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Introduction Aim Methods Results Conclusion Acquired von Willebrand syndrome (AVWS) is a rare haemorrhagic disorder. The prophylaxis and treatment of bleeding before surgery are complex. Since 2018, a new recombinant VWF (rVWF) concentrate that contains no factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France.To describe the real‐world experience of using rVWF in non‐surgical bleeding and surgical procedures in patients with AVWS.Fifteen bleeding episodes in seven patients and 16 surgeries in 10 patients were retrospectively analysed in t French haemostasis centres.During bleeding, the median number of infusions was only 1 (range 1–27) with a median loading dose of 58 IU/kg (range 17–116) rVWF and a total median dose of 65 IU/kg (range 35–1488) rVWF. Bleeding control was rated markedly effective in 73% (11/15) of the cases and ineffective in 27% (4/15).During surgeries, the median number of infusions was 3 (range 1–8) with a preoperative loading dose of 60 IU/kg (range 23–118) rVWF and a total median dose of 123 IU/kg (range 31–542). The overall clinical efficacy was qualified as excellent, good and poor (ISTH criteria) in respectively 7 (43%), 6 (38%) and 3 (19%) procedures.There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events nor adverse events were reported.This French ‘real‐world’ experience shows that rVWF could be of interest in the treatment and prophylaxis of bleeding in patients with AVWS, with no clinically significant safety concern. [ABSTRACT FROM AUTHOR]

Introduction: Patients with von Willebrand disease (VWD) require administration of von Willebrand factor (VWF) concentrates peri‐operatively. Concerns about FVIII accumulation after repetitive injections of a 1:1 ratio VWF/FVIII clotting factor concentrate (CFC) led this study to explore the recovery and FVIII accumulation over time. Methods: This monocentre study examined patients with VWD receiving perioperative 1:1 ratio CFC infusions. CFC dosing was based on body weight and endogenous VWF/FVIII activity. FVIII and VWF activity was monitored at T0 (baseline), T1 (15 min postinfusion), and trough levels at T2‐T6 (24‐120 h). Results: We included 125 patients, undergoing 125 procedures (63 major surgeries, 62 minor), with a median of two CFC infusions (IQR 1–3). With a mean administered dose of 35.7 IU/kg CFC, recovery rates of FVIII and VWF were 2.6 IU/dL per IU/kg and 2.4 IU/dL per IU/kg, respectively. Mean FVIII levels at T0 were 62 (SD 51.9), T1: 164 (SD 80.4), T2: 155 (SD 62.8), T3: 162 (SD 59.8), T4: 124 (SD 78.4), and T5: 120 (SD 65.3) IU/dL. Mean VWF activity levels at T0 were 29 (SD 25.0), T1: 133 (SD 43.7), T2: 92 (SD 37.2), and T3: 86 (SD 37.5) IU/dL. Subgroup analysis in 47 patients with more than three infusions, showed no accumulation of mean FVIII levels. Conclusion: This perioperative study demonstrated excellent FVIII and VWF recovery of a 1:1 ratio VWF product in patients with VWD. Stable FVIII and VWF activity levels were observed after repeated infusions, without accumulation. Most major surgeries required only three CFC infusions. [ABSTRACT FROM AUTHOR]

Introduction: Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options. Aim: Describe current treatments and outcomes for GI BEs in people with VWD. Methods: This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI‐specific morbidities/lesions, treatment and outcomes were analysed descriptively. Results: Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5‐year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non‐haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non‐VWF treatments tended to resolve later. In patients with GI‐specific morbidities/lesions, 84% resolved with first‐line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on‐demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution. Conclusions: This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis. [ABSTRACT FROM AUTHOR]

Acquired bleeding disorders can develop in previously healthy people irrespective of age or gender but are particularly common in patients with certain underlying conditions. Here, we review recent advances in the management of acquired haemophilia A (AHA), acquired von Willebrand syndrome (AVWS), and patients with hemostatic abnormalities due to chronic liver disease (CLD). Patients with AHA can now benefit from prophylaxis with emicizumab, a therapeutic antibody that mimics the function of activated coagulation factor VIII. The treatment of AVWS remains challenging in many situations and requires careful consideration of the underlying condition. Haemostatic abnormalities in CLD are often compensated by proportional reduction in pro and anti‐haemostatic factors resulting in sustained or even increased thrombin generation. Consequently, bleeding in CLD is rarely caused by haemostatic failure and infusion of plasma or coagulation factor concentrates may not be effective. [ABSTRACT FROM AUTHOR]

Manuscript background and aim: The diagnosis and clinical care of patients with von Willebrand disease (VWD) has continued to evolve since the characterization of the von Willebrand factor (VWF) gene in 1985. This condition is almost certainly the most common inherited bleeding disorder, and the major symptomatic burden of the disease is experienced by females during their reproductive years. Diagnosis relies on the identification of a personal and family history of excessive mucocutaneous bleeding, and laboratory features consistent with quantitative and/or qualitative abnormalities of VWF. This review focuses on three aspects of VWD management, with current updates and a look into the future. Manuscript themes: First, we will address the role of genetics in the diagnosis and possible therapies for VWD. With current technologies, VWD genetic diagnosis is usually confined to the confirmation of type 2 subtypes of the disease and type 3 VWD analysis for family planning. While type 3 VWD is a potential candidate for the application of gene therapy, no treatments are currently close to entering the clinic. Second, the peri‐procedural management of patients with VWD remains an important element of care. The choice of product, its dose and schedule all require careful consideration depending upon the type and disruptive nature of the planned procedure. Lastly, in addition to gene therapy, several other novel therapeutic interventions are also being developed for bleeding and prophylaxis in VWD. These include a VWF aptamer interfering with VWF clearance and bioengineered forms of VWF. [ABSTRACT FROM AUTHOR]

Introduction: Guidelines on the management of pregnant individuals with von Willebrand disease (VWD) at the time of delivery recommend that von Willebrand factor (VWF) and factor VIII:C (FVIII:C) levels be ≥50% to prevent postpartum haemorrhage (PPH). Yet, high PPH rates persist despite these levels or with prophylactic factor replacement therapy to achieve these levels. Aims: The current practice at our centre has been to target peak plasma VWF and FVIII:C levels of ≥100 IU/dL at time of delivery. The objective of this study was to describe obstetric outcomes in pregnant individuals with VWD who were managed at our centre. Methods: Demographics and outcomes on pregnant individuals with VWD who delivered between January 2015 and April 2023 were collected. Results: Forty‐seven singleton deliveries (among 41 individuals) resulting in 46 live births and one foetal death were included. Twenty‐one individuals had at least one prior birth by the start date of this study, of which 11 (52.4%) self‐reported a history of PPH. Early PPH occurred in 12.8% (6/47) of deliveries. Two individuals required blood transfusion, of which one also had an unplanned hysterectomy and transfer to ICU. There were no thrombotic events reported. Conclusion: The strategy of targeting higher peak plasma VWF and FVIII:C levels (≥100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery‐associated bleeding complications in VWD patients. Yet, the rate of early PPH remains unsatisfactory compared to the non‐VWD population. [ABSTRACT FROM AUTHOR]

Introduction: VWD diagnosis is challenging requiring multiple VWF activity tests using many individual assays. We have developed an ELISA‐based VWF Multiplex Activity Assay (VWF‐MAA) to address this concern; however, the ability of the VWF‐MAA to discriminate between type 1 VWD, variant VWD, and normal subjects has not been evaluated. Aim: To evaluate the VWF‐MAA and its ability to differentiate between type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding. Methods: A total of 177 plasma samples from the Zimmerman Program: Comparative Effectiveness in the Diagnosis of VWD were evaluated from 11 centres across the US and Canada. The VWF‐MAA was compared to Versiti Blood Research Institute (VBRI) and Local Center (LC) assigned VWD diagnosis. Results: Overall, 129/177 (72.9%) were correctly assigned as normal (non‐VWD), type 1, or variant VWD compared to the VBRI assigned diagnosis. VWF‐MAA assigned non‐VWD accurately in 29/57 (50.9%) samples, and type 1 VWD accurately in 93/110 (84.6%) samples. Considering LC diagnosis where there was agreement with VWF‐MAA and not VBRI diagnosis, type 1 VWD was accurate in 105/110 (95.5%) samples. Bland‐Altman analysis demonstrated good correlation between laboratory methods. VWD, types 2A, 2B, 1C VWD were also assigned by the VWF‐MAA. Conclusions: We demonstrate that the VWF‐MAA has utility in differentiating type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding. [ABSTRACT FROM AUTHOR]

Introduction: Regular, prophylactic intravenous (i.v.) FVIII can be challenging for some patients with haemophilia A. Subcutaneous (s.c.) FVIII administration could provide an alternative treatment option with greater convenience and without the complications associated with venous access. Aim: To assess the safety, pharmacokinetics (PK), bioavailability and efficacy of s.c. OCTA101, a recombinant FVIII with a recombinant von Willebrand factor fragment dimer. Methods: This was a single‐centre, prospective, open‐label, phase I/II study (NCT04046848). Previously treated male patients (≥18 years) with severe haemophilia A were eligible for the study. The primary objective of the study was to assess the safety (including immunogenicity) of OCTA101. Secondary objectives included assessments of PK, bioavailability, and the efficacy of prophylaxis. Results: Thirty patients were treated with OCTA101. FVIII inhibitors developed in five (16.7%) patients during daily prophylaxis with 40–60 IU/kg (three cases) and 12.5 IU/kg (two cases) OCTA101. The trial was therefore terminated. OCTA101 had a 2.5‐fold longer terminal half‐life compared with i.v. rFVIII, and bioavailability was 16.6%. Efficacy data at study termination indicated that daily prophylaxis with 40–60 IU/kg OCTA101 was efficacious in the absence of FVIII inhibitors. Conclusions: Despite promising PK and efficacy results, the trial was terminated due to the incidence of FVIII inhibitors. The occurrence of inhibitors at two dose levels suggests that their development may be related to the subcutaneous route of administration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Structural and chemical modifications of factor VIII (FVIII) products may influence their behaviour in FVIII activity assays. Hence, it is important to assess the performance of FVIII products in these assays. Efanesoctocog alfa is a new class of FVIII replacement therapy designed to provide both high sustained factor activity levels and prolonged plasma half‐life. Aim: Evaluate the accuracy of measuring efanesoctocog alfa FVIII activity in one‐stage clotting assays (OSAs) and chromogenic substrate assays (CSAs). Methods: Human plasma with no detectable FVIII activity was spiked with efanesoctocog alfa or a full‐length recombinant FVIII product comparator, octocog alfa, at nominal concentrations of 0.80 IU/mL, 0.20 IU/mL, or 0.05 IU/mL, based on labelled potency. Clinical haemostasis laboratories (N = 35) tested blinded samples using in‐house assays. Data from 51 OSAs (14 activated partial thromboplastin time [aPTT] reagents) and 42 CSAs (eight kits) were analyzed. Results: Efanesoctocog alfa activity was reliably (±25% of nominal activity) measured across all concentrations using OSAs with Actin FSL and multiple other aPTT reagents. Under‐ and overestimation of FVIII activity occurred with some reagents. No specific trend was observed for any class of aPTT activators. A two‐ to three‐fold overestimation was consistently observed using CSAs and the OSA with Actin FS as the aPTT reagent across evaluated concentrations. Conclusion: Under‐ or overestimation occurred with some specific OSAs and most CSAs, which has been previously observed with other modified FVIII replacement products. Efanesoctocog alfa FVIII activity was measured with acceptable accuracy and reliability using several OSA methods and commercial plasma standards. [ABSTRACT FROM AUTHOR]

Background: Hereditary thrombotic thrombocytopenia purpura (hTTP) is an ultra‐rare disorder resulting from an inherited deficiency of ADAMTS13, a von Willebrand factor (VWF)‐cleaving metalloprotease. The plasma‐derived factor VIII/VWF Koate (FVIII/VWFKoate) has been shown to contain ADAMTS13, allowing for its use to treat hTTP at home by the patient/caregiver. Aim: Based on prior demonstration of safe and effective use of FVIII/VWFKoate in eight patients with hTTP, we conducted a retrospective study to gather additional data regarding the use of FVIII/VWFKoate for hTTP. Methods: This was a multicentre, retrospective, noninterventional chart review of patients who had received FVIII/VWFKoate for the management of hTTP. Data collected included demographics, medical history, relevant family history, past use and tolerability of fresh frozen plasma, and details regarding FVIII/VWFKoate therapy. Results: The cohort included 11 patients (seven males, four females) with hTTP, ranging in age at study entry from 2 to 28 years. The average duration of FVIII/VWFKoate therapy was 4.8 years (range, 0.5–6.5 years). Among nine patients using FVIII/VWFKoate as prophylaxis, the normalized annual rate of breakthrough TTP episodes ranged from 0.2 to 1.1 episodes/year. All nine patients who received FVIII/VWFKoate prophylaxis had thrombocytopenia recorded at baseline, while eight (88.9%) did not have thrombocytopenia after using FVIII/VWFKoate. There was one AE (unspecified) attributed to FVIII/VWFKoate. Conclusion: These data suggest that FVIII/VWFKoate is a safe and well‐tolerated source of the missing ADAMTS13 enzyme in patients with hTTP, producing a marked reduction in thrombocytopenia prevalence, low frequency of TTP episodes, and with the added benefit of self‐ or caregiver‐administration. [ABSTRACT FROM AUTHOR]

Introduction and aims: Mim8 is a next generation bispecific antibody developed for the treatment of haemophilia A (HA). Mim8 has an increased potency compared to first generation molecules. The impact on Mim8 on non‐FVIII measuring haemostasis assays was assessed in plasma containing Mim8. Methods: Congenital severe HA plasma was spiked with increasing concentrations of Mim8 (0–20 μg/mL). 28 routine and specialist haemostasis assays were used to measure activities. These included tests for prothrombin time (PT), fibrinogen, thrombin, D‐dimer, anti‐Xa, heparin induced thrombocytopenia (HIT), clotting factors II–XII, factor XIII, von Willebrand factor (VWF), thrombophilia and DRVVT. Results and conclusions: Less than 10 % difference was calculated between plasma without Mim8 and plasma spiked to 15 μg/mL Mim8 in all assays except thrombin time (−10.5%), APTT‐based factor IX, XI and XII, Werfen VWF:RCo (10.6%) and Siemens LA1 (−26.4%) and LA2 (−16.9%). At the expected therapeutic steady state levels of Mim8 (5–8 μg/mL), less than 10% difference was calculated for thrombin time and Werfen VWF:RCo. APTT‐based assays of FIX, XI and XII are significantly elevated in the presence of Mim8 and should not be performed. A chromogenic FIX assay could be used to accurately measure FIX activity in the presence of Mim8. There was some interference in the DRVVT method we used so local assessment of other DRVVT methods is advised. Differences in all other tests would not be predicted to affect patient management. [ABSTRACT FROM AUTHOR]

Introduction: Diagnosing von Willebrand Disease (VWD) in adolescent females is challenging as menstruation and physiologic stress elevate von Willebrand factor (VWF) laboratory values. Aim: To develop a VWF prediction model for adolescent females based on initial VWF results. Methods: We identified female patients aged 9 to 21 years with any VWF laboratory test over a 5‐year period (2017–2021) at any Texas Children's Hospital facility. Patient demographics, VWF testing, haemoglobin concentration, serum ferritin and site of clinical testing were collected (initial and subsequent laboratory evaluations). A Bayesian linear regression model was developed. Prediction intervals were analysed to identify thresholds for patients in whom repeat testing was unlikely to identify low VWF levels (< 50%), consistent with VWD. Results: A total of 6125 adolescent females underwent VWF testing; 1204 (19.7%) had repeat testing. Based on the prediction model, initial VWF antigen values of 80%, 90% and ≥100% carried a 92.6%, 96.6% and ≥98.0% probability of having repeat normal repeat VWF values, respectively. Subjects assessed in outpatient adolescent medicine or gynaecology clinics were more likely to have low VWF values compared to those assessed in the acute care setting (p <.001). Median presenting haemoglobin and serum ferritin were 12.4 g/dL and 13 ng/mL, respectively and were similar in those with normal versus low VWF antigen values. Conclusion: Repeat testing in adolescent females whose initial VWF antigen values are ≥90% is unlikely to identify additional patients with VWD. Iron deficiency screening should be performed in all adolescent females. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Recent guidelines for von Willebrand Disease (VWD) highlighted the challenges in diagnosis and management. Identifying the number of persons with VWD (PwVWD) internationally will help target support to aid diagnosis of PwVWD. Aim: To examine international registration rates of PwVWD, the influence of income status, geographical region and the age and sex profile. Cumulatively, these data will be used to inform future strategy from the World Federation of Haemophilia (WFH) to address unmet clinical and research needs. Methods: Data from the 2018/2019 WFH Annual Global Survey (AGS) were analysed, providing a global perspective on VWD registration. Results: Registration rates are lowest in South Asia (0.6/million population) and highest in Europe/Central Asia (50.9/million population, 0.005%), but below the expected prevalence rate (0.1%). National economic status impacted VWD registration rates, reflecting variation in access to optimal healthcare infrastructure. Females represented the majority of PwVWD globally, however, in low‐income countries (LIC) males predominated. Age profile varied, with markedly higher rates of paediatric registrations in North America, Middle East and North Africa and South Asia. Rates of type 3 VWD registrations were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings. Conclusion: Significant variation in registration rates of PwVWD exist internationally and is influenced by income status and the presence of HTC networks. Improved understanding of registration rates will enable targeting of advocacy to improve awareness, diagnosis and support for PwVWD internationally. Key points: Registration rates of People with Von Willebrand Disease (PwVWD) vary internationally and are influenced by national income statusAlthough females represent the majority of PwVWD globally, in low income countries (LIC) males predominated, possibly related to stigma surrounding gynaecological bleeding.Rates of type 3 VWD registration were significantly influenced by economic status (81% of VWD diagnoses in LIC), suggesting only the most severe VWD types are diagnosed in resource limited settings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Gene variation in receptors for circulating factor VIII (FVIII) is candidate to explain the large inter‐patient variability of infused FVIII pharmacokinetics (PK) in haemophilia A (HA). Aim: To compare in an Italian HA cohort (n = 26) the influence on FVIII PK of genetic components in four von Willebrand factor (VWF)/FVIII receptors. Methods: Genotypes of low‐density lipoprotein receptor (LDLR), asialoglycoprotein receptor minor subunit (ASGR2), family 4 member M (CLEC4M), stabilin2 (STAB2) and ABO blood‐group, and VWF:Ag levels were included as independent variables in linear regression analyses of two‐compartment model (TCM) – standard half‐life (SHL) FVIII PK parameters. Results: In the initial FVIII distribution phase, the STAB2 rs4981022 AA, ASGR2 rs2289645 TT and LDLR rs688 TT genotypes may contribute to increase Cmax, and prolong or shorten AlphaHL. In the elimination phase, a shorter BetaHL was associated with the CLEC4M rs868875 GG (beta‐coefficient.366, p =.025) and ASGR2 rs2289645 TC (beta‐coefficient.456, p =.006) genotypes, which also showed shorter mean residence time (MRT) than TT genotypes (p =.021). The alpha and beta phase effects were independent of ABO and VWF:Ag levels at baseline. The association of the LDLR rs2228671 genotypes with clearance was independent of ABO (beta‐coefficient −.363, p =.035) but not of other receptors or VWF:Ag, which may point out multiple and competing interactions. Conclusions: With the limitation of the small number of HA patients, these observations highlight multiple genetic components acting in distinct phases of FVIII PK and contributing to explain FVIII PK variability. This analysis provides candidates for genotype‐based, individual tailoring of FVIII substitutive treatment. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about the clinical characteristics of von Willebrand disease (VWD) patients in China, the impact of Covid‐19 on them and their genetic mutation. Aim: To describe the clinical characteristics of a group of VWD patients in China, the impact of Covid‐19 on them and their genetic mutation. Methods: An online survey using a self‐designed questionnaire was conducted among patients within a WeChat group of VWD patients in China. Data were analysed using t‐test, the Chi‐square test, Fisher's exact test and rank sum test. Results: Data from a total of 96 patients were collected. Several important findings are yielded. Above all, type 3 patients accounted for over half of the surveyed patients. Secondly, a surprising rate (>40%) of patients had experience of being misdiagnosed. Thirdly, treatment regimens were dominated by cryoprecipitate, blood‐derived FVIII and plasma, and only a small percentage of patients received prophylaxis. Fourthly, we identified 17 new von Willebrand factor (VWF) mutant genes which merit further investigation. Additionally, Covid‐19 was found to pose some challenges for the patients. Conclusion: In China, the high rates of type 3 patients and misdiagnosis suggest that most of the VWD patients may never be diagnosed in China. When it comes to diagnosis and treatment, there is a large gap between developing countries like China and developed countries. [ABSTRACT FROM AUTHOR]

Introduction: Majority of haemophilia A patients in our comprehensive care centre have switched from standard half‐life (SHL) to extended half‐life (EHL) FVIII products in a short time. Aim: We compared the clinical and laboratory outcomes between SHL and EHL FVIII prophylaxis in product switchers. Methods: This is a retrospective inception cohort of all adult haemophilia A patients switched to EHL (rFVIIIFc or rFVIII‐PEG) prophylaxis in our centre. Dosing, product utilization, annualized bleed rates (ABR), treatment regimen and pharmacokinetics by Web Accessible Population Pharmacokinetic Service (WAPPS)‐Hemo were compared between SHL and EHL. Results: We included 38 patients, whose median age was 38 years (range 17–75). Median FVIII dose was 23 IU/kg for SHL versus 25 IU/kg for EHL. After switching, weekly infusions decreased by 29% from median 2.8 (every 2.5 days) to 2.0 (every 3.5 days) (P = <.001) and factor consumption for prophylaxis by 17% from 60 to 50 IU/kg/week (P = <.001). Weekly infusions decreased in 71% and FVIII utilization in 55% of patients. ABR remained low (1.0 for SHL and.5 for EHL, respectively). In pharmacokinetics, the half‐life of FVIII increased from median 13 to 21 h after switching. Times above.01 and.03 IU/ml improved from 85 to 131 h and from 65 to 106 h. Half‐lives of the SHL products and von Willebrand factor levels predicted half‐lives with the EHL products. Conclusions: Our cohort study confirms the successful experience of switching to EHL FVIII products, with decreased infusion frequency, factor consumption and excellent clinical efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Presence of von Willebrand factor (VWF) in FVIII concentrates offers protection against neutralizing inhibitors in haemophilia A (HA). Whether this protection is more evident in plasma‐derived (pd) FVIII/VWF or recombinant (r) FVIII concentrates remains controversial. Aim: We investigated the protection exerted by VWF against FVIII inhibitors in an in vivo mouse model of HA exposed to pdFVIII/VWF or to various rFVIII concentrates. Methods: Haemophilia A mice received the different FVIII concentrates after administration of vehicle or an inhibitory IgG purified from a commercial pool of HA plasma with inhibitors and FVIII:C recoveries were measured. Furthermore, using a novel clinically oriented ex vivo approach, Bethesda inhibitory activities (BU) of a commercial pool of HA plasma with inhibitors were assessed using normal plasma, or plasma from severe HA patients, without inhibitors, after treatment with the same concentrates. Results: in vivo studies showed that pdFVIII/VWF offers markedly higher protection against inhibitors when compared with any of the FVIII products without VWF. More importantly, in the ex vivo studies, plasma from patients treated with pdFVIII/VWF showed higher protection against inhibitors (P values ranging.05‐.001) in comparison with that observed in plasma from patients who received FVIII products without VWF, regardless of the type of product evaluated. Conclusion: Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates. [ABSTRACT FROM AUTHOR]

Introduction: Type 1 and type 3 von Willebrand disease (VWD) are caused by partial and complete, quantitative deficiency of von Willebrand factor (VWF), respectively, and factor (F)VIII/VWF complex concentrates are used for haemostatic treatment. Emicizumab, mimics activated FVIII, reduces bleeding in haemophilia A patients. The effects of emicizumab on haemostasis in both types of VWD remain to be fully established, however. Aim: To examine the effects of emicizumab on thrombogenesis in type 1 and type 3 VWD. Patients/Methods: Perfusion chamber experiments under high shear conditions (2500 s–1) combined with immunostaining were performed using whole blood samples from patients with type 1 (VWF:Ag 25 U/dl) and type 3 VWD (<1.0 U/dl). Results: The addition of FVIII (1 U/ml) to type 1 blood did not affect thrombus formation, whilst supplementation with VWF (1.6 U/ml) or FVIII/VWF (1 U/ml/1.6 U/ml) enhanced thrombogenesis to a similar extent. FVIII/VWF promoted thrombus formation significantly more than VWF alone, however, in type 3 blood. Emicizumab (100 μg/ml) augmented thrombus formation in type 3 blood compared to FVIII, and this potency seemed to be somewhat greater than that of VWF. Surface coverage of formed thrombus in type 3 VWD was less than that in type 1 VWD, but thrombus height was comparable in both. The addition of emicizumab to type 3 blood enhanced thrombin generation and fibrin formation compared to control IgG. Conclusion: Emicizumab promoted mechanisms of thrombus formation in vitro in type 3 and type 1 VWD, suggesting the possibility of alternative therapeutic protocols in these patients. [ABSTRACT FROM AUTHOR]

Introduction: Desmopressin can be used to prevent bleeding in von Willebrand disease (VWD), but the relationship between desmopressin and von Willebrand factor activity (VWF:Act) has yet to be quantified. Aim: To quantify the relationship between desmopressin dose, its plasma concentration and the VWF:Act response in type 1 VWD patients. Methods: Forty‐seven VWD patients (median age 25 years, IQR: 19–37; median body weight 71 kg, IQR: 59–86) received an IV desmopressin dose of.3 mcg/kg. In total, 177 blood samples were available for analysis. We developed an integrated population pharmacokinetic‐pharmacodynamic (PK‐PD) model using nonlinear mixed effect modelling. Subsequently, we performed Monte Carlo simulations to investigate the efficacy of the current dosing regimen. Results: A one‐compartment PK model best described the time profile of the desmopressin concentrations. In the PD turnover model, the relationship between desmopressin plasma concentration and release of VWF:Act from the vascular endothelium was best described with an Emax model. Typically, VWF:Act increased 452% with an EC50 of.174 ng/ml. Simulations demonstrated that after.3 mcg/kg desmopressin intravenously, >90% patients with a VWF:Act baseline of ≥.20 IU/mL attain a VWF:Act >.5 IU/ml up to ≥4 h after administration. A capped dose of 30 mcg was sufficient in patients weighing over 100 kg. Conclusion: The relationship between desmopressin and VWF:Act was quantified in a PK‐PD model. The simulations provide evidence that recently published international guidelines advising an intravenous desmopressin dose of.3 mcg/kg with a capped dose of 30 mcg > 100 kg gives a sufficient desmopressin response. [ABSTRACT FROM AUTHOR]

Introduction: The sixth Åland Islands Conference on von Willebrand disease (VWD) on the Åland Islands, Finland, was held from 20 to 22 September 2018. Aim: The meeting brought together experts in the field of VWD from around the world to share the latest advances and knowledge in VWD. Results and discussion: The topics covered both clinical aspects of disease management, and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology, diagnosis and treatment of VWD in different countries, management of children with VWD, bleeding control during surgery, specific considerations for the management of type 3 VWD and bleeding control in women with VWD. Current approaches to the management of acquired von Willebrand syndrome were also discussed. Despite significant advances in the understanding and therapeutic options for VWD, there remain many challenges to be overcome in order to optimise patient care. In comparison with haemophilia A, there are very few registries of VWD patients, which would be a valuable source of data on the condition and its management. VWD is still underdiagnosed, and many patients suffer recurrent or severe bleeding that could be prevented. Awareness of VWD among healthcare practitioners, including non‐haematologists, should be improved to allow timely diagnosis and intervention. Diagnosis remains challenging, and the development of fast, simple assays may help to facilitate accurate and rapid diagnosis of VWD. [ABSTRACT FROM AUTHOR]

The first three recommendations, based on the use of a validated bleeding assessment tool[7] (BAT) for diagnosis, endorsed this mechanism only for patients with a low probability of VWD (e.g., primary care [PC] setting). Keywords: 2021 guidelines; diagnosis; survey; von Willebrand disease; von Willebrand factor EN 2021 guidelines diagnosis survey von Willebrand disease von Willebrand factor 925 927 3 05/19/23 20230501 NES 230501 Von Willebrand disease (VWD) is the coagulopathy with more under-, over- and misdiagnosis due to its challenging diagnosis.[1] To improve care for people with VWD, in 2021 the American Society of Haematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Haemophilia Foundation (NHF) and the World Federation of Haemophilia (WFH) published guidelines on the diagnosis[2] and management[3] of VWD. On the other hand, in the case of a patient with a normal bleeding scale result or no assessment scales performed in the centre, 71% of the specialist would not expand the patient study to rule out VWD, while the remaining 29% would directly perform blood laboratory tests. [Extracted from the article]

Summary: Progress in both basic and translational research into the molecular mechanisms of VWD can be seen in multiple fields. Genetics of VWD: In the past several decades, knowledge of the underlying pathogenesis of von Willebrand disease (VWD) has increased tremendously, thanks in no small part to detailed genetic mapping of the von Willebrand Factor (VWF) gene and advances in genetic and bioinformatic technology. However, these advances do not always easily translate into improved management for patients with VWD and low‐VWF levels. VWD and pregnancy: For example, the treatment of pregnant women with VWD both pre‐ and postpartum can be complicated. While knowledge of the VWF genotype at some amino acid positions can aid in knowledge of who may be at increased risk of thrombocytopenia or insufficient increase in VWF levels during pregnancy, in many cases, VWF levels and bleeding severity is highly heterogeneous, making monitoring recommended during pregnancy to optimize treatment strategies. VWF and COVID‐19: New challenges related to the consequences of dysregulation of hemostasis continue to be discovered. The ongoing COVID‐19 pandemic has highlighted that VWF has additional biological roles in the regulation of inflammatory disorders and angiogenesis, disruption of which may contribute to COVID‐19 induced vasculopathy. Increased endothelial cell activation and Weibel‐Palade body exocytosis in severe COVID‐19 lead to markedly increased plasma VWF levels. Coupled with impairment of normal ADAMTS13 multimer regulation, these data suggest a role for VWF in the pathogenesis underlying pulmonary microvascular angiopathy in severe COVID‐19. Conclusion: With the increased affordability and availability of next‐generation sequencing techniques, as well as a push towards a multi‐omic approach and personalized medicine in human genetics, there is hope that translational research will improve VWD patient outcomes. [ABSTRACT FROM AUTHOR]

Deficiency or dysfunction of von Willebrand factor (VWF) is associated with a bleeding disorder known as von Willebrand disease (VWD). The clinical manifestations of VWD are heterogeneous, and are in part dictated by the structural or functional defects of VWF. The tools to control bleeding in VWD are dominated by VWF concentrates, desmopressin and antifibrinolytic therapy. In view of these treatments being considered as effective, it is surprising that quality‐of‐life studies consistently demonstrate a significant mental and physical burden in VWD patients, particularly in women. Apparently, the current weaponry to support the management of VWD is insufficient to fully address the needs of the patients. It is important therefore to continue to search for innovative treatment options which could better serve the VWD patients. In this short review, two of such options are discussed in more detail: emicizumab to correct for the deficiency of factor VIII (FVIII), and the pegylated aptamer BT200 to increase endogenous levels of the VWF/FVIII complex. [ABSTRACT FROM AUTHOR]

Background: Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long‐term prophylaxis. Aim: Systematically summarize the evidence on the clinical outcomes of secondary long‐term prophylaxis in patients with VWD and severe recurrent bleedings. Methods: We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long‐term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non‐Randomized Studies of interventions (ROBINS‐I) tool to assess the quality of the included studies. We conducted random‐effects meta‐analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR],.24; 95% confidence interval [CI],.17–.35; low certainty evidence), and of epistaxis (RR,.38; 95%CI,.21–.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI.12–59.57; low certainty). Evidence from four before‐and‐after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR.34; 95%CI,.25–.46; very low certainty evidence). Conclusion: VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits. [ABSTRACT FROM AUTHOR]

Introduction: von Willebrand disease (VWD) is the common bleeding disorder with a clinically relevant bleeding prevalence of 1:10,000. von Willebrand disease patients lack both von Willebrand factor (VWF) and factor VIII (FVIII), which are critical for normal haemostasis. The conventional treatment for VWD includes desmopressin and replacement therapy with plasma derived FVIII with VWF concentrates or recombinant VWF. Development of alloantibodies is a rare occurrence, there is a paucity in the literature of treatment modalities in these patients. Not many reports are available in literature on the efficacy of emicizumab in VWD patients with or without alloantibodies to VWF. Aim: To do systematic review of literature on emicizumab in VWD and report our experience of emicizumab in two patients of VWD Methods: We used electronic search engines till May 2021 in 'Google scholar' and 'PubMed', to collect the case reports or case series on use of emicizumab for management of VWD. Two of our severe VWD patients were successfully treated with emicizumab. A systematic review was performed and the results discussed. Results: The electronic search revealed six case reports using emicizumab for treatment of VWD. Two were in vitro studies and four in patients with VWD type 3 disease. In vitro studies and in VWD patients on emicizumab, showed improvement in thrombin generation and fibrin formation. Among four patients, three had alloantibodies to VWD and one was negative. All these patients were treated with emicizumab for 6–12 m. After starting emicizumab, none of them had spontaneous bleeding requiring treatment. During treatment with emicizumab, one patient had trauma‐associated soft tissue hematoma, which was treated with rFVIIa and another patient had bleeding following dental exfoliation treated with Humate P. We treated two of our VWD patients one with and one without inhibitors with emicizumab after failure of other therapies. Both the patients showed marked improvement and continued to remain well and free of bleeding episodes. None of the patients had any thrombosis or thrombotic microangiopathy (TMA) during treatment with emicizumab. Conclusion: In conclusion, this review supports the safety and efficacy of emicizumab in type 3 VWD patients with or without alloantibodies. Further large studies are required to confirm the safety and efficacy of emicizumab in VWD. [ABSTRACT FROM AUTHOR]

Thirdly, a high proportion of NASCOLA participants (32%) utilise the VWF:Ab assay, this being one of only two FDA-cleared VWF activity assays (the other being VWF:RCo),6 whereas very few RCPAQAP participants (1%) do so (Table 1). VWF:GPIbR (LIA)4 (4)11 (12)14 (15)2c. VWF:GPIbR (CLIA)0 (0)15 (16)14 (15)2c. VWF:GPIbM (LIA)17 (17)30 (32)39 (41)2d. VWF:Ag (ELISA)3 (3)4 (4)1 (1)1c. VWF:Ag (CLIA)0 (0)8 (8)8 (8)2a. VWF:RCo38 (39)33 (35)27 (28)2b. [Extracted from the article]

Introduction: The large interpatient variability in the pharmacokinetic (PK) parameters of recombinant Factor VIII (rFVIII) observed in haemophilia A hinders efficient and cost‐beneficial prophylactic regimen initiation. Identification of factors influencing the PK of rFVIII may shed more light on personalised treatment. Aim: This study aimed to develop a population PK model in the Taiwanese haemophilia A and evaluate the current national health insurance (NHI) reimbursement guidelines of Taiwan for haemophilia treatment. Methods: A population PK analysis was established based on 69 Taiwanese with moderate or severe haemophilia A. A nonlinear mixed‐effects modelling (NONMEM®) was used to estimate PK parameters and their variabilities. A Monte Carlo simulation was performed to evaluate different prophylactic regimens. Results: A two‐compartment model with first‐order elimination best described the rFVIII data. Weight‐based allometric scaling was related to clearance and central volume of distribution. Blood type and baseline von Willebrand factor (VWF) were significant covariates for clearance. For single dose simulations, a time achieving target level (> 1 IU/dL) was associated with increasing rFVIII dose and VWF level. The multiple dose simulations showed that > 96.4% of patients with high VWF level (> 200%) had predicted trough level > 1 IU/dL for all dosing regimens (15‐40 IU/kg, two to three times weekly). However, for twice weekly dosing, lower percentage (47.62‐62.20%) of patients with blood group O and low VWF level (< 50%) achieved a predicted trough level > 1 IU/dL. Conclusion: The population PK of rFVIII was successfully developed. Dose adjustment based on blood type and VWF level should be considered. [ABSTRACT FROM AUTHOR]

Background: von Willebrand factor propeptide (VWFpp) plays an important role in VWF multimerization and storage. VWFpp mutations have been previously associated with types 1, 3 and 2A/IIC von Willebrand disease (VWD). Aims: To characterize the novel p.Thr274Pro variant identified in two unrelated type 1 VWD patients. Methods: Phenotype tests were performed to evaluate patients' plasma and platelets following the current ISTH‐SSC guidelines. Molecular analysis was performed using next‐generation sequencing. The pcDNA3.1‐VWF‐WT and mutant pcDNA3.1‐VWF‐Thr274Pro expression vectors were transiently transfected into HEK293 cells to evaluate recombinant (r)VWF constitutive and regulated secretion. For the latter, the transfected cells were stimulated with phorbol‐12‐myristate‐13‐acetate. Immunofluorescence staining was performed to assess the localization of WT‐rVWF and Thr274Pro‐rVWF in endoplasmic reticulum, lysosomes, cis‐/trans‐Golgi and pseudo‐Weibel Palade bodies. Results: Biochemical characterization of patients' plasma samples indicated a type 1 VWD diagnosis. Both patients were heterozygous for the p.Thr274Pro variant. Hybrid Thr274Pro/WT‐rVWF showed a secretion reduction of 36±4% according to patients' plasma VWF:Ag levels, whereas Thr274Pro‐rVWF secretion was strongly impaired (21±2%). The amount of rVWF in cell lysates was nearly normal for both Thr274P (62±17%) and Thr274Pro/WT‐rVWF (72±23%). The regulated secretion was impaired for Thr274Pro/WT‐rVWF, whereas Thr274Pro‐rVWF was not released at all. Immunofluorescence staining revealed no particular differences between WT and Thr274Pro‐rVWF, although Thr274Pro‐rVWF showed less pseudo‐Weibel Palade bodies with a rounder shape than WT‐rVWF. Conclusions: The novel p.Thr274Pro mutation has a dominant effect and it is responsible of patients' type 1 VWD phenotype through a combined mechanism of reduced synthesis, impaired secretion and multimerization. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is associated with endothelial dysfunction, haemostatic and fibrinolytic disturbances, however the impact of obesity on von Willebrand factor (VWF) is unclear. Aim: The aim of this study was to test our hypothesis that the prevalence of obesity is higher among participants with low VWF (LVWF) compared to type 1 von Willebrand disease (T1VWD). Methods: A retrospective review of the ATHNdataset as of March 2018 was performed. Participants were categorized as T1VWD if their VWF ristocetin cofactor activity was 30 IU/dL and LVWF if the values were 30–50 IU/dL, and by the NIH definitions for body mass index (BMI) for adult participants (≥ 18 years of age) or BMI z‐score for paediatric participants (< 18 years). Results: The prevalence of obesity was not significantly different between adults with T1VWD (n = 186) and LVWF (n = 362) (32% vs 36%; p =.345). The mean factor VIII (FVIII) increased with increasing BMIs in both groups. In the paediatric cohort (T1VWD, n = 583; LVWF, n = 1702), there was no difference in the prevalence of obesity, but BMI was positively correlated with mean FVIII (p <.001). Children < 10 years were 27.6% more likely to be diagnosed with T1VWD compared to > 10 years. Conclusion: Among participants in the ATHNdataset, the prevalence of obesity was similar among those with LVWF and T1VWD. However, higher BMI levels were associated with elevated FVIII. Further research is needed to evaluate the impact of obesity on bleeding phenotype and treatment practices. [ABSTRACT FROM AUTHOR]

Introduction: Immune Tolerance Induction (ITI) is the first‐choice therapy to eradicate Factor VIII (FVIII) neutralizing antibodies in patients with haemophilia A (HA). There is limited published data on ITI from East Mediterranean countries. Aim: To assess the effectiveness of a low‐dose ITI regimen to eradicate FVIII neutralizing antibodies in children with severe HA and high‐titre inhibitors. Methods: A prospective, single‐arm study was conducted in children with HA (FVIII < 1 IU/dl), high‐titre inhibitors and poor prognostic factors for successful ITI. Patients were treated with ∼50 IU/kg plasma‐derived FVIII containing von Willebrand factor (pdFVIII/VWF) concentrate (Koate‐DVI, Grifols) three times a week. Time to achieve tolerance, total and partial success were analysed after ITI. Annual bleeding rate (ABR), number of target joints, FVIII recovery and school absence were compared before and after ITI. Results: Twenty patients with median (range) age of 6.2 (3–12) years and pre‐ITI inhibitor titre of 36.5 (12–169) BU were enrolled. ITI lasted ≤12 months (early tolerization) in 45% of patients. Median follow‐up was 12 months (3–22) and total response rate was 80% (60% total success; 20% partial success). Patients with two and three poor prognosis factors achieved overall success rate of 60% and 50%, respectively. ABR, target joints and school absence were reduced after ITI by 60%, 50% and 44.1%, respectively. In successful ITI tolerized patients, FVIII recovery was 90 (60–100)%. Conclusion: A low‐dose ITI therapy using a pdFVIII/VWF concentrate achieved at least partial tolerance in 80% of patients, and reduced annual bleeds in children with high inhibitor titres and at least one poor prognosis factor for ITI treatment success. [ABSTRACT FROM AUTHOR]

Von Willebrand's disease (VWD) is the most common hereditary blood-clotting disorder caused by a deficiency of von Willebrand Factor (VWF) and characterized by a defective platelet adhesion and aggregation.1 Replacement therapy with plasma-derived von Willebrand factor-containing factor VIII concentrate (pdVWF/FVIII) is indicated as treatment of choice for surgical and invasive procedures in adult and paediatric patients with severe VWD, when desmopressin (DDAVP) is either ineffective or contraindicated.2,3 The presence of functional VWF is estimated by the VWF:RCo/FVIII:C ratio and may vary among pdVWF/FVIII concentrates.4 Fanhdi SP ® sp (Instituto Grifols S.A., Barcelona, Spain) is a pdVWF/FVIII concentrate characterized by a high content in VWF, with a VWF:RCo/FVIII:C ratio of 1.58±.20.5 Clinical efficacy of Fanhdi SP ® sp has been assessed extensively in VWD patients, to prevent recurrent bleedings in the management of surgery.5-7 However, the available data is retrospective and the only prospective study supporting its use reported interim results only.8 The preliminary interim analysis showed that Fanhdi SP ® sp could be successfully used as a replacement therapy in VWD patients requiring prophylactic treatment during surgeries.8 We report here the final efficacy and safety analysis of this multicentre prospective clinical trial. During the post-surgery period, minor surgeries were treated with 30.6 (19.6-41.7) IU/kg FVIII and 43.6 (25.6-61.7) IU/kg VWF:RCo; and major surgeries with 245.0 (12.5-520.7) IU/kg FVIII and 416.9 (24.6-924.1) IU/kg VWF:RCo. Efficacy and safety evaluation of Fanhdi®, a plasma-derived factor VIII/ von Willebrand factor concentrate, in Von Willebrand's disease patients undergoing surgery or invasive procedures: A prospective clinical study Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P). [Extracted from the article]

Introduction: Type 2N von Willebrand disease (VWD) is characterized by a decreased affinity of von Willebrand factor (VWF) for factor VIII (FVIII). Abnormal binding of FVIII to VWF (VWF:FVIIIB), results in low FVIII plasma levels, which can lead to a misdiagnosis of mild haemophilia A. Accurate diagnosis of type 2N VWD is essential for appropriate genetic counselling and therapy. This disease can be distinguished from haemophilia A by in vitro assays (measurement VWF:FVIIIB activity) and/or genetic analysis. Aim: To identify the current challenges in the diagnosis and treatment of this type of VWD and provide an in‐depth description of the phenotypes and mutations identified. Results: Twenty‐eight patients had at least one type 2N mutation, and 13 of these had a type 2N mutation combined with other variations. Three type 2N mutations were detected: p.Arg816Trp, p.Arg854Gln, and p.Arg763Ser. Two of these are the most frequently described mutations worldwide. This mutational spectrum differs from the broad spectrum seen in neighbouring France, where at least eight distinct 2N mutations have been found. In the PCM‐EVW‐ES cohort, 11 asymptomatic type 2N carriers with borderline FVIII plasma levels would probably have been excluded if the evaluation had been based on clinical and laboratory data only. Likewise, three patients with a severe phenotype would have been classified as homozygous for a 2N mutation if only the phenotype study had been performed. Conclusion: The high detection yield and affordability of next‐generation sequencing support the use of this technology as a first‐line diagnostic tool in this setting. [ABSTRACT FROM AUTHOR]

Background: Laboratory diagnosis of von Willebrand Disease (VWD) is complex. Reliance on laboratory testing can be problematic as different VWD screening panels, assays and methodologies can produce analytic variability in test results. Objectives: To compare the degree of imprecision among the VWD assays and within the platelet binding activity (PBA) assays, to determine the consensus among the VWD assays for correct classification of sample results, and to determine consensus among laboratories' von Willebrand factor (VWF) multimer interpretations and final interpretations of the VWD panels. Patients/Methods: Proficiency testing results from the North American Specialized Coagulation Laboratory Association (NASCOLA) submitted by laboratories from 2010 to 2019 for all normal, type (T) 1 VWD and T2 VWD samples were analysed. Results and Conclusions: Imprecision was lowest for VWF antigen and highest for collagen binding activity (CBA) with median coefficient of variation (CV) of 12% (interquartile range (IQR) 7%) and 23% (IQR 21%) respectively. Within the VWF PBA assays, the gain‐of‐function mutant GP1b binding (VWF: GP1bM) methods had the least imprecision (CV 9%, IQR 10%). All assays, including the various PBA methods had excellent consensus. The majority of laboratories agreed that normal (median consensus‐82%, IQR 16%) and T1 VWD (median consensus‐100%, IQR 9%) samples had normal multimer distribution. Consensus among laboratories for final interpretations was excellent for normal samples (median 81%, IQR 8%), good for T1 VWD samples (median 59%, IQR 9%), and fair for T2 VWD samples (median 44%, IQR 21%). Consensus on final interpretation decreased as sample complexity increased. [ABSTRACT FROM AUTHOR]

Background: Patients with inherited haemorrhagic disorders may bleed during surgery. No questionnaire on bleeding diathesis has been yet validated for the preoperative period and current guidelines provide conflicting recommendations. Aim: We aimed to assess if preoperative assessment with ISTH‐BAT (International Society on Thrombosis and Haemostasis Bleeding Assesment Tool) and laboratory screening tests is useful to identify mild previously undiagnosed bleeding disorders (BDs) and to predict bleeding complications in selected patients undergoing elective surgery. Methods: Consecutive patients undergoing elective surgery received ISTH‐BAT evaluation and laboratory screening for platelet count, Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT). Subjects with an abnormal ISTH‐BAT and/or laboratory results underwent further testing, and they were compared with a 1:1 random gender‐, age‐ and type of surgery‐ matched control group. Results: Overall, 1502 consecutive surgical patients (1186 adults, 316 children) were enrolled. Of these, 83 (5.5%, 95% confidence interval 4.4‐6.8) patients (37 adults and 46 children) had an abnormal ISTH‐BAT, and/or prolonged PT and/or prolonged aPTT and/or low platelet count; of them, one subject had low von Willebrand factor level, three Factor XII deficiency and four anticardiolipin and/or antiB2GPI antibodies. No major bleeding was reported in these 83 patients and their controls. Conclusion: ISTH‐BAT and laboratory screening tests do not accurately detect mild BDs in selected patients undergoing elective surgery. [ABSTRACT FROM AUTHOR]

Background: Antibodies inhibiting von Willebrand factor (VWF) develop in a subset of patients with type 3 von Willebrand disease (VWD3) and may be detected by their inhibition of ristocetin cofactor activity (VWF:RCo). Some also inhibit factor VIII activity (VIII:C). Aim: To describe monitoring of ten VWD3 patients for VWF inhibitors using a quantitative assay. Methods: VWF inhibitor was measured by comparing VWF:RCo activity of a mix of patient and pooled normal plasma (PNP) with a mix of buffer and PNP, using agglutination of fixed normal platelets in microtiter plates or lyophilized platelets in an aggregometer. VIII:C inhibitor was measured by Bethesda assay. Preanalytical heat treatment of patient plasma was used during treatment episodes. Results: Four of 10 patients monitored developed VWF inhibitors, two detected during bleeding episodes refractory to treatment and two on routine screening. Data from the first five patients were used to establish an arbitrary unit, VWU, defined as the amount of inhibitor per millilitre of patient plasma inactivating 25% of the activity of 1 mL of PNP. In three of four patients, both VWF:RCo and VIIII:C were inhibited at some time points, although VIII:C inhibition sometimes disappeared. In one patient, no VIII:C inhibition was seen. Two patients remained inhibitor positive more than 15 years after inhibitor detection, one became negative following immune tolerance induction, and one was deceased. Conclusions: VWF inhibitors can be quantitatively monitored in VWD3 patients. Preanalytical heat treatment may be required for their detection post infusion. [ABSTRACT FROM AUTHOR]

Although this patient did show a response to IV DDAVP, the medical team preferred to use von Willebrand factor concentrate due to her seizure disorder and length of therapy. Keywords: factor X deficiency; neurosurgery; rasmussen encephalitis; rasmussen syndrome; von Willebrand factor EN factor X deficiency neurosurgery rasmussen encephalitis rasmussen syndrome von Willebrand factor e513 e516 4 07/21/21 20210701 NES 210701 Our patient, a 9-year-old female, was initially seen in haematology clinic at 5 years of age for bruising, epistaxis and gum bleeding. The most common bleeding symptom for all levels of severity is epistaxis.3 Women with varying degrees of severity may also experience menorrhagia.5 Some patients with mild deficiency bleed only after haemostatic challenges such as surgery or trauma.3 Such was the case in the patient discussed above. [Extracted from the article]

Background: Kovaltry (BAY81‐8973) is an unmodified full‐length factor VIII (FVIII) concentrate that enhances the pharmacokinetic (PK) profiles as compared to some other standard half‐life time FVIII concentrates. However, the PK of Kovaltry in haemophiliac patients aged <12 years has not been reported previously. Aim: To investigate the pharmacokinetics and clinical outcomes of Kovaltry in 35 paediatric patients aged <12 years. Methods: A total of 35 boys with severe haemophilia A were enrolled from August 2019 to May 2020 in Beijing Children's Hospital. After 72‐hour washout, PK tests were performed post‐infusion of 50 IU/kg Kovaltry in a five‐timepoint assay. WinNonlin software was used to generate individual PK parameters. The dose, frequency and bleeding details were collected within the first 6 months after switching to Kovaltry from other FVIII concentrates. Results: Compared to the blood group O, patients with blood group non‐O showed longer mean half‐life (t1/2) (p <.01), lower mean clearance (CL) (p =.01) and similar in vivo recovery (IVR) (p =.51). Higher von Willebrand factor antigen (VWF:Ag) level was correlated to longer t1/2 (p <.0001) and lower CL (p <.01). IVR was correlated to body mass index (BMI) (p <.0001). Patients with trough level >3 IU/dL demonstrated lower annual bleeding rate (ABR) (p <.01), annual joint bleeding rate (AJBR) (p <.01) and annual spontaneous bleeding rate (ASBR) (p <.01). Conclusion: This study firstly reported the PK profiles of Kovaltry in 35 paediatric patients <12 years old. The great inter‐individual variability of PK parameters was also confirmed in these patients. VWF:Ag and blood group were major influencing factors of t1/2 and CL of Kovaltry, while BMI was a vital predictor for IVR. Patients with high trough FVIII level in routine prophylaxis had reduced bleeding rates. [ABSTRACT FROM AUTHOR]

Introduction: von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays an important role in haemostasis. von Willebrand disease (VWD) is an inherited heterogeneous bleeding disorder caused by either a quantitative or qualitative defect of VWF. Type 3 VWD, the most severe form of the disease, leads to complete quantitative VWF deficiency. Aim: The present study aims to investigate the molecular pathogenesis of type 3 VWD patients from Southern Brazil. Methods: The VWF gene was sequenced in 26 cases clinically diagnosed with type 3 VWD by next‐generation sequencing using Ion Torrent PGM. Results: In 25 patients, we were able to identify both disease‐causing variants. We identified 72 different variants: 31 intronic and 41 exonic. Five novel variants were found: c.6976+5G>T; c.6885_6886insC; c.3378C>T (p.Cys1126); c.3346_3347insCCA; and c.2503G>T (p.Glu835*). Variants p.Pro2063Ser and p.Arg324* co‐segregated in 17 patients, 15 of them in homozygosity. Conclusion: Our results may contribute to the discussion on whether the variant p.Pro2063Ser is pathogenic or not. Finally, the presence of a common haplotype in patients bearing these two variants suggests a founder effect for this variant in our region. [ABSTRACT FROM AUTHOR]

Introduction: Type 2A von Willebrand disease (VWD) is common in type‐2 group caused by qualitative deficiency of von Willebrand factor (VWF). Emicizumab is a bispecific antibody that mimics activated factor VIII (FVIIIa) cofactor function, and emicizumab prophylaxis substantially reduces bleeding in patients with haemophilia A. It is unknown whether emicizumab affects thrombus formation in type 2A VWD characterized by not only low FVIII levels but also the impaired platelet adhesion and aggregation. Aim: To examine the coagulant potential of emicizumab in type 2A VWD. Patients/Methods: Perfusion chamber experiments combined with immunostaining were performed using whole blood from 5 patients with type 2A VWD under high shear condition (2500 s−1). Results: The addition of FVIII to type 2A VWD whole blood did not augment thrombus formation, whilst supplementation with VWF or FVIII/VWF enhanced. FVIII appeared to contribute to thrombus height rather than surface coverage. The addition of emicizumab enhanced thrombus formation in type 2A VWD compared with FVIII, but this potency was less than the presence of VWF. The effect on thrombus formation mediated by emicizumab appeared to be more rapid than that by FVIII for non‐requirement of activation step of FVIII, whilst that by FVIII showed more impact on thrombus formation at the late phase. Conclusion: Emicizumab‐induced enhancing effects of thrombus formation, independent on VWF, may be useful as an alternative therapy for type 2A VWD patients. These results supported a critical role for the FVIII‐VWF complex facilitating thrombus formation under high shear. [ABSTRACT FROM AUTHOR]

Introduction: Von Willebrand Disease is a common inherited haemorrhagic disorder due to a deficiency of Von Willebrand Factor (VWF). In case of surgical procedures in patients who are not responsive or have contraindications to desmopressin, replacement therapy with VWF concentrates is indicated. Until recently, only plasma‐derived VWF concentrates were available. A new recombinant VWF (rVWF) concentrate that contains no Factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France since 2018. Aim: Describe real‐world experience of using rVWF in surgical procedures. Methods: Sixty‐three surgeries for 55 patients were retrospectively analysed in 7 French haemostasis centres. Results: During minor surgeries, the median (range) number of infusions was 1 (1–8) with a preoperative loading dose of 35 (19–56) rVWF IU/kg and a total median dose of 37.5 IU (12–288). During major surgeries, the median (range) number of infusions was only 3 (1–14) with a median preoperative loading dose of 36 IU (12–51) rVWF IU/kg, and a total median dose of 108 IU (22–340) rVWF IU/kg. The overall clinical efficacy was qualified as excellent/good in 61 of the procedures (97%), moderate in 1 (1.5%) and poor in 1 (1.5%). There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events, anti‐VWF antibodies or adverse events were reported. Conclusion: This French 'real‐world' experience shows that a few infusions and low doses of rVWF provided effective prevention of bleeding in major and minor surgeries in inherited VWD, with no clinically significant safety concerns. [ABSTRACT FROM AUTHOR]

von Willebrand disease (VWD) is the most common inherited bleeding disorder. VWD is caused by deficiencies in von Willebrand factor (VWF), a critical adhesive haemostatic protein. This review provides an overview of VWD diagnosis and treatment, special considerations in treating women with VWD, and current genomic approaches to VWD. For diagnosis and treatment in VWD, an accurate diagnosis is critical to providing effective treatments, determining appropriate laboratory monitoring and for counselling the patient and family. Diagnosis of VWD begins with the clinical assessment for the bleeding phenotype, which is usually characterized by mucocutaneous and provoked bleeding. The diagnosis of VWD is then made by laboratory investigation. Multiple assays are used to assess VWF levels and functions. The mainstays of VWD treatment are tailored by VWD type and symptoms, and can include antifibrinolytic treatment, desmopressin and VWF replacement treatment. Women with VWD are also at risk for excessive uterine bleeding, such as with menses and childbirth. In addition to standard VWD treatments, heavy menstrual bleeding can be treated with hormones. Interdisciplinary management of childbirth and prophylaxis in the postpartum period are needed to reduce the risk of postpartum haemorrhage. Genomic approaches to VWD can inform VWD diagnosis, treatment, test assay selection, reproductive planning and family counselling. Most VWD patients have an identifiable VWF gene DNA variant. Next‐generation sequencing is rapidly being adopted to provide more comprehensive VWF sequence information for patients with known or suspected VWD. [ABSTRACT FROM AUTHOR]

Acquired bleeding disorders can accompany hematological, neoplastic, autoimmune, cardiovascular or liver diseases, but can sometimes also arise spontaneously. They can manifest as single factor deficiencies or as complex hemostatic abnormalities. This review addresses (a) acquired hemophilia A, an autoimmune disorder characterized by inhibitory autoantibodies against coagulation factor VIII; (b) acquired von Willebrand syndrome in patients with cardiovascular disorders, where shear stress abnormalities result in destruction of von Willebrand factor; and (c) liver function disorders that comprise complex changes in pro‐ and anti‐hemostatic factors, whose clinical implications are often difficult to predict. The article provides an overview on the pathophysiology, diagnostic tests and state‐of‐the‐art treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: von Willebrand disease (VWD) is the most common inherited bleeding disorder and caused by an absence, deficiency or defect in von Willebrand factor (VWF). VWD is currently classified into six different types: 1, 2A, 2B, 2N, 2M, 3. Notably, 2M VWD is more often misdiagnosed as 2A or type 1 VWD than properly identified as 2M VWD. Aim: To describe an algorithmic approach to better ensure appropriate identification of 2M VWD, and reduce its misdiagnosis, as supported by sequential laboratory testing. Methods: Comparative assessment of types 1, 2A, 2B and 2M VWD using various laboratory tests, including VWF antigen and several VWF activity assays, plus DDAVP challenge data, ristocetin‐induced platelet agglutination (RIPA) data, multimer analysis and genetic testing. Results: Types 1, 2A, 2B and 2M VWD give characteristic test patterns that can provisionally classify patients into particular VWD types. Notably, type 1 VWD shows low levels of VWF, but VWF functional concordance (VWF activity/Ag ratios >0.6), with both baseline assessment and post‐DDAVP. Types 2A, 2B and 2M VWD show VWF functional discordance (low VWF activity/Ag ratio(s)) dependent on the defect, but type 2M separates from 2A/2B VWD based on specific test patterns, especially with collagen binding vs glycoprotein Ib binding assays. RIPA identifies 2B VWD. Multimers separate 2M from 2A/2B. Conclusion: We provide strategies to improve correct diagnosis of VWD, especially focussed on 2M VWD, and which can be used by most diagnostic haemostasis laboratories, reserving genetic analysis (if required) for confirmation. [ABSTRACT FROM AUTHOR]

Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 0.1%, characterised by quantitative or functional deficiency of von Willebrand factor (VWF). VWD diagnosis is based on symptomology, biochemical and genetic tests, but limited laboratory resources and VWD heterogeneity still generate an important subdiagnosis gap worldwide and in our country. Aim: To identify the type and subtype of VWD in a cohort of patients with a history of excessive bleeding in Western Mexico. Methods: This prospective cohort study from 2012 to 2019 included patients with mucocutaneous bleeding or abnormal laboratory tests. A standardised questionnaire and confirmatory tests were applied: FVIII:C, VWF activity, VWF antigen, and VWF multimeric analysis. Results: Of the 297 patients recruited, 207 (69.7%) were excluded because their values exceeded 50% in VWF activity and VWF antigen. Of those 90 remaining, 54 (18.2%) had low VWF, and only 36 patients (12.1%) were diagnosed with VWD. Among them, 17 (47.2%) had quantitative deficiencies, of whom 14 were assigned as type 1 and 3 as type 3.The remaining 19 cases were diagnosed as type 2 (52.8%): type 2A and 2B were the most frequent with 6 and 7 cases respectively; 4 cases were possible type 2M and two suggestive of 2N, however, this was not confirmed. Conclusion: This study highlights the challenges of VWD diagnosis using a comprehensive panel of diagnostic tests which should extend to supplemental tests of VWF:CB, VWF:FVIIIB, and sequencing the VWD gene to confirm the results from the panel assays. [ABSTRACT FROM AUTHOR]

Previous studies have highlighted marked inter‐individual variations in factor VIII (FVIII) clearance between patients with haemophilia (PWH). The half‐life of infused FVIII has been reported to vary from as little as 5.3 hours in some adult PWH, up to as long as 28.8 hours in other individuals. These differences in clearance kinetics have been consistently observed using a number of different plasma‐derived and recombinant FVIII products. Furthermore, recent studies have demonstrated that half‐life for extended half‐life (EHL‐) FVIII products also demonstrates significant inter‐patient variation. Since time spent with FVIII trough levels <1% has been shown to be associated with increased bleeding risk in PWH on prophylaxis therapy, this variability in FVIII clearance clearly has major clinical significance. Recent studies have provided significant novel insights into the cellular basis underlying FVIII clearance pathways. In addition, accumulating data have shown that endogenous plasma VWF levels, ABO blood group and age, all play important roles in regulating FVIII half‐life in PWH. Indeed, multiple regression analysis suggests that together these factors account for approximately 34% of the total inter‐individual variation in FVIII clearance observed between subjects with severe haemophilia A. In this review, we consider these and other putative modulators of FVIII half‐life, and discuss the biological mechanisms through which these factors impact upon FVIII clearance in vivo. [ABSTRACT FROM AUTHOR]

Introduction: Diagnosis of von Willebrand disease (VWD) is challenging due to heterogeneity of VWD and test limitations. Many von Willebrand factor (VWF) assays are utilized, including antigen (Ag), activity and multimer analysis. Activity assays include ristocetin cofactor using platelets (VWF:RCo) or other particles incorporating recombinant glycoprotein I ('VWF:GPIbR'), or other GPI binding assays using gain‐of‐function mutations ('VWF:GPIbM'), or collagen binding (VWF:CB). Aim: To comparatively evaluate modern contemporary VWF activity assays vs VWF multimer analysis using modern contemporary methods. Materials and methods: Several VWF activity assays (VWF:RCo, VWF:GPIbR, VWF:GPIbM, VWF:CB) assessed (typically as a ratio against VWF:Ag) against a new semi‐automated procedure for different types of VWD (1, 3, 2A, 2B, 2M), plus control material (n = 580). The evaluation also focussed on relative loss of high and very high molecular weight multimers (HMWM and VHMWM) by densitometric scanning. Results: All evaluated VWF activity/Ag ratios showed high correlation to the presence/absence of HMWM and VHMWM, although VWF:CB/Ag and VWF:GPIbR/Ag ratios using an automated chemiluminescence method yielded highest correlation coefficients (r =.909 and.874, respectively, for HMWM). Use of the investigative procedure (VHMWM) identified fewer false positives for 'loss' in type 1 VWD. Conclusions: This comparative investigation identified that new automated chemiluminescence VWF activity assays best identified relative loss or presence of HMWM and VHMWM according to activity to Ag ratios and an alternative investigative method for identifying VHMWM in multimer testing for a new commercial multimer method may lead to fewer false identifications of HMW loss in type 1 VWD. [ABSTRACT FROM AUTHOR]