Endothelial cells deliver a vital contribution to the maintenance of hemostasis by constituting an anatomical as well as functional barrier between the blood and the rest of the body. Apart from the physical barrier function, endothelial cells maintain the hemostatic equilibrium by their pro- and anticoagulant functions. An important part of their procoagulant contribution is the production of von Willebrand factor (VWF), which is a carrier protein for coagulation factor VIII (FVIII) and facilitates the formation of a platelet plug. Thus, VWF is indispensable for both the primary and secondary hemostasis, which is exemplified by the bleeding disorder Von Willebrand Disease (VWD) that results from qualitative or quantitative deficiencies in VWF. A cellular model that was found to accurately reflect the endothelium and its secretory organelles are endothelial colony forming cells (ECFCs), which can be readily isolated from peripheral blood and constitute a robust ex vivo model to investigate the donor\'s endothelial cell function. This review summarizes some of the valuable insights on biology of VWF and pathogenic mechanisms of VWD that have been made possible using studies with ECFCs derived from patients with bleeding disorders.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative and qualitative abnormalities of von Willebrand factor (VWF), a multimeric glycoprotein that is the largest of its kind in plasma and is also found in platelet alpha granules and Weibel-Palade bodies of endothelial cells. VWF plays two roles in hemostasis: (1) primary hemostasis via adhesion of platelet GPIb to subendothelial connective tissue and (2) stabilization of coagulation factor VIII. The pathological classification proposed by the International Society of Thrombosis and Haemostasis (ISTH) in 1994 divided VWF into three major categories based on the results of VWF:RCo, VWF:Ag, and multimer analysis. Recent genetic analysis and molecular and cellular analysis of abnormal VWF have revealed a molecular basis for the dominant inheritance form of VWD.

UNASSIGNED: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting about 0.6% to 1.3% of the population, and is characterized primarily by mucocutaneous bleeding secondary to defective platelet adhesion and aggregation. Current therapeutic options for those with severe disease are limited and require frequent intravenous infusions.
UNASSIGNED: This review discusses the current and recently completed clinical trials involving pathways to FVIII augmentation for the treatment of VWD. Clinical trials registered on clinicaltrials.gov and published data via PubMed searches through June 2024 were included.
UNASSIGNED: Available treatment options to those with VWD are limited in part due to limited clinical trials, the complexity of VWD types, and the pharmacokinetics of current treatment options. The development of therapeutic options that reduce treatment burden is necessary to improve quality of life and reduce bleeding complications and in recent years there has been an increased interest from industry to apply novel therapeutics for VWD. The FVIII mimetic, emicizumab, has demonstrated early success in patients with severe VWD and is a promising treatment option for those who require prophylaxis. Furthermore, products like efanesoctocog alfa (Altuviiio®) and BT200 have achieved enhanced VWF/FVIII half-life extension could expand the current treatment landscape while concurrently minimizing treatment burden.

Von Willebrand disease stands as the most prevalent bleeding disorder seen in both medical and surgical practice. Due to recurrent bleeding episodes within the joints, many patients endure arthropathy, leading to substantial pain and restricted function. Total joint arthroplasty emerges as a final option for managing such cases. Nevertheless, the existence of von Willebrand disease presents several challenges in this regard. This review aims to explore the perioperative strategies tailored for patients with von Willebrand disease undergoing elective total joint arthroplasty.

Patients with hemophilia frequently require supplementary interventions, either invasive (suturing, gel foam, or cauterization) or non-invasive (fibrin sealant/glue), to attain hemostasis post dental procedures. This study aimed to compare the efficacy of fibrin sealant against traditional methods for achieving hemostasis post dental surgery. The medical records of patients with factor VIII or IX deficiency, or von Willebrand disease, who underwent dental procedures in the Department of Dentistry, Seth GSMC and KEM Hospital, were evaluated for inclusion in this retrospective matched cohort study. Cohort-1 included those treated with a fibrin sealant (Tisseel Lyo) with/without traditional hemostatic measures post-procedure, while cohort-2 (controls) included those in whom no fibrin sealant was used. A total of 128 patients, 64 in each group, were evaluated. There was no statistically significant difference in demographics, disease-related variables, dental complaints, or preoperative treatment given between the groups. However, there was a significant reduction (P < 0.001) in the requirement for secondary procedures for hemostasis (suturing, gel foam application, and/or cauterization) and postoperative requirement for factor replacement (P = 0.003) in the fibrin glue group as compared to the controls. In this study, fibrin sealant demonstrated superior efficacy in mitigating the necessity for active hemostasis control.

BACKGROUND: Women with VWD have an increased risk of gynaecological complications due to haemostatic challenges of menstruation.
OBJECTIVE: Review gynecological bleeding symptoms and their management in women with moderate-severe VWD.
METHODS: Retrospective cohort analysis of prospectively collected data for women with moderate and severe VWD attending a joint multidisciplinary clinic between January 2010 and December 2020. Data was collected from electronic patient records on response to treatment options using PBAC, quality of life (QoL) assessment using SF-36 scores, haemoglobin and ferritin in comparison to pre-treatment values.
RESULTS: Of the 67 women managed in the clinic; all reported heavy menstrual bleeding (HMB). Combination therapy with concurrent hormonal agents and tranexamic acid was required in 80% of women. There was an overall 64% improvement in PBAC scores in the first year, reflecting on QoL with 35% improvement in SF-36 score and correction of anaemia in 21% of cases. The cumulative effect of continued treatment culminated in greater reduction of blood loss, with an overall 71% improvement in PBAC scores by 5 years. One in 10 women required surgical treatment for a gynaecological pathology. Non-compliance was the cause of excessive unscheduled bleeding in 50% of adolescents. After 3 years, one in five women experienced a relapse of symptom, of whom 46% became perimenopausal and 54% discontinued hormonal treatments due to concerns about fertility, hair loss and weight gain.
CONCLUSIONS: Management of HMB requires careful monitoring and follow-up by MDT with close collaboration between the gynaecology team and HTC. Control of HMB often requires a combination therapy.

Plasma-derived von Willebrand factor-containing factor VIII concentrates (pd-VWF/FVIII-C) are the mainstay of treatment in von Willebrand disease (VWD). Real-world data on efficacy and safety of these pd-VWF/FVIII-C are required. To retrospectively evaluate the efficacy and safety of pd-VWF/FVIII-C (Fanhdi® and Alphanate®, Grifols) in clinical practice in Italy. A multicentric, observational, retrospective study at 10 Italian centers was conducted. Eligible patients diagnosed with inherited VWD (ISTH criteria) were treated with either Fanhdi® or Alphanate® for bleeding episodes, prevention of surgical bleeding and secondary long-term prophylaxis (SLTP) according to clinical practice with medical records collected from January 2007 to December 2019. Efficacy/safety of pd-VWF/FVIII-C was assessed according to FDA-agreed objective criteria following regulatory procedures. Fifty-seven patients (M/F: 21/36) were enrolled in the study with the following VWD types: VWD1 (n = 29, 52%), VWD2A (n = 10, 18%), VWD2B (n = 7, 12%), VWD2M (n = 2, 4%), VWD2N (n = 1, 2%), VWD2 unclassified (n = 1, 2%), and VWD3 (n = 7, 12%). These pd-VWF/FVIII-C were used to manage 58 bleeding episodes (n = 24 patients), 100 surgeries (n = 47 patients), and 7 SLTP (n = 6 patients). Global clinical efficacy with these pd-VWF/FVIII-C was reported to be excellent/good in 85% of bleeding episodes, 98% of surgeries, and 100% of SLTP. As far as safety, no adverse-drug-related episodes, immunogenic or thrombotic events were reported. This study confirmed that Fanhdi® and Alphanate® were effective and safe in the management of bleeding episodes, the prevention of bleeding during surgeries and for SLTP in Italian patients with inherited VWD.

BACKGROUND: Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF).
OBJECTIVE: This large cohort study aims to offer a comprehensive exploration of mutation spectra and laboratory features in quantitative VWF deficiencies, shedding light on genetic underpinnings and genotype-phenotype associations.
METHODS: Our cohort consisted of 221 Caucasian index patients with quantitative VWD, along with 47 individuals whose plasma VWF levels fell within the lower normal boundaries (50-70 IU/dL). We conducted comprehensive VWF assays and genetic analyses, encompassing VWF gene sequencing, copy number variation investigations, and bioinformatic assessments.
RESULTS: Following International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee VWF guidelines, 77 index patients were characterized as having type 1 VWD (VWF antigen [VWF:Ag] < 30 IU/dL), 111 as having type 1 VWD (VWF:Ag, 30-50 IU/dL), and 33 as having type 3 VWD. Mutation detection rates were 88%, 65%, and 92%, respectively. Notably, blood group O overrepresentation was evident in type 1 with VWF:Ag of 30 to 50 IU/dL, particularly among mutation-negative patients, suggesting a potential causal role of blood group O. A total of 223 VWF variants, comprising 147 distinct variations, were identified in quantitative VWD patients, of which 57 were novel variants (39%). Additionally, approximately 70% of individuals with VWF levels within the lower normal boundaries (50-70 IU/dL) displayed VWF variants.
CONCLUSIONS: Our data advance our understanding of the molecular mechanisms underlying quantitative VWD, offering valuable insights for future research and clinical management. Distinct mutation patterns were observed among subgroups, particularly the contrast between type 1 VWD (VWF:Ag < 30 IU/dL) and type 1 VWD (VWF:Ag, 30-50 IU/dL), an area with limited prior investigation.

BACKGROUND: von Willebrand factor (VWF)-R1205H variant (Vicenza) results in markedly enhanced VWF clearance in humans that has been shown to be largely macrophage-mediated. However, the biological mechanisms underlying this enhanced clearance remain poorly understood.
OBJECTIVE: This study aimed to investigate the roles of (i) specific VWF domains and (ii) different macrophage receptors in regulating enhanced VWF-R1205H clearance.
METHODS: In vivo clearance of full-length and truncated wild-type (WT)-VWF and VWF with R1205 substitutions was investigated in VWF-/- mice. Plate-binding assays were employed to characterize VWF binding to purified scavenger receptor class A member 1 (SR-AI), low-density lipoprotein receptor-related protein-1 (LRP1) cluster II or cluster IV receptors, and macrophage galactose-type lectin.
RESULTS: In full-length VWF missing the A1 domain, introduction of R1205H led to significantly enhanced clearance in VWF-/- mice compared with WT-VWF missing the A1 domain. Importantly, R1205H in a truncated VWF-D\'D3 fragment also triggered increased clearance compared with WT-VWF-D\'D3. Additional in vivo studies demonstrated that VWF-R1205K (which preserves the positive charge at 1205) exhibited normal clearance, whereas VWF-R1205E (which results in loss of the positive charge) caused significantly enhanced clearance, pinpointing the importance of the positive charge at VWF-R1205. In vitro plate-binding studies confirmed increased VWF-R1205H interaction with SR-AI compared with WT-VWF. Furthermore, significantly enhanced VWF-R1205H binding to LRP1 cluster IV (P < .001) and less marked enhanced binding to LRP1 cluster II (P = .034) was observed. In contrast, VWF-R1205H and WT-VWF demonstrated no difference in binding affinity to macrophage galactose-type lectin.
CONCLUSIONS: Disruption of the positive charge at amino acid R1205 causes conformational changes in the VWF-D\'D3 domains and triggers enhanced LRP1-mediated and SR-AI-mediated clearance.

BACKGROUND: Females with von Willebrand disease (VWD) do not show the same increases in von Willebrand factor and factor (F)VIII levels during pregnancy as females without VWD and are at higher risk of excessive bleeding associated with childbirth. Data on hemostatic management for childbirth in VWD patients are limited.
OBJECTIVE: To evaluate the dosing, efficacy, and safety of plasma-derived von Willebrand factor/FVIII (wilate) for prevention of excessive bleeding associated with childbirth in females with any type of VWD.
METHODS: Data for females with VWD who received wilate for hemostatic coverage for childbirth during 2 prospective clinical studies were analyzed.
RESULTS: Ten females with VWD and a mean age at enrolment of 29.6 years were treated with wilate to prevent excessive bleeding associated with childbirth. Two patients had type 1, 4 had type 2 (2 2A, 1 2B, and 1 2M), and 4 had type 3 VWD. Of the 10 deliveries, 5 were by cesarean section. Patients received a mean of 9.5 infusions of wilate over 6.8 exposure days, with a mean total dose of 234 IU/kg per delivery and 25 IU/kg per infusion. Hemostatic management for all deliveries was rated excellent or good, with no excessive bleeding during delivery and no postpartum bleeding during the period of wilate treatment in any patient. Two patients experienced 8 possible or probable treatment-related adverse events; all were mild or moderate and resolved. No thromboembolic events were observed.
CONCLUSIONS: The results of this case series indicate that wilate provided effective hemostatic cover for childbirth in females with VWD during delivery and postpartum.