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Background: Residual mitral regurgitation (MR) is associated with worse outcomes after transcatheter edge-to-edge mitral valve repair (TEER). Shear stress induced by MR leads to altered von Willebrand factor activity (vWF:Act) and increased closure time with adenosine diphosphate (CT-ADP)., Objectives: The purpose of this study was to investigate the use of CT-ADP to monitor MR during TEER and the association between the vWF, residual MR, and clinical events post-TEER., Methods: Sixty-five patients undergoing TEER were enrolled. CT-ADP was measured at baseline, after each clip deployment, 1 hour and 24 hours post-TEER. CT-ADP values were related to vWF:Act/vWF antigen (vWF:Ag) ratio at the same time points, and MR severity was assessed by echocardiography at 1 month. Combined events of all-cause mortality and heart failure hospitalizations were evaluated at 1 year., Results: At 1 month, 32 (49%) patients had residual MR > mild (of those, 14% had MR > moderate). There was no significant change in CT-ADP values during the procedure. However, CT-ADP significantly decreased 1-hour post-TEER ( P  < 0.001). Patients with corrected MR demonstrated an increase in vWF:Act/vWF:Ag ratio 1-hour post-TEER. Elevated baseline vWF:Act/vWF:Ag ratio and the periprocedural percentage changes of the vWF:Act/vWF:Ag ratio (1 hour post-TEER - baseline values) were associated with the combined clinical outcome., Conclusions: CT-ADP evolution in time was not quick enough to provide real-time monitoring of MR severity during TEER. However, vWF:Act/vWF:Ag ratio at baseline and its variations following the procedure were associated with clinical outcomes. Those findings will need external validation., Competing Interests: Ms Hadjadj and Dr Beaudoin are funded by Fonds de Recherche du Québec-Santé. This work was supported by Fondation de l’Institut Universitaire de Cardiologie et Pneumologie de Québec. Dr Rodés-Cabau holds the Research Chair “Fondation Famille Jacques Larivière” for the Development of Structural Heart Disease Interventions. Dr Pibarot has received institutional funding from 10.13039/100006520Edwards Lifesciences, 10.13039/100004374Medtronic, Pi-Cardia, and Cardiac Success for echocardiography core laboratory analyses and research studies in the field of interventional and pharmacologic treatment of valvular heart diseases, for which he received no personal compensation. Dr Beaudoin received research support from JAMP-Pharma, not related to the current work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Endothelial cells deliver a vital contribution to the maintenance of hemostasis by constituting an anatomical as well as functional barrier between the blood and the rest of the body. Apart from the physical barrier function, endothelial cells maintain the hemostatic equilibrium by their pro- and anticoagulant functions. An important part of their procoagulant contribution is the production of von Willebrand factor (VWF), which is a carrier protein for coagulation factor VIII and facilitates the formation of a platelet plug. Thus, VWF is indispensable for both primary and secondary hemostasis, which is exemplified by the bleeding disorder von Willebrand disease that results from qualitative or quantitative deficiencies in VWF. A cellular model that was found to accurately reflect the endothelium and its secretory organelles are endothelial colony-forming cells, which can be readily isolated from peripheral blood and constitute a robust ex vivo model to investigate the donor's endothelial cell function. This review summarizes some of the valuable insights on biology of VWF and pathogenic mechanisms of von Willebrand disease that have been made possible using studies with endothelial colony-forming cells derived from patients with bleeding disorders., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Between 2002 and 2011, the incidence of severe primary postpartum hemorrhage (PPH) in Dutch women with von Willebrand disease (VWD) and hemophilia carriers (HCs) was 8% vs 4.5% in the general population., Objectives: To determine the contemporary incidence of severe primary PPH in women with VWD and HCs., Methods: All women with VWD or HCs who delivered between 2012 and 2017 were selected from all 6 Dutch hemophilia treatment centers. Data on patient and disease characteristics, peripartum hematologic and obstetric management, and outcomes were retrospectively collected. Incidence of severe primary (≥1000 mL of blood loss ≤24 hours after childbirth) and primary (≥500 mL within ≤24 hours after childbirth) PPH was compared with the (1) previous cohort and (2) general Dutch population and between (3) women with VWD and HCs with third-trimester coagulation activity levels <50 international units (IU)/dL vs ≥50 IU/dL and (4) women treated with vs without peripartum hemostatic prophylaxis., Results: Three-hundred forty-eight deliveries (151 VWD, 167 hemophilia A, and 30 hemophilia B carriers) were included. The severe primary PPH incidence was 10% (36/348) and remained stable over time, whereas this incidence has increased in the general population (to 8%), leading to a similar risk ( P  = .17). Severe primary PPH risk was comparable between women with coagulation activity levels <50 and ≥50 IU/dL (11% [7/66] vs 10% [29/279]; odds ratio, 1.02; 95% CI, 0.43-2.44) and comparable between those with and those without prophylaxis (12% [11/91] vs 10% [25/254]; odds ratio, 1.26; 95% CI, 0.59-2.68)., Conclusion: Severe primary PPH in women with VWD and HCs remained stable and is comparable with the increasing prevalence in the general population. More research is needed to find the optimal pregnancy management strategy for safe delivery in VWD and HC., (© 2024 The Author(s).)

Background: Patient-reported outcomes measurement information system (PROMIS) measures can be used to measure patient-reported outcomes. PROMIS measures, including computer adaptive tests (CATs) and short forms, have demonstrated the ability to adequately assess outcomes in patients with hemophilia. It is, however, unclear if PROMIS measures are suitable for patients with von Willebrand disease (VWD), inherited platelet function disorders (IPFDs), and rare bleeding disorders (RBDs)., Objectives: To evaluate the feasibility, measurement properties, and relevance of PROMIS measures in adults with VWD, IPFDs, and RBDs., Methods: In this cross-sectional multicenter study, adults with VWD, IPFDs, and RBDs completed 9 PROMIS measures and the Short Form-36 version 2 (SF-36v2) electronically. Feasibility was determined by the number of completed items and floor/ceiling effects. Measurement properties included construct validity based on a multitrait-multimethod analysis and reliability using the reliability coefficient and greatest lower bound. Relevance was evaluated based on comparison with the Dutch general population., Results: In total, 111 patients (median age, 57 years [IQR, 44-67]; 60% VWD, 16% IPFD, 24% RBD) participated. Mean number of items answered varied from 5.3 to 8.7 (range, 4-12) per PROMIS CAT in patients with VWD. Construct validity was supported for all CATs and all instruments had a good reliability (≥0.70). The PROMIS measures had less ceiling effects than the SF-36v2., Conclusion: The PROMIS measures are a feasible, valid, and reliable alternative for the SF-36v2 in patients with primarily nonsevere forms of VWD. The relevance of the selected measures was limited. Additional research is necessary to evaluate the PROMIS measures in adults with IPFDs and RBDs., (© 2024 The Authors.)

Background: Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR., Objectives: To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics., Methods: Moderate or severe MR patients ( n  = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed., Results: At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%)., Conclusion: Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients., (© 2024 The Authors.)

Background: Ε-Aminocaproic acid oral solution (EACA OS) is the only commercially available antifibrinolytic for patients who cannot swallow tablets. Insurance denials and high costs remain barriers to its use., Objectives: To determine the safety and efficacy of crushed tranexamic acid tablets in water (cTXAw) for children with bleeding disorders., Methods: We retrospectively reviewed records of children (<10 years) with bleeding disorders who received cTXAw or EACA OS from 1 December 2018, through 31 July 2022, at Mayo Clinic (Rochester, Minnesota). Bleeding outcomes were defined according to ISTH criteria., Results: Thirty-two patients were included (median age, 3 years; male, n = 23). Diagnoses were VWD (n = 17), haemophilia (n = 5), FVII deficiency (n = 3), inherited platelet disorder (n = 4), ITP (n = 2), and combined FV and FVII deficiencies (n = 1). Thirty-two courses of cTXAw (monotherapy 24/32; mean duration 6 days) and fifteen courses of EACA (monotherapy 12/15; mean duration 5 days) were administered. No surgical procedures (n = 28) were complicated by bleeding. Of the 19 bleeding events, 16 had effective haemostasis, two had no reported outcome, and one had no response. cTXAw and EACA were equally effective in preventing and treating bleeding (p value > .1). No patients had adverse effects. Eight of 19 patients (42%) who were initially prescribed EACA OS did not receive it because of cost or insurance denial. The estimated average wholesale price of one treatment was $94 for cTXAw and $905 for EACA OS., Conclusions: CTXAw appears to be an effective, safe, and low-cost alternative option to EACA OS for young children with bleeding disorders., (© 2024 John Wiley & Sons Ltd.)

We present the case of an elderly man with a history of diastolic congestive heart failure, severe aortic stenosis and atrial fibrillation, who presented with fatigue, weakness, coffee ground emesis and black tarry stool. Haemoglobin was 68 g/L. Lactate dehydrogenase was elevated at 1038. Evaluation by cardiology and gastroenterology specialists revealed reflux oesophagitis and a mild hiatal hernia on oesophagogastroduodenoscopy, normal colonoscopy and small bowel series without obstruction. Capsule endoscopy identified angiodysplasia in the small intestine.The patient was diagnosed with Heyde's syndrome based on the triad of severe aortic stenosis, gastrointestinal bleeding from angiodysplasia and acquired von Willebrand syndrome. The patient underwent transcatheter aortic valve replacement, resulting in the resolution of symptoms.Heyde's syndrome represents a challenging clinical entity requiring a multidisciplinary approach for accurate diagnosis and management. Early recognition, prompt intervention and interdisciplinary collaboration are crucial in optimising patient outcomes., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: A novel variant involving noncanonical splicing acceptor site (c.875-5 T > G) in propeptide coding region of von Willebrand factor (VWF) was identified in a patient with type 2A von Willebrand disease (VWD), who co-inherited with a null variant (p.Tyr271*) and presented characteristic discrepancy of plasma level of VWF antigen and activity, and a selective reduction of both intermediate-molecular-weight (IMWMs) and high-molecular-weight VWF multimers (HMWMs)., Materials and Methods: VWF mRNA transcripts obtained from peripheral leukocytes and platelets of the patients were investigated to analyze the consequence of c.875-5 T > G on splicing. The impact of the variant on expression and multimer assembly was further analyzed by in vitro expression studies in AtT-20 cells. The intracellular processing of VWF mutant and the Weibel-Palade bodies (WPBs) formation was evaluated by immunofluorescence staining and electron microscopy., Results: The mRNA transcript analysis revealed that c.875-5 T > G variant led to exon 8 skipping and an in-frame deletion of 41 amino acids in the D1 domain of VWF (p.Ser292&#95;Glu333delinsLys), yielding a truncated propeptide. Consistent with the patient's laboratory manifestations, the AtT-20 cells transfected with mutant secreted less VWF, with the VWF antigen level in conditioned medium 47 % of wild-type. A slight retention in the endoplasmic reticulum was observed for the mutant. Almost complete loss of IMWMs and HMWMs in the medium and impaired WPBs formation in the cell, indicating truncated VWF propeptide lost its chaperon-like function for VWF multimerization and tubular storage., Conclusions: The VWF splicing site variant (c.875-5 T > G) causes propeptide truncation, severely compromising VWF multimer assembly and tubular storage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Von Willebrand factor (VWF) plays a pathophysiological role in hemostatic disorders. Partial inhibition of the VWF gene through small interfering RNA (siRNA)-mediated allele-selective silencing could be a promising therapeutic strategy. For von Willebrand disease, allele-selectively inhibiting dominant-negative VWF-alleles might ameliorate the phenotype. For thrombotic disorders, partial VWF reduction can lower thrombotic risk, while avoiding bleeding. Previously, we demonstrated the feasibility of Vwf-silencing in homozygous C57BL/6J (B6) or 129S1/SvImJ (129S) mice. The present study investigated allele-selective Vwf-silencing in a complex heterozygous setting of crossed B6 and 129S mice and its subsequent hemostatic impact., Materials and Methods: Heterozygous B6.129S mice were treated with siRNAs targeting Vwf expressed from either B6- (siVwf.B6) or 129S-alleles (siVwf.129S). Plasma VWF and lung Vwf mRNA were determined. siVwf.B6-treated B6.129S mice were subjected to ferric chloride-induced mesenteric vessel thrombosis and tail-bleeding., Results: In B6.129S mice, siVwf.B6 reduced Vwf mRNA of the targeted B6-allele by 72% vs. only 12% of the non-targeted 129S-allele (41% total mRNA reduction), lowering plasma VWF by 46%. Oppositely, siVwf.129S reduced Vwf mRNA by 45%, now selectively inhibiting the 129S-allele over the B6-allele (58% vs. 9%), decreasing plasma VWF by 43%. The allele-selective VWF reduction by siVwf.B6 coincided with decreased thrombus formation in mesenteric arterioles, without prolonging tail-bleeding times., Conclusions: This study demonstrates the feasibility of allele-selective Vwf-silencing in a heterozygous setting, achieving a controlled close to 50% reduction of plasma VWF. The observed thromboprotection and absence of prolonged bleeding times underline the potential of allele-selective Vwf-silencing as a therapeutic strategy in hemostatic disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YKJ and JCJE – Dutch Thrombosis Foundation (TSN) grant #2018-01. NAL and JCJE – Netherlands Organization for Scientific Research (NWO) NWO-AES grant #18712. SNJL and JCJE – Netherlands Organization for Scientific Research (NWO) NWA-ORC grant #1160.18.038. JCJE – CSL Behring research funding. RJD, ESE, JED, BJMvV, CVD declare they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Increasing rate of postpartum haemorrhage (PPH) has been observed between 2003 and 2010 in Canada. Inherited bleeding disorders contribute to the risk of PPH., Aim: To identify the trend in PPH in the last decade, assess the impact of bleeding disorders on pregnancy outcomes and evaluate their coagulation workup during pregnancy., Methods: We conducted a population-based retrospective cohort study using the Alberta Pregnancy Birth Cohort from 2010 to 2018. We included women with von Willebrand disease (VWD) and haemophilia, identified by previously validated algorithm and matched with controls. Logistic regression was used to compute odds of PPH and other pregnancy outcomes., Results: We identified 311,330 women with a total of 454,400 pregnancies with live births. The rate of PPH did not change significantly from 10.13 per 100 deliveries (95% CI 10.10-10.16) in 2010-10.72 (95% CI 10.69-10.75) in 2018 (p for trend = .35). Women with bleeding disorders were significantly more likely to experience PPH (odds ratio [OR] 2.3; 95% CI 1.5-3.6), antepartum haemorrhage (OR 2.9; 95% CI 1.5-5.9) and red cell transfusion (OR 2.8; 95% CI 1.1-7.0). We observed a nonsignificant rise in the rate of PPH in women with VWD and haemophilia. Only 49.5% pregnancies with bleeding disorders had third trimester coagulation factor levels checked. Higher odds of PPH and antepartum haemorrhage were observed even with factor levels ≥0.50 IU/mL in third trimester., Conclusion: Despite comprehensive care in women with bleeding disorders, they are still at higher risk of adverse pregnancy outcomes compared to population controls., (© 2024 John Wiley & Sons Ltd.)

Alterations in von Willebrand factor (VWF) have an important role in human health and disease. Deficiency of VWF is associated with symptoms of bleeding and excesses of VWF are associated with thrombotic outcomes. Understanding the mechanisms that drive VWF regulation can lead to a better understanding of modulation of VWF levels in humans. We identified clusterin (CLU) as a potential candidate regulator of VWF based on a single cell RNA sequencing (scRNA-seq) analysis in control endothelial cells (ECs) and von Willebrand disease (VWD) endothelial colony-forming-cells (ECFCs). We found that patients with deficiencies of VWF (von Willebrand disease, VWD) had decreased CLU expression and ECs with low VWF expression also had low CLU expression. Based on these findings, we sought to evaluate the role of CLU in the regulation of VWF, specifically as it relates to VWD. As CLU is primarily thought to be a golgi protein involved in protein chaperoning, we hypothesized that knockdown of CLU would lead to decreases in VWF and alterations in Weibel-Palade bodies (WPBs). We used both siRNA- and CRISPR-Cas9-based approaches to modulate CLU in human umbilical vein endothelial cells (HUVECs) and evaluated VWF protein levels, VWF mRNA copy number, and WPB quantity and size. We demonstrated that siRNA-based knockdown of CLU resulted in decreases in VWF content in cellular lysates and supernatants, but no significant change in WPB quantity or size. A CRISPR-Cas9-based knockdown of CLU demonstrated similar findings of decreases in intracellular VWF content but no significant change in WPB quantity or size. Our data suggests that CLU knockdown is associated with decreases in cellular VWF content but does not affect VWF mRNA levels or WPB quantity or size., Competing Interests: CJN has served as a consultant for Takeda and CSL Behring in the past. Takeda and CSL Behring did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Cox et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: In patients with mild-to-moderate bleeding disorders (MBD), von Willebrand disease (VWD) is diagnosed at von Willebrand factor (VWF) levels ≤50 IU/dL. Although VWF levels are unstable, repeated testing for VWD diagnosis is not necessarily advised in recent guidelines., Objectives: To analyze the relevance of repeated VWF testing to diagnose VWD in patients with MBD., Methods: Data of 277 patients with MBD from the Vienna Bleeding Biobank with at least 2 separate assessments of VWF antigen (VWF:Ag) and activity (VWF:Act) were analyzed., Results: In repeated VWF measurements, 36 patients (13.0%) had "changing" VWF levels (≤/>50 IU/dL), 27 (9.7%) had persistent levels ≤50 IU/dL ("pathologic"), and 214 (77.3%) had levels >50 IU/dL ("normal"). Of the 36 changing patients, 22 (61%) were diagnosed with VWD at baseline, whereas the others only met VWD diagnostic criteria at repeated measurements. Using logistic regression, we estimated a probability of change of 26.4% (95% CI, 12.5-47.4) at baseline VWF levels of 30 IU/dL, 50.8% (95% CI, 35.6-65.8) at 50 IU/dL, 18.8% (95% CI, 12.3-27.6) at 60 IU/dL, and 1.2% (95% CI, 0.3-4.9) at 80 IU/dL. Baseline VWF was a strong predictor for changing status (Χ 2  = 49.9; P < .001), while age, sex, Vicenza score, and blood type O had limited added value (Χ 2  = 5.1; P = .278). Baseline VWF:Ag or VWF:Act cutoffs of 80 IU/dL had negative predictive values of 98.1% and 99.1% for changing status, respectively., Conclusion: Our data emphasize an overlap between patients with VWD and MBD with bleeding disorder of unknown cause and underline the need for repeated VWF testing, especially in patients with VWF levels <80 IU/dL., Competing Interests: Declaration of competing interest D.M. received honoraria for advisory board meetings from CSL Behring. D.K. received honoraria for advisory board meetings from CSL Behring. C.A. received honoraria from Bayer, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi, and Takeda for lectures and/or participation in advisory board meetings. I.P. has occasionally received honoraria from Bayer, CSL Behring, Novo-Nordisk, Pfizer, Roche, Sobi, and Takeda for lectures and advisory board meetings. J.G. received honoraria for lectures, advisory board meetings, and research funding for the Medical University of Vienna from CSL Behring, Novartis, Amgen, and Sobi. A.T., J.B., P.Q., and H.H. have no conflicts of interest to declare., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction: The genetic variant responsible for haemophilia A (HA) significantly impacts endogenous coagulant factor VIII (FVIII:C) level, thus impacting DDAVP responsiveness. Blood group (BG) also impacts FVIII:C levels, but this is difficult to evaluate in a genetically heterogeneous population. Canada has a large cohort of mild-moderate HA due to a single point variant: c.6104T>C, p.Val2035Ala-the Twillingate variant., Aim: To evaluate the impact of BG on endogenous FVIII:C levels and DDAVP responsiveness in a single genotype of mild-moderate HA., Methods: This was a retrospective, single-centre study. BG and FVIII:C levels were obtained for males with the Twillingate variant. One-hour absolute and fold increases in FVIII:C post-DDAVP were calculated. T-tests and Mann-Whitney U tests were used to compare FVIII:C levels and DDAVP challenge variables between individuals according to BGs (O vs. non-O)., Results: Twenty males were included. There were significant differences between BGs (O vs. non-O) in their lowest FVIII:C level at age <12 years (medians: 0.05 vs. 0.08 IU/mL; P = .05). Fifteen subjects underwent DDAVP challenges. Mean 1-h FVIII:C were 0.29 (O BG) versus 0.41 IU/mL (non-O BG); P = .04. There were no significant differences between BGs (O vs. non-O) in mean absolute FVIII:C increase (0.20 vs. 0.27 IU/mL; P = .10) and FVIII:C fold increase (3.3-fold vs. 3.8-fold; P = .51)., Conclusion: In HA subjects with an identical genotype, BG significantly impacts baseline FVIII:C levels and FVIII:C levels post-DDAVP, but does not impact absolute and fold increases in FVIII:C with DDAVP., (© 2023 John Wiley & Sons Ltd.)

Introduction: Several well-established clinical laboratory methods are available to measure von Willebrand factor (VWF) in plasma samples, but few data are available on their use for analysing recombinant VWF (rVWF)., Aim: To evaluate how clinical diagnostic laboratories analyse rVWF and plasma-derived VWF (pdVWF) spiked in vitro into VWF-deficient plasma using quantitative protein and functional assays of VWF., Methods: Human VWF-deficient plasma samples were spiked with rVWF (vonicog alfa; Takeda) or pdVWF/factor VIII (pdVWF/FVIII; antihemophilic factor/VWF complex [human], CSL Behring), each at final concentrations of 1.0, 0.6, 0.2, 0.1 IU/mL VWF:ristocetin cofactor activity (VWF:RCo) according to labelled VWF activity. The ISTH SSC secondary coagulation standard was used as a control. Participating laboratories received three sets of these blinded aliquots. Mean results per assay were compared with the expected potency based on the labelled VWF:RCo activity., Results: Among 39 laboratories, the most commonly established assay was VWF:RCo; 22 laboratories reported data from 2214 tests. Despite a trend to lower values, VWF:RCo activities for rVWF were in agreement with target concentrations (71%-109%), whereas VWF:platelet glycoprotein Ib (VWF:GpIb) and VWF collagen-binding activity (VWF:CB) assays gave high recoveries (up to 132% and 127%, respectively). In contrast, pdVWF/FVIII was substantially underestimated by VWF:GpIb and VWF:CB assays (56%-86% recoveries), whereas the VWF:RCo assay gave recoveries of 47%-112% for pdVWF/FVIII., Conclusion: The results of VWF assays used in clinical laboratories differ between rVWF and pdVWF, particularly for VWF:GpIb and VWF:CB assays. These differences may arise from the higher multimeric structure of rVWF compared to pdVWF., (© 2023 Takeda Development Center Americas, Inc. Haemophilia published by John Wiley & Sons Ltd.)

Background: von Willebrand factor (VWF) is a multimeric glycoprotein critically involved in hemostasis, thrombosis, and inflammation. VWF function is regulated by its antigen levels, multimeric structures, and the state of enzymatic cleavage. Population studies in the past have focused almost exclusively on VWF antigen levels in cross-sectional study designs., Objective: To identify subjects in the Atherosclerosis Risk in Community study who had persistently low and high VWF antigen over 10 years and to quantify longitudinal changes in the biological activities and cleavage of VWF in these subjects., Methods: We measured VWF antigen, propeptide, adhesive activities, and cleavage by ADAMTS-13 quantified using a mass spectrometry method that detected the cleaved VWF peptide EQAPNLVY, as well as coagulation factor VIII activity., Results: We determined the mean subject-specific increase in VWF to be 22.0 International Units (IU)/dL over 10 years, with 95% between -0.3 and 59.7 IU/dL. This aging-related increase was also detected in VWF propeptide levels, ristocetin cofactor activity, and VWF binding to collagen. We identified 4.1% and 25.0% of subjects as having persistently low (<50 IU/dL) and high (>200 IU/dL) VWF antigen, respectively. Subjects with persistently low VWF had enhanced ristocetin cofactor activity, whereas those with persistently high VWF had elevated levels of ADAMTS-13, resulting in a comparable rate of VWF cleavage between the 2 groups., Conclusions: These results provide new information about the effects of aging on VWF antigens and adhesive activity and identify a functional coordination between VWF and the rate of its cleavage by ADAMTS-13., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Hemophilia and Von Willbrand disease (VWD) are the most well known types of hereditary hemorrhagic disorders (HHD). Hemophilia affects about 200 000 people worldwide, while VWD affects about 80 000. Because there is a scarcity of epidemiologic studies on hemophilia in Iraq, this study was carried out to evaluate the prevalence and incidence trends, as well as to identify some clinical and epidemiological features of hemophilia patients in Najaf province, Iraq. This study was carried out in the Najaf's hemophilia center. The data were obtained by reviewing all patients' documents, as well as the center registration book from 2011 to 2021. In addition, the Ministry of Health provided relevant population data for Najaf. Notably, there are currently 214 patients registered in Najaf province. The results revealed that the severe form of hemophilia A was the permanent type of HHDs in the patients compared with the rest of the types that include HHD with no significant difference Pat least 0.05. The frequency of this group of disorders appeared to increase in the period between 2011 and 2013, especially in 2012 followed by a decline in the incidence until 2021, which recorded a sudden increase in these disorders. These findings highlight that hemophilia types A and B were the most prevalent disorders of HHD in Najaf province, and the increase in number of newly recorded cases because of consanguineous marriage increased recently in this area., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Von Willebrand disease (VWD) is an inherited haemostatic disorder with a wide range of bleeding phenotypes based on von Willebrand factor (VWF) levels. Multiple assays including VWF gene analysis are employed to correctly diagnose VWD and its subtypes. However, data on VWF mutations among Southeast Asian populations are lacking. We, therefore, aimed to explore genetic variations in Thai patients with type 2 and type 3 VWD by whole exome sequencing (WES)., Methods: In this multicentre study, Thai patients with type 2 and type 3 VWD, according to the definitions and VWF levels recommended by the international guidelines, were recruited. WES was performed using DNA extracted from peripheral blood in all cases. The novel variants were verified by Sanger sequencing., Results: Fifteen patients (73% females; median age at diagnosis 3.0 years) with type 2 (n=12) and type 3 VWD (n=3) from 14 families were enrolled. All patients harboured at least one VWF variant. Six missense (p.Arg1374Cys, p.Arg1374His, p.Arg1399Cys, p.Arg1597Trp, p.Ser1613Pro, p.Pro1648Arg) and one splice-site (c.3379+1G>A) variants in the VWF gene were formerly described. Notably, six VWF variants, including three missense (p.Met814Ile, p.Trp856Cys, p.Pro2032Leu), one deletion (c.2251delG) and two splice-site (c.7729+4A>C, c.8115+2delT) mutations were novelly identified. Compound heterozygosity contributed to type 2 and type 3 VWD phenotypes in two and one patients, respectively., Conclusions: Type 2 and type 3 VWD in Thailand demonstrate the mutational variations among VWF exons/introns with several unique variants. The WES-based approach potentially provides helpful information to verify VWD diagnosis and facilitate genetic counselling in clinical practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: VWF (von Willebrand factor) is an endothelial-specific procoagulant protein with a major role in thrombosis. Aging is associated with increased circulating levels of VWF, which presents a risk factor for thrombus formation., Methods: Circulating plasma, cellular protein, and mRNA levels of VWF were determined and compared in young and aged mice. Major organs were subjected to immunofluorescence analyses to determine the vascular pattern of VWF expression and the presence of platelet aggregates. An in vitro model of aging, using extended culture time of endothelial cells, was used to explore the mechanism of age-associated increased VWF levels., Results: Increased circulating plasma levels of VWF with elevated levels of larger multimers, indicative of VWF functional activity, were observed in aged mice. VWF mRNA and cellular protein levels were significantly increased in the brains, lungs, and livers but not in the kidneys and hearts of aged mice. Higher proportion of small vessels in brains, lungs, and livers of aged mice exhibited VWF expression compared with young, and this was concomitant with increased platelet aggregate formation. Prolonged culture of endothelial cells resulted in increased cell senescence that correlated with increased VWF expression; VWF expression was specifically detected in senescent cultured endothelial cells and abolished in response to p53 knockdown. A significantly higher proportion of VWF expressing endothelial cells in vivo exhibited senescence markers SA-β-Gal (senescence-associated β-galactosidase) and p53 in aged mouse brains compared with that of the young., Conclusions: Aging elicits a heterogenic response in endothelial cells with regard to VWF expression, leading to organ-specific increase in VWF levels and alterations in vascular tree pattern of expression. This is concomitant with increased platelet aggregate formation. The age-associated increase in VWF expression may be modulated through the process of cell senescence, and p53 transcription factor contributes to its regulation., Competing Interests: Disclosures None.

Background: To assess patient value, it is essential to regularly measure health outcomes that matter to patients. It is currently unknown which health outcomes are important for patients with autosomal inherited bleeding disorders., Objectives: This study aimed to assess which health outcomes are important for patients with autosomal inherited bleeding disorders, consisting of von Willebrand disease, platelet function disorders, and rare bleeding disorders, as seen from the patients', caregivers', and healthcare professionals' perspectives., Methods: Two panels, one consisting of patients and caregivers, and one consisting of healthcare professionals participated in a Delphi process. A list of 146 health outcomes was identified from the literature. During 3 rounds, both panels rated the importance of health outcomes on a 5-point Likert scale. A health outcome was considered important by a panel if it received a median score of 5 with an IQR of ≤1., Results: In total, 13 patients, 10 caregivers, and 19 healthcare professionals participated in the Delphi study. Both panels reached consensus on the importance of health outcomes related to bleeding episodes, life-threatening complications, and the intensity and impact of menstruation. Patients and caregivers additionally reached consensus on the importance of health outcomes related to menstruation and the impact of the bleeding disorder on their daily lives. Healthcare professionals reached consensus on the importance of health outcomes related to treatment, joint health, and pain., Conclusion: In this study, health outcomes were identified that should be considered when implementing value-based health care in the care of patients with autosomal inherited bleeding disorders., (© 2023 The Authors.)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP), an autoantibody-mediated severe ADAMTS13 deficiency, is caused by insufficient proteolytic processing of von Willebrand factor (VWF) multimers (MMs) and microvascular thrombi. Recurrence of acute iTTP is associated with persistence or reappearance of ADAMTS13 deficiency. Some patients remain in remission despite recurring or persisting severe ADAMTS13 deficiency. In a prospective 2-year observational study, we investigated VWF MM patterns and ADAMTS13 in patients with iTTP in remission and at acute episodes. Of the 83 patients with iTTP, 16 suffered 22 acute episodes whereas 67 remained in clinical remission during follow-up, including 13 with ADAMTS13 <10% and 54 with ADAMTS13 ≥10%. High -molecular weight to low-molecular weight VWF MM ratio based on sodium dodecyl sulfate-agarose gel electrophoresis was compared with ADAMTS13 activity. VWF MM ratio was significantly higher in patients in remission with <10% compared with ≥10% ADAMTS13 activity. Fourteen samples obtained from 13 to 50 days (interquartile range; median, 39) before acute iTTP onset (ADAMTS13 <10% in 9 patients and 10%-26% in 5) showed VWF MM ratios significantly higher than those from 13 patients remaining in remission with ADAMTS13 <10%. At acute iTTP onset, VWF MM ratio decreased significantly and was low in all patients despite <10% ADAMTS13. The VWF MM ratio does not depend exclusively on ADAMTS13 activity. The disappearance of high molecular weight VWF MMs resulting in low VWF MM ratio at iTTP onset may be explained by consumption of larger VWF MMs in the microcirculation. The very high VWF MM ratio preceding acute iTTP recurrence suggests that VWF processing is hampered more than in patients remaining in remission., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Severe aortic stenosis (AS) can lead to degradation of high molecular weight (HMW) von Willebrand factor (VWF) which can result in haemostatic abnormalities. While studies have explored changes in VWF profiles before and after surgical aortic valve replacement (SAVR), the longer-term changes in VWF profiles pre- and post-transcatheter aortic valve implantation (TAVI) are less understood., Aim: Our primary objective was to identify differences in VWF multimer profiles and VWF function pre-TAVI and 1-month post-TAVI. Our secondary objective was to correlate VWF markers with measures of AS severity., Methods: Adult patients with severe AS referred for TAVI at our institution were prospectively enrolled in this cohort study. Blood samples were collected for plasma analysis at three time points for all patients: 1 day pre-TAVI, 3 days post-TAVI, and 1-month post-TAVI. VWF antigen, activity, propeptide, collagen binding, multimers, and factor VIII coagulant activity were determined at each time point. Correlations between VWF parameters and severity of AS were assessed., Results: Twenty participants (15 males, five females) with severe AS were recruited for the study. There was a significant increase in HMW VWF between pre-procedure and 1-month post-TAVI (p < .05). There was a transient increase in VWF antigen levels and activity at 3-days post TAVI that decreased to pre-TAVI levels at 1-month. There were no statistically significant correlations between VWF markers and AS severity., Conclusions: This is the first study to elucidate longer-term (>1 week) improvements in HMW VWF after a TAVI procedure in severe AS patients., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Von Willebrand disease (VWD) and hemophilia A are the most common inherited bleeding disorders. Quantitative or qualitative von Willebrand factor (VWF) anomalies cause this disorder in men and women. VWF, a plasma glycoprotein, relies on platelets for primary hemostasis. It also carries and stabilizes factor VIII in the blood. VWD has several categories. Types 1 and 3 have partial or total VWF quantitative deficiencies. However, type 2 and its subtypes have VWF quality issues. The major treatment is desmopressin (DDAVP), which replaces endogenous VWF and factor VIII (FVIII). Plasma-derived VWF/FVIII products may also be substituted exogenously. Treatment with plasma-derived or recombinant VWF concentrates without FVIII is also possible. The purpose of this retrospective, single-center research was to evaluate DDAVP's efficacy in treating VWD based on many criteria established in the current literature. We looked at the results on Google Scholar, the Cochrane Library, and PubMed/Medline. There were a total of 10 papers found, evaluated, and accepted for inclusion in this study. A comprehensive analysis of DDVAP's role in VWD was compiled from the aforementioned papers. Various aspects of DDVAP were captured by including an analysis of complementary treatments used in surgical and clinical settings. We also describe the treatment's intended impact on the different variations of the disease. Given these results, further investigation is required to determine the most effective method for managing VWD so that it may be included in standard clinical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Beltran et al.)

Background: Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after extensive investigation of coagulation and platelet function and is commonly seen among patients with mild-to-moderate bleeding disorders. Despite increasing awareness among treating physicians, little is known about the health-related quality of life (HrQoL) in BDUC., Objectives: To investigate HrQoL in patients with BDUC in comparison to the general population and patients diagnosed with other established bleeding disorders., Methods: Patients with mild-to-moderate bleeding disorders from the Vienna Bleeding Biobank, a prospective cohort study, were contacted via mail and phone to complete the 36-Item Health Survey Questionnaire form., Results: In total, 333/657 (50.7%) patients completed the 36-Item Health Survey Questionnaire. Patients with BDUC ( n  = 207, 62%) had significantly impaired HrQoL both in physical (47.8 vs 49.2) and mental health parameters (42.9 vs 51.0) compared to the general population ( n  = 2914, 56% females), which remained after adjustment for sex and age in multivariable linear regression. The impairment in HrQoL, compared to patients with von Willebrand disease, platelet function defects, or mild clotting factor deficiencies, did not prevail after adjustment for age and sex. In patients with BDUC, age and the presence of at least 1 comorbidity were associated with impaired physical health but not sex or bleeding severity. Of all analyzed bleeding symptoms, only joint bleeding was associated with impaired physical health and gastrointestinal bleeding with mental health in BDUC., Conclusion: The impairments in HrQoL in patients with BDUC emphasize the burden of BDUC on mental and physical well-being, encouraging early recognition and better counseling of patients with BDUC., (© 2023 The Author(s).)

Quantitative abnormalities in factor VIII (FVIII) and its binding partner, von Willebrand factor (VWF), are associated with an increased risk of bleeding or thrombosis, and pathways that regulate the clearance of VWF-FVIII can strongly influence their plasma levels. In 2010, the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) on genome-wide association study meta-analysis identified variants in the genes for the sinusoidal endothelial receptors C-type lectin domain family 4 member M (CLEC4M), stabilin-2, and scavenger receptor class A member 5 (SCARA5) as being associated with plasma levels of VWF and/or FVIII in normal individuals. The ability of these receptors to bind, internalize, and clear the VWF-FVIII complex from the circulation has now been reported in a series of studies using in vitro and in vivo models. The receptor stabilin-2 has also been shown to modulate the immune response to infused VWF-FVIII concentrates in a murine model. In addition, the influence of genetic variants in CLEC4M, STAB2, and SCARA5 on type 1 von Willebrand disease/low VWF phenotype, FVIII pharmacokinetics, and the risk of venous thromboembolism has been described in a number of patient-based studies. Understanding the role of these receptors in the regulation of VWF-FVIII clearance has led to significant insights into the genomic architecture that modulates plasma VWF and FVIII levels, improving the understanding of pathways that regulate VWF-FVIII clearance and the mechanistic basis of quantitative VWF-FVIII pathologies., Competing Interests: Declaration of competing interests D.L. has received research grants from Bayer, Biomarin, CSL-Behring, Octapharma, and Sanofi. L.L.S. and A.M. declare no competing financial interests., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Von Willebrand disease (VWD) is the most widespread congenital bleeding disorder. Caregivers are highly involved in its treatment, and from the time of the child's bleeding diagnosis, they face new demands such as recognition of bleeds and treatment options., Aim: The aim of this study was to assess Health related quality of life (HRQoL) in caregivers of children with moderate and severe VWD in Sweden, and to describe the impact of psychosocial aspects on the burden., Methods: A multicentre, cross-sectional study. The Short Form 36 Health Survey (SF-36) was used to assess HRQoL. Caregiver burden was measured using The HEMOphilia associated Caregiver Burden scale (HEMOCAB). Children´s clinical data were collected from the Swedish national registry for bleeding disorders., Results: Seventy caregivers of children with moderate or severe VWD were included. Caregivers of children with moderate VWD scored significantly lower in the mental health domains on SF-36, compared to matched normative data. Psychosocial aspects that significantly impacted the caregiver burden negatively measured by HEMOCAB total score were: if the caregiver reported that VWD affected their life in general (p = .001), if the child was absent from preschool/school ≥2 day/12 months due to VWD (p = .002) or that VWD had a financial impact on the family (p = .001)., Conclusion: This study contributes to knowledge about caregivers' HRQoL and highlights the situation of caregivers of children with moderate VWD. Furthermore, the caregiver burden was negatively affected by psychosocial aspects. Clinical follow-ups should include assessment of psychosocial aspects to identify caregivers that are at risk of high burden., (© 2023 John Wiley & Sons Ltd.)

Introduction: Peri-procedural management of von Willebrand disease (VWD) utilizes von Willebrand factor (VWF) concentrates or desmopressin (DDAVP) to increase VWF levels. DDAVP is safe, easily administered, and inexpensive. Currently, a consensus definition for adequate DDAVP response is lacking, and outcomes of peri-procedural DDAVP use in VWD patients are seldom reported., Aim: This single-centre retrospective review aims to characterize DDAVP-responsiveness and assess clinical outcomes of peri-procedural DDAVP use in VWD., Patients and Methods: We reviewed records for all our adult VWD patients (age ≥18 years) who underwent DDAVP challenge testing between January 2007 and January 2022. DDAVP-responsiveness was assessed using six definitions. Bleeding outcomes following procedures covered by DDAVP were classified as excessive or expected bleeding., Results: Eighty-four of 94 (89.4%) patients were DDAVP-responsive by our definition (1-h VWF Activity/Factor VIII ≥0.50 IU/mL). However, the proportion of DDAVP-responders varied from 53.2% to 91.5%, depending on the literature definition used. Ninety-nine procedures pre-treated with DDAVP were performed during the study period. Eighty-six (86.7%) procedures (31 major; 55 minor) were covered with only DDAVP ± tranexamic acid (TXA). Excessive bleeding occurred following 4/31 major procedures and 2/55 minor procedures (both performed in a single patient with a bleeding score of 16). When covered with DDAVP+Factor ± TXA, one each of 10 major and 3 minor procedures (performed in 2 patients with bleeding scores 15-16) resulted in post-procedural bleeding., Conclusions: Peri-procedural DDAVP prophylaxis appears to be effective among individuals with VWD. Beyond DDAVP-responsiveness, patient bleeding history and procedure invasiveness should be considered in determining suitability for DDAVP prophylaxis., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Inherited bleeding disorders (IBDs) including hemophilia, von Willebrand disease, platelet disorders, mucocutaneous bleeding disorders and coagulation factor deficiencies are rarely found and under-recognized in low and lower-middle-income countries. Some patients succumbed to serious bleeding without diagnosis and treatment during childhood., Area Covered: Diagnosis, management, and prevention should be integrated into the existing health care system. Although some countries have not implemented appropriate health care infrastructure, an initiative plan should be set up by cooperation of experienced experts and health care providers. Identification of patients with IBDs should be started in the antenatal setting to search for females at risk of carrier state. The investigations include bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay and mutation detection. Genotypic analysis is helpful for confirming the definite diagnosis, carrier detection as well as prenatal diagnosis for females at risk of bearing an offspring with severe bleeding manifestations. Management involves replacement therapy ranging from blood component to virus-inactivated factor concentrate. Appropriate research is an essential backbone for improving patients' care., Expert Opinion: Effective national strategic advocacy to manage patients with IBDs requires intensive collaboration among policy makers, health care providers, patients, and family members.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a late systemic inflammatory response to a recent mild or asymptomatic coronavirus disease of 2019 infection. The pathophysiology is incompletely understood but it often features significant coagulopathy along with cardiac and endothelial dysfunction. Endothelial inflammation has been primarily described in acute coronavirus disease of 2019 infection, with less characterization in MIS-C. Here we describe novel findings of nearly universal severe and prolonged factor VIII (FVIII) and von Willebrand factor antigen elevations in an institutional cohort of patients with MIS-C ages younger than or 21 years old (N=31). All patients had elevated acute phase reactants and D-dimer at presentation and met published criteria for MIS-C. FVIII was high at presentation in 97% of patients but continued to rise during the ensuing weeks of treatment to a mean 429%, peaking on median day 17 of illness as an outpatient. FVIII levels were >600% in multiple patients. von Willebrand factor antigen was measured less frequently but showed similar trends. These escalations occurred amidst resolving cardiac dysfunction and acute phase reactant normalization and despite patients receiving multimodal anti-inflammatory treatments and aspirin and enoxaparin thromboprophylaxis. No thrombotic events occurred. Endothelial dysfunction represented by very elevated FVIII levels may persist longer than other acute phase reactants may reflect., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT., Objectives: The objectives of this study are to assess the false-positive rate, detection rate, and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with Von Willebrand disease (VWD) or hemophilia., Methods: We performed a multicenter, nationwide cross-sectional study embedded in 2 nationwide studies on VWD and hemophilia in the Netherlands., Results: In total, 493 patients with hemophilia (n = 329) or VWD (n = 164) were included, of whom 351 patients participated in the CRC screening program (71.2%). FIT positivity and false-positive rate in patients with hemophilia and VWD were significantly higher than those in the general population (14.8% vs. 4.3%, p < .001 and 10.3% vs. 2.3%, p <.001, respectively). In patients with hemophilia, the detection rate of CRC/AA was significantly higher than that in the general male population (4.5% vs. 1.8%, p = .02), and the positive predictive value of FIT for CRC/AA was comparable (32.3% vs. 39.7%, n.s.). In patients with VWD, the detection rate was similar to that of the general population (0.8% vs. 1.4%, n.s.), whereas the positive predictive value was significantly lower than that in the general population (6.3% vs. 36.8%, p = .02)., Conclusion: This study indicates that despite a high false-positive rate of FIT in patients with inherited bleeding disorders, the detection rate of CRC and/or AA in hemophilia patients is high. FIT performs different in patients with hemophilia or VWD compared with the general population., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The loss of high molecular weight multimers (HMWM) of von Willebrand factor (vWF) in aortic stenosis (AS) and continuous-flow left ventricular assist devices (cf-LVADs) is believed to be associated with high turbulent blood shear. The objective of this study is to understand the degradation mechanism of HMWM in terms of exposure time (kinetic) and flow regime (dynamics) within clinically relevant pathophysiologic conditions. A custom high-shear rotary device capable of creating fully controlled exposure times and flows was used. The system was set so that human platelet-poor plasma flowed through at 1.75 ml/sec, 0.76 ml/sec, or 0.38 ml/sec resulting in the exposure time ( texp ) of 22, 50, or 100 ms, respectively. The flow was characterized by the Reynolds number (Re). The device was run under laminar (Re = 1,500), transitional (Re = 3,000; Re = 3,500), and turbulent (Re = 4,500) conditions at a given texp followed by multimer analysis. No degradation was observed at laminar flow at all given texp . Degradation of HMWM at a given texp increases with the Re. Re ( p < 0.0001) and texp ( p = 0.0034) are significant factors in the degradation of HMWM. Interaction between Re and texp , however, is not always significant ( p = 0.73)., Competing Interests: The authors have no conflicts of interest to report. The abstract of the study was accepted and presented at the 66th ASAIO Conference., (Copyright © ASAIO 2022.)

Background: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity., Objectives: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH., Methods: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated., Results: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours., Conclusion: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF., Competing Interests: Declaration of competing interests M.L. has served as a consultant for SOBI, CSL Behring, and Band Therapeutics and received indirect funding for the development of educational content from Takeda and speaker’s fees from CSL Behring and Pfizer. N.M.O’C. has acted as a principal investigator on clinical trials sponsored by Baxalta (now Takeda), Freeline, Pfizer, SOBI, and Sanofi; has received research support from SOBI and Takeda; and has received speaker’s fees and/or served on advisory boards for Freeline, Novo Nordisk, Pfizer, Roche, SOBI, Takeda, and uniQure. B.M.R. has served as a consultant for Takeda, Boehringer Ingelheim, and Novo Nordisk. P.L.T. is a full-time employee of Baxalta Innovations GmbH, a member of the Takeda group companies, and a shareholder in Takeda Pharmaceutical Company Limited. J.S.O’D has served on the speaker’s bureau for Baxter, Bayer, Novo Nordisk, SOBI, Boehringer Ingelheim, Leo Pharma, Takeda, and Octapharma; served on the advisory boards of Baxter, SOBI, Bayer, Octapharma, CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, Takeda, and Pfizer; and received research grant funding awards from 3M, Baxter, Bayer, Pfizer, Shire, Takeda, 3M, and Novo Nordisk. The remaining authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients on continuous flow ventricular assist devices (CF-VADs) are at high risk for the development of Acquired von-Willebrand Syndrome (AVWS) and non-surgical bleeding. von Willebrand Factor (vWF) plays an essential role in maintaining hemostasis via platelet binding to the damaged endothelium to facilitate coagulation. In CF-VAD patients, degradation of vWF into low MW multimers that are inefficient in facilitating coagulation occurs and has been primarily attributed to the supraphysiological shear stress associated with the CF-VAD impeller., Methods: In this review, we evaluate information from the literature regarding the unraveling behavior of surface-immobilized vWF under pulsatile and continuous flow pertaining to: (A) the process of arterial endothelial vWF production and release into circulation, (B) the critical shear stress required to unravel surface bound versus soluble vWF which leads to degradation, and (C) the role of pulsatility in on the production and degradation of vWF., Results and Conclusion: Taken together, these data suggests that the loss of pulsatility and its impact on arterial endothelial cells plays an important role in the production, release, unraveling, and proteolytic degradation of vWF into low MW multimers, contributing to the development of AVWS. Restoration of pulsatility can potentially mitigate this issue by preventing AVWS and minimizing the risk of non-surgical bleeding., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Bleeding assessment tools are key screening tests used in the evaluation of patients with suspected inherited bleeding disorders. The International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee endorsed Bleeding Assessment Tool (ISTH-BAT) has differing reference ranges for adult males (0-3), adult females (0-5), and children (0-2), reflecting differing bleeding symptoms and exposure to hemostatic challenges in these healthy population subgroups. Age is known to markedly impact bleeding score in individuals with von Willebrand disease. However, the influence of age on bleeding score in healthy adult controls is poorly understood., Objectives: We aimed to assess variability in ISTH-BAT score with age among healthy control females., Methods: We used the legacy "Merging Project" dataset of normal healthy controls upon which current ISTH-BAT normal ranges are based. We included women, totaling 646 individuals. The normal range (middle 95th percentile) of total ISTH-BAT and grouped subdomain scores between age quartiles was assessed., Results: The normal range of ISTH-BAT scores increased with age, ranging from 0 to 4 in the youngest quartile (age range, 18-30) to 0 to 6 in the oldest (age range, 52-88). This increased variability with aging was related both to high menorrhagia domain scores in older women and an increase in postprocedural bleeding with accumulated exposure to hemostatic challenges., Conclusions: Cumulatively, our data highlight that normal aging leads to increased variability in bleeding scores in healthy adult females. Further refinement of the ISTH-BAT with age-adjusted reference ranges may improve the sensitivity and specificity of the tool among females., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate changes in von Willebrand factor (VWF) concentration, function, and multimers during pediatric extracorporeal membrane oxygenation (ECMO) and determine whether routine monitoring of VWF during ECMO would be useful in predicting bleeding., Design: Prospective observational study of pediatric ECMO patients from April 2017 to May 2019., Setting: The PICU in a large, tertiary referral pediatric ECMO center., Patients: Twenty-five neonates and children (< 18 yr) supported by venoarterial ECMO., Interventions: None., Measurements and Main Results: Arterial blood samples were collected within 24 hours pre-ECMO, daily for the first 5 days of ECMO, every second day until decannulation, and 24 hours post-ECMO. The STA R Max analyzer was used to measure VWF antigen (VWF:Ag) and ristocetin cofactor (VWF:RCo) activity. VWF collagen binding (VWF:CB) was measured using an enzyme-linked immunosorbent assay. VWF multimers were measured using the semi-automated Hydragel 11 VWF Multimer assay. Corresponding clinical data for each patient was also recorded. A total of 25 venoarterial ECMO patients were recruited (median age, 73 d; interquartile range [IQR], 3 d to 1 yr). The median ECMO duration was 4 days (IQR, 3-8 d) and 15 patients had at least one major bleed during ECMO. The percentage of high molecular weight multimers (HMWM) decreased and intermediate molecular weight multimers increased while patients were on ECMO, irrespective of a bleeding status. VWF:Ag increased and the VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios decreased while patients were on ECMO compared with the baseline pre-ECMO samples and healthy children., Conclusions: Neonates and children on ECMO exhibited a loss of HMWM and lower VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios compared with healthy children, irrespective of major bleeding occurring. Therefore, monitoring VWF during ECMO would not be useful in predicting bleeding in these patients and changes to other hemostatic factors should be investigated to further understand bleeding during ECMO., Competing Interests: Ms. Van Den Helm’s, Ms. Letunica’s, Mr. McCafferty’s, and Drs. Ignjatovic’s and Monagle’s institutions received funding from the Australian National Health and Medical Research Council. Dr. MacLaren disclosed that he serves on the Board of Directors of the Extracorporeal Life Support Organization. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Although most plasma FVIII (Factor VIII) circulates in complex with VWF (von Willebrand factor), a minority (3%-5%) circulates as free-FVIII, which is rapidly cleared. Consequently, 20% of total FVIII may be cleared as free-FVIII. Critically, the mechanisms of free-FVIII clearance remain poorly understood. However, recent studies have implicated the MGL (macrophage galactose lectin) in modulating VWF clearance., Methods: Since VWF and FVIII share similar glycosylation, we investigated the role of MGL in FVIII clearance. FVIII binding to MGL was assessed in immunosorbent and cell-based assays. In vivo, FVIII clearance was assessed in MGL1 -/- and VWF -/- /FVIII -/- mice., Results: In vitro-binding studies identified MGL as a novel macrophage receptor that binds free-FVIII in a glycan-dependent manner. MGL1 -/- and MGL1 -/- mice who received an anti-MGL1/2 blocking antibody both showed significantly increased endogenous FVIII activity compared with wild-type mice ( P =0.036 and P <0.0001, respectively). MGL inhibition also prolonged the half-life of infused FVIII in FVIII -/- mice. To assess whether MGL plays a role in the clearance of free FVIII in a VWF-independent manner, in vivo clearance experiments were repeated in dual VWF -/- /FVIII -/- mice. Importantly, the rapid clearance of free FVIII in VWF -/- /FVIII -/- mice was significantly ( P =0.012) prolonged in the presence of anti-MGL1/2 antibodies. Finally, endogenous plasma FVIII levels in VWF -/- mice were significantly increased following MGL inhibition ( P =0.016)., Conclusions: Cumulatively, these findings demonstrate that MGL plays an important role in regulating macrophage-mediated clearance of both VWF-bound FVIII and free-FVIII in vivo. We propose that this novel FVIII clearance pathway may be of particular clinical importance in patients with type 2N or type 3 Von Willebrand disease.

Competing Interests: Declaration of competing interest There are no competing interests to disclose.

Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of type 1 and type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (range, 30-50 IU/dL; low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to the pathobiology of low VWF. Patients with low VWF were recruited to the LoVIC study after ethics approval and receipt of informed consent. Desmopressin was administered IV in 75 patients, and blood samples were drawn at baseline and at the 1-hour and 4-hour time points. As defined by recent ASH/ISTH/NHF/WFH guidelines, 20% of our low-VWF cohort demonstrated significantly enhanced VWF clearance. Importantly, from a clinical perspective, this enhanced VWF clearance was seen after desmopressin infusion, but did not affect the steady-state VWF propeptide (VWFpp)-to-VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) in most cases. The discrepancy between the VWFpp/VWF:Ag ratio and desmopressin fall-off rates in patients with mild quantitative VWD may have reflected alteration in VWFpp clearance kinetics. Finally, bleeding scores were significantly lower in patients with low VWF with enhanced VWF clearance, compared with those in whom reduced VWF biosynthesis represented the principle pathogenic mechanism. This trial was registered at http://www.clinicaltrials.gov as #NCT03167320., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background and Aim: Von Willebrand disease (VWD) is considered the most prevalent inherited bleeding disorder. The current study aims to demonstrate the research status and trends on VWD worldwide., Methods: Bibliometric analysis was used to investigate the global research productivity and trends on VWD. The publications on VWD from 1956 to 2021 were extracted using the Web of Science database. In the VWD domain, a total of 3,643 records were analyzed for authorship and collaboration patterns, yearly productivity, highly cited documents, relevant source of publication, most prolific scholars, productive countries, and organizations., Results: The most productive journal, author, organization, and country were 'Haemophilia' with 439 publications, 'Favaloro EJ' with 119 publications, the 'University of Milan' with 192 publications, and the United States of America (USA) with 1,048 publications, respectively. The document with the highest citations was 'Srivastava A, 2013, Haemophilia,' which received 1,154 citations in total. In 2016, the highest number of publications shared by two author patterns was 28. With 199 publications, the year 2021 remained on the top, while the citation-wise analysis identified 2006 as the top year with 5,379 citations., Conclusions: Research productivity and publication trends on VWD revealed that the USA emerged as the most significant contributing country. The 'University of Milan' was the most significant contributing organization, while 'Favaloro EJ' was the most significant author. 'Hemophilia' was found to be the most significant journal in the field of VWD. It is recommended that researchers from countries with significant contributions to the field should collaborate with researchers from Asian countries and other countries that lack behind in research in the domain of VWD.(www.actabiomedica.it).

The World Federation of Haemophilia (WFH) is a global network of national member organizations (NMOs) that advocate, collectively and individually, to improve lives of people with inherited bleeding disorders. The WFH vision of "Treatment for All" speaks to a future in which all people with an inherited bleeding disorder will have access to care, regardless of their gender or where they live. Over the last several years, initiatives including the WFH Humanitarian Aid program, the World Bleeding Disorders Registry, and Guidelines for the Management of Haemophilia and von Willebrand disease have significantly changed how the WFH and its partners work to improve and sustain care for people with bleeding disorders. Following an extensive consultation that included over 200 stakeholders from 70 countries, a Theory of Change was developed, and strategic priorities identified, to clearly define the WFH's intended impact and point of accountability to its stakeholders, and to determine how and through who those goals will be achieved. Both should help the WFH better support its NMOs and healthcare providers around the world in their efforts to improve access to diagnosis and care, as new therapies revolutionize the treatment landscape and the fallout of the global pandemic continues to challenge the ways in which we work and connect. Global collaboration of all stakeholders, based on their resources, objectives and skills, will be required to achieve these goals and to ensure more people have reliable access to safe treatment and care, regardless of their bleeding disorder, gender, or where they live., (© 2022 John Wiley & Sons Ltd.)