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Background: Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose., Objectives: To study tachyphylaxis of FVIII:C response after multiple administration(s) of desmopressin in perioperative persons with nonsevere hemophilia A., Methods: We studied FVIII:C levels after desmopressin before (day 0 [D0]) and on days 1 (D1) and 2 (D2) after surgery in 26 patients of the DAVID and Little DAVID studies. We studied tachyphylaxis by comparing the responses at D1 and D2 with that at D0. We also assessed the reproducibility of the D0 response in comparison to an earlier performed desmopressin test., Results: The median absolute FVIII:C increase was 0.50 IU/mL (0.35-0.74; n  = 23) at D0, 0.21 IU/mL (0.14-0.28; n  = 17) at D1, and 0.23 IU/mL (0.16-0.30; n  = 11) at D2. The median percentage of FVIII increase after the second administration (D1) compared with the first (D0) was 42.9% (29.2%-52.5%; n  = 17) and that of the third (D2) compared with the first (D0) was 36.4% (23.7%-46.9%; n  = 11). The FVIII:C desmopressin response at D0 was comparable with the desmopressin test response in 74% of the patients., Conclusion: Tachyphylaxis in the surgical setting was considerably more pronounced than previously reported, with FVIII:C at D1 and D2 of 36% to 43% of the initial response. Our results may have important implications for monitoring repeated desmopressin treatment when used perioperatively., (© 2024 The Authors.)

Introduction: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated., Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients., Methods: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 μg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL., Results: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL., Conclusion: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement., Objective: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs., Methods: All Dutch adolescents and young adults aged 12-25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple-choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio-demographic and disease-related factors, treatment adherence, health-related quality of life, and self-efficacy., Results: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12-14 year-olds to 63% in 15-17 year-olds. Nearly all post-transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS-Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9-29), compared to those ready for transition (11, IQR 9-16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs., Conclusions: Nearly all post-transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Aims: Prophylactic treatment of haemophilia A patients with factor VIII (FVIII) concentrate focuses on maintaining a minimal trough FVIII activity level to prevent bleeding. However, due to differences in bleeding tendency, the pharmacokinetic (PK)-guided dosing approach may be suboptimal. An alternative approach could be the addition of haemostatic pharmacodynamic (PD) parameters, reflecting a patient's unique haemostatic balance. Our aim was to develop a population PK/PD model, based on FVIII activity levels and Nijmegen Haemostasis Assay (NHA) patterns, a global haemostatic assay that measures thrombin/plasmin generation simultaneously., Methods: PK/PD measurements were collected from 30 patients treated with standard half-life FVIII concentrate. The relationship between FVIII activity levels and the thrombin/plasmin generation parameters (thrombin potential, thrombin peak height and plasmin peak height), were described by sigmoidal E max functions., Results: The obtained EC 50 value was smallest for the normalized thrombin potential (11.6 IU/dL), followed by normalized thrombin peak height (56.6 IU/dL) and normalized plasmin peak height (593 IU/dL), demonstrating that normalized thrombin potential showed 50% of the maximal effect at lower FVIII activity levels. Substantial inter-individual variability in the PD parameters, such as EC 50 of thrombin potential (86.9%) was observed, indicating that, despite similar FVIII activity levels, haemostatic capacity varies significantly between patients., Conclusion: These data suggest that dosing based on patients' individual PK/PD parameters may be beneficial over dosing solely on individual PK parameters. This model could be used as proof-of-principle to examine the application of PK/PD-guided dosing. However, the relation between the PD parameters and bleeding has to be better defined., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Introduction: Analysis of fibrinolytic disorders is challenging and may potentially lead to underdiagnosis of patients with an increased bleeding tendency., Aim: To compare clinical characteristics, laboratory measurements, and treatment modalities in a monocenter cohort of patients in whom fibrinolytic studies were performed., Methods: Retrospective study of patients in whom fibrinolytic studies were performed between January 2016 and February 2020 in the Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, the Netherlands. Plasminogen activator inhibitor type 1 (PAI-1) antigen and activity level, α2-antiplasmin activity, tissue plasminogen activator, and euglobulin clot lysis time (ECLT) before and after venous compression were determined in all patients. Data of bleeding assessment tool (BAT) score, clinical characteristics, results of primary and secondary hemostasis assays, and general treatment plans were collected., Results: In total, 160 patients were included: 97 (61%) without and 63 (39%) with a laboratory-based fibrinolytic disorder. Mean BAT score did not differ between the groups (9.3 vs 9.8, respectively). The presumptive fibrinolytic disorders were distributed as follows: 34 patients had an increased ECLT ratio or low baseline ECLT, 25 patients had low PAI-1 antigen and activity level, and four patients had both. The majority of these patients were treated with tranexamic acid monotherapy (60%) with only 40% additional treatment options, whereas 80% of patients without a presumptive fibrinolytic disorder had multiple treatment modalities., Discussion: Analysis of fibrinolytic disorders in selected patients has a high diagnostic yield. General incorporation of fibrinolytic analysis in the diagnostic workup of patients with bleeding of unknown cause can improve diagnosis and management of their bleeding episodes., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: An appropriate clinical diagnosis of von Willebrand disease (VWD) can be challenging because of a variable bleeding pattern and laboratory phenotype. Genotyping is a powerful diagnostic tool and may have an essential role in the diagnostic field of VWD., Objectives: To unravel the clinical and laboratory heterogeneity of genetically confirmed VWD type 2M patients and to investigate their relationship., Methods: Patients with a confirmed VWD type 2M genetic variant in the A1 or A3 domain of von Willebrand factor (VWF) and normal or only slightly aberrant VWF multimers were selected from all subjects genotyped at the Radboud university medical center because of a high suspicion of VWD. Bleeding scores and laboratory results were analyzed., Results: Fifty patients had a clinically relevant genetic variant in the A1 domain. Median bleeding score was 5. Compared with the nationwide Willebrand in the Netherlands study type 2 cohort, bleeding after surgery or delivery was reported more frequently and mucocutaneous bleedings less frequently. Median VWF activity/VWF antigen (VWF:Act/VWF:Ag) ratio was 0.32, whereas VWF collagen binding activity/VWF antigen (VWF:CB/VWF:Ag) ratio was 0.80. Variants in the A3 domain were only found in two patients with low to normal VWF:Act/VWF:Ag ratios (0.45, 1.03) and low VWF:CB/VWF:Ag ratios (0.45, 0.63)., Conclusion: Genetically confirmed VWD type 2M patients have a relatively mild clinical phenotype, except for bleeding after surgery and delivery. Laboratory phenotype is variable and depends on the underlying genetic variant. Addition of genotyping to the current phenotypic characterization may improve diagnosis and classification of VWD., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Mutations in the transcription factors GATA binding factor 1 (GATA1), growth factor independence 1B (GFI1B), and Runt-related transcription factor 1 (RUNX1) cause familial platelet and bleeding disorders. Mutant platelets exhibit common abnormalities including an α-granule reduction resulting in a grayish appearance in blood smears. This suggests that similar pathways are deregulated by different transcription factor mutations. To identify common factors, full platelet proteomes from 11 individuals with mutant GATA1R216Q, GFI1BQ287*, RUNX1Q154Rfs, or RUNX1TD2-6 and 28 healthy controls were examined by label-free quantitative mass spectrometry. In total, 2875 platelet proteins were reliably quantified. Clustering analysis of more than 300 differentially expressed proteins revealed profound differences between cases and controls. Among cases, 44 of 143 significantly downregulated proteins were assigned to platelet function, hemostasis, and granule biology, in line with platelet dysfunction and bleedings. Remarkably, none of these proteins were significantly diminished in all affected cases. Similarly, no proteins were commonly overrepresented in all affected cases compared with controls. These data indicate that the studied transcription factor mutations alter platelet proteomes in distinct largely nonoverlapping manners. This work provides the quantitative landscape of proteins that affect platelet function when deregulated by mutated transcription factors in inherited bleeding disorders., (© 2021 by The American Society of Hematology.)

Introduction: People with haemophilia suffer from haemophilic joint disease that may result in physical inactivity and overweight. Shared medical appointments (SMAs) might help limit the consequences of haemophilic arthropathy. SMAs are group meetings supervised by one or more healthcare professionals that can be utilized to improve lifestyle., Aim: To evaluate the feasibility and efficacy of SMAs in people with haemophilia to improve physical activity and eating habits., Methods: A multiple baseline single-case design was used. Overweight people with haemophilia were eligible to participate. Seven weekly SMAs were conducted using multiple behavioural change techniques to improve physical activity and eating habits. Feasibility of SMAs was evaluated using (a) dropout rate, (b) occurrence of adverse events (AEs), (c) adherence rate and (d) patient satisfaction. During 13 weeks, physical activity was measured daily and eating habits were measured three times per week. The efficacy of SMAs was determined using randomization tests and visual data inspection., Results: Out of the six men participating in the study, one participant dropped out. No study-related AEs occurred. The adherence rate of SMAs was 80%, and participants reported to be 'very satisfied' with the SMAs. Randomization tests and visual analyses demonstrated (statistical) improvements in physical activity (p = .03). No effect was found in self-reported eating habits (p = .55)., Conclusion: Shared medical appointments are feasible in people with haemophilia and appear to improve physical activity. The effect on improving eating habits could not be established. Scientific replication of our approach is warranted to confirm or refute the merit of SMAs in people with haemophilia., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

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 <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual., Findings: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred., Interpretation: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care., Funding: Dutch Research Council (NWO)-ZonMw and Takeda., Competing Interests: Declaration of interests REGS has received research support from Bayer, Baxalta, CSL Behring, Novo Nordisk, Pfizer, Sobi, and Sanquin. FJMvdM has received grants from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda, and Sobi for the development of a registry of Hemophilia patients in the Netherlands (HemoNED). KF has received unrestricted research grants from CSL Behring, Sobi, and Novo Nordisk, and her institution has received consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. MC has received research grants from Bayer, CSL Behring, Roche, UniQure, and Novo Nordisk. FWGL has received unrestricted research grants from CSL Behring, Shire/Takeda, Sobi, and UniQure; is a consultant for UniQure, Novo Nordisk, Biomarin and Shire, from which the fees go to their institution; has received travel support from Sobi; and is a member of the data safety and monitoring board for a study sponsored by Roche. KM has received research support from Bayer and Alexion and consulting fees from UniQure, from which all fees go to their institution. RAAM has served as an advisor for Bayer, CSL Behring, Merck Sharp & Dohme, Shire, and Zeria, with all honoraria and fees paid to their department at their institution), and has received unrestricted research grants from Bayer, CSL Behring, and Shire. MHC has received grants from the governmental research institutes Dutch Research Institute (NWO), ZonMW, Innovation fund, NWO-NWA; unrestricted investigator-initiated research grants and educational and travel funding from Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma; and has served as a member on steering boards of Roche, Novartis, and Bayer, with all grants, awards, and fees received going to their institution. JGvdB has received funding for educational activities from Bayer and Novo Nordisk. IvM has received research grants from Sobi and CSL Behring. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 < 25 kg m -2 ), overweight (BMI 25-30 kg m -2 ) and obese haemophilia A patients (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., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P)., (© 2021 by The American Society of Hematology.)

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: β = -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., Competing Interests: JB started working at Sobi after finishing this research project. FA received the CSL Behring-professor Heimburger Award 2018 and a travel grant from Sobi. MHC has received grants from governmental research institutes, such as the Dutch Research institute (NWO), ZonMW, Innovation fund, NWO-Dutch Research Agenda, and unrestricted investigator-initiated research grants as well as educational and travel funding from various companies over the years (Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi, Novo Nordisk, Novartis, and Nordic Pharma); he served as a member on steering boards of Roche and Bayer. All grants, awards, and fees go to the Erasmus MC as an institution. MPMM has received travel support and speaker fees from Roche Diagnostics, Sysmex, Siemens, and Werfen. The institution of KF has received unrestricted research grants from CSL Behring, Sobi, and NovoNordisk, and her institution received consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. KM received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; and consulting fees from Uniqure, of which all fees go to the institution. BAPLG has received unrestricted educational grants from Baxter and CSL Behring. JE received research support from CSL Behring, and he has been a teacher on educational activities of Roche. KPMG received unrestricted research support from CSL Behring and Bayer and speakers fee from Takeda. JGB has been a teacher on educational activities of Bayer and received consultancy fees from Novo Nordisk, paid to the Leiden University Medical Center. FWGL received research support from CSL Behring and Shire/Takeda for performing the Willebrand in the Netherlands (WiN) study and uniQure for a study not related to this article, and he is a consultant for uniQure, Novo Nordisk, BioMarin, and Shire/Takeda, of which the fees go to the institution, and he received a travel grant from Sobi. He is also a data safety monitoring board member for a study by Roche. JM has no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Background: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs))., Methods: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder., Findings: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p  = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years ( p  = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p  = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding., Interpretation: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding., Funding: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant)., Competing Interests: F. Atiq received the CSL Behring-professor Heimburger Award 2018 and a travel grant from Sobi. J.L. Saes and S.E.M. Schols received travel support from Bayer, Takeda and Sobi. F.W.G. Leebeek received research support from CSL Behring and Shire/Takeda for performing the Willebrand in the Netherlands (WiN) study, and from UniQure and Sobi for other studies. He is consultant for UniQure, Novo Nordisk, BioMarin and Shire/Takeda, of which the fees go to the institution, and has received a travel grant from Sobi. He is also a DSMB member for a study by Roche. H.C.J. Eikenboom received research support from CSL Behring and he has been a teacher on educational activities of Roche. K.P.M. van Galen received unrestricted research support from CSL Behring and Bayer and speakers fee from Takeda, CSL Behring and Bayer. J.G. van der Bom has been a teacher on educational activities of Bayer. M.H. Cnossen has received grants from governmental research institutes, such as the Dutch Research institute (NOW), ZonMW, Innovation fund, NWO-NWA and unrestricted investigator initiated research grants as well as educational and travel funding from various companies over the years (Pfizer, Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Sobi Biogen, novo Nordisk, Novartis and Nordic Pharma), and has served as a member on steering boards of Roche and Bayer. All grants, awards and fees go to the Erasmus MC as an institution. The institution of K. Fijnvandraat has received unrestricted research grants from CSL Behring, Sobi and NovoNordisk and her institution received consultancy fees from Grifols, Takeda, Novo Nordisk and Roche. K. Meijer received research support from Bayer, Sanquin and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS and Aspen; consulting fees from Uniqure, of which all fees go to the institution. B.A.P. Laros‐van Gorkom has received unrestricted educational grants from Baxter and CSL Behring. M.J.H.A. Kruip received grants from governmental research institutes, such as the Dutch Research institute (ZonMW/NWO), Dutch Thrombosis Foundation, Innovation fund, unrestricted grants from Bayer, Pfizer, Daiichi Sankyo, Sobi and Boehringer Ingelheim and speakers fee from Bayer. R.E.G. Schutgens received grants from Bayer, grants from Baxalta, Pfizer, NovoNordisk. The institution of M. Peters received an unrestricted research grant from Pfizer. F.J.M. van der Meer received grants from CSL Behring, Pfizer, Bayer, Novo Nordisk, Sobi, Roche, and OctaPharma. W.L. van Heerde reports speaker and consultant and travel fees from Takeda, Bayer, CSL Behring, and Sobi. He is also founder and co-owner of Enzyre. None of the other authors has a conflict of interest to declare., (© 2021 The Authors.)

Background: Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG) and plasmin generation (PG)., Objective: To determine differences in TG and PG between HA patients before and during a pharmacokinetic study and identify best parameters to develop a pharmacodynamic model., Methods: Twenty-five HA patients (baseline FVIII < 1-9 IU/dL) underwent a pharmacokinetic study with a single dose of 25-50 IU/kg standard half-life FVIII concentrate. At baseline and after administration of FVIII TG and PG parameters were measured with the NHA., Results: FVIII activity level increased from median 1.0 IU/dL (interquartile range < 1.0-6.0) to 71 IU/dL (62-82) 15 minutes after administration and decreased to 15 IU/dL (10-26) at 24 hours. TG was enhanced simultaneously, with thrombin peak height (TPH) increasing from 22nM (15-35) to 222nM (159-255), and thrombin potential (TP) from 404nM/min (undetectable-876) to 1834nM/min (1546-2353). Twenty-four hours after infusion, TG parameters remained high (TPH 73nM [58.5-126.3]; TP 1394nM/min [1066-1677]) compared to FVIII activity level. PG showed hyperfibrinolysis in severe HA patients compared to mild patients and controls, which normalized after FVIII supplementation., Conclusion: HA patients showed clear differences in baseline TG and PG despite having comparable FVIII activity levels. These results reveal a discrepancy between FVIII activity level and TG, in which the latter may be a better parameter to monitor individualized treatment in HA patients., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background:  von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is unknown how VWF behaves and what its impact is on FVIII clearance in the perioperative setting., Aim:  To investigate VWF kinetics (VWF antigen [VWF:Ag]), VWF glycoprotein Ib binding (VWF:GPIbM), and VWF propeptide (VWFpp) in severe and moderate perioperative hemophilia A patients included in the randomized controlled perioperative OPTI-CLOT trial., Methods:  Linear mixed effects modeling was applied to analyze VWF kinetics. One-way and two-way analyses of variance were used to investigate perioperative VWFpp/VWF:Ag ratios and associations with surgical bleeding., Results:  Fifty-nine patients with median age of 48.8 years (interquartile range: 34.8-60.0) were included. VWF:Ag and VWF:GPIbM increased significantly postoperatively. Blood type non-O or medium risk surgery were associated with higher VWF:Ag and VWF:GPIbM levels compared with blood type O and low risk surgery. VWFpp/VWF:Ag was significantly higher immediately after surgery than 32 to 57 hours after surgery ( p  < 0.001). Lowest VWF:Ag quartile (0.43-0.92 IU/mL) was associated with an increase of FVIII concentrate clearance of 26 mL/h (95% confidence interval: 2-50 mL/h) compared with highest VWF antigen quartile (1.70-3.84 IU/mL). VWF levels were not associated with perioperative bleeding F (4,227) = 0.54, p  = 0.710., Conclusion:  VWF:Ag and VWF:GPIbM levels increase postoperatively, most significantly in patients with blood type non-O or medium risk surgery. Lower VWF antigen levels did not lead to clinically relevant higher FVIII clearance. VWF:Ag or VWF:GPIbM levels were not associated with perioperative hemorrhage., Competing Interests: R.E.G. Schutgens has received research support from CSL Behring and Sanquin. B. Laros-van Gorkom has received unrestricted educational grants from Baxter and CSL Behring. F. J. M. van der Meer received grants from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sanquin, and Sobi for the development of a registry of Hemophilia patients in the Netherlands (HemoNED). K. Fijnvandraat is a member of the European Hemophilia Treatment and Standardization Board sponsored by Baxalta, has received unrestricted research grants from CSL Behring, Pfizer, and Bayer, and has given lectures at educational symposiums organized by Pfizer, Baxalta, Novonordisk, and Bayer. F.W.G. Leebeek received research support from CSL Behring and Shire for performing the Willebrand in the Netherlands (WiN) study, and is consultant for UniQure, Novo Nordisk, and Shire, of which the fees go to the institution. He is a member of the DSMB for a study of Roche. K. Meijer received research support from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; consulting fees from UniQure (all fees go to the institution). Moniek P.M. de Maat received speaker fees and unconditional research contributions from Werfen, Siemens, Roche, and Stago. J. Eikenboom reports receiving research grants from CSL Behring and honorarium for educational activities from Roche and Celgene. R.A.A. Mathôt has served as advisor for Bayer, CSL Behring, Merck Sharp & Dohme, Shire, and Zeria (all honoraria/fees paid to the department); He has received unrestricted research grants from Bayer, CSL Behring, and Shire. M. H. Cnossen has received grants from governmental research institutes such as Dutch Research Institute (NWO), ZonMW, Innovation fund, NWO-NWA, and unrestricted investigator initiated research grants as well as educational and travel funding from the following companies over the years: Pfizer, Baxter/ Baxalta/ Shire/ Takeda, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a member on steering boards of Roche and Bayer. All grants, awards, and fees go to the institution. The remaining authors declare no competing financial interests., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Many patients with von Willebrand disease (VWD) are treated on demand with von Willebrand factor and factor VIII (FVIII) containing concentrates present with VWF and/or FVIII plasma levels outside set target levels. This carries a risk for bleeding and potentially for thrombosis. Development of a population pharmacokinetic (PK) model based on FVIII levels is a first step to more accurate on-demand perioperative dosing of this concentrate., Methods: Patients with VWD undergoing surgery in Academic Haemophilia Treatment Centers in the Netherlands between 2000 and 2018 treated with a FVIII/VWF plasma-derived concentrate (Haemate® P/Humate P®) were included in this study. Population PK modeling was based on measured FVIII levels using nonlinear mixed-effects modeling (NONMEM)., Results: The population PK model was developed using 684 plasma FVIII measurements of 97 VWD patients undergoing 141 surgeries. Subsequently, the model was externally validated and reestimated with independent clinical data from 20 additional patients undergoing 31 surgeries and 208 plasma measurements of FVIII. The observed PK profiles were best described using a one-compartment model. Typical values for volume of distribution and clearance were 3.28 L/70 kg and 0.037 L/h/70 kg. Increased VWF activity, decreased physical status according to American Society of Anesthesiologists (ASA) classification (ASA class >2), and increased duration of surgery were associated with decreased FVIII clearance., Conclusion: This population PK model derived from real world data adequately describes FVIII levels following perioperative administration of the FVIII/VWF plasma-derived concentrate (Haemate ® P/Humate P ® ) and will help to facilitate future dosing in VWD patients., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Introduction: Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption., Methods and Analysis: In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment., Ethics and Dissemination: The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences., Trial Registration Number: NTR5383; Pre-results., Competing Interests: Competing interests: LMS: received reimbursement from CSL-Behring for attending a symposium, not related to this study. MHC: received unrestricted research/educational funding for various projects as well as travel fees from the following institutions and companies: ZonMW, Innovatiefonds, Pfizer, Baxalta/Shire, Bayer Schering Pharma, Novo Nordisk, Novartis, Roche and CSL Behring, all not related to this study. RMvH, EAMB, MC, MHED, LN, SP: nothing to disclose relevant to the DAVID study. KF: is a member of the European Hemophilia Treatment and Standardization Board sponsored by Baxter, has received unrestricted research grants from CSL Behring and Bayer and has given lectures at educational symposiums organized by Pfizer, Bayer and Baxter. JE: received research funding from CSL Behring and honorarium for educational activity from Roche, not related to this study. BAPL-vG: received unrestricted educational grants from Baxter and CSL Behring and speaker fees from Sanquin. KM: research support from Bayer, Sanquin and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS and Aspen; consulting fees from Uniqure, not related to this study; FWGL: received unrestricted research grants from CSL-Behring and Baxalta/Shire not related to this study. He is consulant for Shire, NovoNordisk and UniQure. Fees go to the university. RAAM: received personal fees from Merck Sharp & Dohme and Zeria and grants from Bayer, UCB Pharma and Hoffman La Roche with no involvement in this study. MJHAK: received unrestricted research grants from Pfizer, Innovatiefonds and Ferring with no involvement in this study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Patients with bleeding disorders may experience limitations in sports participation and physical activity. Several studies on sports participation have been performed in haemophilia patients, but studies in patients with von Willebrand disease (VWD) are lacking., Aim: We assessed the sports participation and physical activity of a large cohort of VWD patients., Methods: Patients were included from the "WiN study." All patients completed a questionnaire on sports participation, physical activity, quality of life and bleeding symptoms (Tosetto bleeding score)., Results: From the 798 included patients, 474 had type 1, 301 type 2 and 23 type 3 VWD. The mean age was 39 ± 20 (standard deviation) years. Five hundred and fifty-two patients (69.3%) participated in various types of sports. Type 3 VWD patients more often did not participate in sports due to fear of bleeding and physical impairment, respectively, OR = 13.24 (95% CI: 2.45-71.53) and OR = 5.90 (95% CI: 1.77-19.72). Patients who did not participate in sports due to physical impairment had a higher bleeding score item for joint bleeds 1.0 (±1.6) vs 0.5 (± 1.1) (P = 0.036). Patients with type 3 VWD and patients with a higher bleeding score frequently had severe limitations during daily activities, respectively, OR = 9.84 (95% CI: 2.83-34.24) and OR = 1.08 (95% CI: 1.04-1.12)., Conclusion: The majority of VWD patients participated in sports. Patients with type 3 VWD, a history of joint bleeds and a more severe bleeding phenotype frequently experienced limitations in sports participation and physical activities during daily life., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Essentials It is unclear whether there are differences between von Willebrand factor (VWF) activity assays. We compared the four most used VWF activity assays in 661 von Willebrand disease (VWD) patients. All assays correlated excellently, but a discrepant classification was seen in 20% of patients. Differences between VWF activity assays have a large impact on the classification of VWD. SUMMARY: Background Measuring the ability of von Willebrand factor (VWF) to bind to platelets is crucial for the diagnosis and classification of von Willebrand disease (VWD). Several assays that measure this VWF activity using different principles are available, but the clinical relevance of different assay principles is unclear. Objective To compare the four most widely used VWF activity assays in a large VWD patient population. Methods We measured VWF:RCo (ristocetin to activate VWF + whole platelets), VWF:GPIbR (ristocetin + platelet glycoprotein Ib receptor [GPIb] fragments), VWF:GPIbM (gain-of-function GPIb fragments that bind VWF spontaneously without ristocetin) and VWF:Ab (monoclonal antibody directed against the GPIb binding epitope of VWF to mimic platelets) in 661 VWD patients from the nationwide 'Willebrand in the Netherlands' (WiN) Study. Results All assays correlated excellently (Pearson r > 0.9), but discrepant results led to a different classification for up to one-fifth of VWD patients. VWF:RCo was not sensitive enough to classify 18% of patients and misclassified half of genotypic 2B VWD patients, especially those with p.Arg1306Trp. VWF:GPIbR was more sensitive, accurately classified the vast majority of patients, and was unaffected by the p.Asp1472His variant that causes artificially low VWF:RCo. VWF:GPIbM was the most precise assay but misclassified over a quarter of genotypic 2A, 2B and 3 patients. VWF:Ab, often not considered an actual VWF activity assay, performed at least equally to the other assays with regard to accurate VWD classification. Conclusion Although the different VWF activity assays are often considered similar, differences between assays have a large impact on the classification of VWD., (© 2018 International Society on Thrombosis and Haemostasis.)

Essentials Factor IX (FIX) dosing using body weight frequently results in under and overdosing during surgery. We aimed to establish a population pharmacokinetic (PK) model describing the perioperative FIX levels. Population PK parameter values for clearance and V1 were 284 mL h -1 70 kg -1 and 5450 mL70 kg -1 . Perioperative PK parameters differ from those during non-surgical prophylactic treatment. SUMMARY: Background Hemophilia B is a bleeding disorder characterized by a deficiency of coagulation factor IX (FIX). In the perioperative setting, patients receive FIX concentrates to ensure hemostasis. Although FIX is usually dosed according to bodyweight, under- and overdosing occurs frequently during surgery. Aim The objective was to quantify and explain the interpatient variability of perioperatively administered plasma-derived (pd) and recombinant (r) FIX concentrates. Methods Data were collected from 118 patients (median age, 40 years [range, 0.2-90]; weight, 79 kg [range, 5.3-132]) with moderate (28%) or severe hemophilia B (72%), undergoing 255 surgical procedures. Population pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effect modeling in NONMEM. Results Measured perioperative FIX level vs. time profiles were adequately described using a three-compartment PK model. For a typical 34-year-old patient receiving rFIX, clearance (CL), intercompartmental clearance (Q2, Q3), distribution volume of the central compartment (V1) and peripheral compartments (V2, V3) plus interpatient variability (%CV) were: CL, 284 mL h -1 70 kg -1 (18%); V1, 5450 mL70 kg -1 (19%); Q2, 110 mL h -1 70 kg -1 ; V2, 4800 mL70 kg -1 ; Q3, 1610 mL h -1 70 kg -1 ; V3, 2040 mL70 kg -1 . From 0.2 years, CL and V1 decreased 0.89% and 1.15% per year, respectively, until the age of 34 years. Patients receiving pdFIX exhibited a lower CL (11%) and V1 (17%) than patients receiving rFIX. Interpatient variability was successfully quantified and explained. Conclusions The estimated perioperative PK parameters of both pdFIX and rFIX are different from those reported for prophylactic treatment. The developed model may be used to apply PK-guided dosing of FIX concentrates during surgery., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Long-term outcome after joint bleeds in von Willebrand disease (VWD) (von Willebrand factor activity ≤ 30 IU/dL) could differ from moderate or severe haemophilia A (HA) (factor VIII [FVIII] 1-5 IU/dL or FVIII < 1 IU/dL). We performed a post hoc analysis on Haemophilia Joint Health Score (HJHS, 0-124), X-ray Pettersson scores (PS, 0-13/joint) and the Haemophilia Activities List (HAL, 0-100), using multivariable regression to adjust for age (rate ratio [RR] or odds ratio [OR] [95% confidence interval]). We included 48 VWD (median age, 47 years, type 3 VWD, n  = 19), 39 moderate HA (median, 39 years) and 59 severe HA patients (median, 25 years) with documented joint bleeds. VWD patients suffered repeated bleeding (lifetime > 5/joint) less often than moderate and severe HA patients (52% vs. 77% vs. 98%). HJHS and PS in VWD were similar to moderate HA (median HJHS 5 vs. 6, RR 0.9 [0.5-1.4] and PS > 3 of ≥ 1 joint OR 0.3 [0.1-1.4]), but better than in severe HA patients (median HJHS 5 vs. 9, RR 1.8 [1.1-2.9]; PS > 3 in any joint OR 0.1 [0.0-0.3]). Self-reported limitations in activities were comparable across VWD, moderate HA (HAL score < 95: 67% vs. 49%; OR 1.4 [0.5-3.6]) and young adults with severe HA (67% vs. 48%; OR 1.7 [0.7-4.4]). Despite fewer joint bleeds, joint outcome after joint bleeds was similar in VWD and moderate HA patients. Type 3 VWD patients had worst joint outcome, comparable to younger intensively treated severe HA patients. Limitations in activities occurred as often in VWD as in both moderate and severe HA., Competing Interests: K.P.M. van Galen received research support from CSL Behring and Bayer for performing the Willebrand arthropathy study. P. de Kleijn has received unrestricted research/educational support from NovoNordisk. F.W.G. Leebeek received research support from CSL Behring for performing the WiN-study, has received unrestricted research grants from Shire for studies outside the submitted work, received a travel fee from Roche and is a consultant for uniQure, NovoNordisk and Shire. J. Eikenboom received research support from CSL Behring and he has been a teacher on educational activities of Roche. E.P. Mauser-Bunschoten received unrestricted research/educational support from CSL Behring, Bayer, Baxter, LFB, Griffols, Novo Nordisk, Pfizer, Biovitrum and Sanquin. K. Fijnvandraat is a member of the European Haemophilia Treatment and Standardization Board sponsored by Shire, has received unrestricted research grants from CSL Behring and Novo Nordisk and has given lectures at educational symposiums organized by Pfizer, Novo Nordisk, Bayer and Baxter. K. Meijer received research support from Bayer, Sanquin and Pfizer, and consulting fees from Uniqure. B. Laros-van Gorkom has received unrestricted educational grants from Baxter and CSL Behring. R. Schutgens has received unrestricted research support from CSL Behring, Shire, Bayer, Novonordisk and Sanquin. K. Fischer received speaker's fees from Bayer, Baxter, CSL Behring, Biotest, Pfizer, NovoNordisk and Octapharma; performed consultancy for Bayer, Baxter, Biogen, CSL Behring, Freeline, NovoNordisk and Pfizer; and received research support from Bayer, Wyeth/Pfizer, Baxter and Novo Nordisk.None of the other authors has a conflict of interest to declare., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy., Aim: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed., Methods: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL -1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines., Results: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL -1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL -1 [IQR 0.10-0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%)., Conclusion: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Some comorbidities, such as hypertension, are associated with higher von Willebrand factor (VWF) levels in the general population. No studies have been conducted to assess this association in patients with von Willebrand disease (VWD). Therefore, we studied this association in patients with type 1 (n = 333) and type 2 (n = 203) VWD from the 'WiN" study. VWF antigen (VWF:Ag) was higher in type 1 VWD patients with hypertension [difference: 0·23 iu/ml, 95% confidence interval (CI): 0·11-0·35], diabetes mellitus (0·11 iu/ml, 95% CI: -0·02 to 0·23), cancer (0·14 iu/ml, 95% CI: 0·03-0·25) and thyroid dysfunction (0·14 iu/ml, 95% CI: 0·03-0·26) than in patients without these comorbidities (all corrected for age, sex and blood group). Similar results were observed for VWF collagen binding capacity (VWF:CB), VWF activity as measured by the VWF monoclonal antibody assay (VWF:Ab) and factor VIII (FVIII) coagulant activity (FVIII:C). In type 1 VWD, age was associated with higher VWF:Ag (0·03 iu/ml; 95% CI: 0·01-0·04), VWF:CB (0·02 iu/ml; 95% CI: 0·00-0·04), VWF:Ab (0·04 iu/ml; 95% CI: 0·02-0·06) and FVIII:C (0·03 iu/ml; 95% CI: 0·01-0·06) per decade increase. After adjustment for relevant comorbidities, these associations were no longer significant. Despite the higher VWF and FVIII levels, type 1 VWD patients with comorbidities had more bleeding episodes, particularly during surgery. There was no association between comorbidities and VWF/FVIII levels or bleeding phenotype in type 2 VWD patients. In conclusion, comorbidities are associated with higher VWF and FVIII levels in type 1 VWD and may explain the age-related increase of VWF and FVIII levels., (© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Introduction: Patients with Von Willebrand disease (VWD) are regularly treated with VWF-containing concentrates in case of acute bleeding, trauma and dental or surgical procedures., Aim: In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate ® P) in patients with VWD was evaluated., Patients/methods: Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate ® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII-based treatment regimens were compared to predefined target levels in national guidelines., Results: In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20 IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act., Conclusion: High VWF:Act and accumulation of FVIII were observed after perioperative FVIII-based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

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., Competing Interests: Disclosures: E.P.M.-B. received research support from CSL Behring, Bayer, Baxter, Griffols, Novo Nordisk, Pfizer and Sanquin. J.G.v.d.B. received unrestricted research/educational funding for various projects from the following companies: Bayer Schering Pharma, Baxter, CSL Behring, Novo Nordisk and Pfizer. M.H.C. received unrestricted research/educational funding for various projects from the following companies: Bayer Schering Pharma, Baxter, Novo Nordisk and Pfizer. B.A.P.L-v.G. received unrestricted educational grants from Baxter and CSL Behring. K.M. received research support from Bayer, Baxter and Sanquin, and served on an advisory board for CSL Behring. J.E. received research support from CSL Behring. F.W.G.L. received research support from CSL Behring for performing the WiN study and from Shire, outside the submitted work. He is a consultant for uniQure and Shire, the fees of which go to the institution. None of the other authors has a conflict of interest to declare., (Schattauer GmbH Stuttgart.)

Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds were matched for age, sex and Factor VIII level or von Willebrand Factor activity in a nested case-control study within the Willebrand in the Netherlands study. Assessments included the Hemophilia Joint Health Score (0-124), Pettersson score (0-13 per joint X-ray), Hemophilia Activity List score (0-100), joint pain (Visual Analog Scale 0-10), and the Impact on Participation and Autonomy questionnaire (0-20). Arthropathy was defined as a Hemophilia Joint Health Score of 10 or higher, or a Pettersson score over 3 of at least one joint. We included 48 patients with verified joint bleeds (cases) and 48 controls: 60% males, mean age 46 years (range 18-80), median von Willebrand Factor activity 5 versus 8 IU/dL and Factor VIII 24 versus 36 IU/dL. Arthropathy occurred in 40% of the cases versus 10% of the controls ( P <0.01). The cases reported more functional limitations compared to the controls (median Hemophilia Activity List score: 88 vs. 100, P <0.01). Arthropathy was related to joint pain and less social participation (Visual Analog Scale>3: 13 of 19 vs. 3 of 28, P <0.01, and median score on the participation questionnaire 6.1 vs. 0.9, P <0.01). In conclusion, arthropathy occurs in 40% of VWD patients after joint bleeds and is associated with pain, radiological abnormalities, functional limitations, and less social participation ( Dutch trial register: NTR4548 )., (Copyright© 2017 Ferrata Storti Foundation.)

Assessment of clinical outcome after joint bleeding is essential to identify joint damage and optimise treatment, to prevent disability. However, disease-specific tools to assess the musculoskeletal status in patients with von Willebrand disease (VWD) are lacking. We aimed to determine validity and reliability of the Haemophilia Joint Health Score (HJHS) and Haemophilia Activities List (HAL) in patients with Von Willebrand disease (VWD). Ninety-six patients with VWD were included (mean age 46 years) of whom 27 had more than five documented joint bleeds. The HJHS was performed in all patients and all patients completed the HAL and Impact on Participation and Autonomy (IPA) questionnaires. Health-related quality of life (SF36) results were obtained from the prior 'Willebrand in the Netherlands' study. Joint X-rays of knees, elbows and ankles were scored according to Pettersson (PS). Internal consistency of the HJHS (Cronbach's α (α)=0.75) and HAL (α=0.89) were good. Inter-observer agreement of the HJHS was good (ICC 0.84; Limits of Agreement ± 10.3). The HJHS showed acceptable correlation with the X-ray PS (Spearman's r (r s )>0.60 all joints) and HAL (r s =0.71). The HAL also showed acceptable correlation with the SF36 physical functioning (r s =0.65) and IPA (r s =0.69). Hypothesis testing showed adequate discriminative power of both instruments: in patients with a history of >5 versus ≤ 5 joint bleeds (median HJHS 10 vs 2 (p<0.01); median HAL 77 vs 98 (p<0.01)), independent from age. In conclusion, both the HJHS and HAL are feasible to assess clinical outcome after joint bleeds in VWD.

Introduction: von Willebrand disease (VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients., Aim: To investigate whether plasminogen activator inhibitor-1 (PAI-1) level influences the variation in bleeding tendency in VWD patients., Methods: PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score., Results: PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [IQR 12-60] vs. 20 [IQR 10-44] ng mL -1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [IQR 7-17] vs. 9 [IQR 5-14] ng mL -1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: -0.170, P = 0.017) in the group of 196 young (age ≤ 45 year) female VWD patients, accounting for 31% of our study population., Conclusion: In young female VWD patients, we observed that low PAI-1 levels were associated with a higher bleeding score, which may partly explain the observed variability in bleeding phenotype in VWD patients., (© 2017 John Wiley & Sons Ltd.)

Background: Joint bleeds are reported by 23% of von Willebrand disease (VWD) patients and associated with orthopaedic surgery. Limited data are available on joint surgery in VWD., Aim: To assess the prevalence, indications, management and complications of joint surgery in VWD patients., Methods: 804 VWD patients with historically lowest von Willebrand factor (VWF) activity ≤30 U dL -1 completed a questionnaire on joint bleeds, joint damage and orthopaedic surgery. We retrieved additional medical file data of patients who underwent surgery on large joints (shoulder, elbow, hip, knee or ankle)., Results: 116 out of 804 patients (14%) reported large joint surgery. Compared to VWD patients without previous orthopaedic surgery, these 116 patients reported more frequently a history of joint bleeds and joint damage (41% vs. 20%, P < 0.001 and 61% vs. 20%, P < 0.001). Medical file data on 126 large joint surgeries in 79 VWD patients revealed that this surgery was associated with joint damage due to prior joint bleeds in 24% of the procedures. Preoperative clotting factor correction (CFC) to prevent bleeding was administered in most cases (81%). Documentation on postoperative bleeding was found in 23 surgeries (18%)., Conclusions: Large joint surgery is reported by 14% of VWD patients, related to joint bleeds in 24% and seems associated with bleeding complications frequently despite perioperative CFC., (© 2015 John Wiley & Sons Ltd.)

Background: Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown., Objectives: The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD., Methods: In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1)] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB., Results: Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05) compared to VWD patients not reporting JB. Of 55 patients with available JB data, 65% had the first JB before age 16. These 55 patients used more clotting factor concentrate (CFC; median dose 43 vs. 0 IE FVIII kg(-1) year(-1) , P < 0.001), more often had X-ray joint damage (44% vs. 11%, P = 0.001] and chronic joint pain (44% vs. 18%, P = 0.008) compared to 55 control VWD patients without JB., Conclusion: In conclusion, joint bleeds are reported by 23% of moderate and severe VWD patients, mostly start in childhood, are associated with more CFC use, joint pain, lower HR-QoL and significantly more radiological and self-reported joint damage., (© 2015 John Wiley & Sons Ltd.)