was unprovoked, or provoked by a non‐surgical trigger. Results: The endogenous thrombin potential (ETP) was the only parameter associated with unprovoked recurrent thrombosis in a multivariate model [hazard ratio (HR) 1.3 per 100 nmol L min−1 increase, 95% confidence interval (CI) 1.0–1.6]. Patients with a high ETP had a significantly higher rate of unprovoked recurrence than those with a low ETP (HR 2.9, 95% CI 1.3–6.6, cumulative recurrence at 4 years 27% vs. 11%). Patients with an unprovoked first event had a significantly higher rate of unprovoked recurrence than those with a provoking factor (HR 2.7, 95% CI 1.2–6.1), and in these patients there was a significantly higher rate of unprovoked recurrence in association with a high ETP (HR 4.0, 95% CI 1.3–11.8). After adjustment for D‐dimer, thrombophilia, sex, and whether or not the first event was unprovoked, a high ETP remained a significant predictor of recurrence (HR 2.6, 95% CI 1.2–6.0). Conclusions: This study demonstrates a high rate of unprovoked recurrent venous thrombosis in patients presenting with a first episode of venous thrombosis and a high ETP.

Venous thrombosis in the elderly: incidence, risk factors and risk groups

Summary.  The incidence of venous thrombosis (VT) increases sharply with age: it is very rare in young individuals (< 1 per 10 000 per year) but increases to ∼ 1% per year in the elderly, which indicates that aging is one of the strongest and most prevalent risk factor for venous thrombosis. The cause of this steep age gradient is as yet, unexplained. The aim of this review was to provide an overview of studies on the effect of conventional risk factors as well as age‐specific risk factors for thrombosis in the elderly. Limited data are available on risk factors for thrombosis in the elderly, i.e. all results are based on small study groups. Results indicate that, of the conventional risk factors, malignant disease, the presence of co‐morbidities and the genetic risk factors factor (F)V Leiden and the prothrombin mutation seem to be associated with an increased risk of venous thrombosis. In the elderly, the population attributable risk (PAR) of malignancy is approximately 35%, for co‐morbidities a PAR up to 25% is found, and the contribution of genetic risk factors to the thrombosis incidence is estimated to be 7–22%. Age‐specific risk factors of thrombosis, i.e. endothelial dysfunction and frailty may be important in the explanation of the increased incidence of VT in the elderly. In conclusion, as aging is a major risk factor for thrombosis, further identification of the risk factors for thrombosis in the elderly is needed to elucidate the age gradient of the incidence of VT and to target preventive measures.

Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence

Measurement of the thrombin generating potential could provide a method for quantifying the composite effect of multiple risk factors. This study assessed the risk of a first as well as a recurrent venous thrombotic event associated with an increased endogenous thrombin potential (ETP). Analyses were performed in 360 patients and 404 control subjects of the Leiden Thrombophilia Study. The ETP was measured directly using a fluorogenic assay (ThrombinoscopeTM). Individuals with an increased ETP, i.e. above 90th percentile measured in control subjects (>2109·0 nM·min) had a 1·5‐fold [95% confidence interval (CI): 0·9–2·3] increased risk of a first deep venous thrombosis. The risk was more pronounced after the analysis was restricted to idiopathic thromboses, i.e. 1·7‐fold (95% CI: 1·0–2·8). Overall, the hazard ratio of a recurrent thrombotic event associated with a high ETP, adjusted for age, sex and oral anticoagulant use was 1·1 (95% CI: 0·5–2·2). Thus, a high ETP was not associated with an increased relative risk of recurrent venous thrombosis. At present, the clinical relevance of the thrombin generation assay in predicting recurrent venous thrombosis remains uncertain.

Venous thrombosis in the elderly

Summary.  While the overall incidence of venous thrombosis is 1–2 per 1000 per year, it is close to 1% per year in the very old. The case–fatality rate of thrombosis is high in the elderly, particularly among those with cancer. The risk of major hemorrhage during anticoagulant treatment is also strongly age‐dependent, contributing to the vulnerability of the old patient with thrombosis. From this perspective it is surprising that far fewer studies into the etiology and treatment of venous thrombosis have focused on the elderly than on young and middle‐aged patients. In this review we discuss that, while environmental risk factors, such as immobilization and cancer, are important causes of thrombosis in the elderly, abnormalities of the coagulation system are equally, or even more, important than in young individuals. In addition to a review of the literature, new data are presented from the MEGA‐study. Thrombosis in the elderly should be a focus of future studies.

The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis

Thrombin activatable fibrinolysis inhibitor (TAFI) is an important inhibitor of fibrinolysis. High TAFI antigen levels are associated with an increased risk of deep venous thrombosis (DVT). Because TAFI levels are partly determined genetically, we assessed the association between three TAFI gene polymorphisms (−438 G/A, 505 A/G and 1040 C/T), TAFI antigen levels and clot lysis times and the risk of DVT. Carriers of the 505G allele, which is associated with lower TAFI antigen levels than the 505A allele, showed an increased risk of DVT. This indicates that the relationship between TAFI and venous thrombosis is more complex than previously suggested.

Hormone therapies and venous thromboembolism: where are we now?

Deep vein thrombosis is a common disease, with an incidence of one to three per 1000 individuals per year [1]. Numerous risk factors are known, which can be divided into genetic and acquired [2]. One of the most well-known acquired risk factors is the use of female hormones, i.e. oral contraceptive use or the use of hormone replacement therapy. Apart from the use of hormones orally, other routes of administration are also available, e.g. intrauterine devices, injectables, subcutaneous implants, or skin patches. While most research regarding the risk of venous thrombosis has been conducted on oral hormone use, an increasing number of studies are focusing on the thrombotic effect of these alternative routes of administration. Here, we will review the current knowledge on the risk of venous thrombosis associated with premenopausal hormone use for contraception and with postmenopausal hormone replacement therapy. The impact of hormone use for women who have an increased risk for venous thrombosis will be discussed. These include carriers of thrombophilia, women with a positive family history of venous thrombosis, and women who have experienced venous thrombosis. Oral contraceptives Combined oral contraceptives (containing an estrogen and a progestagen) were first approved in the USA in 1960. It is estimated that more than 100 million women worldwide use an oral contraceptive [3]. Soon after their introduction, it became apparent that the use of these female hormones was associated with an increased risk of thrombosis. The first report of an increased risk of venous thrombosis associated with oral contraceptive use appeared in 1961 [4]. Subsequently, numerous reports have been published on the increase in thrombotic risk, indicating a two-fold to six-fold increased risk of deep vein thrombosis associated with current oral contraceptive use [5–11]. Most currently available oral contraceptives are combined preparations containing both an estrogen (i.e. ethinylestradiol [EE2]) and a progestagen. Numerous types of oral contraceptives are available, containing different doses of estrogen and different types of progestagen. The first available preparations contained a high dose of the estrogen EE2. However, after the reported increased thrombotic risk associated with combined oral contraceptive use was attributed to the amount of estrogen in the contraceptive pill, the dose of estrogen was reduced stepwise. The initial lowering of the estrogen dose from >5 0l gt o 30lg was indeed shown to be associated with a clear decrease in the risk of venous thrombosis [12,13]. In two recently published studies, it was shown that a further decrease in the estrogen dose to 20 lg led to an additional lowering of the risk of venous thrombosis [10,11]. In the MEGA study, a large case–control study, we showed that, after adjustment for type of progestagen, oral contraceptives containing 20 l go f estrogen were associated with a slightly decreased risk of venous thrombosis as compared with oral contraceptives containing 30 lg of estrogen (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.5–1.2) [10]. The study by Lidegaard et al. [11] also showed that a reduction in estrogen dose from 30 or 40 to 20 lg was associated with an 18% reduction in the risk of venous thrombosis [11].

The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy

Roach REJ, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost 2013; 11: 124–31.

Inter-relation of coagulation factors and D-dimer levels in healthy individuals

Summary.  Recently, high levels of coagulation factor (F)VIII, FIX and FXI have been associated with an increased risk of venous thrombosis. For several coagulation factors a substantial hereditary component was found. If regulatory genes are located outside the clotting factor genes, they may regulate the levels of several proteins in the coagulation system. Thus levels would then cluster in individuals. The aim of the present study was to assess the inter‐relation among levels of the pro‐ and anticoagulant proteins in the coagulation cascade. We also investigated the relation between the coagulation factors and d‐dimer levels (marker of coagulation activity). All analyses were performed in healthy subjects, the control population of the Leiden Thrombophilia Study (LETS), to eliminate the influence of a prior thrombosis on the interpretation of the results (n = 466). Using principal‐components analysis, a method intended to explain relationships among several correlated variables, we found a clustering between the vitamin K‐dependent factors (prothrombin, VII, IX, X) and FXI and FXII. FV and FVIII clustered with fibrinogen and d‐dimer. FXIII remained relatively independent of the other factors. Adding the anticoagulant factors to the analysis resulted in minor changes in the clustering pattern. The anticoagulant factors clustered together. We found relatively independent clusters within the group of pro‐ and anticoagulant factors, which may suggest that the genetic basis for high or low levels of factors in the coagulation system may, at least partly, lie outside the genes coding for these factors.