RARE DISEASE
Von Willebrand disease type 2N
Von Willebrand disease type 2N
Von Willebrand disease type 2N
Drug discovery
139
papers
On emerging therapies
Overview
Von Willebrand Disease Type 2N is a qualitative bleeding disorder caused by mutations in the VWF gene, leading to reduced von Willebrand factor (VWF) binding to factor VIII (FVIII). This results in accelerated FVIII clearance and a phenotype resembling mild hemophilia A. Inheritance is autosomal recessive, requiring molecular testing (e.g., FVIII-binding assays) to differentiate it from hemophilia. Treatment focuses on VWF-containing concentrates to stabilize endogenous FVIII [1][6][9][12].
Burden
Moderate bleeding risk (post-surgical/traumatic soft tissue bleeding), with delayed diagnosis averaging ~3 years [4][17].
Reduced health-related quality of life and increased healthcare utilization due to recurrent interventions [4][9].
Women face obstetric challenges (e.g., postpartum hemorrhage) [12][14].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
139 drug discovery papers about Von Willebrand disease type 2N. Recent publications:
139 drug discovery papers about Von Willebrand disease type 2N. Recent publications:
categories:
Small molecules
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.
2026-02-20 | 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.
2025-12-18 | Genealogical insight: uncovering type 2N von Willebrand disease with homozygous R816W mutation in the VWF gene
Subtype 2N of von Willebrand disease is marked by a qualitative anomaly in von Willebrand factor (VWF), leading to diminished binding capacity with FVIII. Clinically, it mirrors the presentation of classic hemophilia A and follows an autosomal recessive inheritance pattern. A 26-year-old woman was under study for bleeding diathesis, presenting with abnormal uterine bleeding. Laboratory tests showed normal levels of Von Willebrand factor and low factor VIII levels, with no presence of factor VIII inhibitors. Clinical exome sequencing revealed a homozygous R816W mutation in the VWF gene, leading to the diagnosis of von Willebrand disease type 2N. Von Willebrand disease is linked to an autosomal recessive inheritance pattern.In this instance, a familial cluster was pinpointed, underscoring the relevance of genetic examinations in rare diseases.This was exemplified by the detection of the mutation through next-generation sequencing.
2025-11-06 | von Willebrand factor-T441N, a novel missense variant in the von Willebrand factor D2 domain, exhibits impaired multimerization and deformed Weibel-Palade bodies.
von Willebrand factor (VWF) propeptide (VWFpp) located in the D1-D2 domain of pro-VWF, is essential for multimerization and intracellular storage of VWF. Pathogenic variants of VWFpp cause various subtypes of von Willebrand disease, such as type 1, type 2A, type 2N, and type 3. In heterozygotes of these variants, VWFpp derived from the normal allele can rescue the abnormalities observed in the homozygote. This rescue effect may highlight the phenotypic difference between heterozygotes and homozygotes. We investigated the molecular pathogenesis of a novel missense variant of VWFpp, VWF c.1322 C>A (p.T441N), identified in a heterozygous 20-year-old woman. The VWF gene was analyzed using whole-exome sequencing and Sanger sequencing. Recombinant VWF (rVWF) and VWF propeptide (rVWFpp) were overexpressed in HEK293 cells. rVWF production was measured using an in-house enzyme-linked immunosorbent assay and multimer analysis. The morphology of pseudo-Weibel-Palade bodies (WPBs) and WPBs in endothelial colony-forming cells were observed by immunocytochemistry. In the patient's plasma, the VWF antigen level was in the normal range, but VWF ristocetin cofactor activity was slightly decreased, by 0.38 IU/mL, and high-molecular-weight and intermediate-molecular-weight multimers were decreased. Pseudo-WPBs were also shortened and rounded, corresponding with patient-derived endothelial colony-forming cells. These abnormalities were partially rescued by coexpression of wild-type rVWFpp on separate vectors. VWF-T441N results in impaired multimerization and deformed WPBs. In heterozygous VWF-T441N, these abnormalities are partially rescued by VWFpp derived from the normal allele. The observed rescue effect provides further insights for understanding the phenotypic heterogeneity of VWFpp variants.
small molecules
2025-12-03 | Neuraxial labor analgesia in type 2N von Willebrand disease: a case report.
Von Willebrand disease (VWD) is a family of disorders involving quantitative or qualitative deficiencies of von Willebrand factor. Type 2N von Willebrand disease is a rare variant in which defective von Willebrand factor fails to stabilize factor VIII. Factor VIII deficiency may pose increased risks of postpartum hemorrhage and spinal-epidural hematoma after neuraxial analgesia, yet clinical guidance on its peripartum management remains extremely limited. This case reports on the successful administration of neuraxial analgesia in a 23-year-old nulliparous patient with type 2N VWD who presented with active vaginal bleeding and impending preterm delivery. Targeted preprocedural correction of factor VIII and von Willebrand factor levels, with adjunct thromboelastography, enabled uneventful neuraxial analgesia administration and uncomplicated preterm vaginal delivery. No complications from neuraxial were noted. However, despite satisfactory factor VIII and von Willebrand factor levels at discharge, the patient experienced delayed postpartum bleeding requiring readmission. This case demonstrates the feasibility of neuraxial labor analgesia in women with type 2N VWD after thorough risk assessment and mitigation, interdisciplinary collaboration, and individualized care. The occurrence of delayed bleeding additionally underscores the importance of postpartum monitoring as factor levels decline. This report contributes to the limited but growing body of evidence on obstetric anesthesia neuraxial procedures in the setting of rare bleeding disorders.
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.
2022-08-01 | Desmopressin testing in von Willebrand disease: Lowering the burden
Individuals with von Willebrand disease (VWD) require desmopressin testing because of interindividual response differences. However, testing is burdensome, while not all patients may need extensive testing.To provide von Willebrand factor (VWF) cutoffs that predict desmopressin nonresponse and thereby identify individuals who do not need extensive testing in a retrospective cohort. We validated these cutoffs in a prospective cohort.We included 376 patients (Type 1 VWD with VWF activity [VWF:Act] <0.30 IU/ml: n = 112; with VWF:Act 0.30-0.50 IU/ml: n = 206; Type 2 VWD: n = 58; ages, 5-76 years) from January 2000 to July 2020. We collected VWF:Act and factor VIII activity (FVIII:C) at baseline and several time points after desmopressin (T1-T6). We defined response as VWF:Act and FVIII:C 0.50 IU/ml or greater at T1 and T4. We compared VWF:Act and FVIII:C distribution (historically lowest level, baseline, and T1) between responders and nonresponders and determined cutoffs discriminating between these groups. Results were validated in a group of 30 individuals.All individuals with Type 1 VWD and Type 2 VWD, respectively, with baseline VWF:Act 0.34 IU/ml or greater or 0.28 IU/ml or greater were responders. In individuals with T1 VWF:Act ≥0.89 IU/ml (Type 1 VWD) or T1 VWF:Act 1.10 IU/ml or greater (Type 2 VWD), response remained at T4.Desmopressin testing is not needed when lowest historical VWF:Act is 0.30 IU/ml or greater. In patients with Type 1 VWD who require testing, measurements after T1 are often not needed. In patients with Type 2 VWD who require testing, we advise performing T1 and T4 measurements.
2020-07-08 | How I manage severe von Willebrand disease.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Most patients with mild and moderate VWD can be treated effectively with desmopressin. The management of severe VWD patients, mostly affected by type 2 and type 3 disease, can be challenging. In this article we review the current diagnosis and treatment of severe VWD patients. We will also discuss the management of severe VWD patients in specific situations, such as pregnancy, delivery, patients developing alloantibodies against von Willebrand factor and VWD patients with recurrent gastrointestinal bleeding. Moreover, we review emerging treatments that may be applied in future management of patients with severe VWD.
2018-02-15 | Lenalidomide as a novel therapy for gastrointestinal angiodysplasia in von Willebrand disease
Introduction Lenalidomide is a thalidomide analog with anti‐angiogenic properties. Previous case reports suggest its efficacy in preventing gastrointestinal bleeding ( GIB ) secondary to angiodysplasia ( AD ) in hereditary haemorrhagic telangiectasia and potentially in reversing AD . We present the first case series to explore lenalidomide as a treatment for AD ‐related GIB in patients with von Willebrand disease ( VWD ). Methods A retrospective chart review was conducted to include patients with VWD , who were evaluated from 2010 to 2013 and who had received lenalidomide to treat recurrent GIB secondary to AD . All patients had failed single‐agent use of antifibrinolytic agents. Patients were observed for at least 2 years on therapy. Results Five patients (3 males; 68.2 ± 4.9 years) with VWD (3 with type 3 and 1 each with types 1 and 2a) and AD were found. Sites of AD included the stomach, duodenum, jejunum and colon. Lenalidomide was started at 5 mg oral daily. Uptitration to 10 and 15 mg in 1 patient each was necessary due to recurrence of GIB . The mean number of endoscopies performed for control of GIB post lenalidomide was significantly lower compared to pretherapy (0.25 vs 5.50; P = .001). Mean bleed‐free duration on lenalidomide was 12.6 ± 4.7 months. Three patients have reported no GIB on lenalidomide. Conclusion This case series demonstrates significantly reduced number of endoscopies and increased bleed‐free duration with lenalidomide treatment in selected patients with VWD and recurrent GIB from AD . Prospective multicenter trials are needed to further define the role of lenalidomide in the management of GIB from angiodysplasia and VWD .
antibodies
2025-11-11 | Emicizumab enhances the ex vivo coagulant potential in plasma samples from patients with von Willebrand disease.
von Willebrand disease (VWD) is a hereditary bleeding disorder caused by quantitative or qualitative deficiencies in von Willebrand factor (VWF). Our previous studies demonstrated that emicizumab, a bispecific monoclonal antibody that mimics activated factor VIII (FVIII) cofactor activity, enhances thrombus formation under high-shear conditions in whole blood from patients with VWD (PwVWD). However, its effect on plasma coagulation potential remains unclear. To evaluate the coagulation-enhancing effect of emicizumab in plasma samples from PwVWD using global coagulation assays. Plasma samples from PwVWD (type 1, n = 4; type 2, n = 9; type 3, n = 3) were spiked with emicizumab (50 or 100 µg/mL), recombinant VWF (rVWF; 2.4 U/mL), or plasma-derived FVIII/VWF concentrate (pd-FVIII/VWF; 1/2.4 U/mL). Coagulation potential was assessed using clot waveform analysis (Ad|min1|) and thrombin generation assay (Peak-Th). Emicizumab dose-dependently increased Ad|min1| in all type 1 VWD samples and improved Peak-Th in two cases. In type 2 VWD, Ad|min1| increased in all samples, while Peak-Th improved in six cases. In type 3 VWD, emicizumab increased both parameters in all cases. Emicizumab enhanced ex vivo coagulation potential in plasma samples from PwVWD across all subtypes, supporting its potential as a therapeutic option.
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.
2024-11-13 | Current and emerging therapies as potential treatment for people with von Willebrand disease.
Von Willebrand disease (VWD) reflects the most common inherited bleeding disorder, arising from defects or deficiencies in the von Willebrand factor (VWF). VWD treatment mostly relies on the replacement of missing or defective VWF, but additional ('adjunct') therapies are useful in select patients/situations. Patients with VWD are often misdiagnosed and therefore non-optimally managed. We provide a narrative review, following relevant literature searches in PubMed related to the topic up to September 2024. After an overview of VWF, VWD, and current treatments, we explore the use of nonstandard or emerging therapies for VWD. For example, FVIII replacement or antibody-based FVIII bypassing strategies (e.g. emicizumab) may prove useful in some cases or in initial treatment of certain VWD patients, including those with type 2N or 3 VWD, or those with inhibitors. Additional emerging therapies may also be useful, including hemostasis rebalancing agents. Just as hemophilia is experiencing a renaissance of treatment options, so too will the landscape of VWD treatment change over time. This will be fueled by the concept of personalized treatment, meaning potentially different treatments for different VWD patients, or for given patients according to treatment aims.
2023-04-01 | Macrophage Galactose Lectin Contributes to the Regulation of FVIII (Factor VIII) Clearance in Mice—Brief Report
Although most plasma FVIII (Factor VIII) circulates in complex with VWF (von Willebrand factor), a minority (3%-5%) circulates as free-FVIII, which is rapidly cleared. Consequently, 20% of total FVIII may be cleared as free-FVIII. Critically, the mechanisms of free-FVIII clearance remain poorly understood. However, recent studies have implicated the MGL (macrophage galactose lectin) in modulating VWF clearance.Since VWF and FVIII share similar glycosylation, we investigated the role of MGL in FVIII clearance. FVIII binding to MGL was assessed in immunosorbent and cell-based assays. In vivo, FVIII clearance was assessed in MGL1-/- and VWF-/-/FVIII-/- mice.In vitro-binding studies identified MGL as a novel macrophage receptor that binds free-FVIII in a glycan-dependent manner. MGL1-/- and MGL1-/- mice who received an anti-MGL1/2 blocking antibody both showed significantly increased endogenous FVIII activity compared with wild-type mice (P=0.036 and P<0.0001, respectively). MGL inhibition also prolonged the half-life of infused FVIII in FVIII-/- mice. To assess whether MGL plays a role in the clearance of free FVIII in a VWF-independent manner, in vivo clearance experiments were repeated in dual VWF-/-/FVIII-/- mice. Importantly, the rapid clearance of free FVIII in VWF-/-/FVIII-/- mice was significantly (P=0.012) prolonged in the presence of anti-MGL1/2 antibodies. Finally, endogenous plasma FVIII levels in VWF-/- mice were significantly increased following MGL inhibition (P=0.016).Cumulatively, these findings demonstrate that MGL plays an important role in regulating macrophage-mediated clearance of both VWF-bound FVIII and free-FVIII in vivo. We propose that this novel FVIII clearance pathway may be of particular clinical importance in patients with type 2N or type 3 Von Willebrand disease.
2023-02-28 | New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF
Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4–VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4–VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.
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.
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.
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.
2026-02-20 | 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.
2025-12-18 | Genealogical insight: uncovering type 2N von Willebrand disease with homozygous R816W mutation in the VWF gene
Subtype 2N of von Willebrand disease is marked by a qualitative anomaly in von Willebrand factor (VWF), leading to diminished binding capacity with FVIII. Clinically, it mirrors the presentation of classic hemophilia A and follows an autosomal recessive inheritance pattern. A 26-year-old woman was under study for bleeding diathesis, presenting with abnormal uterine bleeding. Laboratory tests showed normal levels of Von Willebrand factor and low factor VIII levels, with no presence of factor VIII inhibitors. Clinical exome sequencing revealed a homozygous R816W mutation in the VWF gene, leading to the diagnosis of von Willebrand disease type 2N. Von Willebrand disease is linked to an autosomal recessive inheritance pattern.In this instance, a familial cluster was pinpointed, underscoring the relevance of genetic examinations in rare diseases.This was exemplified by the detection of the mutation through next-generation sequencing.
2025-11-06 | von Willebrand factor-T441N, a novel missense variant in the von Willebrand factor D2 domain, exhibits impaired multimerization and deformed Weibel-Palade bodies.
von Willebrand factor (VWF) propeptide (VWFpp) located in the D1-D2 domain of pro-VWF, is essential for multimerization and intracellular storage of VWF. Pathogenic variants of VWFpp cause various subtypes of von Willebrand disease, such as type 1, type 2A, type 2N, and type 3. In heterozygotes of these variants, VWFpp derived from the normal allele can rescue the abnormalities observed in the homozygote. This rescue effect may highlight the phenotypic difference between heterozygotes and homozygotes. We investigated the molecular pathogenesis of a novel missense variant of VWFpp, VWF c.1322 C>A (p.T441N), identified in a heterozygous 20-year-old woman. The VWF gene was analyzed using whole-exome sequencing and Sanger sequencing. Recombinant VWF (rVWF) and VWF propeptide (rVWFpp) were overexpressed in HEK293 cells. rVWF production was measured using an in-house enzyme-linked immunosorbent assay and multimer analysis. The morphology of pseudo-Weibel-Palade bodies (WPBs) and WPBs in endothelial colony-forming cells were observed by immunocytochemistry. In the patient's plasma, the VWF antigen level was in the normal range, but VWF ristocetin cofactor activity was slightly decreased, by 0.38 IU/mL, and high-molecular-weight and intermediate-molecular-weight multimers were decreased. Pseudo-WPBs were also shortened and rounded, corresponding with patient-derived endothelial colony-forming cells. These abnormalities were partially rescued by coexpression of wild-type rVWFpp on separate vectors. VWF-T441N results in impaired multimerization and deformed WPBs. In heterozygous VWF-T441N, these abnormalities are partially rescued by VWFpp derived from the normal allele. The observed rescue effect provides further insights for understanding the phenotypic heterogeneity of VWFpp variants.
small molecules
2025-12-03 | Neuraxial labor analgesia in type 2N von Willebrand disease: a case report.
Von Willebrand disease (VWD) is a family of disorders involving quantitative or qualitative deficiencies of von Willebrand factor. Type 2N von Willebrand disease is a rare variant in which defective von Willebrand factor fails to stabilize factor VIII. Factor VIII deficiency may pose increased risks of postpartum hemorrhage and spinal-epidural hematoma after neuraxial analgesia, yet clinical guidance on its peripartum management remains extremely limited. This case reports on the successful administration of neuraxial analgesia in a 23-year-old nulliparous patient with type 2N VWD who presented with active vaginal bleeding and impending preterm delivery. Targeted preprocedural correction of factor VIII and von Willebrand factor levels, with adjunct thromboelastography, enabled uneventful neuraxial analgesia administration and uncomplicated preterm vaginal delivery. No complications from neuraxial were noted. However, despite satisfactory factor VIII and von Willebrand factor levels at discharge, the patient experienced delayed postpartum bleeding requiring readmission. This case demonstrates the feasibility of neuraxial labor analgesia in women with type 2N VWD after thorough risk assessment and mitigation, interdisciplinary collaboration, and individualized care. The occurrence of delayed bleeding additionally underscores the importance of postpartum monitoring as factor levels decline. This report contributes to the limited but growing body of evidence on obstetric anesthesia neuraxial procedures in the setting of rare bleeding disorders.
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.
2022-08-01 | Desmopressin testing in von Willebrand disease: Lowering the burden
Individuals with von Willebrand disease (VWD) require desmopressin testing because of interindividual response differences. However, testing is burdensome, while not all patients may need extensive testing.To provide von Willebrand factor (VWF) cutoffs that predict desmopressin nonresponse and thereby identify individuals who do not need extensive testing in a retrospective cohort. We validated these cutoffs in a prospective cohort.We included 376 patients (Type 1 VWD with VWF activity [VWF:Act] <0.30 IU/ml: n = 112; with VWF:Act 0.30-0.50 IU/ml: n = 206; Type 2 VWD: n = 58; ages, 5-76 years) from January 2000 to July 2020. We collected VWF:Act and factor VIII activity (FVIII:C) at baseline and several time points after desmopressin (T1-T6). We defined response as VWF:Act and FVIII:C 0.50 IU/ml or greater at T1 and T4. We compared VWF:Act and FVIII:C distribution (historically lowest level, baseline, and T1) between responders and nonresponders and determined cutoffs discriminating between these groups. Results were validated in a group of 30 individuals.All individuals with Type 1 VWD and Type 2 VWD, respectively, with baseline VWF:Act 0.34 IU/ml or greater or 0.28 IU/ml or greater were responders. In individuals with T1 VWF:Act ≥0.89 IU/ml (Type 1 VWD) or T1 VWF:Act 1.10 IU/ml or greater (Type 2 VWD), response remained at T4.Desmopressin testing is not needed when lowest historical VWF:Act is 0.30 IU/ml or greater. In patients with Type 1 VWD who require testing, measurements after T1 are often not needed. In patients with Type 2 VWD who require testing, we advise performing T1 and T4 measurements.
2020-07-08 | How I manage severe von Willebrand disease.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Most patients with mild and moderate VWD can be treated effectively with desmopressin. The management of severe VWD patients, mostly affected by type 2 and type 3 disease, can be challenging. In this article we review the current diagnosis and treatment of severe VWD patients. We will also discuss the management of severe VWD patients in specific situations, such as pregnancy, delivery, patients developing alloantibodies against von Willebrand factor and VWD patients with recurrent gastrointestinal bleeding. Moreover, we review emerging treatments that may be applied in future management of patients with severe VWD.
2018-02-15 | Lenalidomide as a novel therapy for gastrointestinal angiodysplasia in von Willebrand disease
Introduction Lenalidomide is a thalidomide analog with anti‐angiogenic properties. Previous case reports suggest its efficacy in preventing gastrointestinal bleeding ( GIB ) secondary to angiodysplasia ( AD ) in hereditary haemorrhagic telangiectasia and potentially in reversing AD . We present the first case series to explore lenalidomide as a treatment for AD ‐related GIB in patients with von Willebrand disease ( VWD ). Methods A retrospective chart review was conducted to include patients with VWD , who were evaluated from 2010 to 2013 and who had received lenalidomide to treat recurrent GIB secondary to AD . All patients had failed single‐agent use of antifibrinolytic agents. Patients were observed for at least 2 years on therapy. Results Five patients (3 males; 68.2 ± 4.9 years) with VWD (3 with type 3 and 1 each with types 1 and 2a) and AD were found. Sites of AD included the stomach, duodenum, jejunum and colon. Lenalidomide was started at 5 mg oral daily. Uptitration to 10 and 15 mg in 1 patient each was necessary due to recurrence of GIB . The mean number of endoscopies performed for control of GIB post lenalidomide was significantly lower compared to pretherapy (0.25 vs 5.50; P = .001). Mean bleed‐free duration on lenalidomide was 12.6 ± 4.7 months. Three patients have reported no GIB on lenalidomide. Conclusion This case series demonstrates significantly reduced number of endoscopies and increased bleed‐free duration with lenalidomide treatment in selected patients with VWD and recurrent GIB from AD . Prospective multicenter trials are needed to further define the role of lenalidomide in the management of GIB from angiodysplasia and VWD .
antibodies
2025-11-11 | Emicizumab enhances the ex vivo coagulant potential in plasma samples from patients with von Willebrand disease.
von Willebrand disease (VWD) is a hereditary bleeding disorder caused by quantitative or qualitative deficiencies in von Willebrand factor (VWF). Our previous studies demonstrated that emicizumab, a bispecific monoclonal antibody that mimics activated factor VIII (FVIII) cofactor activity, enhances thrombus formation under high-shear conditions in whole blood from patients with VWD (PwVWD). However, its effect on plasma coagulation potential remains unclear. To evaluate the coagulation-enhancing effect of emicizumab in plasma samples from PwVWD using global coagulation assays. Plasma samples from PwVWD (type 1, n = 4; type 2, n = 9; type 3, n = 3) were spiked with emicizumab (50 or 100 µg/mL), recombinant VWF (rVWF; 2.4 U/mL), or plasma-derived FVIII/VWF concentrate (pd-FVIII/VWF; 1/2.4 U/mL). Coagulation potential was assessed using clot waveform analysis (Ad|min1|) and thrombin generation assay (Peak-Th). Emicizumab dose-dependently increased Ad|min1| in all type 1 VWD samples and improved Peak-Th in two cases. In type 2 VWD, Ad|min1| increased in all samples, while Peak-Th improved in six cases. In type 3 VWD, emicizumab increased both parameters in all cases. Emicizumab enhanced ex vivo coagulation potential in plasma samples from PwVWD across all subtypes, supporting its potential as a therapeutic option.
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.
2024-11-13 | Current and emerging therapies as potential treatment for people with von Willebrand disease.
Von Willebrand disease (VWD) reflects the most common inherited bleeding disorder, arising from defects or deficiencies in the von Willebrand factor (VWF). VWD treatment mostly relies on the replacement of missing or defective VWF, but additional ('adjunct') therapies are useful in select patients/situations. Patients with VWD are often misdiagnosed and therefore non-optimally managed. We provide a narrative review, following relevant literature searches in PubMed related to the topic up to September 2024. After an overview of VWF, VWD, and current treatments, we explore the use of nonstandard or emerging therapies for VWD. For example, FVIII replacement or antibody-based FVIII bypassing strategies (e.g. emicizumab) may prove useful in some cases or in initial treatment of certain VWD patients, including those with type 2N or 3 VWD, or those with inhibitors. Additional emerging therapies may also be useful, including hemostasis rebalancing agents. Just as hemophilia is experiencing a renaissance of treatment options, so too will the landscape of VWD treatment change over time. This will be fueled by the concept of personalized treatment, meaning potentially different treatments for different VWD patients, or for given patients according to treatment aims.
2023-04-01 | Macrophage Galactose Lectin Contributes to the Regulation of FVIII (Factor VIII) Clearance in Mice—Brief Report
Although most plasma FVIII (Factor VIII) circulates in complex with VWF (von Willebrand factor), a minority (3%-5%) circulates as free-FVIII, which is rapidly cleared. Consequently, 20% of total FVIII may be cleared as free-FVIII. Critically, the mechanisms of free-FVIII clearance remain poorly understood. However, recent studies have implicated the MGL (macrophage galactose lectin) in modulating VWF clearance.Since VWF and FVIII share similar glycosylation, we investigated the role of MGL in FVIII clearance. FVIII binding to MGL was assessed in immunosorbent and cell-based assays. In vivo, FVIII clearance was assessed in MGL1-/- and VWF-/-/FVIII-/- mice.In vitro-binding studies identified MGL as a novel macrophage receptor that binds free-FVIII in a glycan-dependent manner. MGL1-/- and MGL1-/- mice who received an anti-MGL1/2 blocking antibody both showed significantly increased endogenous FVIII activity compared with wild-type mice (P=0.036 and P<0.0001, respectively). MGL inhibition also prolonged the half-life of infused FVIII in FVIII-/- mice. To assess whether MGL plays a role in the clearance of free FVIII in a VWF-independent manner, in vivo clearance experiments were repeated in dual VWF-/-/FVIII-/- mice. Importantly, the rapid clearance of free FVIII in VWF-/-/FVIII-/- mice was significantly (P=0.012) prolonged in the presence of anti-MGL1/2 antibodies. Finally, endogenous plasma FVIII levels in VWF-/- mice were significantly increased following MGL inhibition (P=0.016).Cumulatively, these findings demonstrate that MGL plays an important role in regulating macrophage-mediated clearance of both VWF-bound FVIII and free-FVIII in vivo. We propose that this novel FVIII clearance pathway may be of particular clinical importance in patients with type 2N or type 3 Von Willebrand disease.
2023-02-28 | New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF
Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4–VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4–VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.
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.
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.
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