RARE DISEASE
Von Willebrand disease type 2M
Von Willebrand disease type 2M
Von Willebrand disease type 2M
Drug discovery
84
papers
On emerging therapies
Overview
Von Willebrand disease type 2M is a qualitative bleeding disorder caused by VWF gene mutations impairing von Willebrand factor's binding capacity to platelets (via GPIb) or collagen, despite normal multimer structure. Laboratory findings show reduced VWF activity-to-antigen ratios (<0.7) with preserved collagen binding capacity. Clinical features include mucocutaneous bleeding, menorrhagia, and post-procedural hemorrhage [1][5][17].
Therapies
First-line: VWF/FVIII concentrates (e.g., Humate-P®, Wilate®) for bleeding/surgery due to poor response to desmopressin [3][11]
Adjuncts: Tranexamic acid for mucosal bleeding; individualized surgical prophylaxis targeting VWF activity ≥0.5 IU/mL [7][16]
Monitoring: Avoid overtreatment; manage factor VIII levels to prevent thrombotic risks [13][14]
Categories: rare genetic diseases, rare hematological diseases
Research Papers
84 drug discovery papers about Von Willebrand disease type 2M. Recent publications:
84 drug discovery papers about Von Willebrand disease type 2M. Recent publications:
categories:
Small molecules
proteins
2026-06-01 | Management of von Willebrand disease for orthognathic surgery
OBJECTIVES The objectives of this report are to review available literature regarding management of patients with von Willebrand Disease and other bleeding disorder undergoing orthognathic surgery and to provide a case report regarding the management of a patient vWD type 2M undergoing orthognathic surgery. METHODS A recent case of a patient with type 2M vWD undergoing orthognathic surgery and the perioperative management is presented for consideration. A scoping review of the literature was performed for evaluation of available literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review (PRISMA-ScR). RESULTS Insufficient evidence exists for significant analysis of perioperative management strategies previously reported compared to the currently utilized management strategy for the case presented. A review of the available literature with reference to updated literature regarding management of patients with vWD undergoing surgical procedures other than orthognathic surgery yields primarily case reports, two randomized controlled trials, and one systematic review. The results indicate that an evolution in the general management of patients with vWD undergoing surgery can be applied to patients undergoing orthognathic surgery and that the addition of hemostatic agents such as tranexamic acid may be considered with a low level of evidence. CONCLUSIONS For patients undergoing orthognathic surgery, the use of cryoprecipitate has been replaced with Humate-p infusion and will likely be replaced with the use of recombinant von Willebrand factor (VWF). The timing of infusion of adjuncts preoperatively for patients with vWD can potentially be extended to the previous day, and the addition of medications to aid in hemostasis such as tranexamic acid may be considered. Prophylactic use of additional VWF adjuncts should be considered in the postoperative setting, and close monitoring is prudent. The use of newer agents may allow for the expansion of craniomaxillofacial surgery procedures that can be safely considered in patients with vWD. IMPLICATIONS The findings discussed in this report can aid surgeons in management of patients with vWD undergoing orthognathic surgery.
2026-02-20 | Peripartum management of caesarean delivery in type 2 von Willebrand disease.
We report the case of a successful caesarean delivery in a woman with von Willebrand disease (VWD) which poses significant risk of maternal bleeding during childbirth. The patient, a primigravida with known type 2 VWD, was closely monitored throughout gestation with periodic assessment of coagulation profile, von Willebrand factor activity and factor VIII levels. A multidisciplinary team-including obstetricians, haematologists, transfusion medicine specialists and anaesthesiologists-was involved and delivery was planned at 39 weeks' gestation with preparedness for factor replacement. Prophylactic tranexamic acid was administered at induction of labour. Patient landed up in a caesarean section because of pathological cardiotocography with meconium staining. Prophylactic factor VIII replacement therapy was given at induction of anaesthesia to minimise haemorrhagic risk. A caesarean section was performed uneventfully, with no intraoperative or postoperative bleeding complications. Both mother and neonate had a favourable outcome.
2026-01-20 | Clusterin maintains hemostatic equilibrium by stabilizing VWF multimers in plasma.
The coagulation-anticoagulation balance is tightly regulated by endothelial-derived factors, which have not been clearly defined. Here, we report that clusterin, a component of Weibel-Palade bodies (WPBs), plays a crucial role in maintaining hemostatic equilibrium by stabilizing von Willebrand factor (VWF) multimers in plasma. Clusterin was identified by proteomic analysis as a component of the endothelial secretome under both chemical and physical conditions and demonstrated as a WPB component via immunostaining and cotransfection assays. Notably, a significant reduction of clusterin protein level was observed in plasma from patients with type 2A von Willebrand disease. Furthermore, loss of clusterin in mice led to hemorrhagic diathesis and impaired thrombosis, accompanied by reduced high molecular weight (HMW) VWF levels. These defects were rescued by exogenous clusterin administration, underscoring its therapeutic potential. Mechanistically, clusterin binds to the D4N domain of VWF, which competitively inhibits ADAMTS13-mediated proteolysis under shear stress, and thereby preserves HMW VWF multimers essential for hemostasis. This study redefines WPBs as hubs for regulatory proteins and establishes clusterin as a key modulator of VWF multimer quality, offering a paradigm shift in targeting coagulation dysfunction through multimer stabilization rather than protein replacement. Our findings bridge a critical gap in understanding endothelial-driven coagulation homeostasis and suggest a potential therapeutic strategy targeting VWF multimer quality for bleeding disorder diseases.
2025-12-21 | Surgical intervention with cardiopulmonary bypass in a patient with von Willebrand disease.
This article presents a clinical case of surgical intervention with cardiopulmonary bypass (CPB) in a patient with von Willebrand disease (VWD). VWD is the most common inherited bleeding disorder, significantly complicating surgical procedures due to impaired hemostasis. Surgical treatment of patients with VWD, particularly in the context of cardiovascular surgery involving CPB, requires an individualized approach. This includes the optimization of von Willebrand factor (vWF) and factor VIII (FVIII) levels, which are critical to preventing perioperative bleeding. The article describes the perioperative anesthetic management of the patient, emphasizing the importance of hemostasis monitoring, an individualized approach, and personalized dosing of replacement therapy to ensure effective treatment and minimize the risk of bleeding and thromboembolic complications. A 36-year-old male (181 cm, 92 kg) with type 2 von Willebrand disease and a history of childhood cardiac surgery (atrial septal defect repair, right ventricular outflow tract reconstruction) was admitted for elective aortic valve replacement with a bioprosthesis due to severe aortic regurgitation. Echocardiography revealed residual ventricular septal defect shunting, aortic root dilation, moderate mitral regurgitation, and cusp prolapse. The patient had a significant bleeding history and laboratory evidence of low vWF antigen/activity and FVIII deficiency. Perioperative management included ultrasound-guided vascular access, balanced general anesthesia, moderate hypothermic cardiopulmonary bypass, antifibrinolytic therapy, and tailored hemostatic replacement with vWF concentrate, FVIII, cryoprecipitate, platelets, and plasma. The patient was extubated 6 h after surgery, required minimal transfusion support, and recovered without hemorrhagic or thromboembolic complications. He was discharged on postoperative day 10 in good condition. Proper management of the perioperative period is identified as a complex challenge for anesthesiologists, requiring a clear understanding of therapeutic mechanisms and their impact on coagulation.
2025-11-03 | Pharmacokinetic-pharmacodynamic modelling of von willebrand factor/factor VIII prophylaxis in von willebrand disease
Abstract Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who experience severe and frequent bleeding episodes. Prophylactic therapy may be individualised by pharmacokinetic (PK)-guided dosing. Effective clinical implementation of PK-guided dosing requires knowledge of both the interpatient PK variability and the relationship between drug exposure and bleeding risk. Objective: To develop a population PK model for the plasma-derived VWF/factor VIII (FVIII) 1:1 concentrate (Wilate®) in patients with severe VWD and to explore the relationship between VWF/FVIII activity and bleeding events during prophylaxis. Methods: A nonlinear mixed-effects PK modelling approach was applied to VWF:ristocetin cofactor (VWF:RCo) and FVIII activity (FVIII:C) data from pediatric and adult patients participating in a prospective single-dose (WIL-12) and a 1-year prospective, prophylaxis phase 3 trial (WIL-31; NCT04052698). Individual post-hoc PK profiles were constructed, and VWF/FVIII activity levels were retrospectively assessed at the time of bleeding events. Results: 658 VWF:RCo and 692 FVIII:C levels were obtained from 53 patients with a median age of 23 years (range: 7-68 years) with VWD, comprising 11 with severe type 1, 10 with type 2A, 1 with type 2B, 2 with type 2M, and 29 with type 3. One- and two-compartment turnover population PK models best described the PK profiles for VWF:RCo and FVIII:C, respectively. For VWF:RCo, the typical value of clearance and its interpatient variability were 3.4 dL/h/70 kg and 47%, respectively; for FVIII:C, the corresponding values were 1.8 dL/h/70 kg and 57%. Post hoc analysis revealed that 50% of the 71 spontaneous bleeds during WIL-31 occurred at levels <3.7 IU/dL VWF:RCo and <9.1 IU/dL FVIII:C. Similarly, 50% of the 49 traumatic bleeds occurred at VWF:RCo levels <4.6 IU/dL and FVIII:C levels <14.7 IU/dL. Conclusion: In this study, we developed a population PK model for the plasma-derived VWF/FVIII 1:1 concentrate that can support clinicians in optimising VWD therapy by assessment of exposure PK metrics (trough levels, area under the curve, time above a defined threshold) and VWF:RCo and FVIII:C levels at the time of bleeding. As the population PK model of the VWF/FVIII 1:1 concentrate creates parallel PK profiles of VWF:RCo and FVIII:C, PK-guided may be performed by monitoring FVIII as well as VWF. Our population PK model enables informed treatment decisions, advancing the personalisation of long-term prophylaxis for plasma-derived VWF/FVIII in severe VWD.
small molecules
2024-09-20 | Type 2N von Willebrand disease: genotype drives different bleeding phenotypes and treatment needs.
Type 2 Normandy von Willebrand disease (VWD2N) is usually perceived as a mild bleeding disorder that can be treated with desmopressin (DDAVP). However, VWD2N patients can be compound heterozygous or homozygous for different variants, with p.Arg854Gln (R854Q) being the most frequent causative one. There are limited data about the impact of 2N variants on VWD2N phenotype and DDAVP response. This study aims to describe the phenotype of VWD2N, including DDAVP response, according to genotype. VWD2N patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score, were eligible to be included in the study. Results of the DDAVP trial were also collected. A total of 123 VWD2N patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n = 114) or absence (R854QNeg, n = 9) of at least 1 R854Q allele. Three R854QPos subgroups were further individualized: patients homozygous (R854QHmz, n = 55), compound heterozygous for R854Q and a null allele (R854Q/3, n = 48), or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n = 11). C levels were significantly lower in R854QNeg and R854Q/3 patients compared with R854QHmz ones (P < .001 and P < .0001, respectively). R854QNeg patients were diagnosed earlier due to bleeding symptoms and had a higher bleeding score than R854QPos patients (P < .001). In DDAVP trial, FVIII:C survival was lower in VWD type 2N than in type 1 patients. R854QPos patients had a heterogeneous DDAVP response, which was best predicted by baseline FVIII:C level. The heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP trial to identify patients potentially eligible to alternative therapeutic options.
2022-06-03 | Correlation Analysis of DNA Methylation in the von Willebrand Factor Promoter Region and the Risk of Unexplained Recurrent Hemophilia: Systematic Review and Meta-Analysis
This study systematically reviewed the effect of DNA methylation in the promoter region of the coagulation factor vWF gene on the risk of unexplained recurrent hemophilia. PubMed, Medline, Web of Science, and other computers were used to search the database, and the statistical randomized controlled trials of coagulation factor vWF in the risk analysis of unknown recurrent hemophilia were collected. The Cochrane systematic evaluation method was used to evaluate the quality of the included kinds of literature, and Revman5 software was used to sort out and analyze the kinds of literature. Meta-analysis showed that there was a statistical difference between the experimental group and the control group in case fatality rate (OR = 1.76, 95% CI (1.29, 2.39), P = 0.0003 , I2 = 0%, Z = 3.58), adverse events (OR = 2.38, 95% CI (1.65, 3.45), P < 0.00001 , I2 = 0%, Z = 4.60), incidence of joint hemorrhage (OR = 2.52, 95% CI (1.62, 3.91), P < 0.00001 , I2 = 0%, Z = 4.12), incidence of subcutaneous stasis (OR = 1.76, 95% CI (1.26, 2.45), P = 0.0009 , I2 = 5%, Z = 3.33), and hematoma volume (OR = 1.78, 95% CI (1.32, 2.40), P = 0.0001 , I2 = 23%, Z = 3.80). DNA methylation in the promoter region of the coagulation factor vWF gene was significantly associated with the risk of unexplained recurrent hemophilia. Whether demethylation can improve the bleeding index of patients with recurrent hemophilia remains to be further explored.
2019-09-20 | Shear-Dependent Platelet Aggregation: Mechanisms and Therapeutic Opportunities
Cardiovascular diseases (CVD) are the number one cause of morbidity and death worldwide. As estimated by the WHO, the global death rate from CVD is 31% wherein, a staggering 85% results from stroke and myocardial infarction. Platelets, one of the key components of thrombi, have been well investigated over decades for their pivotal role in thrombus development in healthy as well as diseased blood vessels. In hemostasis, when a vascular injury occurs, circulating platelets are arrested at the site of damage, where they are activated and aggregate to form hemostatic thrombi, thus preventing further bleeding. However, in thrombosis, pathological activation of platelets occurs, leading to uncontrolled growth of a thrombus, which in turn can occlude the blood vessel or embolize, causing downstream ischemic events. The molecular processes causing pathological thrombus development are in large similar to the processes controlling physiological thrombus formation. The biggest challenge of anti-thrombotics and anti-platelet therapeutics has been to decouple the pathological platelet response from the physiological one. Currently, marketed anti-platelet drugs are associated with major bleeding complications for this exact reason; they are not effective in targeting pathological thrombi without interfering with normal hemostasis. Recent studies have emphasized the importance of shear forces generated from blood flow, that primarily drive platelet activation and aggregation in thrombosis. Local shear stresses in obstructed blood vessels can be higher by up to two orders of magnitude as compared to healthy vessels. Leveraging abnormal shear forces in the thrombus microenvironment may allow to differentiate between thrombosis and hemostasis and develop shear-selective anti-platelet therapies. In this review, we discuss the influence of shear forces on thrombosis and the underlying mechanisms of shear-induced platelet activation. Later, we summarize the therapeutic approaches to target shear-sensitive platelet activation and pathological thrombus growth, with a particular focus on the shear-sensitive protein von Willebrand Factor (VWF). Inhibition of shear-specific platelet aggregation and targeted drug delivery may prove to be much safer and efficacious approaches over current state-of-the-art antithrombotic drugs in the treatment of cardiovascular diseases.
2012-10-24 | Two cases of peritonsillar abscess complicated by von Willebrand disease.
Von Willebrand disease (vWD) is a common hereditary bleeding disorder resulting from a quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We report two cases of peritonsillar abscess complicated by vWD. A 46-year-old Japanese man was intravenously administered factor VIII clotting antigen (500U×3 days)and platelet transfusion (10U), when before puncture was performed. After puncture, his symptoms promptly improved with the administration of the antibiotic doripenem (DRPM, 1.5g/day). He left our facility one week later and had no recurrence of symptoms. A 24-year-old Japanese woman was intravenously administered factor VIII clotting antigen (4500U×3 days) and desmopressin (DDAVP) before undergoing a puncture. Her symptoms promptly improved with DRPM treatment (1.5g/day). The patient left our facility one week later. However, the peritonsillar abscess recurred in three weeks. Afterwards, tonsillectomy was enforced three months later. Intravenous factor VIII clotting antigen (4500U×2 days) and platelet transfusion (10U×1 day) had been used before tonsillectomy. We therefore suggest that a peritonsillar abscess in patients with vWD can be safely treated by factor VIII clotting antigen and DDAVP at the appropriate disease stage and by performing paracentesis for the acute phase or tonsillectomy for the chronic phase.
2009-08-06 | How I treat von Willebrand disease
Abstract Recent multicenter studies have clarified the molecular basis underlying the different von Willebrand disease (VWD) types, all of which are caused by the deficiency and/or abnormality of von Willebrand factor (VWF). These studies have suggested a unifying pathophysiologic concept. The diagnosis of VWD, remains difficult because its clinical and laboratory phenotype is very heterogeneous and may overlap with normal subjects. Stringent criteria are therefore required for a clinically useful diagnosis. In this paper, we delineate a practical approach to the diagnosis and treatment of VWD. Our approach is based on the critical importance of a standardized bleeding history that has been condensed into a final bleeding score and a few widely available laboratory tests, such as VWF ristocetin cofactor activity, VWF antigen and factor VIII. This approach would help identify those subjects who will probably benefit from a diagnosis of VWD. The next step involves performing a trial infusion with desmopressin in all patients who fail to exhibit an enhanced responsiveness to ristocetin. On the basis of these results and through a series of illustrative examples, the clinician will be able to select the best approach for the optimal management of VWD, according to the patient's characteristics and clinical circumstances.
oligonucleotides
2025-01-17 | Amelioration of a von Willebrand disease type 2B phenotype in vivo upon treatment with allele-selective siRNAs.
Treatment options for the bleeding disorder von Willebrand disease type 2B (VWD2B) are insufficient and fail to address the negative effects of circulating mutant von Willebrand factor (VWF). The dominant-negative nature of VWD2B makes functionally defective VWF an interesting therapeutic target. Previous in vitro studies have demonstrated the feasibility of allele-selective silencing of mutant VWF using small interfering RNAs (siRNAs) targeting common single nucleotide polymorphisms (SNPs) in the human VWF gene, an approach that can be applied irrespective of the disease-causing VWF mutation. This study aims to extend this concept to a heterozygous VWD2B mouse model (c.3946G>A; p.Val1316Met) here using mouse strain-specific genetic differences as proxy for human SNPs. Homozygous VWD2B C57BL/6J (2B-B6) mice were crossed with homozygous wild-type 129S1/SvImJ (129S) mice to create heterozygous 2B-B6.129S F1 offspring. These 2B-B6.129S mice were intravenously injected with endothelial-specific lipid nanoparticles loaded with the allele-selective siVwf.B6 or control and 96 hours later, lung Vwf messenger RNA, plasma VWF levels, and phenotypic characteristics were evaluated. Treatment with siVwf.B6 reduced total VWF levels by 50%, with an expected selective reduction in mutant VWF protein. This coincided with normalization of multimeric structure, improved VWF collagen binding/VWF antigen ratio, and normalized bleeding times in two-thirds of heterozygous 2B-B6.129S mice. Being a novel approach in the field of hemostasis, we proved, for VWD, in mice, the concept of selectively inhibiting a mutant dominant-negative allele with siRNAs targeting a single nucleotide variation rather than the disease-causing mutation. For dominant-negative VWD, this offers potential for a customized therapeutic strategy.
2022-01-17 | Ex vivo Improvement of a von Willebrand Disease Type 2A Phenotype Using an Allele-Specific Small-Interfering RNA.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is mainly caused by dominant-negative mutations in the multimeric protein von Willebrand factor (VWF). These mutations may either result in quantitative or qualitative defects in VWF. VWF is an endothelial protein that is secreted to the circulation upon endothelial activation. Once secreted, VWF multimers bind platelets and chaperone coagulation factor VIII in the circulation. Treatment of VWD focuses on increasing VWF plasma levels, but production and secretion of mutant VWF remain uninterrupted. Presence of circulating mutant VWF might, however, still affect normal hemostasis or functionalities of VWF beyond hemostasis. We hypothesized that inhibition of the production of mutant VWF improves the function of VWF overall and ameliorates VWD phenotypes. We previously proposed the use of allele-specific small-interfering RNAs (siRNAs) that target frequent VWF single nucleotide polymorphisms to inhibit mutant VWF. The aim of this study is to prove the functionality of these allele-specific siRNAs in endothelial colony-forming cells (ECFCs). We isolated ECFCs from a VWD type 2A patient with an intracellular multimerization defect, reduced VWF collagen binding, and a defective processing of proVWF to VWF. After transfection of an allele-specific siRNA that specifically inhibited expression of mutant VWF, we showed amelioration of the laboratory phenotype, with normalization of the VWF collagen binding, improvement in VWF multimers, and enhanced VWF processing. Altogether, we prove that allele-specific inhibition of the production of mutant VWF by siRNAs is a promising therapeutic strategy to improve VWD phenotypes.
2011-01-06 | The dominant-negative von Willebrand factor gene deletion p.P1127_C1948delinsR: molecular mechanism and modulation.
Understanding molecular mechanisms in the dominant inheritance of von Willebrand disease would improve our knowledge of pathophysiologic processes underlying its prevalence. Cellular models of severe type 2 von Willebrand disease, caused by a heterozygous deletion in the von Willebrand factor (VWF) gene, were produced to investigate the altered biosynthesis. Coexpression of the wild-type and in-frame deleted (p.P1127_C1948delinsR) VWF forms impaired protein secretion, high molecular weight multimer formation and function (VWF collagen-binding 1.9% ± 0.5% of wild-type), which mimicked the patient's phenotype. mRNA, protein, and cellular studies delineated the highly efficient dominant-negative mechanism, based on the key role of heterodimers as multimer terminators. The altered VWF, synthesized in large amounts with the correctly encoded "cysteine knot" domain, formed heterodimers and heterotetramers with wild-type VWF, in addition to deleted homodimers. Impaired multimerization was associated with reduced amounts of VWF in late endosomes. Correction of the dominant-negative effect was explored by siRNAs targeting the mRNA breakpoint, which selectively inhibited the in-frame deleted VWF expression. Although the small amount of the deleted protein synthesized after inhibition still exerted dominant, even though weakened, negative effects, the siRNA treatment restored secretion of large multimers with improved function (VWF collagen-binding 28.0% ± 3.3% of wild-type).
antibodies
2025-11-01 | HTRS2025.O8C.6 Cerebral Sinus Venous Thrombosis in Children and Young Adults: Comprehensive Management and Long-Term Outcomes-A Single Institutional Experience
Background: Non-factor replacement therapies have the potential to provide hemostatic balance in various bleeding disorders with less frequent dosing than factor concentrate prophylaxis.Preclinical studies of VGA039, a fully human, IgG4 monoclonal antibody targeting Protein S, have demonstrated its ability to increase thrombin generation across multiple inherited bleeding disorders, including von Willebrand disease (VWD), and prevent blood loss in vivo in a novel, non-human primate (NHP) VWD model.In healthy volunteers (HVs), single ascending doses (SADs) of subcutaneous (SC) VGA039 increase thrombin generation in a dose-and concentration-dependent manner.Objectives: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SC VGA039 in patients with VWD.Methods: This is an open-label phase I study (NCT05776069) conducted in adult individuals with VWD and approved by local ethics committees.Informed consent was obtained.Key eligibility criteria included: (1) symptomatic VWD of any type or subtype, (2) baseline FVIII activity level 50 IU/dL, (3) and no laboratory evidence of thrombophilia or prior history of thromboembolism.Dose escalations were determined based on emerging D-dimer levels, with a dose limiting toxicity (DLT) threshold set at 4 times the upper limit of normal (2.0 g/mL).Results: As of October 18, 2024, a total of 9 subjects have been dosed with 3.0, 4.5, or 7.0 mg/kg of SC VGA039: 1 with Type 1 VWD, 1 with Type 1 VWD + mild hemophilia A, 1 with Type 2A VWD, 2 with Type 2M VWD, 1 with Type 2N VWD, and 3 with Type 3 VWD.There were no drug-related adverse events, changes in coagulation laboratory parameters, thromboembolic events, DLTs, or injection-site reactions reported to date.VGA039 concentrations predicted to increase thrombin generation in VWD subjects to levels measured in HVs at baseline were sustained for >4 weeks following a single, SC 4.5 mg/kg dose (Figs 1 & 2).Two evaluable 4.5 mg/kg subjects with historical annualized bleeding rates (ABRs) >50 had reductions of 75% and 88% after a single dose of VGA039; the third evaluable subject had only 1 bleed post-VGA039.Efficacy for additional 4.5 and 7.0 mg/kg subjects will become evaluable in time for presentation at the meeting.Conclusions: VGA039 was safe and well tolerated in this SC SAD study in VWD subjects across all types.ABR reductions at VGA039 concentrations associated with increased thrombin generation, in the absence of DLTs, have been observed.SC multi-dose VGA039 investigation is planned.
2024-11-05 | A Phase Ia Study of VGA039, a Protein S-Targeting Monoclonal Antibody, in Individuals with Von Willebrand Disease Demonstrates Concentration-Dependent Increases in Thrombin Generation for Reducing Bleeding
Introduction : Non-factor replacement therapies have the potential to provide hemostatic balance in various bleeding disorders with less frequent dosing than factor concentrate prophylaxis. Preclinical studies of VGA039 have demonstrated its ability to increase thrombin generation across multiple inherited bleeding disorders, including von Willebrand disease (VWD), and prevent blood loss in vivo in a novel, non-human primate (NHP) VWD model. In healthy volunteers (HVs), single ascending doses (SADs) of subcutaneous (SC) VGA039 increase thrombin generation in a dose- and concentration-dependent manner (Schörgenhofer et al., ISTH 2024). The objective of this SAD study is to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SC VGA039 in VWD patients. Methods : This is an open-label phase Ia study (NCT05776069) conducted in adult individuals with VWD and approved by local ethics committees. Informed consent was obtained. Key eligibility criteria included: (1) symptomatic VWD of any type or subtype, (2) baseline FVIII activity level ≤50 IU/dL, (3) and no laboratory evidence of thrombophilia or prior history of thromboembolism. The starting SC SAD of 3.0 mg/kg was the pre-specified maximum dose tested in HVs and selected as the initial SAD to be tested in individuals with VWD. Continued dose escalations in subsequent cohorts were determined based on emerging D-dimer levels, with a dose limiting toxicity (DLT) threshold set at 4 times the upper limit of normal. Results : As of August 1, 2024, a total of 6 subjects equally divided into 2 SAD cohorts (3.0 and 4.5 mg/kg) have been dosed: 1 with Type 1 VWD + mild hemophilia A, 1 with Type 2A VWD, 2 with Type 2M VWD, and 2 with Type 3 VWD. Related to VGA039, there were no adverse events, changes in coagulation laboratory parameters, thromboembolic events, DLTs, or injection-site reactions that have been reported. While mild increases in D-dimer levels were observed in healthy volunteers at 3.0 mg/kg, no significant D-dimer elevations have been observed in VWD subjects at either 3.0 or 4.5 mg/kg. Preliminary thrombin generation results show increased thrombin generation at similar VGA039 concentrations in VWD subjects as in HVs. Additional clinical, PK, and PD data for these and subsequent SAD cohort(s) will be presented at the meeting. Conclusions : Clinical data suggest VGA039 is well tolerated and can increase thrombin generation in the absence of clinically significant D-dimer elevations in individuals with VWD. Drug concentration data continue to support the potential for weekly or less frequent SC prophylactic dosing. Further SAD evaluation of VGA039 in VWD patients is ongoing, and future multi-dose and surgical prophylaxis investigation is planned.
2024-02-02 | Distinct platelet interactions with soluble and immobilized von Willebrand factor modulate platelet adhesion and aggregation with differential impact on hemostasis and thrombosis
Arterial thrombosis is a prevailing and lethal pathological condition that remains difficult to treat or prevent without potentially serious side effects, mostly hemorrhagic in nature. Platelets and von Willebrand factor (VWF) have a recognized major role in the pathogenesis of arterial thrombosis. Platelets bind to surface immobilized VWF for initial adhesion to injured vascular sites, but also interact with soluble VWF to aggregate into thrombi, particularly under flow conditions creating elevated shear stress. Whether the binding of immobilized and soluble VWF to platelets is regulated by separate mechanisms and how they respectively regulate hemostasis and thrombosis remains unclear. Using targeted mutagenesis we engineered VWF to achieve modified binding kinetics with the platelet receptor glycoprotein (GP) Ibα and discovered that the interactions of immobilized and soluble VWF with platelets can be differentially regulated with distinct consequences on platelet adhesion and aggregation. Based on these results, we studied a monoclonal antibody, NMC4, known to bind to an epitope in the VWFA1 domain and to inhibit preferentially platelet aggregation under elevated shear stress conditions. We found that NMC4 was less efficient in reducing platelet adhesion to immobilized VWF than platelet aggregation mediated by soluble VWF and, surprisingly, also inhibited arterial thrombosis in a mouse model of ferric chloride-induced carotid artery occlusion at a dose that failed to prolong post-injury bleeding. Thus, our current findings help delineate interrelated biochemical and biophysical mechanisms underlying VWF function in vascular health; and suggest selective inhibition of VWF-mediated platelet aggregation as opposed to adhesion as a strategy to prevent arterial thrombosis while minimizing bleeding complications.
2022-09-08 | The impact of aberrant von Willebrand factor-GPIbα interaction on megakaryopoiesis and platelets in humanized type 2B von Willebrand disease model mouse.
Type 2B von Willebrand disease (VWD) is caused by gain-of-function mutations in von Willebrand factor (VWF). Increased VWF affinity for GPIba results in loss of high molecular weight multimers and enhanced platelet clearance, both contributing to the bleeding phenotype. Severity of the symptoms vary among type 2B VWD patients, with some developing thrombocytopenia only under stress conditions. Efforts have been made to study underlying pathophysiology for platelet abnormalities, but animal studies have been limited because of species specificity in the VWF-GPIba interaction. Here, we generated a severe form of type 2B VWD (p.V1316M) knockin mice in the context of human VWF exon 28 (encoding A1 and A2 domains) and crossed them with human GPIba transgenic strain. Heterozygous mutant mice recapitulated the phenotype of type 2B VWD in autosomal dominant manner and presented severe macrothrombocytopenia. Of note, platelets remaining in the circulation had extracytoplasmic GPIba shed-off from the cell surface. Reciprocal bone marrow transplantation determined mutant VWF produced from endothelial cells as the major cause of the platelet phenotype in type 2B VWD mice. Moreover, altered megakaryocyte maturation in the bone marrow and enhanced extramedullary megakaryopoiesis in the spleen were observed. Interestingly, injection of anti-VWF A1 blocking antibody (NMC-4) not only ameliorated platelet count and GPIba expression, but also reversed MK ploidy shift. In conclusion, we present a type 2B VWD mouse model with humanized VWF-GPIba interaction which demonstrated direct influence of aberrant VWF-GPIba binding on megakaryocytes.
2022-05-01 | Towards novel treatment options in von Willebrand disease
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.
other
2025-12-18 | Allele-selective disruption of pathogenic VWF variants in type 2 von Willebrand disease using CRISPR/Cas9.
In contrast to major innovations in treating severe hemophilia, the treatment of severe von Willebrand disease (VWD) remains limited to intravenous infusion of von Willebrand factor (VWF) concentrates. To date, no gene therapy-based approaches for the treatment of VWD have been developed, largely owing to the disease's heterogeneous mutational landscape and the challenge of specifically targeting VWF production in endothelial cells. In this study, we developed a novel gene therapy strategy for patients with VWD caused by heterozygous dominant-negative VWF variants. Our strategy permanently inactivates VWF variants by selectively disrupting the pathogenic allele's open reading frame via the introduction of indels by Cas9. To circumvent the challenge of designing variant-specific strategies, we targeted the common single nucleotide polymorphism (SNP) rs1800378 in VWF. We used endothelial colony-forming cells (ECFCs) from patients with VWD2A and VWD2B with heterozygous p.C1190R and p.R1306W variants, respectively, to demonstrate ex vivo proof of principle. Using next-generation sequencing analysis, we show efficient and allele-selective knockout of VWF, while maintaining VWF expression of the nontargeted allele. Variant mapping mass spectrometry that discriminates between wild-type and variant VWF proteoforms confirmed selective reduction of variant allele expression, which was accompanied by reversal of cellular disease phenotypes in ECFCs. This study shows the feasibility of a novel gene editing strategy for VWD that, by virtue of its targeting of a common SNP, can be broadly applicable and can be used to design treatments for VWD without being constrained by the disease-causing variant, pathogenic mechanism, or VWD subtype.
proteins
2026-06-01 | Management of von Willebrand disease for orthognathic surgery
OBJECTIVES The objectives of this report are to review available literature regarding management of patients with von Willebrand Disease and other bleeding disorder undergoing orthognathic surgery and to provide a case report regarding the management of a patient vWD type 2M undergoing orthognathic surgery. METHODS A recent case of a patient with type 2M vWD undergoing orthognathic surgery and the perioperative management is presented for consideration. A scoping review of the literature was performed for evaluation of available literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review (PRISMA-ScR). RESULTS Insufficient evidence exists for significant analysis of perioperative management strategies previously reported compared to the currently utilized management strategy for the case presented. A review of the available literature with reference to updated literature regarding management of patients with vWD undergoing surgical procedures other than orthognathic surgery yields primarily case reports, two randomized controlled trials, and one systematic review. The results indicate that an evolution in the general management of patients with vWD undergoing surgery can be applied to patients undergoing orthognathic surgery and that the addition of hemostatic agents such as tranexamic acid may be considered with a low level of evidence. CONCLUSIONS For patients undergoing orthognathic surgery, the use of cryoprecipitate has been replaced with Humate-p infusion and will likely be replaced with the use of recombinant von Willebrand factor (VWF). The timing of infusion of adjuncts preoperatively for patients with vWD can potentially be extended to the previous day, and the addition of medications to aid in hemostasis such as tranexamic acid may be considered. Prophylactic use of additional VWF adjuncts should be considered in the postoperative setting, and close monitoring is prudent. The use of newer agents may allow for the expansion of craniomaxillofacial surgery procedures that can be safely considered in patients with vWD. IMPLICATIONS The findings discussed in this report can aid surgeons in management of patients with vWD undergoing orthognathic surgery.
2026-02-20 | Peripartum management of caesarean delivery in type 2 von Willebrand disease.
We report the case of a successful caesarean delivery in a woman with von Willebrand disease (VWD) which poses significant risk of maternal bleeding during childbirth. The patient, a primigravida with known type 2 VWD, was closely monitored throughout gestation with periodic assessment of coagulation profile, von Willebrand factor activity and factor VIII levels. A multidisciplinary team-including obstetricians, haematologists, transfusion medicine specialists and anaesthesiologists-was involved and delivery was planned at 39 weeks' gestation with preparedness for factor replacement. Prophylactic tranexamic acid was administered at induction of labour. Patient landed up in a caesarean section because of pathological cardiotocography with meconium staining. Prophylactic factor VIII replacement therapy was given at induction of anaesthesia to minimise haemorrhagic risk. A caesarean section was performed uneventfully, with no intraoperative or postoperative bleeding complications. Both mother and neonate had a favourable outcome.
2026-01-20 | Clusterin maintains hemostatic equilibrium by stabilizing VWF multimers in plasma.
The coagulation-anticoagulation balance is tightly regulated by endothelial-derived factors, which have not been clearly defined. Here, we report that clusterin, a component of Weibel-Palade bodies (WPBs), plays a crucial role in maintaining hemostatic equilibrium by stabilizing von Willebrand factor (VWF) multimers in plasma. Clusterin was identified by proteomic analysis as a component of the endothelial secretome under both chemical and physical conditions and demonstrated as a WPB component via immunostaining and cotransfection assays. Notably, a significant reduction of clusterin protein level was observed in plasma from patients with type 2A von Willebrand disease. Furthermore, loss of clusterin in mice led to hemorrhagic diathesis and impaired thrombosis, accompanied by reduced high molecular weight (HMW) VWF levels. These defects were rescued by exogenous clusterin administration, underscoring its therapeutic potential. Mechanistically, clusterin binds to the D4N domain of VWF, which competitively inhibits ADAMTS13-mediated proteolysis under shear stress, and thereby preserves HMW VWF multimers essential for hemostasis. This study redefines WPBs as hubs for regulatory proteins and establishes clusterin as a key modulator of VWF multimer quality, offering a paradigm shift in targeting coagulation dysfunction through multimer stabilization rather than protein replacement. Our findings bridge a critical gap in understanding endothelial-driven coagulation homeostasis and suggest a potential therapeutic strategy targeting VWF multimer quality for bleeding disorder diseases.
2025-12-21 | Surgical intervention with cardiopulmonary bypass in a patient with von Willebrand disease.
This article presents a clinical case of surgical intervention with cardiopulmonary bypass (CPB) in a patient with von Willebrand disease (VWD). VWD is the most common inherited bleeding disorder, significantly complicating surgical procedures due to impaired hemostasis. Surgical treatment of patients with VWD, particularly in the context of cardiovascular surgery involving CPB, requires an individualized approach. This includes the optimization of von Willebrand factor (vWF) and factor VIII (FVIII) levels, which are critical to preventing perioperative bleeding. The article describes the perioperative anesthetic management of the patient, emphasizing the importance of hemostasis monitoring, an individualized approach, and personalized dosing of replacement therapy to ensure effective treatment and minimize the risk of bleeding and thromboembolic complications. A 36-year-old male (181 cm, 92 kg) with type 2 von Willebrand disease and a history of childhood cardiac surgery (atrial septal defect repair, right ventricular outflow tract reconstruction) was admitted for elective aortic valve replacement with a bioprosthesis due to severe aortic regurgitation. Echocardiography revealed residual ventricular septal defect shunting, aortic root dilation, moderate mitral regurgitation, and cusp prolapse. The patient had a significant bleeding history and laboratory evidence of low vWF antigen/activity and FVIII deficiency. Perioperative management included ultrasound-guided vascular access, balanced general anesthesia, moderate hypothermic cardiopulmonary bypass, antifibrinolytic therapy, and tailored hemostatic replacement with vWF concentrate, FVIII, cryoprecipitate, platelets, and plasma. The patient was extubated 6 h after surgery, required minimal transfusion support, and recovered without hemorrhagic or thromboembolic complications. He was discharged on postoperative day 10 in good condition. Proper management of the perioperative period is identified as a complex challenge for anesthesiologists, requiring a clear understanding of therapeutic mechanisms and their impact on coagulation.
2025-11-03 | Pharmacokinetic-pharmacodynamic modelling of von willebrand factor/factor VIII prophylaxis in von willebrand disease
Abstract Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who experience severe and frequent bleeding episodes. Prophylactic therapy may be individualised by pharmacokinetic (PK)-guided dosing. Effective clinical implementation of PK-guided dosing requires knowledge of both the interpatient PK variability and the relationship between drug exposure and bleeding risk. Objective: To develop a population PK model for the plasma-derived VWF/factor VIII (FVIII) 1:1 concentrate (Wilate®) in patients with severe VWD and to explore the relationship between VWF/FVIII activity and bleeding events during prophylaxis. Methods: A nonlinear mixed-effects PK modelling approach was applied to VWF:ristocetin cofactor (VWF:RCo) and FVIII activity (FVIII:C) data from pediatric and adult patients participating in a prospective single-dose (WIL-12) and a 1-year prospective, prophylaxis phase 3 trial (WIL-31; NCT04052698). Individual post-hoc PK profiles were constructed, and VWF/FVIII activity levels were retrospectively assessed at the time of bleeding events. Results: 658 VWF:RCo and 692 FVIII:C levels were obtained from 53 patients with a median age of 23 years (range: 7-68 years) with VWD, comprising 11 with severe type 1, 10 with type 2A, 1 with type 2B, 2 with type 2M, and 29 with type 3. One- and two-compartment turnover population PK models best described the PK profiles for VWF:RCo and FVIII:C, respectively. For VWF:RCo, the typical value of clearance and its interpatient variability were 3.4 dL/h/70 kg and 47%, respectively; for FVIII:C, the corresponding values were 1.8 dL/h/70 kg and 57%. Post hoc analysis revealed that 50% of the 71 spontaneous bleeds during WIL-31 occurred at levels <3.7 IU/dL VWF:RCo and <9.1 IU/dL FVIII:C. Similarly, 50% of the 49 traumatic bleeds occurred at VWF:RCo levels <4.6 IU/dL and FVIII:C levels <14.7 IU/dL. Conclusion: In this study, we developed a population PK model for the plasma-derived VWF/FVIII 1:1 concentrate that can support clinicians in optimising VWD therapy by assessment of exposure PK metrics (trough levels, area under the curve, time above a defined threshold) and VWF:RCo and FVIII:C levels at the time of bleeding. As the population PK model of the VWF/FVIII 1:1 concentrate creates parallel PK profiles of VWF:RCo and FVIII:C, PK-guided may be performed by monitoring FVIII as well as VWF. Our population PK model enables informed treatment decisions, advancing the personalisation of long-term prophylaxis for plasma-derived VWF/FVIII in severe VWD.
small molecules
2024-09-20 | Type 2N von Willebrand disease: genotype drives different bleeding phenotypes and treatment needs.
Type 2 Normandy von Willebrand disease (VWD2N) is usually perceived as a mild bleeding disorder that can be treated with desmopressin (DDAVP). However, VWD2N patients can be compound heterozygous or homozygous for different variants, with p.Arg854Gln (R854Q) being the most frequent causative one. There are limited data about the impact of 2N variants on VWD2N phenotype and DDAVP response. This study aims to describe the phenotype of VWD2N, including DDAVP response, according to genotype. VWD2N patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score, were eligible to be included in the study. Results of the DDAVP trial were also collected. A total of 123 VWD2N patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n = 114) or absence (R854QNeg, n = 9) of at least 1 R854Q allele. Three R854QPos subgroups were further individualized: patients homozygous (R854QHmz, n = 55), compound heterozygous for R854Q and a null allele (R854Q/3, n = 48), or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n = 11). C levels were significantly lower in R854QNeg and R854Q/3 patients compared with R854QHmz ones (P < .001 and P < .0001, respectively). R854QNeg patients were diagnosed earlier due to bleeding symptoms and had a higher bleeding score than R854QPos patients (P < .001). In DDAVP trial, FVIII:C survival was lower in VWD type 2N than in type 1 patients. R854QPos patients had a heterogeneous DDAVP response, which was best predicted by baseline FVIII:C level. The heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP trial to identify patients potentially eligible to alternative therapeutic options.
2022-06-03 | Correlation Analysis of DNA Methylation in the von Willebrand Factor Promoter Region and the Risk of Unexplained Recurrent Hemophilia: Systematic Review and Meta-Analysis
This study systematically reviewed the effect of DNA methylation in the promoter region of the coagulation factor vWF gene on the risk of unexplained recurrent hemophilia. PubMed, Medline, Web of Science, and other computers were used to search the database, and the statistical randomized controlled trials of coagulation factor vWF in the risk analysis of unknown recurrent hemophilia were collected. The Cochrane systematic evaluation method was used to evaluate the quality of the included kinds of literature, and Revman5 software was used to sort out and analyze the kinds of literature. Meta-analysis showed that there was a statistical difference between the experimental group and the control group in case fatality rate (OR = 1.76, 95% CI (1.29, 2.39), P = 0.0003 , I2 = 0%, Z = 3.58), adverse events (OR = 2.38, 95% CI (1.65, 3.45), P < 0.00001 , I2 = 0%, Z = 4.60), incidence of joint hemorrhage (OR = 2.52, 95% CI (1.62, 3.91), P < 0.00001 , I2 = 0%, Z = 4.12), incidence of subcutaneous stasis (OR = 1.76, 95% CI (1.26, 2.45), P = 0.0009 , I2 = 5%, Z = 3.33), and hematoma volume (OR = 1.78, 95% CI (1.32, 2.40), P = 0.0001 , I2 = 23%, Z = 3.80). DNA methylation in the promoter region of the coagulation factor vWF gene was significantly associated with the risk of unexplained recurrent hemophilia. Whether demethylation can improve the bleeding index of patients with recurrent hemophilia remains to be further explored.
2019-09-20 | Shear-Dependent Platelet Aggregation: Mechanisms and Therapeutic Opportunities
Cardiovascular diseases (CVD) are the number one cause of morbidity and death worldwide. As estimated by the WHO, the global death rate from CVD is 31% wherein, a staggering 85% results from stroke and myocardial infarction. Platelets, one of the key components of thrombi, have been well investigated over decades for their pivotal role in thrombus development in healthy as well as diseased blood vessels. In hemostasis, when a vascular injury occurs, circulating platelets are arrested at the site of damage, where they are activated and aggregate to form hemostatic thrombi, thus preventing further bleeding. However, in thrombosis, pathological activation of platelets occurs, leading to uncontrolled growth of a thrombus, which in turn can occlude the blood vessel or embolize, causing downstream ischemic events. The molecular processes causing pathological thrombus development are in large similar to the processes controlling physiological thrombus formation. The biggest challenge of anti-thrombotics and anti-platelet therapeutics has been to decouple the pathological platelet response from the physiological one. Currently, marketed anti-platelet drugs are associated with major bleeding complications for this exact reason; they are not effective in targeting pathological thrombi without interfering with normal hemostasis. Recent studies have emphasized the importance of shear forces generated from blood flow, that primarily drive platelet activation and aggregation in thrombosis. Local shear stresses in obstructed blood vessels can be higher by up to two orders of magnitude as compared to healthy vessels. Leveraging abnormal shear forces in the thrombus microenvironment may allow to differentiate between thrombosis and hemostasis and develop shear-selective anti-platelet therapies. In this review, we discuss the influence of shear forces on thrombosis and the underlying mechanisms of shear-induced platelet activation. Later, we summarize the therapeutic approaches to target shear-sensitive platelet activation and pathological thrombus growth, with a particular focus on the shear-sensitive protein von Willebrand Factor (VWF). Inhibition of shear-specific platelet aggregation and targeted drug delivery may prove to be much safer and efficacious approaches over current state-of-the-art antithrombotic drugs in the treatment of cardiovascular diseases.
2012-10-24 | Two cases of peritonsillar abscess complicated by von Willebrand disease.
Von Willebrand disease (vWD) is a common hereditary bleeding disorder resulting from a quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We report two cases of peritonsillar abscess complicated by vWD. A 46-year-old Japanese man was intravenously administered factor VIII clotting antigen (500U×3 days)and platelet transfusion (10U), when before puncture was performed. After puncture, his symptoms promptly improved with the administration of the antibiotic doripenem (DRPM, 1.5g/day). He left our facility one week later and had no recurrence of symptoms. A 24-year-old Japanese woman was intravenously administered factor VIII clotting antigen (4500U×3 days) and desmopressin (DDAVP) before undergoing a puncture. Her symptoms promptly improved with DRPM treatment (1.5g/day). The patient left our facility one week later. However, the peritonsillar abscess recurred in three weeks. Afterwards, tonsillectomy was enforced three months later. Intravenous factor VIII clotting antigen (4500U×2 days) and platelet transfusion (10U×1 day) had been used before tonsillectomy. We therefore suggest that a peritonsillar abscess in patients with vWD can be safely treated by factor VIII clotting antigen and DDAVP at the appropriate disease stage and by performing paracentesis for the acute phase or tonsillectomy for the chronic phase.
2009-08-06 | How I treat von Willebrand disease
Abstract Recent multicenter studies have clarified the molecular basis underlying the different von Willebrand disease (VWD) types, all of which are caused by the deficiency and/or abnormality of von Willebrand factor (VWF). These studies have suggested a unifying pathophysiologic concept. The diagnosis of VWD, remains difficult because its clinical and laboratory phenotype is very heterogeneous and may overlap with normal subjects. Stringent criteria are therefore required for a clinically useful diagnosis. In this paper, we delineate a practical approach to the diagnosis and treatment of VWD. Our approach is based on the critical importance of a standardized bleeding history that has been condensed into a final bleeding score and a few widely available laboratory tests, such as VWF ristocetin cofactor activity, VWF antigen and factor VIII. This approach would help identify those subjects who will probably benefit from a diagnosis of VWD. The next step involves performing a trial infusion with desmopressin in all patients who fail to exhibit an enhanced responsiveness to ristocetin. On the basis of these results and through a series of illustrative examples, the clinician will be able to select the best approach for the optimal management of VWD, according to the patient's characteristics and clinical circumstances.
oligonucleotides
2025-01-17 | Amelioration of a von Willebrand disease type 2B phenotype in vivo upon treatment with allele-selective siRNAs.
Treatment options for the bleeding disorder von Willebrand disease type 2B (VWD2B) are insufficient and fail to address the negative effects of circulating mutant von Willebrand factor (VWF). The dominant-negative nature of VWD2B makes functionally defective VWF an interesting therapeutic target. Previous in vitro studies have demonstrated the feasibility of allele-selective silencing of mutant VWF using small interfering RNAs (siRNAs) targeting common single nucleotide polymorphisms (SNPs) in the human VWF gene, an approach that can be applied irrespective of the disease-causing VWF mutation. This study aims to extend this concept to a heterozygous VWD2B mouse model (c.3946G>A; p.Val1316Met) here using mouse strain-specific genetic differences as proxy for human SNPs. Homozygous VWD2B C57BL/6J (2B-B6) mice were crossed with homozygous wild-type 129S1/SvImJ (129S) mice to create heterozygous 2B-B6.129S F1 offspring. These 2B-B6.129S mice were intravenously injected with endothelial-specific lipid nanoparticles loaded with the allele-selective siVwf.B6 or control and 96 hours later, lung Vwf messenger RNA, plasma VWF levels, and phenotypic characteristics were evaluated. Treatment with siVwf.B6 reduced total VWF levels by 50%, with an expected selective reduction in mutant VWF protein. This coincided with normalization of multimeric structure, improved VWF collagen binding/VWF antigen ratio, and normalized bleeding times in two-thirds of heterozygous 2B-B6.129S mice. Being a novel approach in the field of hemostasis, we proved, for VWD, in mice, the concept of selectively inhibiting a mutant dominant-negative allele with siRNAs targeting a single nucleotide variation rather than the disease-causing mutation. For dominant-negative VWD, this offers potential for a customized therapeutic strategy.
2022-01-17 | Ex vivo Improvement of a von Willebrand Disease Type 2A Phenotype Using an Allele-Specific Small-Interfering RNA.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is mainly caused by dominant-negative mutations in the multimeric protein von Willebrand factor (VWF). These mutations may either result in quantitative or qualitative defects in VWF. VWF is an endothelial protein that is secreted to the circulation upon endothelial activation. Once secreted, VWF multimers bind platelets and chaperone coagulation factor VIII in the circulation. Treatment of VWD focuses on increasing VWF plasma levels, but production and secretion of mutant VWF remain uninterrupted. Presence of circulating mutant VWF might, however, still affect normal hemostasis or functionalities of VWF beyond hemostasis. We hypothesized that inhibition of the production of mutant VWF improves the function of VWF overall and ameliorates VWD phenotypes. We previously proposed the use of allele-specific small-interfering RNAs (siRNAs) that target frequent VWF single nucleotide polymorphisms to inhibit mutant VWF. The aim of this study is to prove the functionality of these allele-specific siRNAs in endothelial colony-forming cells (ECFCs). We isolated ECFCs from a VWD type 2A patient with an intracellular multimerization defect, reduced VWF collagen binding, and a defective processing of proVWF to VWF. After transfection of an allele-specific siRNA that specifically inhibited expression of mutant VWF, we showed amelioration of the laboratory phenotype, with normalization of the VWF collagen binding, improvement in VWF multimers, and enhanced VWF processing. Altogether, we prove that allele-specific inhibition of the production of mutant VWF by siRNAs is a promising therapeutic strategy to improve VWD phenotypes.
2011-01-06 | The dominant-negative von Willebrand factor gene deletion p.P1127_C1948delinsR: molecular mechanism and modulation.
Understanding molecular mechanisms in the dominant inheritance of von Willebrand disease would improve our knowledge of pathophysiologic processes underlying its prevalence. Cellular models of severe type 2 von Willebrand disease, caused by a heterozygous deletion in the von Willebrand factor (VWF) gene, were produced to investigate the altered biosynthesis. Coexpression of the wild-type and in-frame deleted (p.P1127_C1948delinsR) VWF forms impaired protein secretion, high molecular weight multimer formation and function (VWF collagen-binding 1.9% ± 0.5% of wild-type), which mimicked the patient's phenotype. mRNA, protein, and cellular studies delineated the highly efficient dominant-negative mechanism, based on the key role of heterodimers as multimer terminators. The altered VWF, synthesized in large amounts with the correctly encoded "cysteine knot" domain, formed heterodimers and heterotetramers with wild-type VWF, in addition to deleted homodimers. Impaired multimerization was associated with reduced amounts of VWF in late endosomes. Correction of the dominant-negative effect was explored by siRNAs targeting the mRNA breakpoint, which selectively inhibited the in-frame deleted VWF expression. Although the small amount of the deleted protein synthesized after inhibition still exerted dominant, even though weakened, negative effects, the siRNA treatment restored secretion of large multimers with improved function (VWF collagen-binding 28.0% ± 3.3% of wild-type).
antibodies
2025-11-01 | HTRS2025.O8C.6 Cerebral Sinus Venous Thrombosis in Children and Young Adults: Comprehensive Management and Long-Term Outcomes-A Single Institutional Experience
Background: Non-factor replacement therapies have the potential to provide hemostatic balance in various bleeding disorders with less frequent dosing than factor concentrate prophylaxis.Preclinical studies of VGA039, a fully human, IgG4 monoclonal antibody targeting Protein S, have demonstrated its ability to increase thrombin generation across multiple inherited bleeding disorders, including von Willebrand disease (VWD), and prevent blood loss in vivo in a novel, non-human primate (NHP) VWD model.In healthy volunteers (HVs), single ascending doses (SADs) of subcutaneous (SC) VGA039 increase thrombin generation in a dose-and concentration-dependent manner.Objectives: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SC VGA039 in patients with VWD.Methods: This is an open-label phase I study (NCT05776069) conducted in adult individuals with VWD and approved by local ethics committees.Informed consent was obtained.Key eligibility criteria included: (1) symptomatic VWD of any type or subtype, (2) baseline FVIII activity level 50 IU/dL, (3) and no laboratory evidence of thrombophilia or prior history of thromboembolism.Dose escalations were determined based on emerging D-dimer levels, with a dose limiting toxicity (DLT) threshold set at 4 times the upper limit of normal (2.0 g/mL).Results: As of October 18, 2024, a total of 9 subjects have been dosed with 3.0, 4.5, or 7.0 mg/kg of SC VGA039: 1 with Type 1 VWD, 1 with Type 1 VWD + mild hemophilia A, 1 with Type 2A VWD, 2 with Type 2M VWD, 1 with Type 2N VWD, and 3 with Type 3 VWD.There were no drug-related adverse events, changes in coagulation laboratory parameters, thromboembolic events, DLTs, or injection-site reactions reported to date.VGA039 concentrations predicted to increase thrombin generation in VWD subjects to levels measured in HVs at baseline were sustained for >4 weeks following a single, SC 4.5 mg/kg dose (Figs 1 & 2).Two evaluable 4.5 mg/kg subjects with historical annualized bleeding rates (ABRs) >50 had reductions of 75% and 88% after a single dose of VGA039; the third evaluable subject had only 1 bleed post-VGA039.Efficacy for additional 4.5 and 7.0 mg/kg subjects will become evaluable in time for presentation at the meeting.Conclusions: VGA039 was safe and well tolerated in this SC SAD study in VWD subjects across all types.ABR reductions at VGA039 concentrations associated with increased thrombin generation, in the absence of DLTs, have been observed.SC multi-dose VGA039 investigation is planned.
2024-11-05 | A Phase Ia Study of VGA039, a Protein S-Targeting Monoclonal Antibody, in Individuals with Von Willebrand Disease Demonstrates Concentration-Dependent Increases in Thrombin Generation for Reducing Bleeding
Introduction : Non-factor replacement therapies have the potential to provide hemostatic balance in various bleeding disorders with less frequent dosing than factor concentrate prophylaxis. Preclinical studies of VGA039 have demonstrated its ability to increase thrombin generation across multiple inherited bleeding disorders, including von Willebrand disease (VWD), and prevent blood loss in vivo in a novel, non-human primate (NHP) VWD model. In healthy volunteers (HVs), single ascending doses (SADs) of subcutaneous (SC) VGA039 increase thrombin generation in a dose- and concentration-dependent manner (Schörgenhofer et al., ISTH 2024). The objective of this SAD study is to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SC VGA039 in VWD patients. Methods : This is an open-label phase Ia study (NCT05776069) conducted in adult individuals with VWD and approved by local ethics committees. Informed consent was obtained. Key eligibility criteria included: (1) symptomatic VWD of any type or subtype, (2) baseline FVIII activity level ≤50 IU/dL, (3) and no laboratory evidence of thrombophilia or prior history of thromboembolism. The starting SC SAD of 3.0 mg/kg was the pre-specified maximum dose tested in HVs and selected as the initial SAD to be tested in individuals with VWD. Continued dose escalations in subsequent cohorts were determined based on emerging D-dimer levels, with a dose limiting toxicity (DLT) threshold set at 4 times the upper limit of normal. Results : As of August 1, 2024, a total of 6 subjects equally divided into 2 SAD cohorts (3.0 and 4.5 mg/kg) have been dosed: 1 with Type 1 VWD + mild hemophilia A, 1 with Type 2A VWD, 2 with Type 2M VWD, and 2 with Type 3 VWD. Related to VGA039, there were no adverse events, changes in coagulation laboratory parameters, thromboembolic events, DLTs, or injection-site reactions that have been reported. While mild increases in D-dimer levels were observed in healthy volunteers at 3.0 mg/kg, no significant D-dimer elevations have been observed in VWD subjects at either 3.0 or 4.5 mg/kg. Preliminary thrombin generation results show increased thrombin generation at similar VGA039 concentrations in VWD subjects as in HVs. Additional clinical, PK, and PD data for these and subsequent SAD cohort(s) will be presented at the meeting. Conclusions : Clinical data suggest VGA039 is well tolerated and can increase thrombin generation in the absence of clinically significant D-dimer elevations in individuals with VWD. Drug concentration data continue to support the potential for weekly or less frequent SC prophylactic dosing. Further SAD evaluation of VGA039 in VWD patients is ongoing, and future multi-dose and surgical prophylaxis investigation is planned.
2024-02-02 | Distinct platelet interactions with soluble and immobilized von Willebrand factor modulate platelet adhesion and aggregation with differential impact on hemostasis and thrombosis
Arterial thrombosis is a prevailing and lethal pathological condition that remains difficult to treat or prevent without potentially serious side effects, mostly hemorrhagic in nature. Platelets and von Willebrand factor (VWF) have a recognized major role in the pathogenesis of arterial thrombosis. Platelets bind to surface immobilized VWF for initial adhesion to injured vascular sites, but also interact with soluble VWF to aggregate into thrombi, particularly under flow conditions creating elevated shear stress. Whether the binding of immobilized and soluble VWF to platelets is regulated by separate mechanisms and how they respectively regulate hemostasis and thrombosis remains unclear. Using targeted mutagenesis we engineered VWF to achieve modified binding kinetics with the platelet receptor glycoprotein (GP) Ibα and discovered that the interactions of immobilized and soluble VWF with platelets can be differentially regulated with distinct consequences on platelet adhesion and aggregation. Based on these results, we studied a monoclonal antibody, NMC4, known to bind to an epitope in the VWFA1 domain and to inhibit preferentially platelet aggregation under elevated shear stress conditions. We found that NMC4 was less efficient in reducing platelet adhesion to immobilized VWF than platelet aggregation mediated by soluble VWF and, surprisingly, also inhibited arterial thrombosis in a mouse model of ferric chloride-induced carotid artery occlusion at a dose that failed to prolong post-injury bleeding. Thus, our current findings help delineate interrelated biochemical and biophysical mechanisms underlying VWF function in vascular health; and suggest selective inhibition of VWF-mediated platelet aggregation as opposed to adhesion as a strategy to prevent arterial thrombosis while minimizing bleeding complications.
2022-09-08 | The impact of aberrant von Willebrand factor-GPIbα interaction on megakaryopoiesis and platelets in humanized type 2B von Willebrand disease model mouse.
Type 2B von Willebrand disease (VWD) is caused by gain-of-function mutations in von Willebrand factor (VWF). Increased VWF affinity for GPIba results in loss of high molecular weight multimers and enhanced platelet clearance, both contributing to the bleeding phenotype. Severity of the symptoms vary among type 2B VWD patients, with some developing thrombocytopenia only under stress conditions. Efforts have been made to study underlying pathophysiology for platelet abnormalities, but animal studies have been limited because of species specificity in the VWF-GPIba interaction. Here, we generated a severe form of type 2B VWD (p.V1316M) knockin mice in the context of human VWF exon 28 (encoding A1 and A2 domains) and crossed them with human GPIba transgenic strain. Heterozygous mutant mice recapitulated the phenotype of type 2B VWD in autosomal dominant manner and presented severe macrothrombocytopenia. Of note, platelets remaining in the circulation had extracytoplasmic GPIba shed-off from the cell surface. Reciprocal bone marrow transplantation determined mutant VWF produced from endothelial cells as the major cause of the platelet phenotype in type 2B VWD mice. Moreover, altered megakaryocyte maturation in the bone marrow and enhanced extramedullary megakaryopoiesis in the spleen were observed. Interestingly, injection of anti-VWF A1 blocking antibody (NMC-4) not only ameliorated platelet count and GPIba expression, but also reversed MK ploidy shift. In conclusion, we present a type 2B VWD mouse model with humanized VWF-GPIba interaction which demonstrated direct influence of aberrant VWF-GPIba binding on megakaryocytes.
2022-05-01 | Towards novel treatment options in von Willebrand disease
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.
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2025-12-18 | Allele-selective disruption of pathogenic VWF variants in type 2 von Willebrand disease using CRISPR/Cas9.
In contrast to major innovations in treating severe hemophilia, the treatment of severe von Willebrand disease (VWD) remains limited to intravenous infusion of von Willebrand factor (VWF) concentrates. To date, no gene therapy-based approaches for the treatment of VWD have been developed, largely owing to the disease's heterogeneous mutational landscape and the challenge of specifically targeting VWF production in endothelial cells. In this study, we developed a novel gene therapy strategy for patients with VWD caused by heterozygous dominant-negative VWF variants. Our strategy permanently inactivates VWF variants by selectively disrupting the pathogenic allele's open reading frame via the introduction of indels by Cas9. To circumvent the challenge of designing variant-specific strategies, we targeted the common single nucleotide polymorphism (SNP) rs1800378 in VWF. We used endothelial colony-forming cells (ECFCs) from patients with VWD2A and VWD2B with heterozygous p.C1190R and p.R1306W variants, respectively, to demonstrate ex vivo proof of principle. Using next-generation sequencing analysis, we show efficient and allele-selective knockout of VWF, while maintaining VWF expression of the nontargeted allele. Variant mapping mass spectrometry that discriminates between wild-type and variant VWF proteoforms confirmed selective reduction of variant allele expression, which was accompanied by reversal of cellular disease phenotypes in ECFCs. This study shows the feasibility of a novel gene editing strategy for VWD that, by virtue of its targeting of a common SNP, can be broadly applicable and can be used to design treatments for VWD without being constrained by the disease-causing variant, pathogenic mechanism, or VWD subtype.
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