Venous and arterial thromboembolism after colorectal cancer in the Netherlands: Incidence, predictors, and prognosis.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer type. CRC-patients are at increased risk of venous and arterial thromboembolism (TE), but the magnitude of the risks, their predictors and consequences are not exactly known. OBJECTIVES: We aimed to determine incidence, predictors and prognosis of TE after incident CRC in a large, unselected population. METHODS: Using data from Statistics Netherlands and the Netherlands Comprehensive Cancer Organization, all incident CRC-patients were identified between 2013 and 2018 plus a sample of 1:2 age- and sex-matched control subjects. Incidence rates and cumulative incidences for TE were estimated. Predictor variables for TE were explored by univariable Cox regression. The association between TE and all-cause mortality was evaluated by multivariable time-dependent Cox regression. RESULTS: 68,238 incident CRC-patients were matched to 136,476 controls. CRC-patients had a 1-year cumulative venous TE (VTE) incidence of 1.93 % (95%CI 1.83-2.04), versus 0.24 % (95%CI 0.21-0.27) in controls (HR 8.85; 95%CI 7.83-9.99). For arterial TE (ATE), this was 2.74 % (95%CI 2.62-2.87) in CRC versus 1.88 % (95%CI 1.81-1.95) in controls (HR 1.57; 95%CI 1.47-1.66). Cancer stage, surgery, chemotherapy and asthma were predictors for VTE, whereas age, prior ATE and Parkinson's disease were predictors for ATE. CRC patients with TE had an increased risk of all-cause mortality (VTE HR; 3.68 (95%CI 3.30-4.10, ATE HR; 3.05 (95%CI 2.75-3.39)) compared with CRC-patients without TE. CONCLUSIONS: This Dutch nationwide cohort study adds detailed knowledge on the risk of VTE and ATE, their predictors and prognosis in CRC-patients. These findings may drive TE prophylactic management decisions.

Short-term outpatient follow-up of COVID-19 patients: A multidisciplinary approach.

BACKGROUND: Short-term follow-up of COVID-19 patients reveals pulmonary dysfunction, myocardial damage and severe psychological distress. Little is known of the burden of these sequelae, and there are no clear recommendations for follow-up of COVID-19 patients.In this multi-disciplinary evaluation, cardiopulmonary function and psychological impairment after hospitalization for COVID-19 are mapped. METHODS: We evaluated patients at our outpatient clinic 6 weeks after discharge. Cardiopulmonary function was measured by echocardiography, 24-hours ECG monitoring and pulmonary function testing. Psychological adjustment was measured using questionnaires and semi-structured clinical interviews. A comparison was made between patients admitted to the general ward and Intensive care unit (ICU), and between patients with a high versus low functional status. FINDINGS: Eighty-one patients were included of whom 34 (41%) had been admitted to the ICU. New York Heart Association class II-III was present in 62% of the patients. Left ventricular function was normal in 78% of patients. ICU patients had a lower diffusion capacity (mean difference 12,5% P = 0.01), lower forced expiratory volume in one second and forced vital capacity (mean difference 14.9%; P<0.001; 15.4%; P<0.001; respectively). Risk of depression, anxiety and PTSD were 17%, 5% and 10% respectively and similar for both ICU and non-ICU patients. INTERPRETATION: Overall, most patients suffered from functional limitations. Dyspnea on exertion was most frequently reported, possibly related to decreased DLCOc. This could be caused by pulmonary fibrosis, which should be investigated in long-term follow-up. In addition, mechanical ventilation, deconditioning, or pulmonary embolism may play an important role.

The association between leptin concentration and blood coagulation: Results from the NEO study.

BACKGROUND: The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study. METHODS: We performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat. RESULTS: In multivariable adjusted analyses a 1 µg/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses. DISCUSSION: This study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant.

High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor.

Essentials Elevated procoagulant levels are associated with an increased risk of venous thrombosis (VT). The dependency on concurrent increased factor levels and VT was analyzed in a large study. Factor VIII (FVIII) and von Willebrand factor (VWF) were associated with the highest VT risk. The risks for other procoagulant factor levels were largely explained by FVIII and VWF. SUMMARY: Background Coagulation factors are essential for robust clot formation. However, elevated levels of procoagulant factors are associated with an increased risk of venous thrombosis (VT). The precise contribution of these factors to the development of VT is not yet understood. Objectives We determined the thrombosis risk for the highest levels of eight selected coagulation factors. Furthermore, we analyzed which of these coagulation factors had the strongest impact on the supposed association. Methods We used data of 2377 patients with a first VT and 2940 control subjects in whom fibrinogen, von Willebrand factor (VWF), factor II, FVII, FVIII, FIX, FX and FXI levels were measured. Results The odds ratios (ORs) for the various coagulation factor levels (> 99th percentile versus ≤ 25th percentile) varied between 1.8 and 4, except for FVIII (OR 23.0; 95% confidence interval [CI] 14.7-36.0) and VWF (OR 24.0; 95% CI 15.3-37.3). Adjustment for FVIII and VWF in a mediation analysis reduced the risks of the other factors to unity, with the exception of FIX and FXI (remaining ORs between 1.7 and 1.9). Conversely, the ORs for FVIII and VWF levels remained high after adjustment for all other procoagulant factors (FVIII: 16.0; 95% CI 9.7-26.3; VWF: 17.6; 95% CI 10.7-28.8). Conclusions Our results imply that the observed relationship between VT and coagulation factor levels can be largely explained by FVIII and VWF. FVIII and VWF levels were also associated with the highest VT risk.

Mild antithrombin deficiency and risk of recurrent venous thromboembolism: results from the MEGA follow-up study.

Essentials Mild antithrombin deficiency may increase the risk of recurrent venous thromboembolism (VTE). In a cohort study, we stratified patients with VTE to various cut-off antithrombin levels. A 1.6-3.7-fold increased risk of recurrent VTE was observed in the lowest antithrombin categories. Mild antithrombin deficiency (activity < 5th percentile of normal) increases recurrent VTE risk. SUMMARY: Background Mild antithrombin deficiency (previously defined as antithrombin activity below 70% or 80%) has been associated with a 2.4-3.5-fold increased risk of recurrent venous thromboembolism (VTE). This finding may have implications for duration of antithrombotic therapy in VTE patients with mild antithrombin deficiency. Objectives To externally validate whether mild antithrombin deficiency is a risk factor for recurrent VTE. Methods In a population-based cohort study, patients with a first VTE (n = 2357) were stratified according to percentile cut-off antithrombin levels (< 5th [< 87%], 5-10th [87-92%], > 10th percentile [> 92%]) and functional antithrombin levels (< 70%, 70-80%, > 80%). Results During a median follow-up of 7.4 years, 361 recurrent events occurred (incidence rate, 2.5/100 patient-years). We observed an increased risk of recurrent VTE in the lowest antithrombin activity category (< 5th percentile; < 87%) as compared with antithrombin activity that was > 10th percentile (> 92%), with an adjusted hazard ratio (HR) of 1.5 (95%CI, 1.0-2.3). When analyses were stratified to antithrombin cut-off criteria of< 70% vs. patients with antithrombin activity > 80%, the adjusted HR for venous recurrence was 3.7 (95% CI, 1.4-9.9). Mild antithrombin deficiency was able to predict recurrent VTE over at least 8 years of follow-up and the association remained present when the population was stratified to the presence or absence of thrombosis risk factors. Restriction analyses, where patients who used anticoagulation at time of blood draw and those who reported drinking ≥ 5 glasses alcohol daily were excluded, did not materially affect these outcomes. Conclusion This study confirms that mild antithrombin deficiency is a risk factor for recurrent VTE.

Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population.

Essentials Why venous thrombosis is more prevalent in chronic kidney disease is unclear. We investigated whether renal and vascular function are associated with hypercoagulability. Coagulation factors showed a procoagulant shift with impaired renal and vascular function. This suggests that renal and vascular function play a role in the etiology of thrombosis. SUMMARY: Background Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear. Objectives We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state. Methods In this cross-sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50th [reference] to < 1st) and UACR (< 50th [reference] to > 99th), and per four categories (< 50th [reference] to > 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C-reactive protein (CRP) and vitamin K antagonists use (FIX). Results Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m- ² and median UACR 0.4 mg mmol-1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL-1 (95% CI, 13-32) higher in the eGFR < 1st percentile compared with the > 50th percentile, and FVIII was 12 IU dL-1 (95% CI, 3-22) higher in the UACR > 99th percentile compared with the < 50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0 IU dL-1 (95% CI, 0.70-3.2) higher. Conclusions Impaired renal and vascular function was associated with higher levels of coagulation factors, underlining the role of renal function and vascular function in the development of venous thrombosis.

Relationship between neighborhood socioeconomic status and venous thromboembolism: results from a population-based study.

Essentials Literature on socioeconomic status (SES) and incidence of venous thromboembolism (VTE) is scarce. We assessed neighborhood SES with VTE risk in a population of over 1.4 million inhabitants. Higher neighborhood SES was associated with lower incidence of VTE. These findings are helpful to inform policy and resource allocation in health systems. SUMMARY: Background The association between socioeconomic status and arterial cardiovascular disease is well established. However, despite its high burden of disability-adjusted life years, little research has been carried out to determine whether socioeconomic status is associated with venous thromboembolism. Objective To determine if neighborhood socioeconomic status is associated with venous thromboembolism in a population-based study from the Netherlands. Methods We identified all patients aged 15 years and older with a first event of venous thromboembolism from inhabitants who lived in the urban districts of The Hague, Leiden and Utrecht in the Netherlands in 2008-2012. Neighborhood socioeconomic status was based on the status score, which combines educational level, income and unemployment on a four-digit postal code level. Incidence rate ratios of venous thromboembolism were calculated for different levels of neighborhood socioeconomic status, with adjustments for age and sex. Results A total of 7373 patients with a first venous thromboembolism (median age 61 years; 50% deep vein thrombosis) were identified among more than 1.4 million inhabitants. Higher neighborhood SES was associated with lower incidence of VTE. In the two highest status score groups (i.e. the 95-99th and > 99th percentile), the adjusted incidence rate ratios were 0.91 (95% confidence interval [CI], 0.84-1.00) and 0.80 (95% CI, 0.69-0.93), respectively, compared with the reference status score group (i.e. 30-70th percentile). Conclusions High neighborhood socioeconomic status is associated with a lower risk of first venous thromboembolism.

Repeated measurements of carotid atherosclerosis and future risk of venous thromboembolism: the Tromsø Study.

Essentials The relationship between atherosclerosis and venous thromboembolism (VTE) is controversial. In total, 10 426 participants recruited from the general population were included. Carotid intima media thickness and total plaque area was not associated with VTE. There was no association between plaque initiation or plaque progression and subsequent VTE. SUMMARY: Background Whether a relationship between atherosclerosis and subsequent venous thromboembolism (VTE) exists is controversial. Objective To investigate the association between carotid atherosclerosis and VTE by using repeated measurements of intima media thickness (IMT) and total plaque area (TPA) in participants recruited from the general population. Methods Participants were recruited from the fourth (1994-1995), fifth (2001-2002) and sixth (2007-2008) surveys of the Tromsø Study. In total, 10 426 participants attended, for whom measurements of carotid IMT and TPA and potential confounders were updated at each available survey. Time-varying Cox regression models were used to calculate hazard ratios (HRs) of VTE across various levels of IMT and TPA adjusted for age, sex, and body mass index. Results There were 368 incident VTE events during a median follow-up of 10.8 years. Participants with increasing IMT were, on average, older and had a less favorable cardiovascular risk profile. There was no association between tertiles of increasing TPA and the risk of VTE in the time-varying model, and increasing IMT was not associated with an increased risk of VTE (HR 0.96, 95% confidence interval [CI] 0.86-1.07). Neither plaque formation nor plaque progression was associated with the risk of VTE (respectively: HR 1.00, 95% CI 0.98-1.02; and HR 0.96, 95% CI 0.84-1.11). Conclusion Carotid IMT and TPA were not associated with an increased risk of VTE in time-varying analyses. Furthermore, there was no association between plaque initiation or plaque progression and subsequent VTE.

Recurrent venous thrombosis related to overweight and obesity: results from the MEGA follow-up study.

Essentials Whether excess body weight influences recurrent venous thrombosis (VT) risk is uncertain. We included 3889 VT patients, classified into body mass index (BMI) strata to estimate recurrent VT risk. No evidence of an increased risk for excess body weight was found. Measuring BMI is not a good tool to identify patients at high risk of VT recurrence. SUMMARY: Background Studies on the risk of recurrent venous thrombosis in patients with excess body weight have yielded conflicting results. Objective To estimate whether excess body weight increases the risk of recurrent venous thrombosis. Patients/Methods We included 3889 patients, followed after a first venous thrombosis for a median of 5.6 years. Body mass index (BMI) was calculated as weight in kilograms/height in meters squared, and classified according to three a priori-defined categories (normal weight, overweight, and obesity), as well as by percentiles. Crude incidence rates with 95% confidence intervals (CIs) of recurrent venous thrombosis were estimated as the number of events over the accumulated follow-up time in each BMI category. Cox regression models were used to compare groups, adjusted for age and sex. Results The incidence rate of recurrent venous thrombosis was 3.3 per 100 patient-years. Adjusted hazard ratios of recurrent venous thrombosis in overweight or obese patients in comparison with patients with normal weight were 1.05 (95% CI 0.88-1.27) and 0.94 (95% CI 0.74-1.19), respectively. Stratification by BMI percentile categories yielded similar results. The association between BMI and recurrent venous thrombosis was also absent after stratification by sex, (although a small effect for overweight, but not for obese women, was found), or into those with a first provoked or unprovoked event, or deep vein thrombosis and pulmonary embolism. Conclusions We found no evidence of an association between excess body weight and recurrent venous thrombosis. Measuring BMI is not a useful tool to identify patients at high risk of recurrence.

Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis.

Essentials Low-molecular-weight-heparins (LMWH) kinetics differ which may result in different bleeding risks. A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding. The absolute major bleeding risk was low among patients registered at the anticoagulation clinic. Once-daily dosing was associated with a lower bleeding risk as compared with twice-daily. SUMMARY: Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials.

Lipid levels and risk of recurrent venous thrombosis: results from the MEGA follow-up study.

Essentials The role of lipid levels in the risk of recurrent venous thrombosis is unclear. Lipids were assessed in patients with a first venous thrombosis (n = 2106) followed for 6.9 years. Lipids were not associated with recurrence, overall or in patients with unprovoked first events. Testing lipid levels is not useful to identify patients at an increased risk of recurrence. SUMMARY: Background Knowledge of risk factors for recurrent venous thrombosis may guide decisions on duration of anticoagulation. The association between lipid levels and first venous thrombosis has been studied extensively. However, data on the role of lipids in the risk of recurrence are scarce. Objective To assess the association between lipid levels and recurrent venous thrombosis. Patients/Methods Patients with a first venous thrombosis from the MEGA study were included. Follow-up started at the date of end of anticoagulant treatment. Percentile categories of total/low-density lipoprotein/high-density lipoprotein cholesterol, triglycerides and apolipoproteins B and A1 were established (< 10th, 10th-25th, 25th-75th [reference], 75th-90th, > 90th percentile). Lipids were measured at least 3 months after discontinuing anticoagulation. Results Of 2106 patients followed for a median of 6.9 years, 326 developed recurrence (incidence rate, 2.7/100 patient-years; 95% confidence interval [CI], 2.5-3.1). With hazard ratios ranging from 0.88 (95% CI, 0.55-1.42) to 1.33 (95% CI, 0.86-2.04) in the highest percentile category vs. the reference, we found no association across percentile categories between recurrence and lipid levels in age- and sex-adjusted models, nor after further adjustments for body mass index, diabetes, estrogen and statin use, and duration of anticoagulation. Subgroup analyses stratified by unprovoked or provoked first events, location (deep vein thrombosis or pulmonary embolism) and sex also did not reveal an association with any of the lipid levels studied. Conclusions Testing lipid levels did not identify patients at an increased risk of recurrent venous thrombosis in this study, including those with unprovoked first events, and these should not influence decisions on duration of anticoagulation.

Statin use decreases coagulation in users of vitamin K antagonists.

PURPOSE: The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). METHODS: We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. RESULTS: Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower. CONCLUSIONS: Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties.

Influence of World Thrombosis Day on digital information seeking on venous thrombosis: a Google Trends study.

Essentials In 2014, World Thrombosis Day (WTD) was initiated to increase global awareness of thrombosis. Google Trends can be used freely to monitor digital information seeking behavior. We used Google Trends data to assess the impact of WTD on internet searches on venous thrombosis. The WTD period was associated with more searches on thrombosis compared to control periods. SUMMARY: Background World Thrombosis Day (WTD) was launched in 2014 and is to be held every year to increase global awareness of venous thrombosis. Measuring the impact of health awareness days is challenging; however, use of internet-based data seems promising. Methods Google Trends data were used to quantify digital searches for 'venous thrombosis' worldwide and 'trombose' in the Netherlands. The relative search volume (RSV), which is the proportion of the term of interest amongst all Google searches for a specific region and timeframe was used. Mean differences for 4 weeks surrounding WTD (period of interest) and the remaining weeks of the year (control period) were estimated with 95% confidence intervals (95% CI). This was done for 2014, 2015 and 2009-2013 (control years). Results and discussion Mean differences in RSV for worldwide searches were 2.9 (95% CI, -8.2, 14.1) in 2014 and 10.5 (95% CI, 0.4, 20.5) in 2015. These figures were 15.3 (95% CI, 4.7, 25.8) and 15.9 (95% CI, 7.8, 24.1) for the Netherlands, respectively. Relatively, this corresponds to an increase in RSV of 3.9% and 13.9% for 2014 and 2015 worldwide and a 21.9% and 23.3% increase for 2014 and 2015 in the Netherlands. There was one control year with an increase in RSV in the WTD period. Conclusion In 2014 and 2015 WTD was associated with an increase in digital information seeking on venous thrombosis worldwide. This association was more pronounced in 2015 than in 2014.

Risk of venous thrombosis in persons with increased body mass index and interactions with other genetic and acquired risk factors.

UNLABELLED: Essentials Obesity, factor V Leiden (FVL) and blood group non-O are common. We studied the combined effect of these factors on the risk of venous thrombosis (VT). The combination of obesity, non-O blood group and FVL increased VT risk up to ten-fold. Identifying high VT may be beneficial in thrombosis prevention. SUMMARY: Background Overweight/obesity has a substantial effect on the occurrence of venous thrombosis (VT). Blood group non-O has a high prevalence in Western populations, and the factor V Leiden mutation could be present in 5% of Caucasians. These frequent prothrombotic risk factors will have a considerable impact on the incidence of VT, especially when combined. Objectives We investigated whether FV Leiden with blood group non-O modifies VT risk in individuals with different body mass index (BMI) strata in a case-control study (n = 11253). Results We observed a progressively increasing risk of VT with higher BMI, with an odds ratio of 1.9 (95% confidence interval [CI] 1.6-2.3) for those in the upper BMI tertile (BMI > 26.7 kg m(-2) ), as compared with the first BMI tertile (BMI < 23.5 kg m(-2) , blood group O, and no FV Leiden) (reference group). The addition of FV Leiden and blood group non-O to the model increased the risk in all BMI tertiles; the odds ratios were 3.8 (95% CI 3.2-4.6) in the third BMI tertile of individuals with blood group non-O, and 5.4 (95% CI 3.5-8.5) in the third BMI tertile of individuals with FV Leiden. When both FV Leiden and blood group non-O were present, the odds ratios were 9.1 (95% CI 5.9-14.0) in the first BMI tertile, 9.4 (95% CI 6.6-13.5) in the second BMI tertile, and 12.5 (95% CI 8.9-17.6) in the third BMI tertile. Conclusion Individuals with a high BMI, blood group non-O and/or FV Leiden have a high VT risk. The high VT risks in some subgroups may justify targeted screening and thromboprophylaxis decisions in these patients.

Platelet reactivity in patients with venous thrombosis who use rosuvastatin: a randomized controlled clinical trial.

UNLABELLED: Essentials Statins, especially rosuvastatin, may reduce venous thrombosis risk, but the mechanism is unclear. We performed a randomized trial investigating the effect of rosuvastatin on platelet reactivity. Thromboxane-A2 mediated platelet aggregation was measured before and after rosuvastatin therapy. Rosuvastatin did not inhibit thromboxane-mediated platelet aggregation in venous thrombosis patients. SUMMARY: Background Statins may exert a protective effect against the risk of venous thrombosis (VT), but the mechanism is unclear. Objectives In this open-label, randomized clinical trial (www.clinicaltrials.gov NCT01613794), we aimed to determine the ex vivo effect of rosuvastatin on platelet reactivity in patients with a history of VT. Methods Platelet reactivity, in platelet reaction units (PRUs), was measured at baseline and after 28 days with VerifyNow, which uses arachidonic acid to determine thromboxane-mediated platelet aggregation, in 50 consecutive patients included in our study (25 receiving rosuvastatin and 25 without intervention). Results Forty-seven of 50 (94.0%) consecutively enrolled patients had two valid PRU measurements. The mean PRUs in rosuvastatin users were 609 at baseline and 613 at the end of the study (mean change 5; 95% confidence interval [CI] - 18 to 27). The mean PRUs in non-users were 620 at baseline and 618 at the end of the study (mean change - 2; 95% CI - 15 to 12). The mean difference in PRU change between users and non-users was 6 (95% CI - 20 to 33). After exclusion of patients who used antiplatelet medication, or had thrombocytopenia, similar results were obtained, i.e. no apparent effect of rosuvastatin on PRUs, with a mean difference in PRU change between users and non-users of - 1 (95% CI - 20 to 19). Conclusions Rosuvastatin does not affect platelet reactivity when arachidonic acid is used as an agonist in patients with a history of VT.

Increased risk of major bleeding after a minor bleed during treatment with vitamin K antagonists is determined by fixed common risk factors.

UNLABELLED: Essentials Minor bleeding is associated with subsequent major bleeding in patients treated with vitamin K antagonists. This study confirms that patients with minor bleeds have a 2.5-fold increased risk of major bleeds. A case-crossover analysis revealed that the increased risk is due to fixed underlying risk factors. Future research may unveil these unknown fixed risk factors and improve major bleeding risk scores. SUMMARY: Background Patients who have a minor bleed during treatment with vitamin K antagonists (VKAs) have a 3-fold increased risk of subsequent major bleeding. The nature of the underlying risk factors is largely unknown. Objectives To indicate why patients with minor bleeds are at increased risk of subsequent major bleeds (e.g. are risk factors of a transient or a fixed nature). Methods Patients who started VKA treatment between 2003 and 2013 were included. Exposure was from the minor bleed until 3 months later. We used two analyses: a Cox model which we adjusted for several known risk factors, and a case-crossover (CCO) design, which corrects for all fixed risk factors (such as chronic diseases and genes) as patients are compared with themselves. The combination of both analyses gives insight into whether the association of minor with major bleeds is a result of fixed or transient risk factors. Results Out of 26 130 patients who were included and followed for '61 672 patient years', 7194 experienced a minor bleed and 913 a major bleed. The Cox model indicated that patients with minor bleeds had a 2.5-fold increased risk of experiencing subsequent major bleeding after adjustment for known risk factors, whereas the CCO gave risk estimates around unity (odds ratio, 0.9; 95% confidence interval, 0.5-1.5). Conclusions The combination of both analyses indicates that minor bleeds are markers for fixed and currently unknown risk factors for major bleeding events.

Elevated levels of factor VIII and subsequent risk of all-cause mortality: results from the MEGA follow-up study.

BACKGROUND: Factor VIII (FVIII) levels are increased in individuals with a non-O blood group and play a role in the etiology of thrombosis. High FVIII levels have also been associated with increased all-cause mortality. OBJECTIVE: We explored whether elevated FVIII levels are associated with an increased risk of death in patients who had venous thrombosis and in individuals from the general population, and to what extent this association is causal. METHODS: We followed 2178 patients with previous venous thrombosis and 2827 age and sex-matched community controls for on average 5.5 years and measured their FVIII levels and ABO blood group. RESULTS: All-cause mortality increased in a dose-response fashion with increasing percentiles of FVIII levels. In the thrombosis patients the risk was highest above the 97.5th percentile (FVIII > 199 IU dL(-1) ) with an adjusted hazard ratio (HR) of 3.1 (95% confidence interval [CI], 0.9-10.8) as compared with patients in the 25th percentile category (FVIII ≤ 85 IU dL(-1) ). The adjusted HR was 4.5 (95% CI, 1.4-14.3) in controls. Using non-O blood group as a measure of genetically elevated FVIII levels to determine a causal relationship between FVIII and death showed observed HRs of 0.99 (95% CI, 0.72-1.36) in patients and 1.25 (95% CI, 0.82-1.90) in controls. CONCLUSIONS: We showed a dose-response relationship between high FVIII levels and risk of death in venous thrombosis patients and in individuals from the general population. However, environmental factors, such as chronic comorbidities and chronic inflammation, are at least in part responsible for the association between factor VIII and mortality.