RARE DISEASE
Von Willebrand disease
Von Willebrand disease
Von Willebrand disease
Synonyms: Hereditary von Willebrand disease
Synonyms: Hereditary von Willebrand disease
Synonyms: Hereditary von Willebrand disease
Drug discovery
15
drugs
With orphan designations
Overview
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF), leading to impaired platelet adhesion and Factor VIII stabilization [4][9][17]. It manifests as mucocutaneous bleeding (epistaxis, menorrhagia, postoperative bleeding), with severity varying by type (1, 2A/B/M/N, 3) [4][14][18]. Diagnosis requires clinical evaluation, VWF antigen/activity testing, and Factor VIII assays [13][17].
Therapies
First-line: Desmopressin (DDAVP) for responsive Type 1/2A/2M [1][5][11]
Replacement therapy: Plasma-derived/recombinant VWF concentrates (e.g., Humate-P, Vonvendi) for severe bleeding/surgery [1][5][19]
Adjuncts: Antifibrinolytics (tranexamic acid), hormonal contraceptives, fibrin sealants [1][3][14]
Categories: rare genetic diseases, rare hematological diseases
Research Papers
1,494 drug discovery papers about Von Willebrand disease, with 3 first-in-class and 23 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,494 drug discovery papers about Von Willebrand disease, with 3 first-in-class and 23 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-12 | Recurrent Hematuria Unveiling Renal Lymphangioma: A Diagnostic Challenge in a Patient with von Willebrand Disease
Abstract Renal lymphangioma is a rare benign lymphatic malformation that may present with hematuria and flank pain. We report the case of a 16-year-old female with type 2A von Willebrand disease who developed recurrent macroscopic hematuria and left lumbar pain. Imaging revealed a multiloculated intrarenal cystic lesion consistent with renal lymphangioma. After recurrence of symptoms and failure of conservative management, percutaneous intrarenal sclerotherapy with doxycycline was performed under factor replacement, resulting in complete symptom resolution and no recurrence on follow-up. This case highlights the diagnostic challenge in coagulopathic patients and supports sclerotherapy as an effective minimally invasive treatment.
2026-06-04 | Novel therapies for von Willebrand Disease.
For the past decades, treatment for von Willebrand disease has essentially consisted of classic approaches and only in the past few years has the need for more innovative strategies been recognised. To address the needs of groups of patients with similar phenotypes and bleeding, personalised therapeutic strategies are being developed, molecules designed for other bleeding disorders are being repositioned, and new haemostatic agents are being tested in patients with von Willebrand disease. New therapeutics include a variety of molecules, including antibodies, engineered factors, synthetic nanoparticles, siRNAs, and genome editing tools. Some promising molecules are still undergoing preclinical testing, while others have already entered clinical evaluation and may soon be available for at least some patients with von Willebrand disease. We believe that new approaches will improve the clinical management and the quality of life for patients with von Willebrand Disease.
2026-04-16 | Practical Advances in the Diagnosis of Haemophilia and von Willebrand Disease Including Monitoring of Non-Factor Replacement Therapies.
Traditional haemophilia therapies act to replace the relevant missing clotting factor, are not interchangeable between haemophilia A and B and cannot be used in patients with high titre inhibitors. Novel non-replacement factor therapies (NFT) target other endogenous coagulation proteins or anticoagulants such as antithrombin (AT) and tissue factor pathway inhibitor (TFPI) to rebalance haemostasis. As such, pharmaceutical clinical trials of these molecules have enrolled patients with haemophilia A or B, with and without inhibitors. The requirement for monitoring the efficacy of NFTs is greatly reduced compared to replacement therapy and global assays such as thrombin generation assay (TGA) have been used extensively in clinical trials to indicate improvement to haemostasis. Comprehensive haemophilia care, including access to and laboratory monitoring of replacement and NFTs, is well established in high income countries, but there are profound global inequities in the diagnosis and treatment of haemophilia which still need to be remedied. The authors examine the challenges of haemophilia and von Willebrand diagnosis and monitoring of NFTs using conventional and global assays of haemostasis.
2026-04-06 | Full-arch dental implant rehabilitation in a patient with Von Willebrand disease: a case report.
Von Willebrand disease (VWD) is the most common congenital bleeding disorder with multiple types. Patients with VWD pose a serious risk for surgical interventions. This case report discusses successful full-mouth dental clearance, bone augmentation, and dental implant rehabilitation in a patient with VWD. A 48-year-old female patient with type 2A VWD suffered from partial edentulism in both the upper and lower arches, as well as badly decayed, heavily restored teeth with multiple periapical abscesses. Dental clearance and immediate implant placement were carried out under general anesthesia with proper antifibrinolytic and Wilate prophylaxis. The patient was in stable condition post-operatively and showed good healing in follow-up visits; the implants were subsequently restored. To the author's knowledge, this is the first case of full-mouth implant rehabilitation in a patient with VWD. Thorough planning and adequate optimization of the patient for surgery, along with careful surgical technique and selection of materials, aid in treating patients with VWD, greatly increasing the chances of success.
2026-03-22 | Managing heavy menstrual bleeding in adolescents with bleeding disorders: Outcomes from a pragmatic LMIC approach.
Heavy menstrual bleeding (HMB) a common manifestation of bleeding disorders in adolescents contributes to anemia, transfusions, and impaired quality-of-life (QOL). Evidence supporting practical management strategies in resource-limited settings remains limited. This observational study in adolescents with confirmed bleeding disorders with HMB at a tertiary hemophilia treatment centre evaluated menstrual blood loss and QOL after a standard regimen of progesterone, tranexamic acid and iron; blood products or clotting factor concentrates were reserved for refractory bleeding. Twenty adolescents were included (2020-2025); von Willebrand disease (n = 11), chronic immune thrombocytopenia (n = 4), congenital aplastic anemia (n = 3), afibrinogenemia (n = 1), and factor VII deficiency (n = 1). Median PBAC score at presentation was 300 (range 190-500). Eighteen patients (90%) had anemia and prior transfusion exposure. After therapy, median PBAC declined to 100 (range 60-150). Hemoglobin improved steadily and no patient required further red cell transfusion during a median follow-up of four years. Hemostatic products were required only in two patients while on this regimen. Quality-of-life scores improved across physical, emotional, and social domains. A low-cost regimen combining progesterone, antifibrinolytic therapy, and iron effectively controls HMB, corrects anemia, reduces transfusion and factor utilization, and improves QOL in adolescents with bleeding disorders in resource-constrained settings.
antibodies
2026-06-04 | An Ex Vivo Pharmacodynamic Study of KN057, a Tissue Factor Pathway Inhibitor Neutralizing Antibody, in Plasma Samples From Patients With Haemophilia or VWD3.
Tissue factor pathway inhibitor (TFPI), a key regulator of tissue factor-initiated coagulation through FXa-dependent inhibition of the tissue factor-FVIIa complex, has emerged as a promising target for restoring thrombin generation. This ex vivo pharmacodynamic study aimed to evaluate the KN057, a novel humanized TFPI-neutralizing antibody, in plasma samples from participants with haemophilia or type 3 von Willebrand disease (VWD3). In this ex vivo spiking study, plasmas obtained from haemophilia or VWD3 participants were supplemented with KN057 at the concentration of 0-140.00 nM. The thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay were performed to assess coagulation responses. Between 26, May 2021, and 3, September 2021, a total of 29 participants were enrolled in this study, including 10 haemophilia A (HA) without inhibitors, 6 haemophilia B (HB) without inhibitors, 6 HA with inhibitors, 3 HB with inhibitors, and 4 VWD3. In participant plasmas supplemented with KN057, peak thrombin and endogenous thrombin potential (ETP) increased notably between 1.12-5.60 nM, and reached a maximal level at 28.00 nM. A dose-dependent decrease in dPT was observed in all participants with haemophilia or VWD3. KN057 exhibited a consistent ex vivo pharmacodynamic profile, including both the response trend and effective concentration range, across plasma samples from patients with HA or HB, irrespective of inhibitor status. Furthermore, its pharmacodynamic activity in plasma from patients with VWD3 was comparable to that observed in haemophilia plasma.
2026-04-28 | Successful use of emicizumab prophylaxis in a patient with von Willebrand disease type 3: A case report
Von Willebrand disease (VWD) type 3 is the most severe form of VWD and is often inadequately controlled with plasma-derived von Willebrand factor (VWF)/FVIII or fresh frozen plasma. Emicizumab, a factor VIII– mimetic antibody approved for hemophilia A, enhances secondary hemostasis and has emerging off-label evidence in severe VWD. A 38-year-old woman with VWD type 3 and recurrent mucocutaneous bleeding despite regular factor therapy was started on emicizumab prophylaxis. Over 6 months, she remained bleed-free without additional factor support. Activated partial thromboplastin time normalized with increased measured FVIII activity; the apparent VWF antigen rise was interpreted cautiously. The treatment was well-tolerated and cost-effective. Emicizumab may offer an effective alternative prophylaxis in selected patients with severe VWD.
2026-04-14 | Monovalent antibody treatment of von Willebrand disease
A commentary on an article recommending a new potential treatment approach for patients with von Willebrand disease (VWD).
2026-03-10 | Graft-derived VWF drives platelet activation and thrombocytopenia during porcine liver xenotransplantation to brain-dead human recipients.
BACKGROUNDGenetically engineered porcine livers are being developed as a bridge therapy for acute liver failure, providing detoxification and restoration of hepatic protein synthesis. Severe xenograft-associated thrombocytopenia remains a major limitation, and human mechanistic data are scarce.METHODSPlatelet kinetics were characterized in 3 human decedents undergoing extracorporeal cross-circulation with transgenic porcine livers. Platelet counts, transfusion requirements, and clearance patterns were assessed to distinguish consumption from marrow suppression or hypersplenism. Antibody- and complement-directed inhibitors were administered to test immune-mediated mechanisms. Mechanistic studies focused on porcine von Willebrand factor-dependent (pVWF-dependent) platelet activation, including ex vivo blockade with the anti-VWF nanobody caplacizumab, a VWF-directed antibody fragment that prevents VWF-platelet binding. A fourth decedent received caplacizumab during porcine liver perfusion.RESULTSIn all 3 initial cases, 80%-90% of circulating and transfused platelets were rapidly cleared, a pattern inconsistent with marrow suppression or hypersplenism. Antibody and complement inhibition failed to ameliorate thrombocytopenia. Recipient plasma induced robust pVWF-mediated platelet activation analogous to human type IIb von Willebrand disease, which was completely abrogated ex vivo by caplacizumab. In a fourth decedent treated with caplacizumab, aberrant platelet activation was prevented, although full hematologic recovery was limited by preexisting disseminated intravascular coagulation.CONCLUSIONSEarly thrombocytopenia during porcine liver xenotransplantation appears to be primarily driven by pVWF-mediated platelet activation rather than by classical immune or splenic mechanisms. Targeted VWF blockade with agents such as caplacizumab may mitigate platelet loss and improve the safety profile of extracorporeal porcine liver support in acute liver failure.
2026-03-01 | 6ER-034 Real-life experience with emicizumab: clinical outcomes and an exceptional case of type III von Willebrand disease with inhibitor
Background and Importance
Emicizumab is a humanised bispecific monoclonal antibody that mimics the cofactor function of activated factor VIII and is primarily indicated for the prophylactic treatment of patients with haemophilia A, irrespective of the presence of inhibitors. While its use in other hereditary bleeding disorders, such as von Willebrand disease, remains off-label and limited, it is increasingly being explored as a therapeutic alternative. We report our real-world experience from a tertiary care centre, highlighting a notable case of type III von Willebrand disease with an inhibitor, in which the use of emicizumab yielded promising clinical outcomes.
Aim and Objectives
To evaluate the efficacy, safety, and clinical applicability of emicizumab in patients with hereditary coagulopathies, with a particular focus on a case of type III von Willebrand disease with an inhibitor.
Material and Methods
This is a single-centre, retrospective observational study involving eight patients treated with emicizumab between December 2019 and May 2025. Clinical, genetic, and follow-up variables were collected, including diagnosis, age at treatment initiation, presence of inhibitors, history of bleeding episodes, post-treatment bleeding events, surgical or invasive interventions and adverse reactions.
Results
The cohort included seven patients with severe haemophilia A (one with an inhibitor) and one patient with type III von Willebrand disease with an inhibitor. The mean age at treatment initiation was 22 years (range: 5–40). All patients had a history of clinically significant bleeding episodes. Following the initiation of emicizumab, six patients did not experience any further bleeding episodes. Mild episodes (epistaxis and muscular hematoma) were recorded in two cases, none of which required additional treatment. The 19-year-old patient with von Willebrand disease, who had a history of epistaxis and deep haematomas, showed a favourable response, with only one mild epistaxis episode during follow-up. No serious adverse effects were reported, with only one patient experiencing transient mild headache.
Conclusion and Relevance
Emicizumab proved to be effective and safe in this cohort of patients with haemophilia A, including those with inhibitors. Notably, the case of the patient with type III von Willebrand disease and an inhibitor demonstrated excellent tolerability and bleeding control. These findings support the potential role of emicizumab as a prophylactic treatment in bleeding disorders beyond haemophilia A.
Conflict of Interest
No conflict of interest
proteins
2026-08-31 | Perioperative von Willebrand Factor and Factor VIII Kinetics in von Willebrand Disease Patients Treated With Different Clotting Factor Concentrates.
Patients with von Willebrand disease (VWD) undergoing surgery require von Willebrand factor (VWF) and factor VIII (FVIII) supplementation for adequate haemostasis. Plasma-derived clotting factor concentrates differ in their VWF:FVIII activity ratios: high-ratio product (HRP, 10:1), intermediate-ratio product (IRP, 2.4:1), and low-ratio product (LRP, 1:1). These differences may affect FVIII kinetics. This single-centre observational study included VWD patients undergoing surgery, treated with an HRP, IRP, or LRP, and with ≥2 perioperative VWF or FVIII measurements between 2009 and 2024. VWF and FVIII trajectories were assessed using linear mixed-effects models. Secondary endpoints were bleeding and venous thromboembolic events (VTE). In total, 123 patients were included; 63% underwent major surgery. Twenty-four patients received HRP, 61 received IRP and 38 received LRP. The median number of infusions was three across groups. Incremental VWF recoveries were 1.7 IU/dL per IU/kg for HRP, 1.3 for IRP, and 2.4 for LRP. FVIII recoveries were 2.5 for IRP and 2.7 for LRP. Over time, HRP showed higher mean VWF levels than IRP (Δ26 IU/dL; p = 0.010). HRP was associated with higher FVIII levels compared with IRP (Δ48 IU/dL; p < 0.001) and LRP (Δ35 IU/dL; p = 0.021). No difference was found between IRP and LRP. In patients receiving three consecutive infusions in 24 h, FVIII levels remained higher with HRP than IRP (Δ38 IU/dL; p = 0.019). No VTEs occurred. IRP and LRP led to greater initial VWF and FVIII peaks, whilst HRP produced more sustained FVIII elevation. Recognising these kinetic differences may guide tailored perioperative management of patients with VWD.
2026-07-13 | The role of von Willebrand factor in gastrointestinal angiodysplasia and obscure gi bleeding: a narrative review.
Gastrointestinal bleeding (GIB) is a major cause of morbidity in von Willebrand disease (vWD), most commonly resulting from angiodysplasia. Current obscure gastrointestinal bleeding (OGIB) algorithms are primarily anatomy-based and often overlook underlying hemostatic disorders, delaying diagnosis and promoting recurrent bleeding. This review summarizes current evidence on the molecular basis, diagnosis, and management of vWD-associated GIB and proposes a mechanism-oriented diagnostic framework. A comprehensive narrative review of experimental, translational, and clinical studies was conducted, focusing on inherited vWD, acquired von Willebrand syndrome (AvWS), gastrointestinal angiodysplasia, endothelial biology, and diagnostic and therapeutic strategies. Deficiency or dysfunction of high-molecular-weight von Willebrand factor (vWF) multimers promotes angiodysplasia by disrupting Weibel-Palade body homeostasis, enhancing Ang-2/Tie2 and VEGF signaling, impairing integrin αvβ3 function, and fostering pro-inflammatory endothelial activation. Genetic and epigenetic modifiers, including FLI1, STXBP5, ABO blood group, and miR-24, further influence vascular susceptibility. Based on these mechanisms, we propose a four-stage diagnostic framework integrating bleeding assessment, platelet function screening, and targeted vWF testing with conventional endoscopic evaluation to facilitate earlier recognition of vWD/AvWS in patients with recurrent or obscure GIB. This strategy supports mechanism-based treatment combining hemostatic replacement therapies with selected anti-angiogenic approaches. vWD-associated GIB should be regarded as a systemic vascular-hemostatic disorder rather than an isolated structural gastrointestinal disease. Integrating hemostatic evaluation into OGIB pathways may improve diagnostic accuracy, reduce unnecessary procedures, and enable personalized management of patients with recurrent bleeding.
2026-07-06 | Navigating hemostasis: anesthetic challenges in a pituitary tumor with type 2 von Willebrand disease—case report
Introduction The anesthetic management of patients with von Willebrand disease (VWD) present a significant perioperative challenge due to the high risk of hemorrhage. This risk is further elevated in neurosurgical procedures, such as transsphenoidal surgery (TSS) for pituitary neuroendocrine tumors (PitNETs), due to the close proximity to critical neurovascular structures. Case presentation This report describes a 42-year-old male with type 2 VWD and hypothyroidism, diagnosed with a Knosp grade 3A PitNET, who underwent an endoscopic endonasal transsphenoidal resection. A multidisciplinary approach was implemented, including hemodynamic monitoring and targeted replacement of VWF/FVIII concentrate calculated according to plasma levels, maintaining paremeters of VWF ristocetin cofactor/activity (VWF:RCo) (%) and FVIII (%): >80% during the intraoperative period and >50% during the postoperative period. The postoperative course was favorable, with no neurovascular, hemostatic, hemodynamic, or endocrine complications. Discussion The coexistence of VWD and a macro-PitNET creates a profound clinical dilemma that exposes the limitations of conventional perioperative care. While TSS demands strict hemostatic control due to its proximity to major neurovascular structures like the cavernous sinuses and internal carotid arteries, the type 2 VWD directly threatens clot stability and initial platelet plug formation. Given the scarce literature surrounding its neuroanesthetic management, this case report discusses the successful implementation of an individualized strategy. By integrating targeted plasma-derived VWF/FVIII replacement with real-time thromboelastography (TEG) and advanced hemodynamic monitoring, we demonstrate how a coordinated multidisciplinary approach can successfully mitigate overlapping hemorrhagic and neurosurgical risks. Conclusions This case highlights the importance of individualized planning and comprehensive management based on the American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF), and World Federation of Hemophilia (WFH) (ASH–ISTH–NHF–WFH, 2021) guidelines to optimize outcomes in patients with VWD undergoing high-complexity surgery.
2026-06-19 | Impaired hemostasis in mechanical circulatory support systems: Monitoring with T-TAS® 01, in vitro correction with VWF concentrates, and impact of membrane oxygenators.
Mechanical circulatory support (MCS) systems assist patients with severe cardiac or respiratory failure, but bleeding linked to acquired von Willebrand disease remains a major complication. The T-TAS® 01 system has emerged as a rapid tool for assessing MCS patients' hemostasis. To evaluate hemostatic changes during and after MCS support. Secondary objectives included assessing the impact of the in vitro addition of von Willebrand factor concentrates and exploring differences according to the presence of a membrane oxygenator (MO). This prospective, bicentric study included adults requiring MCS, with hemostatic parameters assessed at three predefined timepoints using conventional laboratory assays and T-TAS® 01. Data were analyzed using linear mixed-effects models. In vitro addition of a VWF/FVIII concentrate (Haemate-P®) was evaluated as an exploratory analysis. A total of 39 patients were included; 56% experienced bleeding complications, of which 23% were clinically relevant. Significant alterations in hemoglobin, platelet counts, and platelet/VWF function were observed during MCS. T-TAS® 01 demonstrated impaired hemostasis during support, with partial recovery after device removal. In vitro addition of Haemate-P® improved T-TAS® 01 parameters. No consistent differences in overall hemostatic dynamics were observed between MO and non-MO devices. MCS is associated with significant and persistent alterations in primary hemostasis. T-TAS® 01 may represent a useful tool for dynamic assessment of these changes. In vitro VWF supplementation improved functional hemostasis parameters, although its clinical implications remain to be established. Differences related to MO presence were not consistent, supporting a shared mechanism of hemostatic dysregulation across MCS devices.
2026-06-02 | Designing the Future of Hemostasis.
Bleeding disorders arising from dysfunctional platelet-protein interactions pose a significant clinical challenge due to their heterogeneity and complexity. Primary hemostasis is mediated by von Willebrand factor (VWF) and platelet surface receptors GPIbα and αIIbβ3. This protein triad is central to clot formation, and interfering with their associated activity can cause several primary hemostasis-related disorders. While traditional therapies, including factor replacement and monoclonal antibodies, have improved outcomes, they are often limited by availability, cost, immunogenicity, and inadequate precision. Recent advances in computational biology and peptide engineering now offer potential for improved hematologic therapeutics. This review outlines two major strategies in peptide drug design: Structure-based modeling and small motif-based design. These approaches enable the creation of short, stable peptides capable of targeting disease-specific protein-protein interactions (PPIs) with high specificity. We highlight the recent development of G14-an artificial intelligence (AI)-designed peptide that selectively disrupts the aberrant GPIbα-VWF interaction in platelet-type von Willebrand disease. The peptide demonstrated selective inhibition of the enhanced patient-derived platelet aggregation and VWF binding. By combining systems biology, structural modeling, and AI, peptide design can now yield rapid, scalable, and personalized therapies for bleeding disorders. Thus, the growing adoption and integration of intelligently designed peptides offer a new perspective on precision medicine for thrombosis and hemostasis.
gene therapies
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.
2025-10-08 | Rewriting the script: gene therapy and genome editing for von Willebrand Disease.
In recent years gene therapy has emerged as a powerful technology for treatment of a large variety of inherited disorders. With the FDA approval of in vivo gene therapy of hemophilia A and B using AAV-mediated transgene delivery to hepatocytes, the path towards a new treatment era seemed paved. Also, CRISPR-Cas based approaches have reached the clinic, as in the ex vivo treatment of hematopoietic stem cells for sickle cell disease and thalassemia patients. The question arises whether these innovative strategies will also be suitable for patients with von Willebrand Disease (VWD). Whilst in and ex vivo delivery to endothelial cells (ECs) has been demonstrated, and CRISPR-Cas9 gene editing has been successful in ECs, there are currently no gene therapy options available for VWD. The wide variety of pathogenic VWF mutations makes development of broadly applicable, cost-effective gene therapies challenging. While delivery of von Willebrand factor (VWF) as a therapeutic transgene would be optimal, the size of VWF challenges efficient delivery. Therefore, treatment of VWD requires targeted, personalized gene therapy; for instance by using the newest CRISPR-Cas technologies which can be tailored to facilitate alteration and restoration of various pathogenic VWD variants. This review describes the inherited bleeding disorder VWD and potential gene therapy approaches for management of the disease. Thereby we are exploring different CRISPR-Cas technologies and recent developments in the field. Moreover, we will discuss the ongoing advances of in vivo delivery systems, all with the scope on ECs.
2025-05-26 | Von Willebrand Disease: Exploring the Diagnostic and Therapeutic Challenges in Pakistan
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, arising from either a reduced amount or impaired function of von Willebrand factor (VWF), a protein vital to normal clot formation. This article examines the condition in detail, outlining its biological basis, symptoms, diagnostic difficulties, and available treatment options. Particular focus is placed on the situation in Pakistan, where unique challenges shape patient outcomes. The discussion also addresses the development of alloantibodies in some patients, exploring how these immune responses affect treatment success and quality of life. Psychosocial factors and dietary patterns, especially within the Pakistani context, are considered as additional influences on disease management. Worldwide, VWD often remains undetected because its symptoms can vary widely and resemble those of other bleeding disorders. In Pakistan, the problem is aggravated by low public awareness, limited access to diagnostic tools, and financial constraints, all of which lead to late diagnosis and inadequate care. Timely identification and appropriate medical intervention are critical for improving prognosis. The review underscores the need to strengthen diagnostic infrastructure, increase the reach of specialized care, and make effective therapies more accessible, particularly in underserved regions. Advances in genetic research and new treatment options, including the possibility of gene therapy, offer hope for better disease control in the future. The article concludes by urging reforms in healthcare systems, greater educational outreach, and focused measures to close existing gaps in the detection and management of VWD in Pakistan.
2023-01-13 | “iPSC-derived liver organoids and inherited bleeding disorders: Potential and future perspectives”
The bleeding phenotype of hereditary coagulation disorders is caused by the low or undetectable activity of the proteins involved in hemostasis, due to a broad spectrum of genetic alterations. Most of the affected coagulation factors are produced in the liver. Therefore, two-dimensional (2D) cultures of primary human hepatocytes and recombinant overexpression of the factors in non-human cell lines have been primarily used to mimic disease pathogenesis and as a model for innovative therapeutic strategies. However, neither human nor animal cells fully represent the hepatocellular biology and do not harbor the exact genetic background of the patient. As a result, the inability of the current in vitro models in recapitulating the in vivo situation has limited the studies of these inherited coagulation disorders. Induced Pluripotent Stem Cell (iPSC) technology offers a possible solution to overcome these limitations by reprogramming patient somatic cells into an embryonic-like pluripotent state, thus giving the possibility of generating an unlimited number of liver cells needed for modeling or therapeutic purposes. By combining this potential and the recent advances in the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology, it allows for the generation of autologous and gene corrected liver cells in the form of three-dimensional (3D) liver organoids. The organoids recapitulate cellular composition and organization of the liver, providing a more physiological model to study the biology of coagulation proteins and modeling hereditary coagulation disorders. This advanced methodology can pave the way for the development of cell-based therapeutic approaches to treat inherited coagulation disorders. In this review we will explore the use of liver organoids as a state-of-the-art methodology for modeling coagulation factors disorders and the possibilities of using organoid technology to treat the disease.
2021-08-16 | DNA variant classification–reconsidering “allele rarity” and “phenotype” criteria in ACMG/AMP guidelines
Recent guidance suggested modified DNA variant pathogenicity assignments based on genome-wide allele rarity. Different a priori probabilities of pathogenicity operate where patients already have clinical diagnoses, and are found to have a very rare variant in a gene known to cause their disease, compared to predictive testing of a clinically unaffected individual. We tested new recommendations from the ClinGen Sequence Variant Interpretation Working Group for ClinVar-listed, loss-of-function variants meeting the very strong evidence of pathogenicity criterion [PVS1] in genes for 3 specific diseases where causal gene identification can modify clinical care of an individual- Von Willebrand disease, cystic fibrosis and hereditary haemorrhagic telangiectasia. Across these diseases, current rules leave 20/1,278 (1.6%) of loss-of-function variants as variants of uncertain significance (VUS that may not be reported to clinicians), and 207/1,278 (17.2%) as likely pathogenic. Applying the new ClinGen rule enabling PVS1 and the allele rarity criterion PM2 to delineate likely pathogenicity still left 8/1,278 (0.9%) as VUS (reflecting non-PVS1 calls by the submitters), and the majority of null alleles meeting PVS1 as merely likely pathogenic. We favour an approach whereby, for PVS1 variants in patients who personally meet the phenotypic PP4 criterion for a disease where casual variants are commonly family-specific, that PM2 is upgraded to permit a pathogenic call. Of 1,278 ClinVar-listed frameshift, nonsense and canonical splice site variants that met PVS1 in the 3 conditions, 16.0% (204/1,278) would be newly designated as pathogenic, avoiding misinterpretation outside of clinical genetics communities. We suggest further discussion around variant assessment across different clinical applications, potentially guided by PP4 alerts to distinguish personal versus family phenotypic history.
other
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.
2025-01-13 | Heyde's Syndrome Manifesting as Recurrent Gastrointestinal Bleeding After Valve Replacement.
Heyde's syndrome is a clinical entity that combines aortic stenosis, gastrointestinal angiodysplasia, and an acquired von Willebrand factor disorder. This syndrome is characterized by the association between aortic stenosis and recurrent gastrointestinal bleeding episodes, typically linked to angiodysplasias. Effective treatment requires addressing the underlying condition, specifically aortic stenosis, which leads to the structural destruction of coagulation proteins, resulting in the acquired von Willebrand factor disorder and perpetuating the bleeding. Therefore, managing gastrointestinal bleeding alone is insufficient. Although initially underestimated by physicians due to its nonspecific presentation and overlapping symptoms, this syndrome has significant implications for diagnosis and management, particularly in older adults. Many patients with Heyde's Syndrome are often misdiagnosed with unrelated gastrointestinal conditions until the association with aortic stenosis is identified. This diagnostic delay can lead to repeated hospitalizations, chronic anemia, and a decline in quality of life. Aortic valve pathology and coagulopathy should be actively suspected and investigated, directing treatment toward correcting the aortic stenosis. The objective of this case report is to highlight the importance of suspecting this syndrome in patients with valvular disease, such as aortic stenosis, and recurrent bleeding episodes, as these conditions may not always represent two independent problems, even if the patient has previously undergone valve replacement. This is demonstrated in the presented case, where a 74-year-old female patient with cardiovascular disease treated years earlier with valve replacement developed valve dysfunction, leading to new episodes of gastrointestinal bleeding. This illustrates the need to reevaluate the valve to prevent recurrent complications.
2024-07-12 | The aptamer BT200 blocks interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1.
Rondaptivon pegol (previously BT200) is a pegylated RNA aptamer that binds to the A1 domain of von Willebrand factor (VWF). Recent clinical trials demonstrated that BT200 significantly increased plasma VWF-factor VIII levels by attenuating VWF clearance. The biological mechanism(s) through which BT200 attenuates in vivo clearance of VWF has not been defined. We hypothesized that BT200 interaction with the VWF-A1 domain may increase plasma VWF levels by attenuating macrophage-mediated clearance. We observed that full-length and VWF-A1A2A3 binding to macrophages and VWF-A1 domain binding to lipoprotein receptor-related protein 1 (LRP1) cluster II and cluster IV were concentration-dependently inhibited by BT200. Additionally, full-length VWF binding to LRP1 expressed on HEK293T (HEK-LRP1) cells was also inhibited by BT200. Importantly, BT200 interacts with the VWF-A1 domain in proximity to a conserved cluster of 4 lysine residues (K1405, K1406, K1407, and K1408). Alanine mutagenesis of this K1405-K1408 cluster (VWF-4A) significantly (P < .001) attenuated binding of VWF to both LRP1 clusters II and IV. Furthermore, in vivo clearance of VWF-4A was significantly (P < .001) reduced than that of wild-type VWF. BT200 did not significantly inhibit binding of VWF-4A to LRP1 cluster IV or HEK-LRP1 cells. Finally, BT200 interaction with the VWF-A1 domain also inhibited binding to macrophage galactose lectin and the SR-AI scavenger receptor. Collectively, our findings demonstrate that BT200 prolongs VWF half-life by attenuating macrophage-mediated clearance and specifically the interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1. These data support the concept that targeted inhibition of VWF clearance pathways represents a novel therapeutic approach for von Willebrand disease and hemophilia A.
2024-02-23 | Clusterin knockdown has effects on intracellular and secreted von Willebrand factor in human umbilical vein endothelial cells.
Alterations in von Willebrand factor (VWF) have an important role in human health and disease. Deficiency of VWF is associated with symptoms of bleeding and excesses of VWF are associated with thrombotic outcomes. Understanding the mechanisms that drive VWF regulation can lead to a better understanding of modulation of VWF levels in humans. We identified clusterin (CLU) as a potential candidate regulator of VWF based on a single cell RNA sequencing (scRNA-seq) analysis in control endothelial cells (ECs) and von Willebrand disease (VWD) endothelial colony-forming-cells (ECFCs). We found that patients with deficiencies of VWF (von Willebrand disease, VWD) had decreased CLU expression and ECs with low VWF expression also had low CLU expression. Based on these findings, we sought to evaluate the role of CLU in the regulation of VWF, specifically as it relates to VWD. As CLU is primarily thought to be a golgi protein involved in protein chaperoning, we hypothesized that knockdown of CLU would lead to decreases in VWF and alterations in Weibel-Palade bodies (WPBs). We used both siRNA- and CRISPR-Cas9-based approaches to modulate CLU in human umbilical vein endothelial cells (HUVECs) and evaluated VWF protein levels, VWF mRNA copy number, and WPB quantity and size. We demonstrated that siRNA-based knockdown of CLU resulted in decreases in VWF content in cellular lysates and supernatants, but no significant change in WPB quantity or size. A CRISPR-Cas9-based knockdown of CLU demonstrated similar findings of decreases in intracellular VWF content but no significant change in WPB quantity or size. Our data suggests that CLU knockdown is associated with decreases in cellular VWF content but does not affect VWF mRNA levels or WPB quantity or size.
2023-10-01 | OC 13.5 Whole-Genome Characterization of Low-VWF and VWD Type 1 Patients with No Known Pathogenic VWF Variant Reveals Novel Genetic Associations
Background:The pegylated aptamer BT200 binds to the A1 domain of VWF and significantly prolongs VWF half-life in vivo.Although the mechanism(s) involved have not been defined, the LRP1 scavenger receptor binds to the VWF A1 domain and contributes to physiological VWF clearance.Aims: To determine the molecular mechanisms through which the BT200 pegylated aptamer extends VWF half-life.Methods: Binding of full-length and selected VWF truncations to bone marrow-derived macrophages (BMDM) was assessed by flow cytometry in the presence or absence of BT200.Immunosorbent plate-binding assays were used to characterize binding to purified LRP1-ClusterII or Cluster IV receptors respectively.Finally, clearance of HEK293T-expressed VWF variants were investigated in VWF-/-mice.Results: BT200 dose-dependently inhibited binding of recombinant VWF (Vonvendi) & plasma-derived VWF (Fandhi) to BMDMs (maximal binding inhibition: 88.55 ± 4.73% at 10 μM BT200).In addition, BT200 significantly inhibited binding of full-length rVWF to purified LRP1-Cluster-IV ( p = 0.0005).Plate binding assays confirmed that the truncated VWF-A1A2A3 fragment and the isolated VWF-A1 domain both bound to LRP1 Cluster-II and Cluster-IV.In both cases, binding was again inhibited by BT200 in a dose-dependent manner, recapitulating the BMDM results.Finally, interaction of VWF-A1A2A3 fragment with HEK-293 T transfected with full length LRP1 cDNA was ablated by BT200.In contrast, BT200 had no inhibitory effects on VWF-A1A2A3 binding to either MGL or SR-A1 macrophage clearance receptors.Since BT200 binds close to Lys 1405 in VWF-A1, site-directed mutagenesis of Lys 1405 study was performed.VWFA1-K1405A did not bind BMDMs, nor to coated LRP1-Cluster-IV.Furthermore, full-length rVWF-K1405A demonstrated a significantly increased half-life in VWF-/-mice compared to wild type VWF (P = 0.0049).Conclusion(s): Our novel findings demonstrate that Lys1405 in VWFA1 is critical for interaction with the LRP1 scavenger receptor.BT200 binds to VWFA1 close to this key Lys1405 residue, thereby preventing interaction with LRP1 and consequently extending VWF half-life.
small molecules
2026-08-12 | Recurrent Hematuria Unveiling Renal Lymphangioma: A Diagnostic Challenge in a Patient with von Willebrand Disease
Abstract Renal lymphangioma is a rare benign lymphatic malformation that may present with hematuria and flank pain. We report the case of a 16-year-old female with type 2A von Willebrand disease who developed recurrent macroscopic hematuria and left lumbar pain. Imaging revealed a multiloculated intrarenal cystic lesion consistent with renal lymphangioma. After recurrence of symptoms and failure of conservative management, percutaneous intrarenal sclerotherapy with doxycycline was performed under factor replacement, resulting in complete symptom resolution and no recurrence on follow-up. This case highlights the diagnostic challenge in coagulopathic patients and supports sclerotherapy as an effective minimally invasive treatment.
2026-06-04 | Novel therapies for von Willebrand Disease.
For the past decades, treatment for von Willebrand disease has essentially consisted of classic approaches and only in the past few years has the need for more innovative strategies been recognised. To address the needs of groups of patients with similar phenotypes and bleeding, personalised therapeutic strategies are being developed, molecules designed for other bleeding disorders are being repositioned, and new haemostatic agents are being tested in patients with von Willebrand disease. New therapeutics include a variety of molecules, including antibodies, engineered factors, synthetic nanoparticles, siRNAs, and genome editing tools. Some promising molecules are still undergoing preclinical testing, while others have already entered clinical evaluation and may soon be available for at least some patients with von Willebrand disease. We believe that new approaches will improve the clinical management and the quality of life for patients with von Willebrand Disease.
2026-04-16 | Practical Advances in the Diagnosis of Haemophilia and von Willebrand Disease Including Monitoring of Non-Factor Replacement Therapies.
Traditional haemophilia therapies act to replace the relevant missing clotting factor, are not interchangeable between haemophilia A and B and cannot be used in patients with high titre inhibitors. Novel non-replacement factor therapies (NFT) target other endogenous coagulation proteins or anticoagulants such as antithrombin (AT) and tissue factor pathway inhibitor (TFPI) to rebalance haemostasis. As such, pharmaceutical clinical trials of these molecules have enrolled patients with haemophilia A or B, with and without inhibitors. The requirement for monitoring the efficacy of NFTs is greatly reduced compared to replacement therapy and global assays such as thrombin generation assay (TGA) have been used extensively in clinical trials to indicate improvement to haemostasis. Comprehensive haemophilia care, including access to and laboratory monitoring of replacement and NFTs, is well established in high income countries, but there are profound global inequities in the diagnosis and treatment of haemophilia which still need to be remedied. The authors examine the challenges of haemophilia and von Willebrand diagnosis and monitoring of NFTs using conventional and global assays of haemostasis.
2026-04-06 | Full-arch dental implant rehabilitation in a patient with Von Willebrand disease: a case report.
Von Willebrand disease (VWD) is the most common congenital bleeding disorder with multiple types. Patients with VWD pose a serious risk for surgical interventions. This case report discusses successful full-mouth dental clearance, bone augmentation, and dental implant rehabilitation in a patient with VWD. A 48-year-old female patient with type 2A VWD suffered from partial edentulism in both the upper and lower arches, as well as badly decayed, heavily restored teeth with multiple periapical abscesses. Dental clearance and immediate implant placement were carried out under general anesthesia with proper antifibrinolytic and Wilate prophylaxis. The patient was in stable condition post-operatively and showed good healing in follow-up visits; the implants were subsequently restored. To the author's knowledge, this is the first case of full-mouth implant rehabilitation in a patient with VWD. Thorough planning and adequate optimization of the patient for surgery, along with careful surgical technique and selection of materials, aid in treating patients with VWD, greatly increasing the chances of success.
2026-03-22 | Managing heavy menstrual bleeding in adolescents with bleeding disorders: Outcomes from a pragmatic LMIC approach.
Heavy menstrual bleeding (HMB) a common manifestation of bleeding disorders in adolescents contributes to anemia, transfusions, and impaired quality-of-life (QOL). Evidence supporting practical management strategies in resource-limited settings remains limited. This observational study in adolescents with confirmed bleeding disorders with HMB at a tertiary hemophilia treatment centre evaluated menstrual blood loss and QOL after a standard regimen of progesterone, tranexamic acid and iron; blood products or clotting factor concentrates were reserved for refractory bleeding. Twenty adolescents were included (2020-2025); von Willebrand disease (n = 11), chronic immune thrombocytopenia (n = 4), congenital aplastic anemia (n = 3), afibrinogenemia (n = 1), and factor VII deficiency (n = 1). Median PBAC score at presentation was 300 (range 190-500). Eighteen patients (90%) had anemia and prior transfusion exposure. After therapy, median PBAC declined to 100 (range 60-150). Hemoglobin improved steadily and no patient required further red cell transfusion during a median follow-up of four years. Hemostatic products were required only in two patients while on this regimen. Quality-of-life scores improved across physical, emotional, and social domains. A low-cost regimen combining progesterone, antifibrinolytic therapy, and iron effectively controls HMB, corrects anemia, reduces transfusion and factor utilization, and improves QOL in adolescents with bleeding disorders in resource-constrained settings.
antibodies
2026-06-04 | An Ex Vivo Pharmacodynamic Study of KN057, a Tissue Factor Pathway Inhibitor Neutralizing Antibody, in Plasma Samples From Patients With Haemophilia or VWD3.
Tissue factor pathway inhibitor (TFPI), a key regulator of tissue factor-initiated coagulation through FXa-dependent inhibition of the tissue factor-FVIIa complex, has emerged as a promising target for restoring thrombin generation. This ex vivo pharmacodynamic study aimed to evaluate the KN057, a novel humanized TFPI-neutralizing antibody, in plasma samples from participants with haemophilia or type 3 von Willebrand disease (VWD3). In this ex vivo spiking study, plasmas obtained from haemophilia or VWD3 participants were supplemented with KN057 at the concentration of 0-140.00 nM. The thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay were performed to assess coagulation responses. Between 26, May 2021, and 3, September 2021, a total of 29 participants were enrolled in this study, including 10 haemophilia A (HA) without inhibitors, 6 haemophilia B (HB) without inhibitors, 6 HA with inhibitors, 3 HB with inhibitors, and 4 VWD3. In participant plasmas supplemented with KN057, peak thrombin and endogenous thrombin potential (ETP) increased notably between 1.12-5.60 nM, and reached a maximal level at 28.00 nM. A dose-dependent decrease in dPT was observed in all participants with haemophilia or VWD3. KN057 exhibited a consistent ex vivo pharmacodynamic profile, including both the response trend and effective concentration range, across plasma samples from patients with HA or HB, irrespective of inhibitor status. Furthermore, its pharmacodynamic activity in plasma from patients with VWD3 was comparable to that observed in haemophilia plasma.
2026-04-28 | Successful use of emicizumab prophylaxis in a patient with von Willebrand disease type 3: A case report
Von Willebrand disease (VWD) type 3 is the most severe form of VWD and is often inadequately controlled with plasma-derived von Willebrand factor (VWF)/FVIII or fresh frozen plasma. Emicizumab, a factor VIII– mimetic antibody approved for hemophilia A, enhances secondary hemostasis and has emerging off-label evidence in severe VWD. A 38-year-old woman with VWD type 3 and recurrent mucocutaneous bleeding despite regular factor therapy was started on emicizumab prophylaxis. Over 6 months, she remained bleed-free without additional factor support. Activated partial thromboplastin time normalized with increased measured FVIII activity; the apparent VWF antigen rise was interpreted cautiously. The treatment was well-tolerated and cost-effective. Emicizumab may offer an effective alternative prophylaxis in selected patients with severe VWD.
2026-04-14 | Monovalent antibody treatment of von Willebrand disease
A commentary on an article recommending a new potential treatment approach for patients with von Willebrand disease (VWD).
2026-03-10 | Graft-derived VWF drives platelet activation and thrombocytopenia during porcine liver xenotransplantation to brain-dead human recipients.
BACKGROUNDGenetically engineered porcine livers are being developed as a bridge therapy for acute liver failure, providing detoxification and restoration of hepatic protein synthesis. Severe xenograft-associated thrombocytopenia remains a major limitation, and human mechanistic data are scarce.METHODSPlatelet kinetics were characterized in 3 human decedents undergoing extracorporeal cross-circulation with transgenic porcine livers. Platelet counts, transfusion requirements, and clearance patterns were assessed to distinguish consumption from marrow suppression or hypersplenism. Antibody- and complement-directed inhibitors were administered to test immune-mediated mechanisms. Mechanistic studies focused on porcine von Willebrand factor-dependent (pVWF-dependent) platelet activation, including ex vivo blockade with the anti-VWF nanobody caplacizumab, a VWF-directed antibody fragment that prevents VWF-platelet binding. A fourth decedent received caplacizumab during porcine liver perfusion.RESULTSIn all 3 initial cases, 80%-90% of circulating and transfused platelets were rapidly cleared, a pattern inconsistent with marrow suppression or hypersplenism. Antibody and complement inhibition failed to ameliorate thrombocytopenia. Recipient plasma induced robust pVWF-mediated platelet activation analogous to human type IIb von Willebrand disease, which was completely abrogated ex vivo by caplacizumab. In a fourth decedent treated with caplacizumab, aberrant platelet activation was prevented, although full hematologic recovery was limited by preexisting disseminated intravascular coagulation.CONCLUSIONSEarly thrombocytopenia during porcine liver xenotransplantation appears to be primarily driven by pVWF-mediated platelet activation rather than by classical immune or splenic mechanisms. Targeted VWF blockade with agents such as caplacizumab may mitigate platelet loss and improve the safety profile of extracorporeal porcine liver support in acute liver failure.
2026-03-01 | 6ER-034 Real-life experience with emicizumab: clinical outcomes and an exceptional case of type III von Willebrand disease with inhibitor
Background and Importance
Emicizumab is a humanised bispecific monoclonal antibody that mimics the cofactor function of activated factor VIII and is primarily indicated for the prophylactic treatment of patients with haemophilia A, irrespective of the presence of inhibitors. While its use in other hereditary bleeding disorders, such as von Willebrand disease, remains off-label and limited, it is increasingly being explored as a therapeutic alternative. We report our real-world experience from a tertiary care centre, highlighting a notable case of type III von Willebrand disease with an inhibitor, in which the use of emicizumab yielded promising clinical outcomes.
Aim and Objectives
To evaluate the efficacy, safety, and clinical applicability of emicizumab in patients with hereditary coagulopathies, with a particular focus on a case of type III von Willebrand disease with an inhibitor.
Material and Methods
This is a single-centre, retrospective observational study involving eight patients treated with emicizumab between December 2019 and May 2025. Clinical, genetic, and follow-up variables were collected, including diagnosis, age at treatment initiation, presence of inhibitors, history of bleeding episodes, post-treatment bleeding events, surgical or invasive interventions and adverse reactions.
Results
The cohort included seven patients with severe haemophilia A (one with an inhibitor) and one patient with type III von Willebrand disease with an inhibitor. The mean age at treatment initiation was 22 years (range: 5–40). All patients had a history of clinically significant bleeding episodes. Following the initiation of emicizumab, six patients did not experience any further bleeding episodes. Mild episodes (epistaxis and muscular hematoma) were recorded in two cases, none of which required additional treatment. The 19-year-old patient with von Willebrand disease, who had a history of epistaxis and deep haematomas, showed a favourable response, with only one mild epistaxis episode during follow-up. No serious adverse effects were reported, with only one patient experiencing transient mild headache.
Conclusion and Relevance
Emicizumab proved to be effective and safe in this cohort of patients with haemophilia A, including those with inhibitors. Notably, the case of the patient with type III von Willebrand disease and an inhibitor demonstrated excellent tolerability and bleeding control. These findings support the potential role of emicizumab as a prophylactic treatment in bleeding disorders beyond haemophilia A.
Conflict of Interest
No conflict of interest
proteins
2026-08-31 | Perioperative von Willebrand Factor and Factor VIII Kinetics in von Willebrand Disease Patients Treated With Different Clotting Factor Concentrates.
Patients with von Willebrand disease (VWD) undergoing surgery require von Willebrand factor (VWF) and factor VIII (FVIII) supplementation for adequate haemostasis. Plasma-derived clotting factor concentrates differ in their VWF:FVIII activity ratios: high-ratio product (HRP, 10:1), intermediate-ratio product (IRP, 2.4:1), and low-ratio product (LRP, 1:1). These differences may affect FVIII kinetics. This single-centre observational study included VWD patients undergoing surgery, treated with an HRP, IRP, or LRP, and with ≥2 perioperative VWF or FVIII measurements between 2009 and 2024. VWF and FVIII trajectories were assessed using linear mixed-effects models. Secondary endpoints were bleeding and venous thromboembolic events (VTE). In total, 123 patients were included; 63% underwent major surgery. Twenty-four patients received HRP, 61 received IRP and 38 received LRP. The median number of infusions was three across groups. Incremental VWF recoveries were 1.7 IU/dL per IU/kg for HRP, 1.3 for IRP, and 2.4 for LRP. FVIII recoveries were 2.5 for IRP and 2.7 for LRP. Over time, HRP showed higher mean VWF levels than IRP (Δ26 IU/dL; p = 0.010). HRP was associated with higher FVIII levels compared with IRP (Δ48 IU/dL; p < 0.001) and LRP (Δ35 IU/dL; p = 0.021). No difference was found between IRP and LRP. In patients receiving three consecutive infusions in 24 h, FVIII levels remained higher with HRP than IRP (Δ38 IU/dL; p = 0.019). No VTEs occurred. IRP and LRP led to greater initial VWF and FVIII peaks, whilst HRP produced more sustained FVIII elevation. Recognising these kinetic differences may guide tailored perioperative management of patients with VWD.
2026-07-13 | The role of von Willebrand factor in gastrointestinal angiodysplasia and obscure gi bleeding: a narrative review.
Gastrointestinal bleeding (GIB) is a major cause of morbidity in von Willebrand disease (vWD), most commonly resulting from angiodysplasia. Current obscure gastrointestinal bleeding (OGIB) algorithms are primarily anatomy-based and often overlook underlying hemostatic disorders, delaying diagnosis and promoting recurrent bleeding. This review summarizes current evidence on the molecular basis, diagnosis, and management of vWD-associated GIB and proposes a mechanism-oriented diagnostic framework. A comprehensive narrative review of experimental, translational, and clinical studies was conducted, focusing on inherited vWD, acquired von Willebrand syndrome (AvWS), gastrointestinal angiodysplasia, endothelial biology, and diagnostic and therapeutic strategies. Deficiency or dysfunction of high-molecular-weight von Willebrand factor (vWF) multimers promotes angiodysplasia by disrupting Weibel-Palade body homeostasis, enhancing Ang-2/Tie2 and VEGF signaling, impairing integrin αvβ3 function, and fostering pro-inflammatory endothelial activation. Genetic and epigenetic modifiers, including FLI1, STXBP5, ABO blood group, and miR-24, further influence vascular susceptibility. Based on these mechanisms, we propose a four-stage diagnostic framework integrating bleeding assessment, platelet function screening, and targeted vWF testing with conventional endoscopic evaluation to facilitate earlier recognition of vWD/AvWS in patients with recurrent or obscure GIB. This strategy supports mechanism-based treatment combining hemostatic replacement therapies with selected anti-angiogenic approaches. vWD-associated GIB should be regarded as a systemic vascular-hemostatic disorder rather than an isolated structural gastrointestinal disease. Integrating hemostatic evaluation into OGIB pathways may improve diagnostic accuracy, reduce unnecessary procedures, and enable personalized management of patients with recurrent bleeding.
2026-07-06 | Navigating hemostasis: anesthetic challenges in a pituitary tumor with type 2 von Willebrand disease—case report
Introduction The anesthetic management of patients with von Willebrand disease (VWD) present a significant perioperative challenge due to the high risk of hemorrhage. This risk is further elevated in neurosurgical procedures, such as transsphenoidal surgery (TSS) for pituitary neuroendocrine tumors (PitNETs), due to the close proximity to critical neurovascular structures. Case presentation This report describes a 42-year-old male with type 2 VWD and hypothyroidism, diagnosed with a Knosp grade 3A PitNET, who underwent an endoscopic endonasal transsphenoidal resection. A multidisciplinary approach was implemented, including hemodynamic monitoring and targeted replacement of VWF/FVIII concentrate calculated according to plasma levels, maintaining paremeters of VWF ristocetin cofactor/activity (VWF:RCo) (%) and FVIII (%): >80% during the intraoperative period and >50% during the postoperative period. The postoperative course was favorable, with no neurovascular, hemostatic, hemodynamic, or endocrine complications. Discussion The coexistence of VWD and a macro-PitNET creates a profound clinical dilemma that exposes the limitations of conventional perioperative care. While TSS demands strict hemostatic control due to its proximity to major neurovascular structures like the cavernous sinuses and internal carotid arteries, the type 2 VWD directly threatens clot stability and initial platelet plug formation. Given the scarce literature surrounding its neuroanesthetic management, this case report discusses the successful implementation of an individualized strategy. By integrating targeted plasma-derived VWF/FVIII replacement with real-time thromboelastography (TEG) and advanced hemodynamic monitoring, we demonstrate how a coordinated multidisciplinary approach can successfully mitigate overlapping hemorrhagic and neurosurgical risks. Conclusions This case highlights the importance of individualized planning and comprehensive management based on the American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF), and World Federation of Hemophilia (WFH) (ASH–ISTH–NHF–WFH, 2021) guidelines to optimize outcomes in patients with VWD undergoing high-complexity surgery.
2026-06-19 | Impaired hemostasis in mechanical circulatory support systems: Monitoring with T-TAS® 01, in vitro correction with VWF concentrates, and impact of membrane oxygenators.
Mechanical circulatory support (MCS) systems assist patients with severe cardiac or respiratory failure, but bleeding linked to acquired von Willebrand disease remains a major complication. The T-TAS® 01 system has emerged as a rapid tool for assessing MCS patients' hemostasis. To evaluate hemostatic changes during and after MCS support. Secondary objectives included assessing the impact of the in vitro addition of von Willebrand factor concentrates and exploring differences according to the presence of a membrane oxygenator (MO). This prospective, bicentric study included adults requiring MCS, with hemostatic parameters assessed at three predefined timepoints using conventional laboratory assays and T-TAS® 01. Data were analyzed using linear mixed-effects models. In vitro addition of a VWF/FVIII concentrate (Haemate-P®) was evaluated as an exploratory analysis. A total of 39 patients were included; 56% experienced bleeding complications, of which 23% were clinically relevant. Significant alterations in hemoglobin, platelet counts, and platelet/VWF function were observed during MCS. T-TAS® 01 demonstrated impaired hemostasis during support, with partial recovery after device removal. In vitro addition of Haemate-P® improved T-TAS® 01 parameters. No consistent differences in overall hemostatic dynamics were observed between MO and non-MO devices. MCS is associated with significant and persistent alterations in primary hemostasis. T-TAS® 01 may represent a useful tool for dynamic assessment of these changes. In vitro VWF supplementation improved functional hemostasis parameters, although its clinical implications remain to be established. Differences related to MO presence were not consistent, supporting a shared mechanism of hemostatic dysregulation across MCS devices.
2026-06-02 | Designing the Future of Hemostasis.
Bleeding disorders arising from dysfunctional platelet-protein interactions pose a significant clinical challenge due to their heterogeneity and complexity. Primary hemostasis is mediated by von Willebrand factor (VWF) and platelet surface receptors GPIbα and αIIbβ3. This protein triad is central to clot formation, and interfering with their associated activity can cause several primary hemostasis-related disorders. While traditional therapies, including factor replacement and monoclonal antibodies, have improved outcomes, they are often limited by availability, cost, immunogenicity, and inadequate precision. Recent advances in computational biology and peptide engineering now offer potential for improved hematologic therapeutics. This review outlines two major strategies in peptide drug design: Structure-based modeling and small motif-based design. These approaches enable the creation of short, stable peptides capable of targeting disease-specific protein-protein interactions (PPIs) with high specificity. We highlight the recent development of G14-an artificial intelligence (AI)-designed peptide that selectively disrupts the aberrant GPIbα-VWF interaction in platelet-type von Willebrand disease. The peptide demonstrated selective inhibition of the enhanced patient-derived platelet aggregation and VWF binding. By combining systems biology, structural modeling, and AI, peptide design can now yield rapid, scalable, and personalized therapies for bleeding disorders. Thus, the growing adoption and integration of intelligently designed peptides offer a new perspective on precision medicine for thrombosis and hemostasis.
gene therapies
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.
2025-10-08 | Rewriting the script: gene therapy and genome editing for von Willebrand Disease.
In recent years gene therapy has emerged as a powerful technology for treatment of a large variety of inherited disorders. With the FDA approval of in vivo gene therapy of hemophilia A and B using AAV-mediated transgene delivery to hepatocytes, the path towards a new treatment era seemed paved. Also, CRISPR-Cas based approaches have reached the clinic, as in the ex vivo treatment of hematopoietic stem cells for sickle cell disease and thalassemia patients. The question arises whether these innovative strategies will also be suitable for patients with von Willebrand Disease (VWD). Whilst in and ex vivo delivery to endothelial cells (ECs) has been demonstrated, and CRISPR-Cas9 gene editing has been successful in ECs, there are currently no gene therapy options available for VWD. The wide variety of pathogenic VWF mutations makes development of broadly applicable, cost-effective gene therapies challenging. While delivery of von Willebrand factor (VWF) as a therapeutic transgene would be optimal, the size of VWF challenges efficient delivery. Therefore, treatment of VWD requires targeted, personalized gene therapy; for instance by using the newest CRISPR-Cas technologies which can be tailored to facilitate alteration and restoration of various pathogenic VWD variants. This review describes the inherited bleeding disorder VWD and potential gene therapy approaches for management of the disease. Thereby we are exploring different CRISPR-Cas technologies and recent developments in the field. Moreover, we will discuss the ongoing advances of in vivo delivery systems, all with the scope on ECs.
2025-05-26 | Von Willebrand Disease: Exploring the Diagnostic and Therapeutic Challenges in Pakistan
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, arising from either a reduced amount or impaired function of von Willebrand factor (VWF), a protein vital to normal clot formation. This article examines the condition in detail, outlining its biological basis, symptoms, diagnostic difficulties, and available treatment options. Particular focus is placed on the situation in Pakistan, where unique challenges shape patient outcomes. The discussion also addresses the development of alloantibodies in some patients, exploring how these immune responses affect treatment success and quality of life. Psychosocial factors and dietary patterns, especially within the Pakistani context, are considered as additional influences on disease management. Worldwide, VWD often remains undetected because its symptoms can vary widely and resemble those of other bleeding disorders. In Pakistan, the problem is aggravated by low public awareness, limited access to diagnostic tools, and financial constraints, all of which lead to late diagnosis and inadequate care. Timely identification and appropriate medical intervention are critical for improving prognosis. The review underscores the need to strengthen diagnostic infrastructure, increase the reach of specialized care, and make effective therapies more accessible, particularly in underserved regions. Advances in genetic research and new treatment options, including the possibility of gene therapy, offer hope for better disease control in the future. The article concludes by urging reforms in healthcare systems, greater educational outreach, and focused measures to close existing gaps in the detection and management of VWD in Pakistan.
2023-01-13 | “iPSC-derived liver organoids and inherited bleeding disorders: Potential and future perspectives”
The bleeding phenotype of hereditary coagulation disorders is caused by the low or undetectable activity of the proteins involved in hemostasis, due to a broad spectrum of genetic alterations. Most of the affected coagulation factors are produced in the liver. Therefore, two-dimensional (2D) cultures of primary human hepatocytes and recombinant overexpression of the factors in non-human cell lines have been primarily used to mimic disease pathogenesis and as a model for innovative therapeutic strategies. However, neither human nor animal cells fully represent the hepatocellular biology and do not harbor the exact genetic background of the patient. As a result, the inability of the current in vitro models in recapitulating the in vivo situation has limited the studies of these inherited coagulation disorders. Induced Pluripotent Stem Cell (iPSC) technology offers a possible solution to overcome these limitations by reprogramming patient somatic cells into an embryonic-like pluripotent state, thus giving the possibility of generating an unlimited number of liver cells needed for modeling or therapeutic purposes. By combining this potential and the recent advances in the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology, it allows for the generation of autologous and gene corrected liver cells in the form of three-dimensional (3D) liver organoids. The organoids recapitulate cellular composition and organization of the liver, providing a more physiological model to study the biology of coagulation proteins and modeling hereditary coagulation disorders. This advanced methodology can pave the way for the development of cell-based therapeutic approaches to treat inherited coagulation disorders. In this review we will explore the use of liver organoids as a state-of-the-art methodology for modeling coagulation factors disorders and the possibilities of using organoid technology to treat the disease.
2021-08-16 | DNA variant classification–reconsidering “allele rarity” and “phenotype” criteria in ACMG/AMP guidelines
Recent guidance suggested modified DNA variant pathogenicity assignments based on genome-wide allele rarity. Different a priori probabilities of pathogenicity operate where patients already have clinical diagnoses, and are found to have a very rare variant in a gene known to cause their disease, compared to predictive testing of a clinically unaffected individual. We tested new recommendations from the ClinGen Sequence Variant Interpretation Working Group for ClinVar-listed, loss-of-function variants meeting the very strong evidence of pathogenicity criterion [PVS1] in genes for 3 specific diseases where causal gene identification can modify clinical care of an individual- Von Willebrand disease, cystic fibrosis and hereditary haemorrhagic telangiectasia. Across these diseases, current rules leave 20/1,278 (1.6%) of loss-of-function variants as variants of uncertain significance (VUS that may not be reported to clinicians), and 207/1,278 (17.2%) as likely pathogenic. Applying the new ClinGen rule enabling PVS1 and the allele rarity criterion PM2 to delineate likely pathogenicity still left 8/1,278 (0.9%) as VUS (reflecting non-PVS1 calls by the submitters), and the majority of null alleles meeting PVS1 as merely likely pathogenic. We favour an approach whereby, for PVS1 variants in patients who personally meet the phenotypic PP4 criterion for a disease where casual variants are commonly family-specific, that PM2 is upgraded to permit a pathogenic call. Of 1,278 ClinVar-listed frameshift, nonsense and canonical splice site variants that met PVS1 in the 3 conditions, 16.0% (204/1,278) would be newly designated as pathogenic, avoiding misinterpretation outside of clinical genetics communities. We suggest further discussion around variant assessment across different clinical applications, potentially guided by PP4 alerts to distinguish personal versus family phenotypic history.
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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.
2025-01-13 | Heyde's Syndrome Manifesting as Recurrent Gastrointestinal Bleeding After Valve Replacement.
Heyde's syndrome is a clinical entity that combines aortic stenosis, gastrointestinal angiodysplasia, and an acquired von Willebrand factor disorder. This syndrome is characterized by the association between aortic stenosis and recurrent gastrointestinal bleeding episodes, typically linked to angiodysplasias. Effective treatment requires addressing the underlying condition, specifically aortic stenosis, which leads to the structural destruction of coagulation proteins, resulting in the acquired von Willebrand factor disorder and perpetuating the bleeding. Therefore, managing gastrointestinal bleeding alone is insufficient. Although initially underestimated by physicians due to its nonspecific presentation and overlapping symptoms, this syndrome has significant implications for diagnosis and management, particularly in older adults. Many patients with Heyde's Syndrome are often misdiagnosed with unrelated gastrointestinal conditions until the association with aortic stenosis is identified. This diagnostic delay can lead to repeated hospitalizations, chronic anemia, and a decline in quality of life. Aortic valve pathology and coagulopathy should be actively suspected and investigated, directing treatment toward correcting the aortic stenosis. The objective of this case report is to highlight the importance of suspecting this syndrome in patients with valvular disease, such as aortic stenosis, and recurrent bleeding episodes, as these conditions may not always represent two independent problems, even if the patient has previously undergone valve replacement. This is demonstrated in the presented case, where a 74-year-old female patient with cardiovascular disease treated years earlier with valve replacement developed valve dysfunction, leading to new episodes of gastrointestinal bleeding. This illustrates the need to reevaluate the valve to prevent recurrent complications.
2024-07-12 | The aptamer BT200 blocks interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1.
Rondaptivon pegol (previously BT200) is a pegylated RNA aptamer that binds to the A1 domain of von Willebrand factor (VWF). Recent clinical trials demonstrated that BT200 significantly increased plasma VWF-factor VIII levels by attenuating VWF clearance. The biological mechanism(s) through which BT200 attenuates in vivo clearance of VWF has not been defined. We hypothesized that BT200 interaction with the VWF-A1 domain may increase plasma VWF levels by attenuating macrophage-mediated clearance. We observed that full-length and VWF-A1A2A3 binding to macrophages and VWF-A1 domain binding to lipoprotein receptor-related protein 1 (LRP1) cluster II and cluster IV were concentration-dependently inhibited by BT200. Additionally, full-length VWF binding to LRP1 expressed on HEK293T (HEK-LRP1) cells was also inhibited by BT200. Importantly, BT200 interacts with the VWF-A1 domain in proximity to a conserved cluster of 4 lysine residues (K1405, K1406, K1407, and K1408). Alanine mutagenesis of this K1405-K1408 cluster (VWF-4A) significantly (P < .001) attenuated binding of VWF to both LRP1 clusters II and IV. Furthermore, in vivo clearance of VWF-4A was significantly (P < .001) reduced than that of wild-type VWF. BT200 did not significantly inhibit binding of VWF-4A to LRP1 cluster IV or HEK-LRP1 cells. Finally, BT200 interaction with the VWF-A1 domain also inhibited binding to macrophage galactose lectin and the SR-AI scavenger receptor. Collectively, our findings demonstrate that BT200 prolongs VWF half-life by attenuating macrophage-mediated clearance and specifically the interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1. These data support the concept that targeted inhibition of VWF clearance pathways represents a novel therapeutic approach for von Willebrand disease and hemophilia A.
2024-02-23 | Clusterin knockdown has effects on intracellular and secreted von Willebrand factor in human umbilical vein endothelial cells.
Alterations in von Willebrand factor (VWF) have an important role in human health and disease. Deficiency of VWF is associated with symptoms of bleeding and excesses of VWF are associated with thrombotic outcomes. Understanding the mechanisms that drive VWF regulation can lead to a better understanding of modulation of VWF levels in humans. We identified clusterin (CLU) as a potential candidate regulator of VWF based on a single cell RNA sequencing (scRNA-seq) analysis in control endothelial cells (ECs) and von Willebrand disease (VWD) endothelial colony-forming-cells (ECFCs). We found that patients with deficiencies of VWF (von Willebrand disease, VWD) had decreased CLU expression and ECs with low VWF expression also had low CLU expression. Based on these findings, we sought to evaluate the role of CLU in the regulation of VWF, specifically as it relates to VWD. As CLU is primarily thought to be a golgi protein involved in protein chaperoning, we hypothesized that knockdown of CLU would lead to decreases in VWF and alterations in Weibel-Palade bodies (WPBs). We used both siRNA- and CRISPR-Cas9-based approaches to modulate CLU in human umbilical vein endothelial cells (HUVECs) and evaluated VWF protein levels, VWF mRNA copy number, and WPB quantity and size. We demonstrated that siRNA-based knockdown of CLU resulted in decreases in VWF content in cellular lysates and supernatants, but no significant change in WPB quantity or size. A CRISPR-Cas9-based knockdown of CLU demonstrated similar findings of decreases in intracellular VWF content but no significant change in WPB quantity or size. Our data suggests that CLU knockdown is associated with decreases in cellular VWF content but does not affect VWF mRNA levels or WPB quantity or size.
2023-10-01 | OC 13.5 Whole-Genome Characterization of Low-VWF and VWD Type 1 Patients with No Known Pathogenic VWF Variant Reveals Novel Genetic Associations
Background:The pegylated aptamer BT200 binds to the A1 domain of VWF and significantly prolongs VWF half-life in vivo.Although the mechanism(s) involved have not been defined, the LRP1 scavenger receptor binds to the VWF A1 domain and contributes to physiological VWF clearance.Aims: To determine the molecular mechanisms through which the BT200 pegylated aptamer extends VWF half-life.Methods: Binding of full-length and selected VWF truncations to bone marrow-derived macrophages (BMDM) was assessed by flow cytometry in the presence or absence of BT200.Immunosorbent plate-binding assays were used to characterize binding to purified LRP1-ClusterII or Cluster IV receptors respectively.Finally, clearance of HEK293T-expressed VWF variants were investigated in VWF-/-mice.Results: BT200 dose-dependently inhibited binding of recombinant VWF (Vonvendi) & plasma-derived VWF (Fandhi) to BMDMs (maximal binding inhibition: 88.55 ± 4.73% at 10 μM BT200).In addition, BT200 significantly inhibited binding of full-length rVWF to purified LRP1-Cluster-IV ( p = 0.0005).Plate binding assays confirmed that the truncated VWF-A1A2A3 fragment and the isolated VWF-A1 domain both bound to LRP1 Cluster-II and Cluster-IV.In both cases, binding was again inhibited by BT200 in a dose-dependent manner, recapitulating the BMDM results.Finally, interaction of VWF-A1A2A3 fragment with HEK-293 T transfected with full length LRP1 cDNA was ablated by BT200.In contrast, BT200 had no inhibitory effects on VWF-A1A2A3 binding to either MGL or SR-A1 macrophage clearance receptors.Since BT200 binds close to Lys 1405 in VWF-A1, site-directed mutagenesis of Lys 1405 study was performed.VWFA1-K1405A did not bind BMDMs, nor to coated LRP1-Cluster-IV.Furthermore, full-length rVWF-K1405A demonstrated a significantly increased half-life in VWF-/-mice compared to wild type VWF (P = 0.0049).Conclusion(s): Our novel findings demonstrate that Lys1405 in VWFA1 is critical for interaction with the LRP1 scavenger receptor.BT200 binds to VWFA1 close to this key Lys1405 residue, thereby preventing interaction with LRP1 and consequently extending VWF half-life.
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Drug Discovery Landscape
15 orphan drug designations for Von Willebrand disease, including 8 approved therapies.
15 orphan drug designations for Von Willebrand disease, including 8 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
RNA, (Um-sp-(2′-deoxy-2′-fluoro)A-sp-Gm-Am-Am-(2′-deoxy-2′-fluoro)A-Cm-Um-Cm-Am-Um-Am-Gm-(2′-deoxy-2′-fluoro)C-Gm-(2′-deoxy-2′-fluoro)A-Um-Um-Gm-Cm-Am-sp-Cm-sp-Am), complex with RNA (Um-sp-Gm-sp-Cm-Am-Am-Um-(2′-deoxy-2′-fluoro)C-Gm-(2′-deoxy-2′-fluoro)C-(2′-deoxy-2′-fluoro)U-(2′-deoxy-2′-fluoro)A-Um-Gm-Am-Gm-Um-Um-Um-Cm-Um-Am) 3′-[[(2S,4R)-1-[29-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[3-[[5-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-1-oxopentyl]amino]propyl]amino]-3-oxopropoxy]methyl]-1,12,19,25-tetraoxo-16-oxa-13,20,24-triazanonacos-1-yl]-4-hydroxy-2-pyrrolidinyl]methyl hydrogen phosphate] (1:1) | RNAs | EMA | Alnylam Netherlands B.V. | |
recombinant humanized anti-TFPI monoclonal antibody | antibodies | FDA | — | Suzhou Alphamab Co., Ltd. |
IgG4 monoclonal antibody directed against protein S | antibodies | FDA | Vega Therapeutics, Inc. | |
PEGylated aptamer targeting Von Willebrand Factor A1 domain | oligonucleotides | FDA | Band Therapeutics, LLC | |
von Willebrand Factor Human Concentrate | proteins | FDA | LFB USA, Inc. | |
Vonicog alfa [Veyvondi] | proteins | EMA | BAXALTA INNOVATIONS GmbH | |
von Willebrand factor (recombinant) [Vonvendi] | proteins | FDA | Approved | Takeda Pharmaceuticals U.S.A., Inc. |
recombinant von Willebrand factor (rhVWF) | proteins | FDA | Approved | Takeda Pharmaceuticals U.S.A., Inc. |
recombinant von Willebrand factor (rhVWF) [Vonvendi] | proteins | FDA | Approved | Takeda Pharmaceuticals U.S.A., Inc. |
recombinant von Willebrand factor (rhVWF) [Vonvendi] | proteins | FDA | Approved | Takeda Pharmaceuticals U.S.A., Inc. |
Microvesiculated modified glycosylated tissue factor | proteins | FDA | — | Thrombotargets Corp. |
von Willebrand Factor/Coagulation Factor VIII Complex (Human) [Wilate] | proteins | FDA | Approved | Octapharma USA, Inc. |
Antihemophilic factor (human) [Alphanate] | proteins | FDA | Approved | Grifols Biologicals Inc. |
Antihemophilic factor/von Willebrand factor complex (human), dried, pasteurized [Humate-P] | proteins | FDA | Approved | CSL Behring |
Desmopressin acetate | small molecules | FDA | Approved | Ferring Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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