RARE DISEASE
Von Willebrand disease type 2A
Von Willebrand disease type 2A
Von Willebrand disease type 2A
Drug discovery
99
papers
On emerging therapies
Overview
Von Willebrand disease type 2A is a qualitative clotting disorder caused by dysfunctional von Willebrand factor (VWF) with deficient high-molecular-weight multimers, impairing platelet adhesion. It presents with mucocutaneous bleeding (epistaxis, menorrhagia), prolonged post-traumatic/surgical bleeding, and moderate-to-severe hemorrhagic phenotypes due to reduced VWF-platelet binding [1][5][10]. Diagnosis relies on VWF activity-to-antigen ratio <0.7 and abnormal multimer analysis [5][8].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
99 drug discovery papers about Von Willebrand disease type 2A. Recent publications:
99 drug discovery papers about Von Willebrand disease type 2A. Recent publications:
categories:
Small molecules
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.
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.
2021-12-06 | von Willebrand disease: what does the future hold?
von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin, and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal of reaching superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches, such as gene therapy using dual-vector adenoassociated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase factor FVIII levels in VWD-type 3 or 2N patients are discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) are presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.
2021-09-24 | Emicizumab improves thrombus formation of type 2A von willebrand disease under high shear condition.
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. To examine the coagulant potential of emicizumab in type 2A VWD. 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 ). 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. 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.
small molecules
2026-09-17 | DDAVP Challenges in 170 Children With von Willebrand Disease: Response Classification Varies According to Criteria Used.
Individuals diagnosed with types 1/1C/2A/2M von Willebrand disease (VWD) typically undergo a desmopressin (DDAVP) challenge to assess therapeutic benefit. This involves measuring von Willebrand factor antigen (VWF:Ag), activity (VWF:Act; VWF:RCo/VWF:GPIbM/VWF:Ab), and coagulant factor VIII (FVIII:C) levels 0 (pre), 1, and 4-h post-DDAVP administration. Diverse systems exist to classify DDAVP response (complete (CR), partial (PR), and non-responders (NR)). These have not been compared in a paediatric population. To compare DDAVP response classification systems in children with VWD and to explore predictors of DDAVP response: VWD subtype, age, blood group, and baseline VWF:Act. In this retrospective single-centre study, subjects were included if they had type 1/1C/2A/2M VWD and underwent a DDAVP challenge. DDAVP response was classified according to two recent classification systems: Castaman (2020) and Connell et al. (2021). 170 subjects were included (124, 12, 13, and 21 with types 1/1C/2A/2M VWD, respectively; 84 male, 86 female). Median age at DDAVP challenge was 7.1 years [IQR 4.8-10.8]. CR rate varied from 59% (Connell et al.) to 81% (Castaman). Those with type 1 had higher rates of CR compared to types 1C/2A/2M VWD. Age and blood group did not predict DDAVP response. 90%-98% of those with baseline VWF:Act ≥0.30 had a CR. Inconsistent DDAVP response criteria between classification systems may lead to inconsistent use of DDAVP. As the Castaman system does not require a >2-fold increase in VWF:Act, it may be more realistic in children who may already have a stress-induced increase in levels at time 0-h of the challenge.
2026-08-12 | Recurrent Hematuria Unveiling Renal Lymphangioma: A Diagnostic Challenge in a Patient with von Willebrand Disease
Abstract Renal lymphangioma is a rare benign lymphatic malformation that may present with hematuria and flank pain. We report the case of a 16-year-old female with type 2A von Willebrand disease who developed recurrent macroscopic hematuria and left lumbar pain. Imaging revealed a multiloculated intrarenal cystic lesion consistent with renal lymphangioma. After recurrence of symptoms and failure of conservative management, percutaneous intrarenal sclerotherapy with doxycycline was performed under factor replacement, resulting in complete symptom resolution and no recurrence on follow-up. This case highlights the diagnostic challenge in coagulopathic patients and supports sclerotherapy as an effective minimally invasive treatment.
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.
2023-01-27 | Enhanced VWF clearance in low VWF pathogenesis: limitations of the VWFpp/VWF:Ag ratio and clinical significance.
Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of type 1 and type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (range, 30-50 IU/dL; low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to the pathobiology of low VWF. Patients with low VWF were recruited to the LoVIC study after ethics approval and receipt of informed consent. Desmopressin was administered IV in 75 patients, and blood samples were drawn at baseline and at the 1-hour and 4-hour time points. As defined by recent ASH/ISTH/NHF/WFH guidelines, 20% of our low-VWF cohort demonstrated significantly enhanced VWF clearance. Importantly, from a clinical perspective, this enhanced VWF clearance was seen after desmopressin infusion, but did not affect the steady-state VWF propeptide (VWFpp)-to-VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) in most cases. The discrepancy between the VWFpp/VWF:Ag ratio and desmopressin fall-off rates in patients with mild quantitative VWD may have reflected alteration in VWFpp clearance kinetics. Finally, bleeding scores were significantly lower in patients with low VWF with enhanced VWF clearance, compared with those in whom reduced VWF biosynthesis represented the principle pathogenic mechanism. This trial was registered at http://www.clinicaltrials.gov as #NCT03167320.
2018-10-03 | LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B.
von Willebrand disease type 2B (VWD-type 2B) is characterized by gain-of-function mutations of von Willebrand factor (vWF) that enhance its binding to platelet glycoprotein Ibα and alter the protein's multimeric structure. Patients with VWD-type 2B display variable extents of bleeding associated with macrothrombocytopenia and sometimes with thrombopathy. Here, we addressed the molecular mechanism underlying the severe macrothrombocytopenia both in a knockin murine model for VWD-type 2B by introducing the p.V1316M mutation in the murine Vwf gene and in a patient bearing this mutation. We provide evidence of a profound defect in megakaryocyte (MK) function since: (a) the extent of proplatelet formation was drastically decreased in 2B MKs, with thick proplatelet extensions and large swellings; and (b) 2B MKs presented actin disorganization that was controlled by upregulation of the RhoA/LIM kinase (LIMK)/cofilin pathway. In vitro and in vivo inhibition of the LIMK/cofilin signaling pathway rescued actin turnover and restored normal proplatelet formation, platelet count, and platelet size. These data indicate, to our knowledge for the first time, that the severe macrothrombocytopenia in VWD-type 2B p.V1316M is due to an MK dysfunction that originates from a constitutive activation of the RhoA/LIMK/cofilin pathway and actin disorganization. This suggests a potentially new function of vWF during platelet formation that involves regulation of actin dynamics.
proteins
2026-08-20 | A Rare Combination of von Willebrand Disease Type 2A and 2M: Diagnostic and Therapeutic Challenges - A case report.
Combined von Willebrand disease (VWD) type 2A/2M is a rare phenotype characterized by overlapping qualitative defects affecting both multimer structure and von Willebrand factor (VWF) function. How can congenital VWD be distinguished from acquired von Willebrand syndrome (AVWS) when both conditions contribute to an abnormal laboratory phenotype? A 73-year-old man with a previous diagnosis of VWD type 2M presented with severe gastrointestinal bleeding and severe aortic stenosis. Repeat VWF analysis showed loss of high-molecular-weight multimers, consistent with AVWS secondary to shear stress. Treatment with recombinant VWF (Veyvondi) restored high-molecular-weight multimers and achieved hemostatic control. Following transcatheter aortic valve implantation, the abnormal multimer pattern persisted. Subsequent genetic testing identified a pathogenic VWF variant, p.Leu1446Pro, confirming congenital VWD type 2A/2M. This case demonstrates how AVWS may obscure an underlying congenital VWD phenotype. Combined phenotypic and molecular diagnostics are essential for accurate classification, therapeutic decision making, and interpretation of complex VWD phenotypes.
2026-07-25 | Functional Characterization of the VWF p.Cys2163Tyr Variant Reveals Impaired Secretion and Intracellular Processing
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet the contribution of specific VWF domains to its pathogenesis remains incompletely understood. In particular, the role of the D4 domain in VWF secretion, intracellular maturation, and multimer formation has not been fully elucidated. Here, we investigated the functional impact of a heterozygous p.Cys2163Tyr variant located in the D4 domain, identified in a patient with a severe bleeding phenotype, using clinical evaluation, genetic analysis, family studies, and in vitro expression assays. Laboratory testing revealed markedly reduced VWF:Ag (6.8 IU/dL), VWF:GPIbR (0.1 IU/dL), and FVIII:C levels, indicating a severe VWD phenotype in the proband. Plasma VWF multimer analysis showed a markedly reduced overall VWF signal with an almost complete absence of high-molecular-weight multimers, supporting classification of the phenotype as severe type 2A VWD. The heterozygous c.6488G>A (p.Cys2163Tyr) variant was also present in asymptomatic family members, indicating incomplete segregation with the severe phenotype and suggesting that this variant alone is insufficient to explain the proband’s disease severity. Notably, the proband’s mother exhibited mildly reduced VWF levels in the absence of this variant, suggesting the possible contribution of an additional unidentified defect or modifier affecting the maternal allele. In vitro expression demonstrated preserved intracellular VWF antigen, markedly reduced secretion of mutant VWF, and loss of high-molecular-weight VWF multimers. Together, these findings indicate that VWF p.Cys2163Tyr is a functionally deleterious variant that markedly impairs VWF secretion and high-molecular-weight multimer formation in vitro. However, the incomplete segregation observed in the family suggests that this heterozygous variant alone may not fully account for the proband’s severe type 2A VWD phenotype.
2026-03-27 | Isolated Low von Willebrand Factor Collagen-Binding Activity in Patients with a Positive Bleeding Phenotype: Diagnostic Implications for Von Willebrand Disease
Introduction von Willebrand disease (VWD) is the most commonly inherited bleeding disorder worldwide.[ 1 ] [ 2 ] [ 3 ] Diagnostic guidelines from the American Society of Hematology (ASH), the International Society of Thrombosis and Hemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) define VWD as the presence of reduced von Willebrand factor (VWF) antigen (VWF:Ag) or platelet-dependent VWF activity, specifically levels <0.30 IU/mL, or <0.50 IU/mL in the presence of a positive bleeding phenotype.[ 1 ] Patients with type 1 VWD are known to demonstrate a preserved platelet-dependent VWF activity/VWF:Ag ratio (>0.7), reflecting a predominantly quantitative deficiency of VWF, whereas type 2 variants show qualitative functional abnormalities associated with reduced platelet-dependent VWF activity/VWF:Ag ratios.[ 1 ] VWF is known to play a central role in hemostasis by mediating platelet adhesion, stabilizing coagulation factor VIII (FVIII), and binding to subendothelial collagen at sites of vascular injury. The VWF collagen-binding activity (VWF:CB) assay measures this latter function and is commonly interpreted as a ratio with VWF:Ag to aid in subtyping type 2 VWD.[ 1 ] [ 4 ] [ 5 ] Low VWF:CB/VWF:Ag ratios (<0.6–0.7) characterize type 2A and 2B VWD due to decreased or absent high-molecular-weight VWF multimers.[ 4 ] Type 2M VWD is defined by qualitative VWF defects with normal multimer distribution and reduced VWF activity/VWF:Ag ratios.[ 4 ] Although collagen-binding defects may be present in select cases, VWF:CB/VWF:Ag ratios are usually preserved, and isolated reductions in VWF:CB are not characteristic of this subtype.[ 1 ] In type 1 VWD, VWF:CB is generally proportionate to VWF:Ag, resulting in preserved VWF:CB/VWF:Ag ratios. Current diagnostic algorithms do not incorporate VWF:CB into the initial evaluation of suspected VWD.[ 1 ] [ 3 ] [ 6 ] Consequently, a subset of patients with clinically significant bleeding phenotypes who present with isolated reductions in VWF:CB, despite normal VWF:Ag, VWF activity levels, and VWF activity/VWF:Ag ratios, are at risk of remaining undiagnosed under existing VWD diagnostic criteria.[ 7 ] Whether these individuals with isolated VWF:CB deficiency represent a variant of type 1 VWD, or a distinct phenotype, remains unclear. Here, we describe a cohort of children, adolescents, and young adults with isolated low VWF:CB and compare their clinical and laboratory features with those of patients diagnosed with type 1 VWD. Contributors' Statement R.S.K.: Conceptualization, data curation, formal analysis, writing–original draft, writing–review and editing. K.M.R.: Data curation, writing–review and editing. J.A.D.: Conceptualization, writing–review and editing. F.F.C-M.: Conceptualization, investigation, writing–original draft, writing–review and editing. Publication History Received: 16 December 2025 Accepted after revision: 10 March 2026 Article published online: 27 March 2026 © 2026. Thieme. All rights reserved. Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
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.
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.
2021-05-14 | In vivo modulation of a dominant-negative variant in mouse models of von Willebrand disease type 2A.
Essentials Treatment options for von Willebrand disease (VWD) patients are limited. The p.P1127_C1948delinsR deletion/variant is a useful model to study VWD in vitro and in vivo. Counteracting dominant-negative effects restores von Willebrand factor multimerization in mice. This is the first siRNA-based treatment applied to a mouse model of VWD-type 2A. ABSTRACT: Background Treatment options for patients suffering from von Willebrand disease (VWD) are limited. Von Willebrand factor (VWF) is a polymeric protein that undergoes regulated dimerization and subsequent multimerization during its biosynthesis. Numerous heterozygous variants within the VWF gene display a dominant-negative effect and result in severe VWD. Previous studies have suggested that preventing the assembly of wild-type and mutant heteropolymers using siRNAs may have beneficial effects on VWF phenotypes in vitro. Objectives To study heterozygous dominant-negative variants in vivo, we developed a mouse model of VWD-type 2A and tested two independent strategies to modulate its detrimental effect. Methods The p.P1127_C1948delinsR deletion/variant, causing defective VWF multimerization, was expressed in mice as a model of VWD-type 2A variant. Two corrective strategies were applied. For the first time in a mouse model of VWD, we applied siRNAs selectively inhibiting translation of the mutant transcripts and we combined the VWD-type 2A deletion with the Cys to Arg substitution at position 2773, which is known to prevent dimerization. Results The RNA silencing approach induced a modest but consistent improvement of the VWF multimer profile. However, due to incomplete efficiency, the dominant-negative effect of the original variant could not be completely prevented. In contrast, the DNA approach resulted in increased antigen levels and restoration of a normal multimer profile. Conclusions Our data showed that preventing the detrimental impact of dominant-negative VWF variants by independent molecular mechanisms has beneficial consequences in vivo, in mouse models of dominant VWD.
2019-09-16 | Correction of a dominant-negative von Willebrand factor multimerization defect by small interfering RNA-mediated allele-specific inhibition of mutant von Willebrand factor.
Essentials Substitution therapy for von Willebrand (VW) disease leaves mutant VW factor (VWF) unhindered. Presence of mutant VWF may negatively affect phenotypes despite treatment. Inhibition of VWF by allele-specific siRNAs targeting single-nucleotide polymorphisms is effective. Allele-specific inhibition of VWF p.Cys2773Ser improves multimerization. Background Treatment of the bleeding disorder von Willebrand disease (VWD) focuses on increasing von Willebrand factor (VWF) levels by administration of desmopressin or VWF-containing concentrates. Both therapies leave the production of mutant VWF unhindered, which may have additional consequences, such as thrombocytopenia in patients with VWD type 2B, competition between mutant and normal VWF for platelet receptors, and the potential development of intestinal angiodysplasia. Most cases of VWD are caused by dominant-negative mutations in VWF, and we hypothesize that diminishing expression of mutant VWF positively affects VWD phenotypes. Objectives To investigate allele-specific inhibition of VWF by applying small interfering RNAs (siRNAs) targeting common single-nucleotide polymorphisms (SNPs) in VWF. This approach allows allele-specific knockdown irrespective of the mutations causing VWD. Methods Four SNPs with a high predicted heterozygosity within VWF were selected, and siRNAs were designed against both alleles of the four SNPs. siRNA efficiency, allele specificity and siRNA-mediated phenotypic improvements were determined in VWF-expressing HEK293 cells. Results Twelve siRNAs were able to efficiently inhibit single VWF alleles in HEK293 cells that stably produce VWF. Transient cotransfections of these siRNAs with two VWF alleles resulted in a clear preference for the targeted allele over the untargeted allele for 11 siRNAs. We also demonstrated siRNA-mediated phenotypic improvement of the VWF multimerization pattern of the VWD type 2A mutation VWF p.Cys2773Ser. Conclusions Allele-specific siRNAs are able to distinguish VWF alleles on the basis of one nucleotide variation, and are able to improve a severe multimerization defect caused by VWF p.Cys2773Ser. This holds promise for the therapeutic application of allele-specific siRNAs in dominant-negative VWD.
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).
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.
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.
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.
2021-12-06 | von Willebrand disease: what does the future hold?
von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin, and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal of reaching superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches, such as gene therapy using dual-vector adenoassociated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase factor FVIII levels in VWD-type 3 or 2N patients are discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) are presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.
2021-09-24 | Emicizumab improves thrombus formation of type 2A von willebrand disease under high shear condition.
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. To examine the coagulant potential of emicizumab in type 2A VWD. 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 ). 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. 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.
small molecules
2026-09-17 | DDAVP Challenges in 170 Children With von Willebrand Disease: Response Classification Varies According to Criteria Used.
Individuals diagnosed with types 1/1C/2A/2M von Willebrand disease (VWD) typically undergo a desmopressin (DDAVP) challenge to assess therapeutic benefit. This involves measuring von Willebrand factor antigen (VWF:Ag), activity (VWF:Act; VWF:RCo/VWF:GPIbM/VWF:Ab), and coagulant factor VIII (FVIII:C) levels 0 (pre), 1, and 4-h post-DDAVP administration. Diverse systems exist to classify DDAVP response (complete (CR), partial (PR), and non-responders (NR)). These have not been compared in a paediatric population. To compare DDAVP response classification systems in children with VWD and to explore predictors of DDAVP response: VWD subtype, age, blood group, and baseline VWF:Act. In this retrospective single-centre study, subjects were included if they had type 1/1C/2A/2M VWD and underwent a DDAVP challenge. DDAVP response was classified according to two recent classification systems: Castaman (2020) and Connell et al. (2021). 170 subjects were included (124, 12, 13, and 21 with types 1/1C/2A/2M VWD, respectively; 84 male, 86 female). Median age at DDAVP challenge was 7.1 years [IQR 4.8-10.8]. CR rate varied from 59% (Connell et al.) to 81% (Castaman). Those with type 1 had higher rates of CR compared to types 1C/2A/2M VWD. Age and blood group did not predict DDAVP response. 90%-98% of those with baseline VWF:Act ≥0.30 had a CR. Inconsistent DDAVP response criteria between classification systems may lead to inconsistent use of DDAVP. As the Castaman system does not require a >2-fold increase in VWF:Act, it may be more realistic in children who may already have a stress-induced increase in levels at time 0-h of the challenge.
2026-08-12 | Recurrent Hematuria Unveiling Renal Lymphangioma: A Diagnostic Challenge in a Patient with von Willebrand Disease
Abstract Renal lymphangioma is a rare benign lymphatic malformation that may present with hematuria and flank pain. We report the case of a 16-year-old female with type 2A von Willebrand disease who developed recurrent macroscopic hematuria and left lumbar pain. Imaging revealed a multiloculated intrarenal cystic lesion consistent with renal lymphangioma. After recurrence of symptoms and failure of conservative management, percutaneous intrarenal sclerotherapy with doxycycline was performed under factor replacement, resulting in complete symptom resolution and no recurrence on follow-up. This case highlights the diagnostic challenge in coagulopathic patients and supports sclerotherapy as an effective minimally invasive treatment.
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.
2023-01-27 | Enhanced VWF clearance in low VWF pathogenesis: limitations of the VWFpp/VWF:Ag ratio and clinical significance.
Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of type 1 and type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (range, 30-50 IU/dL; low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to the pathobiology of low VWF. Patients with low VWF were recruited to the LoVIC study after ethics approval and receipt of informed consent. Desmopressin was administered IV in 75 patients, and blood samples were drawn at baseline and at the 1-hour and 4-hour time points. As defined by recent ASH/ISTH/NHF/WFH guidelines, 20% of our low-VWF cohort demonstrated significantly enhanced VWF clearance. Importantly, from a clinical perspective, this enhanced VWF clearance was seen after desmopressin infusion, but did not affect the steady-state VWF propeptide (VWFpp)-to-VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) in most cases. The discrepancy between the VWFpp/VWF:Ag ratio and desmopressin fall-off rates in patients with mild quantitative VWD may have reflected alteration in VWFpp clearance kinetics. Finally, bleeding scores were significantly lower in patients with low VWF with enhanced VWF clearance, compared with those in whom reduced VWF biosynthesis represented the principle pathogenic mechanism. This trial was registered at http://www.clinicaltrials.gov as #NCT03167320.
2018-10-03 | LIM kinase/cofilin dysregulation promotes macrothrombocytopenia in severe von Willebrand disease-type 2B.
von Willebrand disease type 2B (VWD-type 2B) is characterized by gain-of-function mutations of von Willebrand factor (vWF) that enhance its binding to platelet glycoprotein Ibα and alter the protein's multimeric structure. Patients with VWD-type 2B display variable extents of bleeding associated with macrothrombocytopenia and sometimes with thrombopathy. Here, we addressed the molecular mechanism underlying the severe macrothrombocytopenia both in a knockin murine model for VWD-type 2B by introducing the p.V1316M mutation in the murine Vwf gene and in a patient bearing this mutation. We provide evidence of a profound defect in megakaryocyte (MK) function since: (a) the extent of proplatelet formation was drastically decreased in 2B MKs, with thick proplatelet extensions and large swellings; and (b) 2B MKs presented actin disorganization that was controlled by upregulation of the RhoA/LIM kinase (LIMK)/cofilin pathway. In vitro and in vivo inhibition of the LIMK/cofilin signaling pathway rescued actin turnover and restored normal proplatelet formation, platelet count, and platelet size. These data indicate, to our knowledge for the first time, that the severe macrothrombocytopenia in VWD-type 2B p.V1316M is due to an MK dysfunction that originates from a constitutive activation of the RhoA/LIMK/cofilin pathway and actin disorganization. This suggests a potentially new function of vWF during platelet formation that involves regulation of actin dynamics.
proteins
2026-08-20 | A Rare Combination of von Willebrand Disease Type 2A and 2M: Diagnostic and Therapeutic Challenges - A case report.
Combined von Willebrand disease (VWD) type 2A/2M is a rare phenotype characterized by overlapping qualitative defects affecting both multimer structure and von Willebrand factor (VWF) function. How can congenital VWD be distinguished from acquired von Willebrand syndrome (AVWS) when both conditions contribute to an abnormal laboratory phenotype? A 73-year-old man with a previous diagnosis of VWD type 2M presented with severe gastrointestinal bleeding and severe aortic stenosis. Repeat VWF analysis showed loss of high-molecular-weight multimers, consistent with AVWS secondary to shear stress. Treatment with recombinant VWF (Veyvondi) restored high-molecular-weight multimers and achieved hemostatic control. Following transcatheter aortic valve implantation, the abnormal multimer pattern persisted. Subsequent genetic testing identified a pathogenic VWF variant, p.Leu1446Pro, confirming congenital VWD type 2A/2M. This case demonstrates how AVWS may obscure an underlying congenital VWD phenotype. Combined phenotypic and molecular diagnostics are essential for accurate classification, therapeutic decision making, and interpretation of complex VWD phenotypes.
2026-07-25 | Functional Characterization of the VWF p.Cys2163Tyr Variant Reveals Impaired Secretion and Intracellular Processing
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet the contribution of specific VWF domains to its pathogenesis remains incompletely understood. In particular, the role of the D4 domain in VWF secretion, intracellular maturation, and multimer formation has not been fully elucidated. Here, we investigated the functional impact of a heterozygous p.Cys2163Tyr variant located in the D4 domain, identified in a patient with a severe bleeding phenotype, using clinical evaluation, genetic analysis, family studies, and in vitro expression assays. Laboratory testing revealed markedly reduced VWF:Ag (6.8 IU/dL), VWF:GPIbR (0.1 IU/dL), and FVIII:C levels, indicating a severe VWD phenotype in the proband. Plasma VWF multimer analysis showed a markedly reduced overall VWF signal with an almost complete absence of high-molecular-weight multimers, supporting classification of the phenotype as severe type 2A VWD. The heterozygous c.6488G>A (p.Cys2163Tyr) variant was also present in asymptomatic family members, indicating incomplete segregation with the severe phenotype and suggesting that this variant alone is insufficient to explain the proband’s disease severity. Notably, the proband’s mother exhibited mildly reduced VWF levels in the absence of this variant, suggesting the possible contribution of an additional unidentified defect or modifier affecting the maternal allele. In vitro expression demonstrated preserved intracellular VWF antigen, markedly reduced secretion of mutant VWF, and loss of high-molecular-weight VWF multimers. Together, these findings indicate that VWF p.Cys2163Tyr is a functionally deleterious variant that markedly impairs VWF secretion and high-molecular-weight multimer formation in vitro. However, the incomplete segregation observed in the family suggests that this heterozygous variant alone may not fully account for the proband’s severe type 2A VWD phenotype.
2026-03-27 | Isolated Low von Willebrand Factor Collagen-Binding Activity in Patients with a Positive Bleeding Phenotype: Diagnostic Implications for Von Willebrand Disease
Introduction von Willebrand disease (VWD) is the most commonly inherited bleeding disorder worldwide.[ 1 ] [ 2 ] [ 3 ] Diagnostic guidelines from the American Society of Hematology (ASH), the International Society of Thrombosis and Hemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) define VWD as the presence of reduced von Willebrand factor (VWF) antigen (VWF:Ag) or platelet-dependent VWF activity, specifically levels <0.30 IU/mL, or <0.50 IU/mL in the presence of a positive bleeding phenotype.[ 1 ] Patients with type 1 VWD are known to demonstrate a preserved platelet-dependent VWF activity/VWF:Ag ratio (>0.7), reflecting a predominantly quantitative deficiency of VWF, whereas type 2 variants show qualitative functional abnormalities associated with reduced platelet-dependent VWF activity/VWF:Ag ratios.[ 1 ] VWF is known to play a central role in hemostasis by mediating platelet adhesion, stabilizing coagulation factor VIII (FVIII), and binding to subendothelial collagen at sites of vascular injury. The VWF collagen-binding activity (VWF:CB) assay measures this latter function and is commonly interpreted as a ratio with VWF:Ag to aid in subtyping type 2 VWD.[ 1 ] [ 4 ] [ 5 ] Low VWF:CB/VWF:Ag ratios (<0.6–0.7) characterize type 2A and 2B VWD due to decreased or absent high-molecular-weight VWF multimers.[ 4 ] Type 2M VWD is defined by qualitative VWF defects with normal multimer distribution and reduced VWF activity/VWF:Ag ratios.[ 4 ] Although collagen-binding defects may be present in select cases, VWF:CB/VWF:Ag ratios are usually preserved, and isolated reductions in VWF:CB are not characteristic of this subtype.[ 1 ] In type 1 VWD, VWF:CB is generally proportionate to VWF:Ag, resulting in preserved VWF:CB/VWF:Ag ratios. Current diagnostic algorithms do not incorporate VWF:CB into the initial evaluation of suspected VWD.[ 1 ] [ 3 ] [ 6 ] Consequently, a subset of patients with clinically significant bleeding phenotypes who present with isolated reductions in VWF:CB, despite normal VWF:Ag, VWF activity levels, and VWF activity/VWF:Ag ratios, are at risk of remaining undiagnosed under existing VWD diagnostic criteria.[ 7 ] Whether these individuals with isolated VWF:CB deficiency represent a variant of type 1 VWD, or a distinct phenotype, remains unclear. Here, we describe a cohort of children, adolescents, and young adults with isolated low VWF:CB and compare their clinical and laboratory features with those of patients diagnosed with type 1 VWD. Contributors' Statement R.S.K.: Conceptualization, data curation, formal analysis, writing–original draft, writing–review and editing. K.M.R.: Data curation, writing–review and editing. J.A.D.: Conceptualization, writing–review and editing. F.F.C-M.: Conceptualization, investigation, writing–original draft, writing–review and editing. Publication History Received: 16 December 2025 Accepted after revision: 10 March 2026 Article published online: 27 March 2026 © 2026. Thieme. All rights reserved. Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
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.
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.
2021-05-14 | In vivo modulation of a dominant-negative variant in mouse models of von Willebrand disease type 2A.
Essentials Treatment options for von Willebrand disease (VWD) patients are limited. The p.P1127_C1948delinsR deletion/variant is a useful model to study VWD in vitro and in vivo. Counteracting dominant-negative effects restores von Willebrand factor multimerization in mice. This is the first siRNA-based treatment applied to a mouse model of VWD-type 2A. ABSTRACT: Background Treatment options for patients suffering from von Willebrand disease (VWD) are limited. Von Willebrand factor (VWF) is a polymeric protein that undergoes regulated dimerization and subsequent multimerization during its biosynthesis. Numerous heterozygous variants within the VWF gene display a dominant-negative effect and result in severe VWD. Previous studies have suggested that preventing the assembly of wild-type and mutant heteropolymers using siRNAs may have beneficial effects on VWF phenotypes in vitro. Objectives To study heterozygous dominant-negative variants in vivo, we developed a mouse model of VWD-type 2A and tested two independent strategies to modulate its detrimental effect. Methods The p.P1127_C1948delinsR deletion/variant, causing defective VWF multimerization, was expressed in mice as a model of VWD-type 2A variant. Two corrective strategies were applied. For the first time in a mouse model of VWD, we applied siRNAs selectively inhibiting translation of the mutant transcripts and we combined the VWD-type 2A deletion with the Cys to Arg substitution at position 2773, which is known to prevent dimerization. Results The RNA silencing approach induced a modest but consistent improvement of the VWF multimer profile. However, due to incomplete efficiency, the dominant-negative effect of the original variant could not be completely prevented. In contrast, the DNA approach resulted in increased antigen levels and restoration of a normal multimer profile. Conclusions Our data showed that preventing the detrimental impact of dominant-negative VWF variants by independent molecular mechanisms has beneficial consequences in vivo, in mouse models of dominant VWD.
2019-09-16 | Correction of a dominant-negative von Willebrand factor multimerization defect by small interfering RNA-mediated allele-specific inhibition of mutant von Willebrand factor.
Essentials Substitution therapy for von Willebrand (VW) disease leaves mutant VW factor (VWF) unhindered. Presence of mutant VWF may negatively affect phenotypes despite treatment. Inhibition of VWF by allele-specific siRNAs targeting single-nucleotide polymorphisms is effective. Allele-specific inhibition of VWF p.Cys2773Ser improves multimerization. Background Treatment of the bleeding disorder von Willebrand disease (VWD) focuses on increasing von Willebrand factor (VWF) levels by administration of desmopressin or VWF-containing concentrates. Both therapies leave the production of mutant VWF unhindered, which may have additional consequences, such as thrombocytopenia in patients with VWD type 2B, competition between mutant and normal VWF for platelet receptors, and the potential development of intestinal angiodysplasia. Most cases of VWD are caused by dominant-negative mutations in VWF, and we hypothesize that diminishing expression of mutant VWF positively affects VWD phenotypes. Objectives To investigate allele-specific inhibition of VWF by applying small interfering RNAs (siRNAs) targeting common single-nucleotide polymorphisms (SNPs) in VWF. This approach allows allele-specific knockdown irrespective of the mutations causing VWD. Methods Four SNPs with a high predicted heterozygosity within VWF were selected, and siRNAs were designed against both alleles of the four SNPs. siRNA efficiency, allele specificity and siRNA-mediated phenotypic improvements were determined in VWF-expressing HEK293 cells. Results Twelve siRNAs were able to efficiently inhibit single VWF alleles in HEK293 cells that stably produce VWF. Transient cotransfections of these siRNAs with two VWF alleles resulted in a clear preference for the targeted allele over the untargeted allele for 11 siRNAs. We also demonstrated siRNA-mediated phenotypic improvement of the VWF multimerization pattern of the VWD type 2A mutation VWF p.Cys2773Ser. Conclusions Allele-specific siRNAs are able to distinguish VWF alleles on the basis of one nucleotide variation, and are able to improve a severe multimerization defect caused by VWF p.Cys2773Ser. This holds promise for the therapeutic application of allele-specific siRNAs in dominant-negative VWD.
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).
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.