RARE DISEASE
Von Willebrand disease type 2B
Von Willebrand disease type 2B
Von Willebrand disease type 2B
Drug discovery
99
papers
On emerging therapies
Overview
Von Willebrand disease type 2B (VWD2B) is a rare autosomal dominant bleeding disorder caused by gain-of-function mutations in the VWF gene, leading to hyperactive von Willebrand factor (VWF) that binds platelets prematurely. This results in spontaneous platelet aggregation, thrombocytopenia, and loss of high-molecular-weight multimers. Patients experience mucocutaneous bleeding (epistaxis, menorrhagia) and variable bleeding severity despite normal-to-reduced VWF levels. Diagnosis hinges on heightened ristocetin-induced platelet aggregation and genetic testing [2][5][9].
Burden
High bleeding burden: 72–94% of patients experience recurrent mucocutaneous bleeding [4][10].
Diagnostic delays average 16 years, with frequent misdiagnosis due to variable thrombocytopenia and overlapping symptoms [4][10].
Increased healthcare utilization and reduced quality of life linked to chronic bleeding, iron deficiency, and disease complications [4][12].
Therapies
VWF replacement therapy (plasma-derived or recombinant concentrates) remains the cornerstone for bleeding prophylaxis and management [5][7][11].
Desmopressin is contraindicated due to risk of worsening thrombocytopenia [3][7][11].
Adjunct antifibrinolytics (e.g., tranexamic acid) and platelet transfusions (limited utility due to rapid clearance) [5][12].
Emerging therapies: Allele-selective siRNA targeting mutant VWF shows promise in preclinical models [3][19].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
99 drug discovery papers about Von Willebrand disease type 2B. Recent publications:
99 drug discovery papers about Von Willebrand disease type 2B. Recent publications:
categories:
Small molecules
antibodies
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.
2021-09-24 | 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.
2021-06-17 | Activated factor VIII-mimicking effect by emicizumab on thrombus formation in type 2N von Willebrand disease under high shear flow conditions.
Type 2N von Willebrand disease (2NVWD) is characterized by a mild to moderate reduction in plasma levels of factor (F)VIII associated with defective binding of von Willebrand factor (VWF) to FVIII and accelerated proteolysis and clearance of FVIII. The clinical phenotype in 2NVWD is often indistinguishable from mild/moderate hemophilia (H)A. Emicizumab is a bispecific antibody to FIX/FIXa and FX/FXa that mimics FVIIIa cofactor function, and emicizumab prophylaxis significantly reduces bleeding events in patients with severe HA. We investigated the potential benefits of emicizumab in the hemostatic management of 2NVWD. Perfusion chamber experiments were performed using whole blood from three 2NVWD patients with different clinical phenotypes (bleeding scores: 0, 6 and 20; mutations: p.R816W, p.R816W, and p.R365X/p.T791M, respectively). Furthermore, the impact of specific FVIII-VWF interactions on thrombus formation was investigated. Defective thrombus formation that correlated with bleeding phenotype was evident in these 2NVWD patients. Emicizumab improved surface coverage and thrombus height in all cases. Multi-color immunostaining of thrombi further demonstrated that emicizumab enhanced thrombin generation and fibrin formation. The addition of FVIII alone to 2NVWD whole blood did not augment thrombus formation, while supplementation with FVIII/VWF complex enhanced platelet-fibrin interactions. Furthermore, an anti-FVIII monoclonal antibody known to interrupt the release of FVIIIa from VWF depressed these effects. Emicizumab-induced enhancing effects of thrombus formation, independent on VWF, might be useful as an alternative therapy for 2NVWD patients. The extent of FVIII-VWF interaction should be optimal to deliver and release FVIII/FVIIIa on the activated platelet surface.
2013-08-23 | Antigenic Peptides Capable of Inducing Specific Antibodies for Detection of the Major Alterations Found in Type 2B Von Willebrand Disease.
Von Willebrand disease (VWD) is an inherited hemorrhagic disorder promoted by either quantitative or qualitative defects of the von Willebrand factor (VWF). The disease represents the most common human coagulopathy afflicting 1.3% of the population. Qualitative defects are subdivided into four subtypes and classified according to the molecular dysfunction of the VWF. The differential diagnosis of the VWD is a difficult task, relying on a panel of tests aimed to assess the plasma levels and function of the VWF. Here, we propose biochemical approaches for the identification of structural variants of the VWF. A bioinformatic analysis was conducted to design seven peptides among which three were representatives of specific amino acid sequences belonging to normal VWF and four encompassed sequences found in the most common VWD subtype 2B. These peptides were used to immunize mice, after which, peptide-specific immunoglobulins were purified. This resulted in four Ig preparations capable of detecting alterations in the subtype 2B VWD plus additional three antibody fractions targeting the normal VWF. The panel of antibodies could serve many applications among them (1) assessment of VWF: antigen interaction, (2) VWF multimer analysis, and (3) production of monoclonal antibodies against VWF for therapeutic purposes as in thrombotic thrombocytopenic purpura.
2010-11-25 | Targeting von Willebrand factor and platelet glycoprotein Ib receptor
Atherothrombotic events, such as acute coronary syndrome or stroke, are the result of platelet activation. Von Willebrand factor (vWF), a multimeric glycoprotein, plays a key role in aggregation of platelets, especially under high-shear conditions. Acting as bridging element or ligand between damaged endothelial sites and the glycoprotein Ib (GPIb) receptor on platelets, vWF is responsible for platelet adhesion and aggregation. This vWF activation and further platelet aggregation mainly occurs under high shear stress present in small arterioles or during deficiency of the vWF-cleaving protease ADAMTS13. There are several substances targeting vWF itself or its binding receptor GPIb on platelets. Two antibodies are directed against vWF: AJW200, an IgG4 humanized monoclonal antibody, and 82D6A3, a monoclonal antibody of the collagen-binding A-3 domain of vWF. ALX-0081 and ALX-0681 are bivalent humanized nanobodies targeting the GPIb binding site of vWF. Aptamers are oligonucleotides with drug-like properties that share some of the attributes of monoclonal antibodies. ARC1779 is a second-generation, nuclease-resistant aptamer, binding to the activated vWF A1 domain and ARC15105 is a chemically advanced follower with an assumed higher affinity to vWF. Antibodies targeting GPIbα are h6B4-Fab, a murine monoclonal antibody; GPG-290, a recombinant, chimeric protein containing the amino-terminal 290 amino acids of GPIbα linked to human IgG1 Fc; and the monoclonal antibody SZ2. There are a number of promising preclinical results and development of some agents (AJW 200, ARC1779 and ALX-0081) has already reached Phase II trials.
small molecules
2026-08-28 | Platelet Type Von Willebrand Disease - Diagnostic and Therapeutic Challenges.
Platelet-type von Willebrand disease (PT-VWD) is a rare thrombocytopathy caused by gain-of-function variants in GP1BA, leading to increased binding of von Willebrand factor (VWF). Because its phenotype closely resembles VWD type 2B (VWD 2B), misdiagnosis is common, and distinction requires Ristocetin-induced platelet agglutination (RIPA) mixing studies and molecular genetic analysis. Although individual case reports, case series, and earlier summaries exist, an updated and comprehensive synthesis of all published cases has been lacking. We report a 4-year-old boy presenting with easy bruising, prolonged epistaxis, reduced VWF parameters (VWF collagen-binding activity 0.07 U/mL, VWF-antigen 0.33 U/mL), absence of high-molecular-weight multimers, and enhanced RIPA. Genetic testing identified the pathogenic GP1BA variant p.Met255Val, causing PT-VWD. RIPA mixing studies confirmed the diagnosis. In the course of the disease, the patient developed recurrent mucosal bleeding and a hypersensitivity reaction to tranexamic acid. Therefore, desmopressin was used, and he showed partial clinical benefit from desmopressin without developing thrombocytopenia. To contextualize this case, we performed a literature review (PubMed, May 2025) and identified 67 documented patients with PT-VWD. Over 40% were initially misclassified as VWD 2B. p.Gly249Val and p.Met255Val were the most frequent variants. Baseline thrombocytopenia occurred in approximately one-third of cases, and pregnancy-associated thrombocytopenia was common. According to the literature, platelet transfusions were most effective (in case of major hemorrhage or surgical setting); VWF concentrates or desmopressin showed variable efficacy and occasional transient thrombocytopenia. These data demonstrate the diagnostic challenges of PT-VWD and emphasize the importance of clinical case collection to improve therapeutical management.
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.
2021-03-22 | How I treat gastrointestinal bleeding in congenital and acquired von Willebrand disease.
Gastrointestinal (GI) bleeding is distinctive of severe von Willebrand disease (VWD), generally arising in older patients; in most cases, blood transfusion and hospitalization are required. The presence of arteriovenous malformations is often described when endoscopic examinations are performed. Patients with congenital type 3, 2A, and 2B are those most frequently affected by this symptom, possibly due to the loss of high-molecular-weight multimers of von Willebrand factor (VWF). GI bleeding can also occur in patients affected by acquired von Willebrand syndrome. Endoscopic examination of the GI tract is necessary to exclude ulcers and polyps or cancer as possible causes of GI bleeding. In congenital VWD, prophylaxis with VWF/factor VIII concentrates is generally started after GI-bleeding events, but this therapy is not always successful. Iron supplementation must be prescribed to avoid chronic iron deficiency. Possible rescue therapies (high-dose statins, octreotide, thalidomide, lenalidomide, and tamoxifen) were described in a few case reports and series; however, surgery may be necessary in emergency situations or if medical treatment fails to stop bleeding. In this article, we present several clinical cases that highlight the clinical challenges of these patients and possible strategies for their long-term management.
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.
2019-04-16 | Protein kinase C signaling dysfunction in von Willebrand disease (p.V1316M) type 2B platelets.
von Willebrand disease (VWD) type 2B is characterized by gain-of-function mutations in von Willebrand factor (VWF), enhancing its binding affinity for the platelet receptor glycoprotein (GP)Ibα. VWD type 2B patients display a bleeding tendency associated with loss of high-molecular-weight VWF multimers and variable thrombocytopenia. We recently demonstrated that a marked defect in agonist-induced activation of the small GTPase, Rap1, and integrin αIIbβ3 in VWD (p.V1316M) type 2B platelets also contributes to the bleeding tendency. Here, we investigated the molecular mechanisms underlying impaired platelet Rap1 signaling in this disease. Two distinct pathways contribute to Rap1 activation in platelets: rapid activation mediated by the calcium-sensing guanine nucleotide exchange factor CalDAG-GEF-I (CDGI) and sustained activation that is dependent on signaling by protein kinase C (PKC) and the adenosine 5'-diphosphate receptor P2Y12. To investigate which Rap1 signaling pathway is affected, we expressed VWF/p.V1316M by hydrodynamic gene transfer in wild-type and Caldaggef1-/- mice. Using αIIbβ3 integrin activation as a read-out, we demonstrate that platelet dysfunction in VWD (p.V1316M) type 2B affects PKC-mediated, but not CDGI-mediated, activation of Rap1. Consistently, we observed decreased PKC substrate phosphorylation and impaired granule release in stimulated VWD type 2B platelets. Interestingly, the defect in PKC signaling was caused by a significant increase in baseline PKC substrate phosphorylation in circulating VWD (p.V1316M) type 2B platelets, suggesting that the VWF-GPIbα interaction leads to preactivation and exhaustion of the PKC pathway. Consistent with PKC preactivation, VWD (p.V1316M) type 2B mice also exhibited marked shedding of platelet GPIbα. In summary, our studies identify altered PKC signaling as the underlying cause of platelet hypofunction in p.V1316M-associated VWD type 2B.
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.
2025-12-21 | Surgical intervention with cardiopulmonary bypass in a patient with von Willebrand disease.
This article presents a clinical case of surgical intervention with cardiopulmonary bypass (CPB) in a patient with von Willebrand disease (VWD). VWD is the most common inherited bleeding disorder, significantly complicating surgical procedures due to impaired hemostasis. Surgical treatment of patients with VWD, particularly in the context of cardiovascular surgery involving CPB, requires an individualized approach. This includes the optimization of von Willebrand factor (vWF) and factor VIII (FVIII) levels, which are critical to preventing perioperative bleeding. The article describes the perioperative anesthetic management of the patient, emphasizing the importance of hemostasis monitoring, an individualized approach, and personalized dosing of replacement therapy to ensure effective treatment and minimize the risk of bleeding and thromboembolic complications. A 36-year-old male (181 cm, 92 kg) with type 2 von Willebrand disease and a history of childhood cardiac surgery (atrial septal defect repair, right ventricular outflow tract reconstruction) was admitted for elective aortic valve replacement with a bioprosthesis due to severe aortic regurgitation. Echocardiography revealed residual ventricular septal defect shunting, aortic root dilation, moderate mitral regurgitation, and cusp prolapse. The patient had a significant bleeding history and laboratory evidence of low vWF antigen/activity and FVIII deficiency. Perioperative management included ultrasound-guided vascular access, balanced general anesthesia, moderate hypothermic cardiopulmonary bypass, antifibrinolytic therapy, and tailored hemostatic replacement with vWF concentrate, FVIII, cryoprecipitate, platelets, and plasma. The patient was extubated 6 h after surgery, required minimal transfusion support, and recovered without hemorrhagic or thromboembolic complications. He was discharged on postoperative day 10 in good condition. Proper management of the perioperative period is identified as a complex challenge for anesthesiologists, requiring a clear understanding of therapeutic mechanisms and their impact on coagulation.
2025-12-03 | 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.
2025-11-03 | Pharmacokinetic-pharmacodynamic modelling of von willebrand factor/factor VIII prophylaxis in von willebrand disease
Abstract Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who experience severe and frequent bleeding episodes. Prophylactic therapy may be individualised by pharmacokinetic (PK)-guided dosing. Effective clinical implementation of PK-guided dosing requires knowledge of both the interpatient PK variability and the relationship between drug exposure and bleeding risk. Objective: To develop a population PK model for the plasma-derived VWF/factor VIII (FVIII) 1:1 concentrate (Wilate®) in patients with severe VWD and to explore the relationship between VWF/FVIII activity and bleeding events during prophylaxis. Methods: A nonlinear mixed-effects PK modelling approach was applied to VWF:ristocetin cofactor (VWF:RCo) and FVIII activity (FVIII:C) data from pediatric and adult patients participating in a prospective single-dose (WIL-12) and a 1-year prospective, prophylaxis phase 3 trial (WIL-31; NCT04052698). Individual post-hoc PK profiles were constructed, and VWF/FVIII activity levels were retrospectively assessed at the time of bleeding events. Results: 658 VWF:RCo and 692 FVIII:C levels were obtained from 53 patients with a median age of 23 years (range: 7-68 years) with VWD, comprising 11 with severe type 1, 10 with type 2A, 1 with type 2B, 2 with type 2M, and 29 with type 3. One- and two-compartment turnover population PK models best described the PK profiles for VWF:RCo and FVIII:C, respectively. For VWF:RCo, the typical value of clearance and its interpatient variability were 3.4 dL/h/70 kg and 47%, respectively; for FVIII:C, the corresponding values were 1.8 dL/h/70 kg and 57%. Post hoc analysis revealed that 50% of the 71 spontaneous bleeds during WIL-31 occurred at levels <3.7 IU/dL VWF:RCo and <9.1 IU/dL FVIII:C. Similarly, 50% of the 49 traumatic bleeds occurred at VWF:RCo levels <4.6 IU/dL and FVIII:C levels <14.7 IU/dL. Conclusion: In this study, we developed a population PK model for the plasma-derived VWF/FVIII 1:1 concentrate that can support clinicians in optimising VWD therapy by assessment of exposure PK metrics (trough levels, area under the curve, time above a defined threshold) and VWF:RCo and FVIII:C levels at the time of bleeding. As the population PK model of the VWF/FVIII 1:1 concentrate creates parallel PK profiles of VWF:RCo and FVIII:C, PK-guided may be performed by monitoring FVIII as well as VWF. Our population PK model enables informed treatment decisions, advancing the personalisation of long-term prophylaxis for plasma-derived VWF/FVIII in severe VWD.
2025-10-01 | S4681 Recurrent Gastrointestinal Bleeding in Type 2M Von Willebrand Disease: A Diagnostic and Therapeutic Challenge
Introduction: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, with type 2M representing a rare qualitative defect in von Willebrand Factor (VWF) that impairs platelet adhesion despite normal multimer distribution. Gastrointestinal (GI) bleeding is well-described in types 2A, 2B, and 3 due to loss of high-molecular-weight multimers, but less so in type 2M. Type 2M is often misclassified as type 1 or 2A, which can delay appropriate therapy. Management of VWD-related gastrointestinal bleeding is complex, often requiring endoscopic intervention, hormonal or antifibrinolytic agents, and VWF replacement. We present a rare case of recurrent, transfusion-dependent GI bleeding in type 2M VWD successfully managed with recombinant VWF (rVWF) prophylaxis. Case Description/Methods: We present a case of a 72-year-old woman diagnosed with type 2M VWD at age 48, with a history of menorrhagia, easy bruising, and past surgical procedures managed with DDAVP. At age 69, she developed recurrent melena and symptomatic anemia. Initial labs showed hemoglobin of 7.5 g/dL. Extensive GI evaluation, including EGD, colonoscopy, capsule endoscopy, computed tomography enterography, and device-assisted enteroscopy, failed to localize a bleeding source. Medical therapies—Desmopressin (DDAVP), tranexamic acid, and atorvastatin—were ineffective. Between ages 69 and 71, she required 13 PRBC transfusions, 19 iron infusions, multiple doses of DDVAP, and Humate P. Ultimately, she was started on weekly rVWF which resolved her GI bleeding, her hemoglobin stabilized, and she has remained completely transfusion-independent for over 12 months. The dosing interval was successfully extended to every 3 weeks with sustained improvement in symptoms and quality of life. Discussion: Recurrent GI bleeding in type 2M VWD is underreported and likely underrecognized due to diagnostic misclassification and lack of awareness. Angiodysplasia is a suspected mechanism, though frequently undetectable with standard imaging. This case illustrates the limited utility of DDAVP in type 2M and supports rVWF prophylaxis as a viable option when conventional therapies fail. Accurate VWD subtyping is essential for optimizing treatment. To our knowledge, this is the first reported case of successful long-term rVWF use in type 2M VWD with recurrent GI bleeding, resulting in complete transfusion independence.
oligonucleotides
2026-09-09 | Type 2B VWD substitutions trigger enhanced macrophage-mediated clearance that is attenuated by the BT200 aptamer
ABSTRACT Type 2B von Willebrand disease (VWD) is characterized by missense variants in exon 28 of the von Willebrand factor (VWF) gene that encodes the VWF-A1 domain. These missense mutations result in single amino acid residue substitutions that cause activation of VWF-A1 and promote spontaneous interaction with platelet GPIbα. Importantly, enhanced VWF clearance has been shown to play a key pathogenic role in >90% patients with Type 2B VWD. Although this VWF clearance occurs via mechanisms that are independent of VWF-platelet complex formation, the biological mechanisms responsible for the increased clearance of type 2B VWD variants remain poorly understood. In this study, we investigated a series of different type 2B amino acid substitutions within the VWF-A1 domain (R1306W, R1308C, W1313C and R1379L). We demonstrate that these variants all exhibit significantly increased macrophage binding. In part, the enhanced macrophage interactions are mediated via increased binding of type 2B VWD variants to LRP1 extracellular cluster II and IV. Our findings further demonstrate that the K1405-K1408 lysine cluster in the VWF-A1 domain plays a key role in enabling enhanced LRP1 interactions for type 2B VWD variants. In addition, we show that type 2B VWF variants demonstrate significantly enhanced interaction with the macrophage MGL receptor. Finally, and importantly from a clinical perspective, we demonstrate that the increase in macrophage binding for type 2B variants is significantly attenuated in the presence of BT200. Collectively, our findings have direct translational relevance with respect to the clinical heterogeneity and treatment of type 2B VWD.
2026-08-11 | Embryo-Fetal Development and Maternal-Fetal Exposure of the Von Willebrand Factor Binding Aptamer Rondaptivon Pegol (BT200) in Rabbits.
Rondaptivon pegol (BT200) is a PEGylated RNA aptamer that prolongs von Willebrand factor (VWF) and factor VIII half-lives in patients with hemophilia A and von Willebrand disease (VWD) type 2B. Embryo-fetal safety is particularly relevant given the disproportionate disease burden in women with VWD. Data on placental transfer and developmental safety of PEGylated aptamers remain limited. An embryo-fetal development study was conducted in pregnant rabbits. Animals received rondaptivon pegol subcutaneously (0, 1.5, 5, or 15 mg/kg/day) from gestational days (GDs) 7-19. Maternal toxicokinetic samples and pooled fetal plasma concentrations were collected during gestation to quantify transplacental exposure. Rondaptivon pegol was well tolerated, with no maternal toxicity, no effects on implantation, and no treatment-related fetal malformations. Dose-related reductions in mean fetal body weight (<11%) were considered adverse only at the highest dose level. Maternal systemic exposure was supratherapeutic, with mean Cmax ranging from 133 to 807 µg/mL on GD19, far exceeding the human target concentration (∼1.2 µg/mL). Fetal plasma concentrations were <0.25% of maternal levels across all dose groups, confirming minimal placental transfer. The no-observed-adverse-effect level was 5 mg/kg/day. At maternal systemic exposures ranging from 110- to 670-fold above anticipated clinical levels, rondaptivon pegol did not adversely affect implantation, embryonic viability, or fetal development. These findings provide the first quantitative maternal-fetal pharmacokinetic and developmental safety data for a PEGylated aptamer, supporting further clinical evaluation of rondaptivon pegol in women of reproductive age.
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.
2024-12-25 | Conformation-specific RNA aptamers for phenotypic distinction between normal von Willebrand factor and type 2B von Willebrand disease.
The A1 domain in Von Willebrand Factor (VWF) initiates coagulation through binding to platelet glycoprotein GPIbα receptors. Von Willebrand Disease (VWD)-Mutations in A1 that either impair (type 2M) or enhance (type 2B) platelet adhesion to VWF can locally destabilize and even misfold the domain. We leveraged misfolding in the gain-of-function type 2B VWD phenotype as a target, distinct from the normal conformation. Two nuclease-resistant 2'-fluoropyrimidine RNA aptamers were selected to discriminate normal A1 domains from a type 2B V1314D A1 variant in a glycosylated A1A2A3 tri-domain VWF-fragment. Two aptamers, W9 and V1, were isolated that selectively recognize, bind, and inhibit the A1-GPIbα interaction with WT A1A2A3 and V1314D A1A2A3, respectively. These aptamers were tested against their respective recombinant targets, plasma VWF, VWF concentrates, and patient plasma with the heterozygous type 2B VWD R1306W variant using clinical assays, surface plasmon resonance and inhibition assays of platelet adhesion to recombinant A1 and A1A2A3 domains under shear stress. The specificity of W9 and V1 aptamers confirms that pathological conformations of VWD Type 2B proteins are different from normal VWF. The availability of aptamers that distinguish normal plasma-derived VWF from VWD suggests potential applicability in clinical diagnosis of severe gain-of-function phenotypes.
2024-11-05 | Rondaptivon Pegol (BT200) to Correct Thrombocytopenia in a Peri-Interventional Setting in Type 2B Von Willebrand Disease (VWD)
Introduction Type 2B von Willebrand disease (VWD) is a qualitative VWF defect with increased binding of VWF to platelets, increased platelet clearance, potential thrombocytopenia and a substantial risk of bleeding. Rondaptivon pegol (BT200) is an aptamer binding to the A1 domain of von Willebrand Factor (VWF), which increases VWF antigen, GpIbM, collagen binding activity, multimers and platelet counts in type 2B VWD. Methods, intervention and outcome Two thrombocytopenic patients with type 2B VWD received BT200 peri-interventionally. Patient #1 had a suspect lesion in the lung and required bronchoscopy. As she had received BT200 in a previous phase 2 trial, she now received a loading dose of 10 mg BT200 prior to the procedure, which increased platelet counts from 46 to 108 x10E9/L after one week. Subsequent doses of BT200 normalized her platelet counts. Two months later, she received a loading dose of 12mg, 7.5 and 7.5mg BT200 at weekly intervals before an enteroscopy with thermocoagulation because of frequent bleedings due to jejunal angiodysplasia. Her platelet counts reached 160 before and 153 x10E9/L after the intervention. In both cases BT200 made it possible to conduct those diagnostic procedures, for which threshold platelet counts above the patient's baseline are required. No bleeding complications occurred. The second patient had a femoral neck fracture that required hip surgery under prophylactic substitution wirh Haemate P, which increased VWF activity to 101%. Nevertheless, platelet counts continued to fall to 14 x10E9/L, and the patient not only showed extensive local hematomas, but also developed bleedings at distant sites (buccal, extremities). This strongly indicates that those bleedings resulted from severe thrombocytopenia, because VWF activity was normal under substitution therapy. BT200 (4.5mg) was injected four days after surgery which increased platelet counts from 25 to 49 x10E9/L after one week. A second dose of 7.5 mg increased platelet counts to 278 x10E9/L after another week. Conclusion BT200 corrected platelet counts facilitating two successful interventions without bleeding complications in one patient and a cessation of bleeding in a second patient, which indicates the utility of BT200 in the peri-interventional setting. Literature Ay C, et al. The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease. Blood Advances. 2022;27;6(18):5467-5476. Cihon A, et al. Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1. Blood. 2024 Jul 12:blood.2024024055
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
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.
2021-09-24 | 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.
2021-06-17 | Activated factor VIII-mimicking effect by emicizumab on thrombus formation in type 2N von Willebrand disease under high shear flow conditions.
Type 2N von Willebrand disease (2NVWD) is characterized by a mild to moderate reduction in plasma levels of factor (F)VIII associated with defective binding of von Willebrand factor (VWF) to FVIII and accelerated proteolysis and clearance of FVIII. The clinical phenotype in 2NVWD is often indistinguishable from mild/moderate hemophilia (H)A. Emicizumab is a bispecific antibody to FIX/FIXa and FX/FXa that mimics FVIIIa cofactor function, and emicizumab prophylaxis significantly reduces bleeding events in patients with severe HA. We investigated the potential benefits of emicizumab in the hemostatic management of 2NVWD. Perfusion chamber experiments were performed using whole blood from three 2NVWD patients with different clinical phenotypes (bleeding scores: 0, 6 and 20; mutations: p.R816W, p.R816W, and p.R365X/p.T791M, respectively). Furthermore, the impact of specific FVIII-VWF interactions on thrombus formation was investigated. Defective thrombus formation that correlated with bleeding phenotype was evident in these 2NVWD patients. Emicizumab improved surface coverage and thrombus height in all cases. Multi-color immunostaining of thrombi further demonstrated that emicizumab enhanced thrombin generation and fibrin formation. The addition of FVIII alone to 2NVWD whole blood did not augment thrombus formation, while supplementation with FVIII/VWF complex enhanced platelet-fibrin interactions. Furthermore, an anti-FVIII monoclonal antibody known to interrupt the release of FVIIIa from VWF depressed these effects. Emicizumab-induced enhancing effects of thrombus formation, independent on VWF, might be useful as an alternative therapy for 2NVWD patients. The extent of FVIII-VWF interaction should be optimal to deliver and release FVIII/FVIIIa on the activated platelet surface.
2013-08-23 | Antigenic Peptides Capable of Inducing Specific Antibodies for Detection of the Major Alterations Found in Type 2B Von Willebrand Disease.
Von Willebrand disease (VWD) is an inherited hemorrhagic disorder promoted by either quantitative or qualitative defects of the von Willebrand factor (VWF). The disease represents the most common human coagulopathy afflicting 1.3% of the population. Qualitative defects are subdivided into four subtypes and classified according to the molecular dysfunction of the VWF. The differential diagnosis of the VWD is a difficult task, relying on a panel of tests aimed to assess the plasma levels and function of the VWF. Here, we propose biochemical approaches for the identification of structural variants of the VWF. A bioinformatic analysis was conducted to design seven peptides among which three were representatives of specific amino acid sequences belonging to normal VWF and four encompassed sequences found in the most common VWD subtype 2B. These peptides were used to immunize mice, after which, peptide-specific immunoglobulins were purified. This resulted in four Ig preparations capable of detecting alterations in the subtype 2B VWD plus additional three antibody fractions targeting the normal VWF. The panel of antibodies could serve many applications among them (1) assessment of VWF: antigen interaction, (2) VWF multimer analysis, and (3) production of monoclonal antibodies against VWF for therapeutic purposes as in thrombotic thrombocytopenic purpura.
2010-11-25 | Targeting von Willebrand factor and platelet glycoprotein Ib receptor
Atherothrombotic events, such as acute coronary syndrome or stroke, are the result of platelet activation. Von Willebrand factor (vWF), a multimeric glycoprotein, plays a key role in aggregation of platelets, especially under high-shear conditions. Acting as bridging element or ligand between damaged endothelial sites and the glycoprotein Ib (GPIb) receptor on platelets, vWF is responsible for platelet adhesion and aggregation. This vWF activation and further platelet aggregation mainly occurs under high shear stress present in small arterioles or during deficiency of the vWF-cleaving protease ADAMTS13. There are several substances targeting vWF itself or its binding receptor GPIb on platelets. Two antibodies are directed against vWF: AJW200, an IgG4 humanized monoclonal antibody, and 82D6A3, a monoclonal antibody of the collagen-binding A-3 domain of vWF. ALX-0081 and ALX-0681 are bivalent humanized nanobodies targeting the GPIb binding site of vWF. Aptamers are oligonucleotides with drug-like properties that share some of the attributes of monoclonal antibodies. ARC1779 is a second-generation, nuclease-resistant aptamer, binding to the activated vWF A1 domain and ARC15105 is a chemically advanced follower with an assumed higher affinity to vWF. Antibodies targeting GPIbα are h6B4-Fab, a murine monoclonal antibody; GPG-290, a recombinant, chimeric protein containing the amino-terminal 290 amino acids of GPIbα linked to human IgG1 Fc; and the monoclonal antibody SZ2. There are a number of promising preclinical results and development of some agents (AJW 200, ARC1779 and ALX-0081) has already reached Phase II trials.
small molecules
2026-08-28 | Platelet Type Von Willebrand Disease - Diagnostic and Therapeutic Challenges.
Platelet-type von Willebrand disease (PT-VWD) is a rare thrombocytopathy caused by gain-of-function variants in GP1BA, leading to increased binding of von Willebrand factor (VWF). Because its phenotype closely resembles VWD type 2B (VWD 2B), misdiagnosis is common, and distinction requires Ristocetin-induced platelet agglutination (RIPA) mixing studies and molecular genetic analysis. Although individual case reports, case series, and earlier summaries exist, an updated and comprehensive synthesis of all published cases has been lacking. We report a 4-year-old boy presenting with easy bruising, prolonged epistaxis, reduced VWF parameters (VWF collagen-binding activity 0.07 U/mL, VWF-antigen 0.33 U/mL), absence of high-molecular-weight multimers, and enhanced RIPA. Genetic testing identified the pathogenic GP1BA variant p.Met255Val, causing PT-VWD. RIPA mixing studies confirmed the diagnosis. In the course of the disease, the patient developed recurrent mucosal bleeding and a hypersensitivity reaction to tranexamic acid. Therefore, desmopressin was used, and he showed partial clinical benefit from desmopressin without developing thrombocytopenia. To contextualize this case, we performed a literature review (PubMed, May 2025) and identified 67 documented patients with PT-VWD. Over 40% were initially misclassified as VWD 2B. p.Gly249Val and p.Met255Val were the most frequent variants. Baseline thrombocytopenia occurred in approximately one-third of cases, and pregnancy-associated thrombocytopenia was common. According to the literature, platelet transfusions were most effective (in case of major hemorrhage or surgical setting); VWF concentrates or desmopressin showed variable efficacy and occasional transient thrombocytopenia. These data demonstrate the diagnostic challenges of PT-VWD and emphasize the importance of clinical case collection to improve therapeutical management.
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.
2021-03-22 | How I treat gastrointestinal bleeding in congenital and acquired von Willebrand disease.
Gastrointestinal (GI) bleeding is distinctive of severe von Willebrand disease (VWD), generally arising in older patients; in most cases, blood transfusion and hospitalization are required. The presence of arteriovenous malformations is often described when endoscopic examinations are performed. Patients with congenital type 3, 2A, and 2B are those most frequently affected by this symptom, possibly due to the loss of high-molecular-weight multimers of von Willebrand factor (VWF). GI bleeding can also occur in patients affected by acquired von Willebrand syndrome. Endoscopic examination of the GI tract is necessary to exclude ulcers and polyps or cancer as possible causes of GI bleeding. In congenital VWD, prophylaxis with VWF/factor VIII concentrates is generally started after GI-bleeding events, but this therapy is not always successful. Iron supplementation must be prescribed to avoid chronic iron deficiency. Possible rescue therapies (high-dose statins, octreotide, thalidomide, lenalidomide, and tamoxifen) were described in a few case reports and series; however, surgery may be necessary in emergency situations or if medical treatment fails to stop bleeding. In this article, we present several clinical cases that highlight the clinical challenges of these patients and possible strategies for their long-term management.
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.
2019-04-16 | Protein kinase C signaling dysfunction in von Willebrand disease (p.V1316M) type 2B platelets.
von Willebrand disease (VWD) type 2B is characterized by gain-of-function mutations in von Willebrand factor (VWF), enhancing its binding affinity for the platelet receptor glycoprotein (GP)Ibα. VWD type 2B patients display a bleeding tendency associated with loss of high-molecular-weight VWF multimers and variable thrombocytopenia. We recently demonstrated that a marked defect in agonist-induced activation of the small GTPase, Rap1, and integrin αIIbβ3 in VWD (p.V1316M) type 2B platelets also contributes to the bleeding tendency. Here, we investigated the molecular mechanisms underlying impaired platelet Rap1 signaling in this disease. Two distinct pathways contribute to Rap1 activation in platelets: rapid activation mediated by the calcium-sensing guanine nucleotide exchange factor CalDAG-GEF-I (CDGI) and sustained activation that is dependent on signaling by protein kinase C (PKC) and the adenosine 5'-diphosphate receptor P2Y12. To investigate which Rap1 signaling pathway is affected, we expressed VWF/p.V1316M by hydrodynamic gene transfer in wild-type and Caldaggef1-/- mice. Using αIIbβ3 integrin activation as a read-out, we demonstrate that platelet dysfunction in VWD (p.V1316M) type 2B affects PKC-mediated, but not CDGI-mediated, activation of Rap1. Consistently, we observed decreased PKC substrate phosphorylation and impaired granule release in stimulated VWD type 2B platelets. Interestingly, the defect in PKC signaling was caused by a significant increase in baseline PKC substrate phosphorylation in circulating VWD (p.V1316M) type 2B platelets, suggesting that the VWF-GPIbα interaction leads to preactivation and exhaustion of the PKC pathway. Consistent with PKC preactivation, VWD (p.V1316M) type 2B mice also exhibited marked shedding of platelet GPIbα. In summary, our studies identify altered PKC signaling as the underlying cause of platelet hypofunction in p.V1316M-associated VWD type 2B.
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.
2025-12-21 | Surgical intervention with cardiopulmonary bypass in a patient with von Willebrand disease.
This article presents a clinical case of surgical intervention with cardiopulmonary bypass (CPB) in a patient with von Willebrand disease (VWD). VWD is the most common inherited bleeding disorder, significantly complicating surgical procedures due to impaired hemostasis. Surgical treatment of patients with VWD, particularly in the context of cardiovascular surgery involving CPB, requires an individualized approach. This includes the optimization of von Willebrand factor (vWF) and factor VIII (FVIII) levels, which are critical to preventing perioperative bleeding. The article describes the perioperative anesthetic management of the patient, emphasizing the importance of hemostasis monitoring, an individualized approach, and personalized dosing of replacement therapy to ensure effective treatment and minimize the risk of bleeding and thromboembolic complications. A 36-year-old male (181 cm, 92 kg) with type 2 von Willebrand disease and a history of childhood cardiac surgery (atrial septal defect repair, right ventricular outflow tract reconstruction) was admitted for elective aortic valve replacement with a bioprosthesis due to severe aortic regurgitation. Echocardiography revealed residual ventricular septal defect shunting, aortic root dilation, moderate mitral regurgitation, and cusp prolapse. The patient had a significant bleeding history and laboratory evidence of low vWF antigen/activity and FVIII deficiency. Perioperative management included ultrasound-guided vascular access, balanced general anesthesia, moderate hypothermic cardiopulmonary bypass, antifibrinolytic therapy, and tailored hemostatic replacement with vWF concentrate, FVIII, cryoprecipitate, platelets, and plasma. The patient was extubated 6 h after surgery, required minimal transfusion support, and recovered without hemorrhagic or thromboembolic complications. He was discharged on postoperative day 10 in good condition. Proper management of the perioperative period is identified as a complex challenge for anesthesiologists, requiring a clear understanding of therapeutic mechanisms and their impact on coagulation.
2025-12-03 | 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.
2025-11-03 | Pharmacokinetic-pharmacodynamic modelling of von willebrand factor/factor VIII prophylaxis in von willebrand disease
Abstract Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who experience severe and frequent bleeding episodes. Prophylactic therapy may be individualised by pharmacokinetic (PK)-guided dosing. Effective clinical implementation of PK-guided dosing requires knowledge of both the interpatient PK variability and the relationship between drug exposure and bleeding risk. Objective: To develop a population PK model for the plasma-derived VWF/factor VIII (FVIII) 1:1 concentrate (Wilate®) in patients with severe VWD and to explore the relationship between VWF/FVIII activity and bleeding events during prophylaxis. Methods: A nonlinear mixed-effects PK modelling approach was applied to VWF:ristocetin cofactor (VWF:RCo) and FVIII activity (FVIII:C) data from pediatric and adult patients participating in a prospective single-dose (WIL-12) and a 1-year prospective, prophylaxis phase 3 trial (WIL-31; NCT04052698). Individual post-hoc PK profiles were constructed, and VWF/FVIII activity levels were retrospectively assessed at the time of bleeding events. Results: 658 VWF:RCo and 692 FVIII:C levels were obtained from 53 patients with a median age of 23 years (range: 7-68 years) with VWD, comprising 11 with severe type 1, 10 with type 2A, 1 with type 2B, 2 with type 2M, and 29 with type 3. One- and two-compartment turnover population PK models best described the PK profiles for VWF:RCo and FVIII:C, respectively. For VWF:RCo, the typical value of clearance and its interpatient variability were 3.4 dL/h/70 kg and 47%, respectively; for FVIII:C, the corresponding values were 1.8 dL/h/70 kg and 57%. Post hoc analysis revealed that 50% of the 71 spontaneous bleeds during WIL-31 occurred at levels <3.7 IU/dL VWF:RCo and <9.1 IU/dL FVIII:C. Similarly, 50% of the 49 traumatic bleeds occurred at VWF:RCo levels <4.6 IU/dL and FVIII:C levels <14.7 IU/dL. Conclusion: In this study, we developed a population PK model for the plasma-derived VWF/FVIII 1:1 concentrate that can support clinicians in optimising VWD therapy by assessment of exposure PK metrics (trough levels, area under the curve, time above a defined threshold) and VWF:RCo and FVIII:C levels at the time of bleeding. As the population PK model of the VWF/FVIII 1:1 concentrate creates parallel PK profiles of VWF:RCo and FVIII:C, PK-guided may be performed by monitoring FVIII as well as VWF. Our population PK model enables informed treatment decisions, advancing the personalisation of long-term prophylaxis for plasma-derived VWF/FVIII in severe VWD.
2025-10-01 | S4681 Recurrent Gastrointestinal Bleeding in Type 2M Von Willebrand Disease: A Diagnostic and Therapeutic Challenge
Introduction: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, with type 2M representing a rare qualitative defect in von Willebrand Factor (VWF) that impairs platelet adhesion despite normal multimer distribution. Gastrointestinal (GI) bleeding is well-described in types 2A, 2B, and 3 due to loss of high-molecular-weight multimers, but less so in type 2M. Type 2M is often misclassified as type 1 or 2A, which can delay appropriate therapy. Management of VWD-related gastrointestinal bleeding is complex, often requiring endoscopic intervention, hormonal or antifibrinolytic agents, and VWF replacement. We present a rare case of recurrent, transfusion-dependent GI bleeding in type 2M VWD successfully managed with recombinant VWF (rVWF) prophylaxis. Case Description/Methods: We present a case of a 72-year-old woman diagnosed with type 2M VWD at age 48, with a history of menorrhagia, easy bruising, and past surgical procedures managed with DDAVP. At age 69, she developed recurrent melena and symptomatic anemia. Initial labs showed hemoglobin of 7.5 g/dL. Extensive GI evaluation, including EGD, colonoscopy, capsule endoscopy, computed tomography enterography, and device-assisted enteroscopy, failed to localize a bleeding source. Medical therapies—Desmopressin (DDAVP), tranexamic acid, and atorvastatin—were ineffective. Between ages 69 and 71, she required 13 PRBC transfusions, 19 iron infusions, multiple doses of DDVAP, and Humate P. Ultimately, she was started on weekly rVWF which resolved her GI bleeding, her hemoglobin stabilized, and she has remained completely transfusion-independent for over 12 months. The dosing interval was successfully extended to every 3 weeks with sustained improvement in symptoms and quality of life. Discussion: Recurrent GI bleeding in type 2M VWD is underreported and likely underrecognized due to diagnostic misclassification and lack of awareness. Angiodysplasia is a suspected mechanism, though frequently undetectable with standard imaging. This case illustrates the limited utility of DDAVP in type 2M and supports rVWF prophylaxis as a viable option when conventional therapies fail. Accurate VWD subtyping is essential for optimizing treatment. To our knowledge, this is the first reported case of successful long-term rVWF use in type 2M VWD with recurrent GI bleeding, resulting in complete transfusion independence.
oligonucleotides
2026-09-09 | Type 2B VWD substitutions trigger enhanced macrophage-mediated clearance that is attenuated by the BT200 aptamer
ABSTRACT Type 2B von Willebrand disease (VWD) is characterized by missense variants in exon 28 of the von Willebrand factor (VWF) gene that encodes the VWF-A1 domain. These missense mutations result in single amino acid residue substitutions that cause activation of VWF-A1 and promote spontaneous interaction with platelet GPIbα. Importantly, enhanced VWF clearance has been shown to play a key pathogenic role in >90% patients with Type 2B VWD. Although this VWF clearance occurs via mechanisms that are independent of VWF-platelet complex formation, the biological mechanisms responsible for the increased clearance of type 2B VWD variants remain poorly understood. In this study, we investigated a series of different type 2B amino acid substitutions within the VWF-A1 domain (R1306W, R1308C, W1313C and R1379L). We demonstrate that these variants all exhibit significantly increased macrophage binding. In part, the enhanced macrophage interactions are mediated via increased binding of type 2B VWD variants to LRP1 extracellular cluster II and IV. Our findings further demonstrate that the K1405-K1408 lysine cluster in the VWF-A1 domain plays a key role in enabling enhanced LRP1 interactions for type 2B VWD variants. In addition, we show that type 2B VWF variants demonstrate significantly enhanced interaction with the macrophage MGL receptor. Finally, and importantly from a clinical perspective, we demonstrate that the increase in macrophage binding for type 2B variants is significantly attenuated in the presence of BT200. Collectively, our findings have direct translational relevance with respect to the clinical heterogeneity and treatment of type 2B VWD.
2026-08-11 | Embryo-Fetal Development and Maternal-Fetal Exposure of the Von Willebrand Factor Binding Aptamer Rondaptivon Pegol (BT200) in Rabbits.
Rondaptivon pegol (BT200) is a PEGylated RNA aptamer that prolongs von Willebrand factor (VWF) and factor VIII half-lives in patients with hemophilia A and von Willebrand disease (VWD) type 2B. Embryo-fetal safety is particularly relevant given the disproportionate disease burden in women with VWD. Data on placental transfer and developmental safety of PEGylated aptamers remain limited. An embryo-fetal development study was conducted in pregnant rabbits. Animals received rondaptivon pegol subcutaneously (0, 1.5, 5, or 15 mg/kg/day) from gestational days (GDs) 7-19. Maternal toxicokinetic samples and pooled fetal plasma concentrations were collected during gestation to quantify transplacental exposure. Rondaptivon pegol was well tolerated, with no maternal toxicity, no effects on implantation, and no treatment-related fetal malformations. Dose-related reductions in mean fetal body weight (<11%) were considered adverse only at the highest dose level. Maternal systemic exposure was supratherapeutic, with mean Cmax ranging from 133 to 807 µg/mL on GD19, far exceeding the human target concentration (∼1.2 µg/mL). Fetal plasma concentrations were <0.25% of maternal levels across all dose groups, confirming minimal placental transfer. The no-observed-adverse-effect level was 5 mg/kg/day. At maternal systemic exposures ranging from 110- to 670-fold above anticipated clinical levels, rondaptivon pegol did not adversely affect implantation, embryonic viability, or fetal development. These findings provide the first quantitative maternal-fetal pharmacokinetic and developmental safety data for a PEGylated aptamer, supporting further clinical evaluation of rondaptivon pegol in women of reproductive age.
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.
2024-12-25 | Conformation-specific RNA aptamers for phenotypic distinction between normal von Willebrand factor and type 2B von Willebrand disease.
The A1 domain in Von Willebrand Factor (VWF) initiates coagulation through binding to platelet glycoprotein GPIbα receptors. Von Willebrand Disease (VWD)-Mutations in A1 that either impair (type 2M) or enhance (type 2B) platelet adhesion to VWF can locally destabilize and even misfold the domain. We leveraged misfolding in the gain-of-function type 2B VWD phenotype as a target, distinct from the normal conformation. Two nuclease-resistant 2'-fluoropyrimidine RNA aptamers were selected to discriminate normal A1 domains from a type 2B V1314D A1 variant in a glycosylated A1A2A3 tri-domain VWF-fragment. Two aptamers, W9 and V1, were isolated that selectively recognize, bind, and inhibit the A1-GPIbα interaction with WT A1A2A3 and V1314D A1A2A3, respectively. These aptamers were tested against their respective recombinant targets, plasma VWF, VWF concentrates, and patient plasma with the heterozygous type 2B VWD R1306W variant using clinical assays, surface plasmon resonance and inhibition assays of platelet adhesion to recombinant A1 and A1A2A3 domains under shear stress. The specificity of W9 and V1 aptamers confirms that pathological conformations of VWD Type 2B proteins are different from normal VWF. The availability of aptamers that distinguish normal plasma-derived VWF from VWD suggests potential applicability in clinical diagnosis of severe gain-of-function phenotypes.
2024-11-05 | Rondaptivon Pegol (BT200) to Correct Thrombocytopenia in a Peri-Interventional Setting in Type 2B Von Willebrand Disease (VWD)
Introduction Type 2B von Willebrand disease (VWD) is a qualitative VWF defect with increased binding of VWF to platelets, increased platelet clearance, potential thrombocytopenia and a substantial risk of bleeding. Rondaptivon pegol (BT200) is an aptamer binding to the A1 domain of von Willebrand Factor (VWF), which increases VWF antigen, GpIbM, collagen binding activity, multimers and platelet counts in type 2B VWD. Methods, intervention and outcome Two thrombocytopenic patients with type 2B VWD received BT200 peri-interventionally. Patient #1 had a suspect lesion in the lung and required bronchoscopy. As she had received BT200 in a previous phase 2 trial, she now received a loading dose of 10 mg BT200 prior to the procedure, which increased platelet counts from 46 to 108 x10E9/L after one week. Subsequent doses of BT200 normalized her platelet counts. Two months later, she received a loading dose of 12mg, 7.5 and 7.5mg BT200 at weekly intervals before an enteroscopy with thermocoagulation because of frequent bleedings due to jejunal angiodysplasia. Her platelet counts reached 160 before and 153 x10E9/L after the intervention. In both cases BT200 made it possible to conduct those diagnostic procedures, for which threshold platelet counts above the patient's baseline are required. No bleeding complications occurred. The second patient had a femoral neck fracture that required hip surgery under prophylactic substitution wirh Haemate P, which increased VWF activity to 101%. Nevertheless, platelet counts continued to fall to 14 x10E9/L, and the patient not only showed extensive local hematomas, but also developed bleedings at distant sites (buccal, extremities). This strongly indicates that those bleedings resulted from severe thrombocytopenia, because VWF activity was normal under substitution therapy. BT200 (4.5mg) was injected four days after surgery which increased platelet counts from 25 to 49 x10E9/L after one week. A second dose of 7.5 mg increased platelet counts to 278 x10E9/L after another week. Conclusion BT200 corrected platelet counts facilitating two successful interventions without bleeding complications in one patient and a cessation of bleeding in a second patient, which indicates the utility of BT200 in the peri-interventional setting. Literature Ay C, et al. The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease. Blood Advances. 2022;27;6(18):5467-5476. Cihon A, et al. Aptamer BT200 blocks interaction of K1405-1408 in the VWF-A1 domain with macrophage LRP1. Blood. 2024 Jul 12:blood.2024024055
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2025-12-18 | Allele-selective disruption of pathogenic VWF variants in type 2 von Willebrand disease using CRISPR/Cas9.
In contrast to major innovations in treating severe hemophilia, the treatment of severe von Willebrand disease (VWD) remains limited to intravenous infusion of von Willebrand factor (VWF) concentrates. To date, no gene therapy-based approaches for the treatment of VWD have been developed, largely owing to the disease's heterogeneous mutational landscape and the challenge of specifically targeting VWF production in endothelial cells. In this study, we developed a novel gene therapy strategy for patients with VWD caused by heterozygous dominant-negative VWF variants. Our strategy permanently inactivates VWF variants by selectively disrupting the pathogenic allele's open reading frame via the introduction of indels by Cas9. To circumvent the challenge of designing variant-specific strategies, we targeted the common single nucleotide polymorphism (SNP) rs1800378 in VWF. We used endothelial colony-forming cells (ECFCs) from patients with VWD2A and VWD2B with heterozygous p.C1190R and p.R1306W variants, respectively, to demonstrate ex vivo proof of principle. Using next-generation sequencing analysis, we show efficient and allele-selective knockout of VWF, while maintaining VWF expression of the nontargeted allele. Variant mapping mass spectrometry that discriminates between wild-type and variant VWF proteoforms confirmed selective reduction of variant allele expression, which was accompanied by reversal of cellular disease phenotypes in ECFCs. This study shows the feasibility of a novel gene editing strategy for VWD that, by virtue of its targeting of a common SNP, can be broadly applicable and can be used to design treatments for VWD without being constrained by the disease-causing variant, pathogenic mechanism, or VWD subtype.
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