Explore the vast range of titles available.

To provide a comprehensive overview of cardiovascular disease (CVD) risk prediction models for women and models that include female-specific predictors. We performed a systematic review of CVD risk prediction models for women in the general population by updating a previous review. We searched Medline and Embase up to July 2017 and included studies in which; (a) a new model was developed, (b) an existing model was validated, or (c) a predictor was added to an existing model. A total of 285 prediction models for women have been developed, of these 160 (56%) were female-specific models, in which a separate model was developed solely in women and 125 (44%) were sex-predictor models. Out of the 160 female-specific models, 2 (1.3%) included one or more female-specific predictors (mostly reproductive risk factors). A total of 591 validations of sex-predictor or female-specific models were identified in 206 papers. Of these, 333 (56%) validations concerned nine models (five versions of Framingham, SCORE, Pooled Cohort Equations and QRISK). The median and pooled C statistics were comparable for sex-predictor and female-specific models. In 260 articles the added value of new predictors to an existing model was described, however in only 3 of these female-specific predictors (reproductive risk factors) were added. There is an abundance of models for women in the general population. Female-specific and sex-predictor models have similar predictors and performance. Female-specific predictors are rarely included. Further research is needed to assess the added value of female-specific predictors to CVD models for women and provide physicians with a well-performing prediction model for women.

Men seem to have a higher intrinsic risk of venous thromboembolism (VTE) than women, regardless of age. To date, this difference has not been explained. By integrating state‐of‐the‐art research presented at the International Society on Thrombosis and Haemostasis Congress of 2021 with the available literature, we address potential explanations for this intriguing risk difference between men and women. We discuss the role of exogenous and endogenous sex hormones as the most important known sex‐specific determinants of VTE risk. In addition, we highlight clues on the role of sex hormones and VTE risk from clinical scenarios such as pregnancy and the polycystic ovary syndrome. Furthermore, we address new potential sex‐specific risk factors and unanswered research questions, which could provide more insight in the intrinsic risk difference between men and women, such as body height and differences in body fat distribution, leading to dysregulation of metabolism and inflammation.

Elvira Grandone and colleagues are correct that about half of the pregnancy losses might have been because of fetal aneuploidy.4 Had LMWH prevented euploid losses, we would have expected some difference in livebirth rates, because aneuploidy losses are distributed randomly between the intervention and control groups. The ALIFE2 trial1 is consistent with a meta-analysis of the subgroups of women with inherited thrombophilia who were included in previous randomised controlled trials of women with recurrent miscarriages, which showed no benefit of LMWH.5 We adhere to the principle of first, do no harm, and with the strong evidence of an absence of effect, LMWH should not be prescribed to prevent recurrent miscarriages in women with inherited thrombophilia. ALIFE2 recruited women who were at high risk of pregnancy loss, with 92 (28%) of 326 women having a further loss. Because LMWH did not prevent pregnancy loss, we recommend that future research is aimed at assessing non-thrombotic causes and treatments.

Anticoagulant therapy might reduce the number of miscarriages and adverse pregnancy outcomes in women with recurrent pregnancy loss and inherited thrombophilia. We aimed to assess use of low-molecular-weight heparin (LMWH) versus standard care in this population. The ALIFE2 trial was an international open-label, randomised controlled trial undertaken in hospitals in the UK (n=26), the Netherlands (n=10), the USA (n=2), Belgium (n=1), and Slovenia (n=1). Women aged 18–42 years who had two or more pregnancy losses and confirmed inherited thrombophilia, and who were trying to conceive or were already pregnant (≤7 weeks' gestation), were eligible for inclusion. Women were randomly assigned (1:1) to use low-dose LMWH or not (alongside standard care in both groups) once they had a positive urine pregnancy test. LMWH was started at or before 7 weeks' gestation and continued until the end of pregnancy. The primary outcome measure was livebirth rate, assessed in all women with available data. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions, and were assessed in all randomly assigned women who reported a safety event. The trial was registered within the Dutch Trial Register (NTR3361) and EudraCT (UK: 2015-002357-35). Between Aug 1, 2012, and Jan 30, 2021, 10 625 women were assessed for eligibility, 428 were registered, and 326 conceived and were randomly assigned (164 to LMWH and 162 to standard care). 116 (72%) of 162 women with primary outcome data in the LMWH group and 112 (71%) of 158 in the standard care group had livebirths (adjusted odds ratio 1·08, 95% CI 0·65 to 1·78; absolute risk difference, 0·7%, 95% CI –9·2% to 10·6%). 39 (24%) of 164 women in the LMWH group and 37 (23%) of 162 women in the standard care group reported adverse events. LMWH did not result in higher livebirth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. We do not advise use of LMWH in women with recurrent pregnancy loss and inherited thrombophilia, and we advise against screening for inherited thrombophilia in women with recurrent pregnancy loss. National Institute for Health and Care Research and the Netherlands Organization for Health Research and Development.

Patients with venous thrombosis (VT) are at increased risk of future arterial cardiovascular disease (CVD) (i.e., myocardial infarction, ischemic stroke or peripheral artery disease). We investigated whether shared risk factors for VT and CVD are associated with the levels of procoagulant factors (fibrinogen, factor VIII, and von Willebrand factor), and whether the relationship between these risk factors and subsequent CVD was mediated through these procoagulant factors in patients with VT. In a follow‐up study consisting of 4956 patients with VT, 2176 patients (44%) provided blood samples and were linked to the Dutch Hospital registry of Statistics Netherlands to identify hospital admissions or procedures for subsequent CVD. In total, 52 CVD events occurred over a follow‐up of 11,124 years, with an incidence rate of 4.7 per 1000 patient years (95% confidence intervals 3.5–6.1). Increasing age, male sex, smoking history, major illnesses, dyslipidemia, and impaired fasting glucose levels were associated with increased CVD risk. Procoagulant factor levels were also associated with CVD risk. When adjusted for these procoagulant factors, the association between the risk factors and CVD attenuated partially. This study provides evidence that procoagulant factors can partially explain the association between increased risks of subsequent CVD in patients with previous VT.

In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA). Treatment with the direct oral thrombin inhibitor dabigatran appears to be associated with a reduced risk of HMB compared with VKA. These findings come from small observational studies or post hoc analyses of trials in which HMB was not a primary outcome. Use of tranexamic acid during the menstrual period may be effective in patients with HMB, but prospective data regarding efficacy and safety in patients on anticoagulant treatment are lacking. A direct comparison of a factor Xa inhibitor and a thrombin inhibitor with HMB as primary outcome, as well as an evaluation of the effects of adding tranexamic acid in women with anticoagulant‐associated HMB is highly relevant for clinical practice. The MEDEA study is a randomized, open‐label, pragmatic clinical trial to evaluate management strategies in premenopausal women with HMB associated with factor Xa inhibitor therapy. Women using factor Xa inhibitors with proven HMB, as assessed by a pictorial blood loss assessment chart (PBAC) score of >150, will be randomized to one of three study arms: (i) switch to dabigatran; (ii) continue factor Xa inhibitor with addition of tranexamic acid during the menstrual period; or (iii) continue factor Xa inhibitor without intervention. The primary outcome is the difference in PBAC score before and after randomization. Here, we present the rationale and highlight several unique features in the design of the study.

Unlabelled Box Venous thrombosis is a major contributor to the global disease burden. In this review we aim to answer two important questions: (1) are we making progress in reducing this disease burden and (2) how can we further improve? To answer these questions, we first evaluated the disease burden, that is, the incidence of first venous thrombosis over the past decade(s) and discuss its most important determinants. We found that the incidence of first venous thrombosis remained relatively unchanged, despite an increase in risk factor prevalence and a rise in identification of subsegmental pulmonary emboli due to enhanced image quality and utilization. This is, however, balanced by improved thromboprophylaxis strategies, resulting in an overall unchanged venous thrombosis incidence. We can further improve by developing, validating, and implementing risk assessment strategies, allowing us to identify persons at high or low risk in whom thromboprophylaxis can be provided or withheld, respectively.

Prediction models for venous thromboembolism recurrence will likely be improved by adding levels of coagulation factors. Risk assessment is ideally performed during anticoagulant treatment, however, the influence of direct oral anticoagulants on coagulation factors is uncertain. To assess the influence of rivaroxaban and apixaban on several coagulation factor levels. In two crossover trials we assessed the influence of rivaroxaban and apixaban intake on factor (F)VIII, FXI and FXII‐activity and fibrinogen, von Willebrand factor (VWF:Ag), and d‐dimer levels. At three sessions with a washout period in between, blood was taken from 12 healthy male individuals immediately before intake of rivaroxaban 15 mg twice daily (n = 6) or apixaban 10 mg twice daily (n = 6) and three hours after the last intake. Overall, measured levels were lower after rivaroxaban/apixaban intake. The paired mean difference after rivaroxaban intake was −38 IU/dL (95% CI −43; −33) for FVIII:C, −29 U/dL (95% CI −45; −12) for FXI:C, −22 IU/dL (95% CI −43; −1) for FXII:C, −0.11 g/L (95% CI −0.25; 0.03) for fibrinogen, −7 IU/dL (95% CI −18; 3) for VWF:Ag, −27 ng/mL (95% CI −50; −4) for d‐dimer and −0.36 (95% CI −0.57; −0.15) for Ln d‐dimer. After apixaban intake this was −29 IU/dL (95% CI −38; −21) for FVIII:C, −29 IU/dL (95% CI −36; −22) for FXI:C, −19 IU/dL (95% CI −24; −15) for FXII:C, −0.18 g/L (95% CI −0.33; 0.03) for fibrinogen, −52 ng/mL (95% CI −100; −4) for d‐dimer, 0.25 (−0.60; 0.09) for Ln d‐dimer and 1 IU/dL (95% CI −7; 9) for VWF:Ag. FVIII:C, FXI:C, FXII:C, and d‐dimer measurements were influenced by rivaroxaban/apixaban intake, while fibrinogen and VWF:Ag were not.

Unlabelled Box Vitamin K antagonists (VKA) are used for the treatment of thromboembolism. Patients with severe VKA‐associated bleeding require immediate restoration of haemostasis. Clinical studies on the effect of prothrombin complex concentrate (PCC) are heterogeneous with respect to outcome of bleeding. To evaluate the clinical outcome of patients treated with PCC for VKA‐associated bleeding. We performed a cohort study of consecutive patients who received PCC for VKA‐related bleeding in five Dutch hospitals. Data were collected by chart review on the bleeding event, international normalized ratio (INR), haemostatic efficacy, thromboembolic (TE) complications, and mortality. The primary outcome was effective haemostasis, assessed by an adaptation of the Sarode criteria with a surrogate outcome for patients with ICH without repeat CT. One hundred patients were included. Mean age was 74 years, 54% were male and 79% received VKA for atrial fibrillation. Most patients presented with ICH (41%) or GI bleeding (36%). Effective haemostasis was achieved in 67/98 (68%) patients using the adapted classification. Surrogate outcomes were applied for 32 patients and data for two patients was missing. Median pre‐treatment INR was 3.9 (IQR 2.9‐5.8). One hour after PCC infusion, the INR was available for 50 patients and of these, 35 (70%) had an INR ≤1.4. TE complications occurred in five patients and 22 died (60% bleeding‐related) within 30 days. PCC achieved effective haemostasis in 68% of evaluable patients with VKA‐associated bleeding. TE complication rates were low, but mortality rates were high, due to the large number of patients with ICH.