Search

Contains fulltext : 237493.pdf (Publisher’s version ) (Closed access) BACKGROUND: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of

Summary Autoimmune disease is a risk factor for first incident venous thromboembolism (VTE). However, data on the risk of recurrent VTE in people with autoimmune disease is sparse. We explored the risk of recurrent VTE using the RIETE registry, comparing people with autoimmune disease (n = 1305) to those without (n = 50608). Overall rates were 6.5 and 5.1 recurrent VTE/100 years for patients with autoimmune disease vs controls, respectively. After adjustment for sex and unprovoked/provoked VTE yielded an adjusted hazard ratio of 1.29 (95%CI 1.03‐1.62). The analysis was limited by short median follow up time (161 days overall), precluding definitive conclusions on recurrent VTE risks.

Introduction: The phase 2/3 PROTECT VIII main study demonstrated efficacy and safety of BAY 94–9027 (damoctocog alfa pegol; Jivi®), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life. Aim: To report the final efficacy and safety data for BAY 94–9027 from the PROTECT VIII extension. Methods: Previously treated males aged 12–65 years with severe haemophilia A (FVIII

Intracranial hemorrhage (ICH) is the most feared complication of anticoagulation with a high mortality and morbidity. Before registration of a specific reversal agent for factor Xa inhibitors (FXa-I), international guidelines recommended prothrombin complex concentrate (PCC), which also is the specific reversal agent for vitamin K antagonists (VKA). In two contemporary cohorts, we compared clinical outcomes between patients with FXa-I and VKA related ICH treated with PCC between 2014 and 2018. Primary outcome was effective hemostasis after 24 h, according to the International Society of Thrombosis and Hemostasis definition. Safety outcomes were defined as venous and arterial thromboembolic complications and death within 30 days. Thirty-six patients with FXa-I-ICH and 39 patients with VKA-ICH were available for analysis. Baseline characteristics were comparable between both groups, except for time from start of symptoms to presentation at the hospital. In the FXa-I-ICH cohort, 24 (73%) patients achieved effective hemostasis compared to 23 (62%) patients in the VKA-ICH cohort (crude odds ratio [OR] 1.62 [95%CI 0.59-4.48], adjusted OR 1.45 [95%CI 0.44-4.83]). Eight (24%) patients with FXa-I-ICH deceased compared to 17 (45%) patients with VKA-ICH (crude OR 0.38 [95%CI 0.14-1.24], adjusted OR 0.41 [95%CI 0.12-1.24]). In this observational cohort study, the outcome of ICH managed with PCC was similar in patients with FXa-I-ICH and in patients with VKA-ICH.

Patients with hereditary rare bleeding disorders (RBDs) present with diverse hemorrhagic symptoms. Correlation between factor activity levels and clinical bleeding severity is poor for most RBDs. Threshold factor activity levels have been previously described in relation to bleeding severity but have not yet been validated. The Rare Bleeding Disorders in the Netherlands (RBiN) study is a nationwide cross-sectional study of patients registered in all 6 Dutch Haemophilia Treatment Centers with a known RBD and who are age 1 to 99 years. Bleeding scores were determined, and laboratory and clinical data were extracted from patient files. In all, 263 patients were included, of whom 202 (77%) attended the scheduled study visit. The median International Society of Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) score was 9. Correlations between baseline factor activity levels and ISTH BAT scores were strong for deficiencies in factor II (FII) (r = –0.792) and FX (r = –0.838) and were moderate for deficiencies of fibrinogen (r = –0.683), FV (r = –0.623), FVII (r = –0.516), FXIII (r = –0.516), and α2-antiplasmin (r = –0.594). There was no correlation for FXI deficiency (r = –0.218). The RBD BAT identified more women (94% vs 83%) and children (100% vs 71%) with an RBD than the ISTH BAT did. Importantly, 48% of patients had more severe bleeding than predicted for their baseline factor activity level. In addition, 34% of patients were predicted to be asymptomatic, but they actually had grade 2 (31%) or 3 (3%) bleeding. Bleeding severity in patients with RBDs is more pronounced than previously anticipated. The previously determined threshold factor activity levels to ensure no (spontaneous) bleeding in patients with an RBD are inaccurate. This trial was registered at www.clinicaltrials.gov as #NCT03347591.

PURPOSE: Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients.METHODS: We included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group.RESULTS: In the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47-9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37-4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79-9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing.CONCLUSION: Co-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently.

BACKGROUND: Direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA) prevent thromboembolism in atrial fibrillation (AF). DOAC have a fixed dosing regimen and obviate INR monitoring. Therefore, DOAC presumably affect quality of life (QoL) less than VKA. However, some VKA users appreciate the monitoring. A high time in the therapeutic range (TTR) leads to a lower impact on QoL. We assessed the influence of switching from well-controlled VKA to a DOAC on QoL.METHODS: In the GAInN study, 241 patients with AF, a TTR ≥ 70%, and neither bleeding nor thrombosis while on VKA were randomised to switching to DOAC (n = 121) or continuing VKA (n = 120). Health-related (SF-36) and anticoagulation-related QoL (PACT-Q) was assessed at baseline and after six and twelve months of follow-up.RESULTS AND CONCLUSION: SF-36 development did not differ between groups. After one year, average PACT-Q Convenience improvement was 2.5 (0.3-4.7) higher on DOAC. DOAC users were 6percentage points (95%CI -4-16) more likely to improve >5 points on Convenience; 22 pp. (95%CI 1-43) in patients who scored

Background The objective of this study was to describe the prevalence, incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients receiving contemporary thrombosis prophylaxis. Methods We conducted a pooled analysis of two prospective cohort studies. The outcomes of interest were in-hospital pulmonary embolism or lower extremity deep vein thrombosis (PE-LDVT), in-hospital nonleg deep vein thrombosis (NLDVT), and 90-day mortality. Multivariable logistic regression analysis was used to evaluate the association between predefined baseline prognostic factors and PE-LDVT or NLDVT. Cox regression analysis was used to evaluate the association between PE-LDVT or NLDVT and 90-day mortality. Results A total of 2208 patients were included. The prevalence of any venous thromboembolism during 3 months before ICU admission was 3.6% (95% CI 2.8–4.4%). Out of 2166 patients, 47 (2.2%; 95% CI 1.6–2.9%) developed PE-LDVT and 38 patients (1.8%; 95% CI 1.2–2.4%) developed NLDVT. Renal replacement therapy (OR 3.5 95% CI 1.4–8.6), respiratory failure (OR 2.0; 95% CI 1.1–3.8), and previous VTE (OR 3.6; 95% CI 1.7–7.7) were associated with PE-LDVT. Central venous catheters (OR 5.4; 95% CI 1.7–17.8) and infection (OR 2.2; 95% CI 1.1–4.3) were associated with NLDVT. Occurrence of PE-LDVT but not NLDVT was associated with increased 90-day mortality (HR 2.7; 95% CI 1.6–4.6, respectively, 0.92; 95% CI 0.41–2.1). Conclusion Thrombotic events are common in critically ill patients, both before and after ICU admittance. Development of PE-LDVT but not NLDVT was associated with increased mortality. Prognostic factors for developing PE-LDVT or NLDVT despite prophylaxis can be identified at ICU admission and may be used to select patients at higher risk in future randomized clinical trials. Trial registration NCT03773939.

Background Whether factor V Leiden is associated with lower bleeding risk in patients with acute coronary syndromes using (dual) antiplatelet therapy has yet to be investigated. Methods and Results We pooled data from 3 randomized clinical trials, conducted in patients with acute coronary syndromes, with adjudicated bleeding outcomes. Cox regression models were used to obtain overall and cause‐specific hazard ratios (HRs) to account for competing risk of atherothrombotic outcomes (ie, composite of ischemic stroke, myocardial infarction, and cardiovascular death) in each study. Estimates from the individual studies were pooled using fixed effect meta‐analysis. The 3 studies combined included 17 623 patients of whom 969 (5.5%) were either heterozygous or homozygous (n=23) carriers of factor V Leiden. During 1 year of follow‐up, a total of 1289 (7.3%) patients developed major (n=559) or minor bleeding. Factor V Leiden was associated with a lower risk of combined major and minor bleeding (adjusted cause‐specific HR, 0.75; 95% CI, 0.56–1.00; P =0.046; I 2 =0%) but a comparable risk of major bleeding (adjusted cause‐specific HR, 0.93; 95% CI, 0.62–1.39; P =0.73; I 2 =0%). Adjusted pooled cause‐specific HRs for the association of factor V Leiden with atherothrombotic events alone and in combination with bleeding events were 0.75 (95% CI, 0.55–1.02; P =0.06; I 2 =0%) and 0.75 (95% CI, 0.61–0.92; P =0.007; I 2 =0%), respectively. Conclusions Given that the lower risk of bleeding conferred by factor V Leiden was not counterbalanced by a higher risk of atherothrombotic events, these findings warrant future assessment for personalized medicine such as selecting patients for extended or intensive antiplatelet therapy.

BACKGROUND: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin. METHODS: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire. RESULTS: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score. CONCLUSION: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time. ispartof: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS vol:5 issue:5 ispartof: location:United States status: published

Contains fulltext : 245042.pdf (Publisher’s version ) (Open Access) AIMS: Under- and, especially, overdosing of replacement therapy in haemophilia A patients may be prevented by application of other morphometric variables than body weight (BW) to dose factor VIII (FVIII) concentrates. Therefore, we aimed to investigate which morphometric variables best describe interindividual variability (IIV) of FVIII concentrate pharmacokinetic (PK) parameters. METHODS: PK profiling was performed by measuring 3 FVIII levels after a standardized dose of 50 IU kg(-1) FVIII concentrate. A population PK model was constructed, in which IIV for clearance (CL) and central volume of distribution (V1) was quantified. Relationships between CL, V1 and 5 morphometric variables (BW, ideal BW [IBW], lean BW, adjusted BW, and body mass index [BMI]) were evaluated in normal weight (BMI 30 kg m(-2) ). RESULTS: In total, 57 haemophilia A patients (FVIII≤0.05 IU mL(-1) ) were included with median BW of 83 kg (range: 53-133) and median age of 48 years (range: 18-77). IBW best explained observed variability between patients, as IIV for CL and V1 was reduced from 45.1 to 37.6 and 26.% to 14.1%, respectively. CL, V1 and half-life were similar for all BMI categories. The national recommended dosing schedule did not result in adequate trough levels, both in case of dosing based on BW and IBW. However, dosing based on IBW prevented unnecessary high FVIII peaks. CONCLUSION: IBW is the most suitable morphometric variable to explain interindividual FVIII PK variability and is more appropriate to dose overweight and obese patients.

BACKGROUND: The risk of venous thrombotic events is elevated in people with HIV, but overall risk estimates and estimates specific to immune status and antiretroviral medication remain i mprecise. In this study, we aimed to estimate these parameters in a large cohort of people with HIV in the Netherlands.METHODS: In this retrospective cohort study, we used the Dutch ATHENA cohort to estimate crude, age and sex standardised, and risk period-specific incidences of a first venous thrombotic event in people with HIV aged 18 years or older attending 12 HIV treatment centres in the Netherlands. Crude and standardised incidences were compared with European population-level studies of venous thrombotic events. We used time-updated Cox regression to estimate the risk of a first venous thrombotic event in association with HIV-specific factors (CD4 cell count, viral load, recent opportunistic infections, antiretroviral medication use) adjusted for traditional risk factors for venous thrombotic events.FINDINGS: With data collected from Jan 1, 2003, to April 1, 2015, our study cohort included 14 389 people with HIV and 99 762 person-years of follow-up, with a median follow-up of 7·2 years (IQR 3·3-11·1). During this period, 232 first venous thrombotic events occurred, yielding a crude incidence of 2·33 events per 1000 person-years (95% CI 2·04-2·64) and an incidence standardised for age and sex of 2·50 events per 1000 (2·18-2·82). CD4 counts less than 200 cells per μL were independently associated with higher risk of a venous thrombotic event: adjusted hazard ratio (aHR) 3·40 (95% CI 2·28-5·08) relative to counts of 500 cells per μL. A high viral load (aHR 3·15, 95% CI 2·00-5·02; >100 000 copies per mL vs INTERPRETATION: Our findings support neither prescribing primary outpatient thromboprophylaxis nor avoiding any type of antiretroviral medication in people with HIV at high risk of a venous thrombotic event.FUNDING: Dutch Ministry of Health, Welfare and Sport.

Item does not contain fulltext AIMS: Because practice-based data on the usage of idarucizumab for urgent dabigatran reversal is unavailable, we evaluated the appropriateness of idarucizumab usage, its haemostatic effectiveness and clinical outcomes. METHODS AND RESULTS: An observational cohort study was performed including consecutive patients who were treated with idarucizumab between 2016 and 2018. Appropriate usage was assessed with predefined criteria. Post-reversal effectiveness was evaluated according to International Society on Thrombosis and Haemostasis (ISTH) recommendations. Patients were followed for 90 days for occurrence of thromboembolism, (re-)bleeding and death. Idarucizumab was used in 88 patients, of whom 53 (60%) presented with severe bleeding (20 gastrointestinal and 18 intracranial) and 35 (40%) requiring urgent surgical intervention. Use of idarucizumab was judged inappropriate in 25 patients (28%). Effective haemostasis was achieved in 32 of 48 (67%) bleeding patients in whom assessment was possible. Seven of 16 patients with major bleeding who did not achieve effective haemostasis (five intracranial) died, compared with two of 32 patients with effective haemostasis (relative risk 7.0, 95% confidence interval 1.6-30). Four patients (4.2%) developed thromboembolism [2 (2.1%) within 30 days] and four patients (4.2%) re-bleeding, all within 10 days. Seventeen patients (19%) died; 10 (11%) within 5 days. CONCLUSION: In this practice-based cohort, idarucizumab use was considered inappropriate in 28% of patients. Effective haemostasis was achieved in two-third of bleeding patients and was associated with lower mortality risk. Clinical outcomes were similar to those observed in the RE-VERSE AD trial, comprising re-bleeds and thromboembolism, and a high-mortality rate.

Background: Andexanet alfa (andexanet) and prothrombin complex concentrate (PCC) are both reversal agents for major bleeding in patients using factor Xa inhibitors (FXaIs). Our aim was to evaluate the current evidence for the effectiveness and safety of andexanet and PCC in a systematic review and meta-analysis.Objectives: Primary objective was hemostatic effectiveness. Secondary objectives were thromboembolic event rate and mortality.Methods: A systematic review was performed in PubMed and Embase. Studies describing the effectiveness and/or safety of PCC or andexanet in patients with major bleeding using FXaIs were included. Meta-analysis was performed using a random-effects model.Results: Seventeen PCC studies, 3 andexanet studies, and 1 study describing PCC and andexanet were included, comprising 1428 PCC-treated and 396 and exanet-treated patients. None of the included studies had control groups, hampering a pooled meta-analysis to compare the two reversal agents. Separate analyses for andexanet and PCC were performed. In subgroup analysis, the pooled proportion of patients with effective hemostasis in studies that used Annexa-4 criteria demonstrated a hemostatic effectiveness of 0.85 (95% confidence interval [CI], 0.80-0.90) in PCC and 0.82 (95% CI, 0.78-0.87) in andexanet studies. The pooled proportion of patients with thromboembolic events was 0.03 (95% CI, 0.02-0.04) in PCC and 0.11 (95% CI, 0.04-0.18) in andexanet studies.Conclusion: Based on the available evidence with low certainty from observational studies, PCC and andexanet demonstrated a similar, effective hemostasis in the treatment of major bleeding in patients using FXaIs. Compared to PCC, the thromboembolic event rate appeared higher in and exanet-treated patients.

Von Willebrand factor (VWF) multimer analysis is important in the classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is time consuming and inaccurate in detecting subtle changes in multimer patterns. Although VWF multimer densitometric analysis may be useful, the accuracy needs further investigation before it can be widely applied. In this study we aimed to validate VWF multimer densitometric analysis in a large cohort of VWD patients and to identify patient characteristics associated with densitometric outcomes. Patients were included from the Willebrand in the Netherlands (WiN) study, in which a bleeding score (BS) was obtained, and blood was drawn. For multimer analysis, citrated blood was separated on an agarose gel and visualized by Western blotting. IMAGEJ was used to generate densitometric images and medium-large VWF multimer index was calculated. We included 560 VWD patients: 328 type 1, 211 type 2, and 21 type 3 patients. Medium-large VWF multimer index performed excellent in distinguishing visually classified normal VWF multimers from reduced high-molecular-weight (HMW) multimers (area under the curve [AUC]: 0.96 [0.94-0.98], P < 0.001), normal multimers from absence of HMW multimers (AUC 1.00 [1.00-1.00], P < 0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 [0.94-0.99], P < 0.001). Additionally, higher medium-large VWF multimer index was associated with lower BS in type 1 VWD: beta = -7.6 (-13.0 to -2.1), P = 0.007, adjusted for confounders. Densitometric analysis of VWF multimers had an excellent accuracy compared with visual multimer analysis and may contribute to a better understanding of the clinical features such as the bleeding phenotype of VWD patients.

Background The prothrombotic defect factor V Leiden (FVL) may confer higher risk of ST‐segment–elevation myocardial infarction (STEMI), compared with non–ST‐segment–elevation acute coronary syndrome, and may be associated with more myocardial necrosis caused by higher thrombotic burden. Methods and Results Patients without history of cardiovascular disease were selected from 2 clinical trials conducted in patients with acute coronary syndrome. FVL was defined as G‐to‐A substitution at nucleotide 1691 in the factor V (factor V R506Q) gene. Odds ratios were calculated for the association of FVL with STEMI adjusted for age and sex in the overall population and in the subgroups including sex, age (≥70 versus P =0.59) for the association of FVL with STEMI. Subgroup analysis did not show any differences. In patients with STEMI, neither the median peak creatine kinase‐myocardial band nor the peak high‐sensitivity troponin ratio showed any differences between wild‐type and FVL carriers ( P for difference: creatine kinase‐myocardial band=0.33; high sensitivity troponin ratio=0.54). Conclusions In a general population with acute coronary syndrome, FVL did not discriminate between a STEMI or non–ST‐segment–elevation acute coronary syndrome presentation and was unrelated to peak cardiac necrosis markers in patients with STEMI. Registration URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00391872 and NCT01761786.

Contains fulltext : 244121.pdf (Publisher’s version ) (Open Access) AIMS: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. METHODS: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. RESULTS: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL(-1) . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h(-1) 68 kg(-1) , 2930 mL 68 kg(-1) , 1810 mL 68 kg(-1) , and 172 mL h(-1) 68 kg(-1) , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL(-1) . CONCLUSIONS: This study emphasizes the importance of external validation of population PK models using real-life data.

Contains fulltext : 229340.pdf (Publisher’s version ) (Open Access) BACKGROUND: The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS-13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS-13 is in individuals with VWD. OBJECTIVES: We therefore studied how ADAMTS-13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD. METHODS: We measured ADAMTS-13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross-sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score. RESULTS: ADAMTS-13 activity was similar in individuals with VWD (109% ± 20.6%) and controls (110% ± 19.7%). ADAMTS-13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%-20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%-25.1%). ADAMTS-13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS-13 increase, 95% CI, -0.2 to 0.3). Furthermore, ADAMTS-13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, -2.1% to 4.9%). CONCLUSION: ADAMTS-13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS-13 activity does not influence the bleeding phenotype in individuals with VWD.

Background Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population. Methods and findings PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003–2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999–2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23–2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04–2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67–0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period. Conclusions Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE., Casper Rokx and colleagues study the risk of recurrent venous thromboembolism in people with HIV infection., Author summary Why was this study done? The HIV pandemic affects approximately 40 million people and causes significant morbidity, including a markedly increased risk of a venous thromboembolism (VTE). The recurrence risk of VTE in people living with HIV (PWH) is unknown, although this risk drives the anticoagulant therapy duration after a first VTE. Our study determined the recurrent VTE risk in PWH compared to uninfected controls. What did the researchers do and find? We performed an observational cohort study using data from the national ATHENA PWH cohort (2003–2015) in the Netherlands and the Dutch Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) cohort (1999–2009) of HIV-uninfected controls with a first VTE. The recurrent VTE incidence rate per 100 person-years of follow-up (PYFU) was higher in PWH (5.2) compared to controls (3.1) yielding a 1.70 hazard ratio (HR; 95% CI 1.23–2.36). Incidence rates were consistently higher for PWH in subgroups stratified by sex or the cause of the first VTE. PWH with lower cluster of differentiation 4 (CD4)+ T-cell counts at their first VTE had fewer recurrent events, which was driven by PWH experiencing a better CD4+ T-cell recovery on HIV treatment prior to anticoagulant discontinuation. What do these findings mean? The risk of recurrent VTE is apparently increased in PWH but is ameliorated with better immune reconstitution. HIV-associated immunodeficiency reflects a reversible risk factor for VTE specific to PWH and is of relevance for decisions on anticoagulant therapy duration.

Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (–1.0%, 95% CI: –9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.

Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 × 1012 or 2 × 1013 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n = 1) and higher-dose (n = 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.

Inhibition of von Willebrand factor (VWF) expression in endothelial cells results in enhanced, possible dysfunctional angiogenesis, consistent with observations of severe gastrointestinal bleedings caused by vascular malformations in patients with von Willebrand disease (VWD). VWF is stored in endothelial Weibel–Palade bodies (WPB) with several other mediators of angiogenesis, like angiopoietin-2, osteoprotegerin and galectin-3. Increased release of angiopoietin-2 has been observed in medium of endothelial cells lacking VWF, but data on circulating levels of angiogenic factors in patients with VWD are lacking. The aim of this study was therefore to investigate plasma levels of angiogenic factors in patients with various types of VWD to obtain more insight into the pathogenesis of vascular malformations in these patients. We hypothesized that VWF deficiency leads to increased circulating levels of other WPB components. We therefore measured plasma levels of the WPB components angiopoietin-2, osteoprotegerin and galectin-3 as well as two other angiogenic factors (angiopoietin-1 and vascular endothelial growth factor [VEGF]) that are not stored within WPB. We observed that various angiogenic mediators are significantly different between types of VWD patients. Type 2A VWD patients had higher angiopoietin-1 levels compared with type 2B patients. Patients who have increased VWF clearance had higher angiopoietin-2 levels, whereas patients who have impaired VWF synthesis had higher galectin-3 levels. VEGF levels were negatively associated with VWF levels as type 3 VWD patients had the highest VEGF levels. However, complete VWF deficiency did not lead to increased circulating levels of other WPB components.

In a previous study it was shown that lower factor XI (FXI) levels in women with heavy menstrual bleeding (HMB). Our aim was to determine the single-nucleotide variants (SNVs) in the F11 gene in women with HMB. In addition, an extensive literature search was performed to determine the clinical significance of each SNV. Patients referred for HMB (PBAC-score100) were included. With direct sequencing analysis of all 15 exons and flanking introns of the F11 gene, 29 different non-structural SNVs were detected in 49 patients with HMB. Interestingly, most of these SNVs have previously been associated with venous thrombosis instead of bleeding. These findings have not helped to elucidate the molecular basis of HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB. IMPACT STATEMENT Women with mild deficiencies of factor XI (FXI) ( 70%) are prone to excessive bleeding during menstruation. Bleeding manifestations are not well correlated with plasma FXI levels and bleeding episodes can vary widely among patients with similar low FXI levels. In a previous study we showed that women with heavy menstrual bleeding (HMB) had normal, but on average, lower levels of FXI than controls. In light of these findings, we performed F11 gene analysis to determine the single-nucleotide variants (SNVs) in women with HMB and performed an extensive literature search to determine the clinical significance of each SNV. By direct sequencing analysis of the F11 gene we found 29 different non-structural SNVs in 49 women with heavy menstrual bleeding. Remarkably, a number of these SNVs have previously been implicated in thrombosis. These findings have not helped to elucidate the molecular basis of lower FXI levels in HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB.

Introduction Von Willebrand factor (VWF) multimer analysis is an essential tool in the diagnosis and classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is observer dependent, time consuming and is inaccurate in detecting subtle changes in multimer patterns. Therefore, recent studies have investigated VWF multimer quantification using semiautomatic densitometric analysis. The accuracy of VWF multimer densitometric analysis in clinical practice needs further investigation before it can be widely used. The aim of the study was to validate the accuracy of VWF multimer densitometric analysis in clinical practice. Additionally, we aimed to identify patient characteristics associated with VWF multimer densitometry outcomes in type 1 and type 2 VWD patients, and we investigated whether subtle differences in VWF multimer pattern are associated with the bleeding phenotype of VWD patients. Methods We included patients from the nationwide Willebrand in the Netherlands (WiN) study. The inclusion criteria of the WiN study were a personal hemorrhagic diathesis or family history of VWD, and historically lowest VWF antigen (VWF:Ag), VWF activity (measured with the monoclonal antibody assay: VWF:Ab) or VWF collagen binding (VWF:CB) ≤0.30 IU/mL or FVIII activity (FVIII:C) ≤0.40 IU/mL in case of type 2N VWD. At inclusion in the WiN study, blood was drawn and patients filled in an extensive questionnaire containing a self-administered Tosetto bleeding score (BS). For multimer analysis, citrated blood samples were separated on 0.9% agarose gel and visualized by Western blotting. We used IMAGEJ for densitometric analysis. The five smallest bands on densitometric images were defined as small multimers, next five bands were defined as medium multimers and the remaining bands were defined as large multimers. Medium-large VWF multimer index was calculated by dividing the patient's multimer ratio (intensity of the medium and large multimers divided by the total intensity of all multimers) by the multimer ratio of a normal control in the same western blot. If no multimers could be detected, the multimer index was set as 0. Results We included 561 VWD patients: 328 type 1, 211 type 2 and 21 type 3 patients. The median age was 44 [IQR 29-58] and 351 patients (62.7%) were female (Table 1). Figure 1 illustrates typical densitometric outcomes of a type 1 VWD patient with normal VWF multimers (A) and a type 2A patient with reduced high-molecular-weight (HMW) VWF multimers (B). Medium-large VWF multimer index was 1.06 [0.99-1.12] in type 1 and 0.53 [0.29-0.89] in type 2 and 0.00 [0.00-0.00] in type 3 VWD. Medium-large VWF multimer index was in patients visually classified as normal, reduced and absent HMW VWF multimers, respectively 1.07 [1.02-1.12], 0.84 [0.71-0.91] and 0.31 [0.20-0.44] (p From VWF activity measurements, medium-large VWF multimer index was strongest correlated with VWF:CB (ρ=0.79, p In type 1 VWD, an increased clearance of VWF (defined as VWFpropeptide/VWF:Ag ratio ≥2.2) was independently associated with lower medium-large VWF multimer index (β=-0.10 (-0.14; -0.07), p In the total population, higher medium-large VWF multimer index was associated with a lower bleeding score: β=-4.6 (-7.2; -2.0), p=0.001, adjusted for age, sex, blood group and type of VWD. Conclusion Semiautomatic densitometric analysis of VWF multimers has an excellent accuracy in clinical practice, and may have an additional value in providing a better understanding of the clinical features such as the bleeding phenotype of VWD patients. Disclosures Atiq: CSL Behring: Research Funding; SOBI: Other: travel grant. Boender:SOBI: Current Employment; CSL Behring: Research Funding. Cnossen:Bayer: Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; Sobi: Research Funding; Takeda: Research Funding; CSL behring: Research Funding; Pfizer: Research Funding; Shire: Research Funding; Baxter: Research Funding. van der Bom:Bayer: Speakers Bureau. Fijnvandraat:SOBI: Research Funding; NovoNordisk: Consultancy; Grifols: Consultancy; Takeda: Consultancy; Roche: Consultancy; CSL Behring: Research Funding; NovoNordisk: Research Funding. Van Galen:Bayer: Research Funding; Takeda: Speakers Bureau; CSL Behring: Research Funding. Laros-Van Gorkom:Baxter: Other: Educational grant; CSL Behring: Other: Educational grant. Meijer:Bayer: Research Funding; Sanquin: Research Funding; Pfizer: Research Funding; Bayer: Speakers Bureau; Sanquin: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. Eikenboom:CSL Behring: Research Funding; Roche: Other: Teacher on educational activities. Leebeek:Roche: Other: DSMB member for a study; SOBI: Other: Travel grant; Novo Nordisk: Consultancy; Shire/Takeda: Consultancy; Uniqure: Consultancy; Shire/Takeda: Research Funding; CSL Behring: Research Funding.

Background The benefit of vitamin K antagonists depends on the time within the therapeutic range (TTR). A patient's previous TTR could be a factor in the decision to change the anticoagulation regimen. However, the predictive value of a previous TTR for a future TTR is not well established, nor is it clear which TTR should prompt action.Objectives To investigate the predictive performance of a TTR and identify a threshold below which no recovery of TTR should be expected.Patients/Methods From 18 031 patients who used acenocoumarol in a first-line anticoagulation clinic, a TTR was calculated over multiple periods of 90, 180, and 365 days each. We assessed the correlation between baseline and later TTR and the separation between groups by quintile of baseline TTR. We describe the proportion of patients who obtain a TTR >= 70% conditional on baseline TTR.Results The correlation between baseline and later TTR was 0.25 (95% confidence interval [CI], 0.24-0.26), 0.27 (95% CI, 0.26-0.28) and 0.34 (95% CI, 0.32-0.35) for analyses over 90, 180, and 365 days. Corresponding c statistics for discrimination by baseline group were 0.60, 0.61, and 0.63. The probability to obtain a TTR >= 70% increased with baseline TTR: from 42% with a baseline TTR of 50%-65% when TTR was 100% (TTR calculated over 180 days).Conclusions We conclude that a current TTR hardly predicts a future TTR. Physicians and patients should deliberate together which probabilities to accept, take measures to improve TTR, and consider potential alternatives.

Different doses of low-molecular-weight heparin (LMWH) are registered and used for thrombosis prophylaxis. We assessed benefits and harms of thrombosis prophylaxis with a predefined intermediate-dose LMWH compared with placebo or no treatment in patients at risk of venous thromboembolism (VTE). We performed a systematic review with meta-analyses and trial sequential analyses (TSA) following The Cochrane Handbook for Systematic Reviews of Interventions. Medline, Cochrane CENTRAL, Web of Science, and Embase were searched up to December 2018. Trials were evaluated for risk of bias and quality of evidence was assessed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seventy randomized trials with 34,046 patients were included. Eighteen (26%) had overall low risk of bias. There was a small statistically significant effect of LMWH on all-cause mortality (risk ratio [RR]: 0.96; TSA-adjusted confidence interval [TSA-adjusted CI]: 0.94–0.98) which disappeared in sensitivity analyses excluding ambulatory cancer patients (RR: 0.99; TSA-adjusted CI: 0.84–1.16). There was moderate-quality evidence for a statistically significant beneficial effect on symptomatic VTE (odds ratio [OR]: 0.59; TSA-adjusted CI: 0.53–0.67; number needed to treat [NNT]: 76; 95% CI: 60–106) and a statistically significant harmful effect on major bleeding (Peto OR: 1.66; TSA-adjusted CI: 1.31–2.10; number needed to harm [NNH]: 212; 95% CI: 142–393). There were no significant intervention effects on serious adverse events. The use of intermediate-dose LMWH for thrombosis prophylaxis compared with placebo or no treatment was associated with a small statistically significant reduction of all-cause mortality that disappeared in sensitivity analyses excluding trials that evaluated LMWH for anticancer treatment. Intermediate-dose LMWH provides benefits in terms of VTE prevention while it increases major bleeding.

International guidelines recommend low-molecular-weight heparin (LMWH) as first-line pharmacological option for the prevention of venous thromboembolism (VTE) in many patient categories. Guidance on the optimal prophylactic dose is lacking. We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials to assess benefits and harms of low-dose LMWH versus placebo or no treatment for thrombosis prophylaxis in patients at risk of VTE. PubMed, Cochrane Library, Web of Science, and Embase were searched up to June 2019. Results were presented as relative risk (RR) with conventional and TSA-adjusted confidence intervals (CI). Forty-four trials with a total of 22,579 participants were included. Six (14%) had overall low risk of bias. Low-dose LMWH was not statistically significantly associated with all-cause mortality (RR 0.99; 95%CI 0.85−1.14; TSA-adjusted CI 0.89−1.16) but did reduce symptomatic VTE (RR 0.62; 95%CI 0.48−0.81; TSA-adjusted CI 0.44−0.89) and any VTE (RR 0.61; 95%CI 0.50−0.75; TSA-adjusted CI 0.49−0.82). Analyses on major bleeding (RR 1.07; 95%CI 0.72−1.59), as well as serious adverse events (SAE) and clinically relevant non-major bleeding were inconclusive. There was very low to moderate-quality evidence that low-dose LMWH for thrombosis prophylaxis did not decrease all-cause mortality but reduced the incidence of symptomatic and asymptomatic VTE, while the analysis of the effects on bleeding and adverse events remained inconclusive.

Introduction: Heparins exert their anticoagulant effect through activation of antithrombin. Whether antithrombin deficiency leads to clinically relevantly reduced anti-Xa activity of heparins is unknown. We investigated the relation between antithrombin deficiency and anti-Xa activity measurements of plasma samples spiked with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).Materials and methods: Plasma samples from 34 antithrombin-deficient subjects and 17 family controls were spiked with UFH and LMWH (nadroparin) aimed to correspond with an anti-Xa activity of 0.8 IU/mL. Antithrombin, beta-antithrombin and anti-Xa activities were measured.Results: Mean anti-Xa activity with LWMH was 0.55 IU/mL (0.30-0.74) (recovery 69%, 38-93%) in antithrombin-deficient subjects and 0.82 (0.71-0.89) IU/mL in controls (recovery 103%, 89-111%). Expected anti-Xa measurements after LMWH spiking were found in 17/17 non-deficient subjects and in 8/34 antithrombin-deficient subjects. Anti-Xa measurements in the expected range (0.6-1.0 IU/mL) after UFH spiking were found in 17/17 non-deficient subjects and in 1/22 antithrombin-deficient subjects. Antithrombin activity correlated with anti-Xa activity of UFH (R= 0.77) and LMWH (R= 0.66). Mixing studies of pooled normal plasma and antithrombin-deficient plasma showed that anti-Xa recovery was linearly reduced with antithrombin activity decreasing below 100%.Conclusions: Reduced antithrombin activity causes significantly reduced anti-Xa levels. Standard LWMH- or UFH-doses are likely to lead to under treatment in antithrombin-deficient individuals.

Contains fulltext : 202865.pdf (Publisher’s version ) (Closed access)

Background— Vitamin K antagonists (VKA) use is challenging because of frequent blood monitoring and complex dosing. Therefore, many patients and physicians are reluctant to start VKA. However, it is unclear whether VKA use actually lowers quality of life. We aimed to determine the impact of VKA initiation on quality of life and to analyze the correlation between patient and treatment characteristics and VKA perception in atrial fibrillation patients. Methods and Results— In a prospective cohort of 240 new and 567 long-term VKA users, general quality of life and VKA perception (satisfaction and convenience) were measured at inclusion and at 3 months by the validated Study Short-Form 36 and Perception of Anticoagulant Treatment Questionnaire. Scores were converted to a 0 to 100 scale. Higher scores are more favorable. In the new patients, Medical Outcomes Study Short-Form 36 scores improved during the initial 3 months to a level comparable with the general population. At 3 months, the median convenience score was 95 (Q1–Q3, 88–98) and was higher in older patients (regression coefficient, 0.47 per year; 95% confidence interval, 0.25–0.69) and lower after bleeding (regression coefficient, −12; 95% confidence interval, −20 to −4.7). The median satisfaction score was 64. For the long-term patients, VKA perception scores were highly comparable with the new patients. The convenience score mildly improved in patients with increased individual time in therapeutic range (regression coefficient, 0.03; 95% confidence interval, 0.01–0.05; r 2 =0.01), and satisfaction scores decreased in patients with new comedication (regression coefficient, −7.0; 95% confidence interval, −12 to −1.9; r 2 =0.02). Conclusions— VKA were well tolerated in real-life, and the influences of patient and treatment related factors on VKA perception were very limited.

Essentials Few data exist on outcome of upper extremity deep and superficial vein thrombosis (UEDVT and UESVT). We followed 102 and 55 patients with UEDVT or UESVT, respectively, for a median of 3.5 years. Risk of recurrent venous thromboembolism was low in both diseases, and the mortality high. Postthrombotic symptoms were infrequent and cancer patients had a higher risk of recurrent VTE. Background There is scant information on the optimal management and clinical outcome of deep and superficial vein thrombosis of the upper extremity (UEDVT and UESVT). Objectives To explore treatment strategies and the incidence of recurrent venous thromboembolism (VTE), mortality, postthrombotic symptoms, and bleeding in patients with UEDVT and UESVT and to assess the prognosis of cancer patients with UEDVT. Patients/methods Follow-up of patients with UEDVT or UESVT, who were enrolled previously in a diagnostic management study. Results We followed 102 and 55 patients with UEDVT and UESVT, respectively, both for a median of 3.5 years. Anticoagulant treatment was started in 100 patients with UEDVT (98%) and in 40 (73%) with UESVT. Nine patients with UEDVT (9%) developed recurrent VTE, 26 (26%) died, 6 (8%) of 72 patients had moderate postthrombotic symptoms, and 5 (5%) experienced major bleeding. One patient with UESVT had a recurrent VTE, 18 (33%) died, none had moderate postthrombotic symptoms, and none had major bleeding. Of the cancer patients with UEDVT, 18% had recurrent VTE vs. 7.5% in non-cancer patients (adjusted hazard ratio 2.2, 95%CI 0.6-8.2). The survival rate was 50% in cancer patients with UEDVT vs. 60% in those without (adjusted HR 0.8, 95%CI 0.4-1.4). Conclusions The risk of recurrent VTE was low in patients with UEDVT, and negligible for UESVT. Mortality was high for both diseases. Postthrombotic symptoms were infrequent and mild. Anticoagulant therapy of UEDVT carried a substantial risk of major bleeding. Cancer patients had a significant risk of recurrent VTE

Venous thromboembolism occurs commonly in patients with cancer. Direct oral anticoagulants are non-inferior to conventional anticoagulants for the treatment of venous thromboembolism. We hypothesised that edoxaban, a direct oral inhibitor of activated clotting factor Xa, might be more suitable than conventional anticoagulants in the management of cancer-associated venous thromboembolism. The aim of this study was to assess the efficacy and safety of edoxaban compared with warfarin in a subgroup of patients with cancer enrolled in the Hokusai-VTE trial. We did a prespecified subgroup analysis in August, 2013, and a post-hoc analysis of non-inferiority and safety in March, 2016, of the patients with cancer enrolled in the randomised, double-blind, double-dummy, multicentre, Hokusai-VTE trial done between Jan 28, 2010, and Oct 31, 2012. In this study, patients aged at least 18 years with acute symptomatic deep-vein thrombosis or acute symptomatic pulmonary embolism (with or without deep-vein thrombosis) were assigned to receive edoxaban 60 mg once per day (or 30 mg once per day for patients with a creatinine clearance of 30-50 mL/min, bodyweight

BACKGROUND: Treatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control.AIMS: We assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability.METHODS AND RESULTS: In a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2-3, 269 patients in target range 2-3.5 and 98 patients in target range 2.5-3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers' TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2-3, 2-3.5 and 2.5-3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers' INRs were much more stable than non-switchers'.CONCLUSION: Eventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase.

BACKGROUND: Vitamin K antagonist (VKA) therapy is safer and more effective when patients have a high time within the therapeutic range and low international normalised ratio variability. The SAMe-TT2R2 score aims to identify those at risk for poor VKA control.OBJECTIVES: To evaluate the predictive value and clinical usefulness of the SAMe-TT2R2 score to identify those at risk for poor VKA control.METHODS: We performed a systematic review in MEDLINE and Embase for original research papers assessing the SAMe-TT2R2's relation to poor TTR. We performed a meta-analysis where scores ≥ 2 and ≥ 3 predicting TTR < 70%. When studies evaluated other cutoffs for TTR or SAMe-TT2R2, they were harmonised by multiple simulations with patient characteristics from the individual studies, if the data were available.RESULTS: 16 studies were identified and used in the meta-analysis: 4 and 2 times directly, 8 and 8 times harmonised for scores ≥ 2 and ≥ 3, respectively (not all studies provided information about both cutoffs). The sensitivities and specificities were too heterogeneous to pool. The positive likelihood ratios were 1.25 (1.14-1.38) for a score ≥ 2, and 1.24 (1.09-1.40) for a score ≥ 3; the negative ones were 0.87 (0.82-0.93) and 0.96 (0.91-1.02), respectively. This shows that the post-test probabilities hardly differ from the prior probability (prevalence).CONCLUSION: The SAMe-TT2R2 score does predict low TTR, but the effect is small. Its effect on individual patients is too limited to be clinically useful.

Antithrombin deficiency is a strong risk factor for venous thromboembolism (VTE), but the absolute risk of the first and recurrent VTE is unclear. The objective of this paper is to establish the absolute risks of the first and recurrent VTE and mortality in individuals with antithrombin deficiency. The databases Embase, Medline Ovid, Web of Science, the Cochrane Library, and Google Scholar were systematically searched for case–control and cohort studies. Bayesian random-effects meta-analysis was used to calculate odds ratios (ORs), absolute risks, and probabilities of ORs being above thresholds. Thirty-five publications were included in the systematic review and meta-analysis. Based on 19 studies, OR estimates for the first VTE showed a strongly increased risk for antithrombin deficient individuals, OR 14.0; 95% credible interval (CrI), 5.5 to 29.0. Based on 10 studies, meta-analysis showed that the annual VTE risk was significantly higher in antithrombin-deficient than in non-antithrombin-deficient individuals: 1.2% (95% CrI, 0.8–1.7) versus 0.07% (95% CrI, 0.01–0.14). In prospective studies, the annual VTE risk in antithrombin deficient individuals was as high as 2.3%; 95% CrI, 0.2–6.5%. Data on antithrombin deficiency subtypes are very limited for reliable risk-differentiation. The OR for recurrent VTE based on 10 studies was 2.1; 95% CrI, 0.2 to 4.0. The annual recurrence risk without long-term anticoagulant therapy based on 4 studies was 8.8% (95% CrI, 4.6–14.1) for antithrombin-deficient and 4.3% (95% CrI, 1.5–7.9) for non-antithrombin-deficient VTE patients. The probability of the recurrence risk being higher in antithrombin-deficient patients was 95%. The authors conclude that antithrombin deficient individuals have a high annual VTE risk, and a high annual recurrence risk. Antithrombin deficient patients with VTE require long-term anticoagulant therapy.

Hereditary antithrombin deficiency is associated with a high incidence of venous thromboembolism (VTE), but VTE risk differs between families. Beta-antithrombin is reported to be the most active isoform of antithrombin in vivo. Whether beta-antithrombin activity and subtypes in antithrombin deficiency have impact on VTE risk has not been investigated outside the proband setting.We performed a retrospective family cohort study to investigate whether subtypes of antithrombin deficiency or beta-antithrombin levels are associated with the risk of first or recurrent VTE.Eighty-one subjects from 21 families were included, of which 52 were antithrombin deficient. Beta-antithrombin levels were decreased in most type I and type IIPE subjects, but normal levels were found in all subtypes of antithrombin deficiency.The annual incidence of VTE in antithrombin-deficient family members was 1.24%, 95%CI: 0.72-1.99%, in low beta-antithrombin 1.36% (95%CI: 0.76-2.25%) and in normal beta-antithrombin 0.79% (95%CI: 0.10-2.77). The annual incidence of recurrence in family members was 3.1% (95%CI: 0.9-7.1%). Duration of anticoagulation had an impact on recurrence risk: In family members annual recurrence with fixed duration was 10% (95%CI: 2.1-29.2%), with indefinite duration 1.5% (95%CI: 0.2-5.4%), p Conclusions: In this high-risk antithrombin-deficient population, both subjects with low and normal plasma beta-antithrombin activity had high risks of first and recurrent VTE. This puts the importance of beta-antithrombin into question. Long-term anticoagulation is warranted in antithrombin-deficient VTE patients.

SummaryVitamin K antagonists (VKA) are widely used in atrial fibrillation and venous thromboembolism (VTE). Their efficacy and safety depend on individual time in the therapeutic range (iTTR). Due to the variable dose-response relationship within patients, also patients with initially stable VKA treatment may develop extreme overanticoagulation (EO). EO is associated with an immediate bleeding risk, but it is unknown whether VKA treatment will subsequently restabilise. We evaluated long-term quality of VKA treatment and clinical outcome after EO. EO was defined as international normalized ratio (INR) ≥ 8.0 and/or unscheduled vitamin K supplementation. We included a consecutive cohort of initially stable atrial fibrillation and venous thromboembolism patients. In EO patients, the 90 days pre- and post-period were compared. In addition, patients with EO were compared with patients without EO using a matched 1:2 cohort. Of 14,777 initially stable patients, 800 patients developed EO. The pre-period was characterised by frequent overanticoagulation, and half of EO patients had an inadequate iTTR (< 65 %). After EO, underanticoagulation became more prevalent. Although the mean time between INR-measurements decreased from 18.6 to 13.2 days, after EO inadequate iTTR became more frequent (62 %), p-value < 0.001. A 2.3 times (95 % confidence interval [CI] 2.0–2.5) higher risk for iTTR< 65 % after EO, was accompanied by increased risk of bleeding (hazard ratio [HR] 2.1;CI 1.4–3.2), VKA-related death 17.0 (HR 17.0;CI 2.1–138) and thrombosis (HR 5.7;CI 1.5–22.2), compared to the 1600 controls. In conclusion, patients continuing VKA after EO have long-lasting inferior quality of VKA treatment despite intensified INR-monitoring, and an increased risk of bleeding, thrombosis and VKA-related death.Note: There have been no previous presentations, reports or publications of the complete data that appear in the article. Parts of the data in this article have been presented as a poster at the American Society of Hematology (ASH) congress 2013, New Orleans, United States.

SummaryVitamin K antagonists (VKA) are used to prevent recurrent disease in patients with venous thromboembolism (VTE). Their efficacy and safety depend on individual time in therapeutic range (iTTR) and variability of International Normalised Ratios (INR). We aimed to identify independent predictors of poor VKA control > 28 days. In a prospective cohort of 3825 VTE patients, separate logistic regression analyses were performed to identify predictors of low iTTR (first quartile) and instability (iTTR median). Subsequently, the association between these predictors and clinical outcomes was investigated. Weight < 50 kg (odds ratio [OR]=1.89; 95 % confidence interval [CI] 1.03–3.49), active cancer at baseline (OR=1.52; CI1.05–2.19), secondary VTE (OR=1.42; CI1.20–1.68), and INR < 2.0 at stop of double therapy (OR=1.35; CI1.09–1.67) were independent predictors of low iTTR. The first two were also predictive for instability (OR=1.96; CI1.06–3.63 and OR=1.95; CI1.36–2.80, respectively). ORs of early ( 28 days) low iTTR and instability depended on VKA type. In acenocoumarol users, early low iTTR was an independent predictor of subsequent low iTTR (OR=1.92; CI1.31–2.80) and instability (OR=1.55; CI1.07–2.23). In warfarin users, early low iTTR (OR=1.36; CI1.09–1.69) and instability (OR=1.25; CI1.01–1.55) were additionally predictive for low iTTR, but only the latter was predictive for instability (OR=1.91; CI1.57–2.32). Many predictors of VKA control also predicted premature discontinuation, but only region was prognostic for clinical outcome. In conclusion, we identified several independent predictors of low iTTR and instability > 28 days, which showed some similarities but did not fully overlap. Early VKA control was of additional value for prediction of both, but had to be interpreted in the context of VKA type.

Recently, analyses on inhibitor development according to concentrate in previously untreated patients (PUPs) from two national cohort studies have been published. A similar analysis has been performed on the first 4 years of data collection of the European Haemophilia Safety Surveillance System (EUHASS) project. Together with the initial report from the RODIN study published in 2013 [4], these publications provide data on a very considerable number of patients, almost exclusively originating from Europe. Reporting to multiple registries is common, and a rare disease such as haemophilia is no exception. Although the FranceCoag study, the UKHCDO study and the EUHASS study excluded patients overlapping with the RODIN study from their analyses, the additional overlap between the EUHASS, the FranceCoag and UKHCDO studies has not been previously reported. The analysis of non-overlapping data from the EUHASS study has the potential to contribute to the ongoing discussion about the perceived increased inhibitor risk associated with the use of specific recombinant Factor VIII concentrates. Thus, we hereby provide additional analyses of the data from the EUHASS study., peer-reviewed

Although cancer in general is a strong risk factor for developing venous thromboembolism (VTE), the risk factors for venous thromboembolic events in patients with differentiated thyroid carcinoma (DTC) have never been assessed. This is remarkable, as several parts of the treatment comprise a hypercoagulable state that could in subgroups of DTC patients lead to an increased risk of VTE. The aim of this study was to assess which risk factors could cause DTC patients to develop VTE. We performed a nested case–control study, involving cases of DTC patients treated between 1980 and 2014 with confirmed VTE after diagnosis of DTC. Controls were defined as DTC patients without VTE. In all subjects, we collected information about thyroid cancer characteristics, treatment characteristics, traditional risk factors for VTE and additional clinical data, and we performed univariable and multivariable regression analyses. We included 28 cases and 56 controls matched for age at DTC diagnosis, sex and date of DTC diagnosis. In the univariable regression analysis, histology, distant metastases, DTC risk classification, recent surgery and other active malignancy were associated with VTE. In the multivariable analysis, distant metastases (odds ratio 7.9) and recent surgery (odds ratio 6.1) were independently associated with VTE. In conclusion, surgery and presence of distant metastases are independent risk factors for developing VTE in DTC patients. The risk factors identified in this study could be considered when making decisions regarding thromboprophylaxis for patients with thyroid cancer.

Background: Considering the relationship between inflammation and thrombosis, patients with tuberculosis (TB) patients might be at high risk of venous thrombosis.Aim: To evaluate the risk of venous thromboembolism in patients admitted to the Beatrixoord Tuberculosis Centre (BTBC), a tertiary centre for TB. We specifically explored which cofactors elevate the risk of venous thrombosis (VTE), and whether the timing of venous thrombotic events would justify extended primary prophylaxis.Design: retrospective cohort study.Methods: We performed a retrospective chart review of all patients with TB discharged from BTBC between 2000 and 2010. We excluded patients who were already on therapeutic anticoagulation before their TB episode, below the age of 18 years and patients in which TB diagnosis was withdrawn. For evaluating the timing of venous thrombosis, we calculated the time between commencement of anti TB therapy and the VTE.Results: Of 750 included in the final analysis, 18 (2.4%) suffered a venous thrombotic event. 3 of these events were not related to classic risk factors or hospitalization. Most (13/18) VTE's occurred in the time window of two weeks before starting TB medication. In the multivariate analysis, only Human Immunodeficiency Virus (HIV) infection was strongly associated with risk of VTE (adjusted Odds ratio 8.2 (95% confidence interval: 2.9-22.7)).Conclusions: This high risk in HIV co-infected TB patients suggests that standard thrombo-prophylaxis should be routinely considered in this group. However, our findings might not be generalizable due to referral bias. Further prospective studies in unselected HIV co-infected TB patients are needed to corroborate our findings.

BackgroundBleeding disorders have been recognized as important etiologic or contributory factors in women with heavy menstrual bleeding. Fibrinolysis in the endometrium plays a role in heavy menstrual bleeding. It is unknown whether increased systemic fibrinolysis might also increase the risk of heavy menstrual bleeding.ObjectiveTo investigate fibrinolytic parameters, including clot lysis time, in women with heavy menstrual bleeding.MethodsWe included 102 patients referred for heavy menstrual bleeding (Pictorial Bleeding Assessment Chart score of >100) in our cohort. Patients and controls (28 healthy volunteers without heavy menstrual bleeding) underwent hemostatic testing in the first week after menstruation. For 79 patients and all controls, fibrinolytic parameters (thrombin-activatable fibrinolysis inhibitor activity, and plasminogen activator inhibitor-1, tissue-type plasminogen activator and plasmin inhibitor levels) and clot lysis time were available.ResultsFibrinolytic parameters were similar between patients and controls, except for thrombin-activatable fibrinolysis inhibitor (89.4% vs. 82.5%) and plasmin inhibitor (106% vs. 96%), the levels of which which were significantly higher in patients. In women with menorrhagia without gynecologic abnormalities, we found lower thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels than in women with gynecologic abnormalities (thrombin-activatable fibrinolysis inhibitor, 85.4% vs. 94.8%; plasminogen activator inhibitor-1, 16.0gL(-1) vs. 24.5gL(-1)).ConclusionSystemic fibrinolytic capacity is not increased in women with heavy menstrual bleeding. Overall, levels of the fibrinolytic inhibitors thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor were even higher in patients than in controls. However, in a subgroup of women without gynecologic abnormalities, relatively lower levels of inhibitors may contribute to the heavy menstrual bleeding.

Introduction and Objectives: Neutralizing antibodies (inhibitors) directed against the FVIII protein may increase the bleeding frequency and compromise the management of bleeding episodes in nonsevere haemophilia A patients. The median annual bleeding frequency in patients without inhibitors is described to be 0 (IQR 0-3) for mild haemophilia and 1 (IQR 0-13) for moderate haemophilia. The aim of this study was to evaluate the burden of bleeding and to describe the treatment strategies that are used for bleeding episodes in a large group of unselected inhibitor patients with nonsevere haemophilia A. Materials and Methods: We included all inhibitor patients from the INSIGHT study, an international multicentre cohort study including all 2709 nonsevere HA patients (FVIII:C 2-4 IU/dL) that received at least 1 exposure to FVIII concentrate between 1980-2011. Data of the 1st inhibitor period were analyzed. Results: We included 107 nonsevere HA inhibitor patients (median baseline FVIII:C 9 IU/dL (IQR 6-16); median age of 38 years (IQR 15-61)). A high titre inhibitor (> 5 BU/mL) was present in 57 (53%) patients. In 30 (28%) patients the FVIII:C level was decreased ≤1 IU/dL. Eighty-nine patients (83%) received treatment for bleeding episodes. Most patients had spontaneous bleeds (n = 49, 46%); a higher proportion of high titre patients had spontaneous bleeds compared to low titre patients (83% vs. 53%, relative risk (RR) 2.7, 95% confidence interval (CI) 1.3-5.8). The median number of bleeding episodes per inhibitor year was 2 (IQR 1-5); this did not differ between patients with FVIII:C ≤ 1 IU/dL and those with measurable FVIII levels (p = 0.5), patients with low titre and high titre inhibitors (p = 0.5) and patients receiving eradication treatment or not (p = 0.7). In order to treat bleedings, FVIII concentrate was used in 59 patients (55%), FVIII bypassing agents in 50 (47%) and desmopressin in 18 patients (17%). Desmopressin was used more often in patients with remaining circulating FVIII:C levels compared to patients with a FVIII:C ≤ 1 IU/dL and in patients without eradication treatment compared to patients with eradication treatment (25% vs. 3%; RR 7.4, CI 1.0-53.5 and 25% vs. 0%; RR 14.0, CI 0.9 - 224.6, respectively). Conclusion: Inhibitor development in nonsevere HA patients aggravates the burden of bleeding with the majority (83%) of the patients needing treatment for bleeding episodes, at a median of 2 bleeding episodes per year.

Introduction: Joint bleeds (JB) have been reported to occur in 8-45% of von Willebrand disease (VWD) patients, depending on VWD severity. The consequences of JB in VWD are largely unknown. Therefore, we started a patient control study based on retrospective medical files (MF) examination in all Dutch haemophilia treatment centres to analyse the nature and consequences of self-reported JB. Methods: All moderate and severe VWD patients who participated in the Willebrand in The Netherlands (WiN) study, a large nationwide cross-sectional study on VWD (defined as VWF ≤ 30 U dL-1), completed a comprehensive self-reported questionnaire including JB and treatment questions. To select for patients most likely to have developed arthropathy due to JB, MF were studied from all participants who selfreported that they recieved JB treatment with desmopressin or clotting factor concentrate (plasma FVIII/VWF; CFC). For comparison 2:1 controls were selected from the same WiN database, matched for gender, age, FVIII and VWF activity. Results: Treated JB were reported by 81/804 WiN participants (10%), MF were available in 98% (79 patients, 156 controls). Mean age was 37 years (range 1- 75), mean FVIII level 42 U dL-1 ± 32 and mean VWF activity 22 U dL-1 ± 28. JB treatment was found in MF in 70% (55/79) of patients and 9% (14/156) controls. A larger proportion of the patients with treated JB had type 3 VWD (21/79, 27% vs. 17/156, 11%, P = 0.002). Compared to the controls, JB patients were more likely to have spontaneous JB (20/79 vs. 2/155, P

IMPORTANCE Previous studies have shown that, despite the higher risk of bleeding, the elderly still benefit from taking anticoagulants if they have a stringent indication. However, owing to the relatively low number of patients older than 90 years in these studies, it is unknown whether this benefit is also seen with the eldest patients.OBJECTIVE To determine how the risk of bleeding and thrombosis is associated with age in patients older than 70 years who were treated with a vitamin K antagonist (VKA).DESIGN, SETTING, AND PARTICIPANTS A matched cohort study was conducted of patients at a thrombosis service who were treated with a VKA between January 21, 2009, and June 30, 2012. All 1109 patients 90 years or older who were treated with a VKA were randomly matched 1: 1: 1 with 1100 patients aged 80 to 89 years and 1104 patients aged 70 to 79 years based on duration of VKA treatment. Data analysis was conducted from April 2015 to April 2016.MAIN OUTCOMES AND MEASURES The primary outcome was a composite of clinically relevant nonmajor and major bleeding. Secondary outcomes included thromboses and quality of VKA control.RESULTS During 6419 observation-years, 713 of the 3313 patients (1394 men and 1919 women) had 1050 bleeding events. The risk of bleeding was not significantly increased in patients aged 80 to 89 years (event rate per 100 patient-years [ER], 16.7; hazard ratio [HR], 1.07; 95% CI, 0.89-1.27) and mildly increased in patients 90 years or older (ER, 18.1; HR, 1.26; 95% CI, 1.05-1.50) compared with patients aged 70 to 79 years (ER, 14.8). The point estimates for major bleeding (including fatal) were comparable for patients aged 80 to 89 years (ER, 1.0; HR, 1.09; 95% CI, 0.60-1.98) and those 90 years or older (ER, 1.1; HR, 1.20; 95% CI, 0.65-2.22) compared with those aged 70 to 79 years (ER, 0.9). The increase in bleeding risk was sharper in men than in women. Eighty-five patients (2.6%) developed a thrombotic event. Risk of thrombosis was higher for patients in their 90s (HR, 2.14; 95% CI, 1.22-3.75) and 80s (HR, 1.75; 95% CI, 1.002-3.05) than for patients in their 70s. Vitamin K antagonist control became significantly poorer with rising age, which partly explained the increased bleeding risk in patients 90 years or older, but most of the increased risk of thrombosis was not mediated by VKA control.CONCLUSIONS AND RELEVANCE These clinical practice data of patients considered eligible for anticoagulation show that the bleeding risk with a VKA only mildly increases after the age of 80 years, while there is a sharp increase in the risk of thrombosis in the same age group.

Background— Hereditary thrombophilia is associated with a slightly increased risk of arterial thromboembolism (ATE). Whether hereditary thrombophilia interacts with traditional cardiovascular risk factors on the risk of ATE has yet to be established. Methods and Results— A total of 1891 individuals belonging to 4 family cohorts from the Netherlands were included in the analyses. Five hereditary thrombophilic defects, including factor V Leiden, prothrombin G20210A defect, and deficiencies of the natural anticoagulants (ie, antithrombin, protein C, and protein S), were assessed, and data on risk factors and previous ATE were collected. Thrombophilia was associated with elevated risk of ATE (hazard ratio =1.74, 95% confidence interval, 1.18–2.58; P =0.005). Overall, the association of thrombophilia with ATE tended to be stronger in the presence of traditional cardiovascular risk factors, especially the synergistic effect of thrombophilia with diabetes mellitus was striking (hazard ratio of thrombophilia–ATE association was 1.41 in nondiabetics versus 8.11 in diabetics). Moreover, the association of thrombophilia with ATE tended to be stronger in females and before the age of 55 years as compared with males and individuals >55 years of age, respectively. Conclusions— Thrombophilia is associated with ATE. This association may be stronger in the presence of traditional cardiovascular risk factors in particular in individuals with diabetes mellitus. Future studies on thrombophilia–ATE risk should focus on high-risk populations with high prevalence of traditional cardiovascular risk factors.