Deficiency Of Von Willebrand Factor Research Articles

Retrospectively diagnosed autoimmune VWF deficiency in a patient with repeated hemorrhagic events after two common colds.

Autoimmune von Willebrand factor (VWF) deficiency (AiVWFD) caused by anti-VWF autoantibodies is a rare bleeding disorder, whereas "non-immune" acquired von Willebrand syndrome (AVWS) caused by other etiologies is more common. Therefore, only 40 patients with AiVWFD have been identified in Japan through an ongoing nationwide survey on autoimmune coagulation factor deficiencies. This may be due to the inability to efficiently detect anti-VWF antibodies, as anti-VWF antibody testing is not routine. An 80-year-old Japanese woman developed AVWS and experienced bleeding after two separate common colds. She took the same cold medicine each time and recovered spontaneously after discontinuation of the medicine. Severe VWF deficiency normalized each time. Initial immunological tests did not detect anti-VWF autoantibodies, and thus a diagnosis of "non-immune" AVWS of unknown origin was made. However, after 6years, new ELISA assays using purified VWF proteins detected free anti-VWF autoantibodies, which led to a retrospective diagnosis of AiVWFD. It is probable that the cold medicine (and/or cold virus infection) induced the autoantibodies, as the recurrence and normalization of the same coagulation abnormality and the clinical course (including drug administration and discontinuation) were completely synchronized. If AiVWFD is suspected, highly sensitive autoantibody tests should be performed.

Evaluation of an automated von Willebrand factor glycoprotein IbM activity assay compared with 3 alternative von Willebrand factor activity assays

BackgroundTo overcome deficiencies of the traditional von Willebrand factor (VWF) ristocetin cofactor activity assay (VWF:RCo), several automated assays for VWF platelet-binding activity have been developed. Information on the performance of these assays and their diagnostic utility remains limited. ObjectivesTo validate the VWF:glycoprotein IbM assay INNOVANCE VWF Ac and compare it with an automated VWF:RCo assay as well as with an automated assay and a manual VWF:Ab assay and to generate reference ranges and analyze reproducibility of the VWF:glycoprotein IbM assay. MethodsClinical sites enrolled healthy subjects and patients representing the intended use population; VWF activity assays were performed, and results were analyzed. The performance of the INNOVANCE VWF Ac assay was also compared between the BCS XP System and the CS-2500 and CS-5100 analyzers. ResultsThe INNOVANCE VWF Ac assay correlated well with the VWF:RCo assay and the automated HemosIL VWF:Ab assay, with Pearson coefficients of >.9 and a predicted bias of ≤5.0 IU/dL at VWF levels of 30 IU/dL and ≤5.8 IU/dL at the levels of 50 IU/dL, but correlation and bias were not as good when compared with the REAADS manual VWF:Ab assay. Reference ranges observed for healthy subjects correlated well with previously published findings. Reproducibility of the INNOVANCE VWF Ac assay on the BCS XP System and the CS analyzers was excellent, as was correlation among devices. ConclusionThe characteristics of the INNOVANCE VWF Ac assay regarding comparability with other VWF activity assays, reference ranges, and precision support the use of this assay for evaluation of patients with concern for von Willebrand disease.

Variant mapping using mass spectrometry–based proteotyping as a diagnostic tool in von Willebrand disease

Backgroundvon Willebrand disease (VWD) is the most common inherited bleeding disorder, characterized by either partial or complete von Willebrand factor (VWF) deficiency or by the occurrence of VWF proteoforms of altered functionality. The gene encoding VWF is highly polymorphic, giving rise to a variety of proteoforms with varying plasma concentrations and clinical significance. ObjectivesTo address this complexity, we translated genomic variation in VWF to corresponding VWF proteoforms circulating in blood. MethodsVWF was characterized in VWD patients (n = 64) participating in the Willebrand in the Netherlands study by conventional laboratory testing, DNA sequencing and complementary discovery, and targeted mass spectrometry–based plasma proteomic strategies. ResultsUnbiased plasma profiling combined with immune enrichment of VWF verified VWF and its binding partner factor VIII as key determinants of VWD and revealed a remarkable heterogeneity in VWF amino acid sequence coverage among patients. Subsequent VWF proteotyping enabled identification of both polymorphisms (eg, p.Thr789Ala, p.Gln852Arg, and p.Thr1381Ala), as well as pathogenic variants (n = 16) along with their corresponding canonical sequences. Targeted proteomics using stable isotope–labeled peptides confirmed unbiased proteotyping for 5 selected variants and suggested differential proteoform quantities in plasma. The variant-to-wild-type peptide ratio was determined in 6 type 2B patients heterozygous for p.Arg1306Trp, confirming the relatively low proteoform concentration of the pathogenic variant. The elevated VWF propeptide/VWF ratio indicated increased clearance of specific VWF proteoforms. ConclusionThis study highlights how VWF proteotyping from plasma could be the first step to bridge the gap between genotyping and functional testing in VWD.

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.

Von willebrand disease and gastrointestinal bleeding: case presentation

Introduction: Von Willebrand diseases is a hereditary bleeding disorder caused by a quantitative or qualitative deficiency of von Willebrand factor, characterized by light mucocutaneous bleeding, although other bleeding such as gastrointestinal and joint bleeding may occur in severely affected patients. It treatment is fundamentally based on replacement therapy and the use of desmoprecin. Objective: Describe the characteristics and clinical evolution of a patient who presented upper gastrointestinal bleeding as a form of presentation of von Willebrand disease. Conclusions: von Willebrand diseases hould be suspected in patients with abnormal bleeding symptoms without apparent causes.

Abstract 19: Von Willebrand Factor Deficiency Improves Long Term Stroke Outcomes in Mice With Respiratory Infections

Background: Preceding respiratory tract infections (RTI) due to bacteria or virus has been linked to an increasing risk of stroke likely by potentiating an inflammatory immune response, endothelial dysfunction, platelet activation, and coagulopathy. Von Willebrand factor (VWF) plays a crucial role in hemostasis and thrombosis by promoting platelet adhesion to the subendothelial matrix and factor VIII stabilization. VWF activity is regulated by the protease ADAMTS13. Prior population-based studies suggest increased VWF levels and reduced ADAMTS13 activity as independent risk factors for stroke; however, a causal role of the VWF/ADAMTS13 axis in RTI-mediated stroke exacerbation is not investigated yet. Objective: To determine the causal role of the VWF/ADAMTS13 axis in a mouse model of preceding RTI and ischemic stroke. Methods: Wild-type (WT) mice were infected intranasally with sub-lethal doses of S. aureus or vehicle on days 0, 2, and 5. On day 6, infection was measured in the lungs (MRI), brain, and blood. VWF levels and ADTMTS13 activity were quantified by ELISA in the plasma on day 6 post-infection. In another set of experiments, on day 6 post-infection S. aureus -infected WT, Vwf -/- , Adamts13 -/- mice were subjected to transient (30 min) middle cerebral artery ischemia using a filament model. Functional outcomes (modified neurological severity score, rota-rod, corner, novel object recognition, and wire-hanging test) were measured in the same cohort of mice up to 4 weeks. Controls were mock-infected WT mice. Result: We demonstrate that a sustained S. aureus infection localized to lungs in WT mice, increases plasma VWF levels (~2-fold) and reduces ADAMTS13 activity that were associated with larger infarcts and worsened long-term functional outcomes (P<0.05 vs. mock-infected mice). S. aureus infected VWF-deficient mice exhibited reduced infarcts and better long-term functional outcomes (P <0.05 vs. S. aureus infected WT). In contrast, S. aureus infected ADAMTS13-deficient mice exhibited larger infarcts and worse long-term functional outcomes (P <0.05 vs. S. aureus infected WT). Conclusion: In a model of respiratory tract infection during the week preceding stroke, VWF has a causal role in worsening stroke outcomes while ADAMTS13 is protective.

Optimal design of infusion tests for the identification of physiological models of acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AVWS) is a bleeding disorder resembling inherited Von Willebrand disease (VWD) characterised by a qualitative and/or quantitative deficiency of von Willebrand factor (VWF) that occurs in patients with no personal or family history of bleeding as a result of underlying pathological conditions. To treat AVWS patients, desmopressin (DDAVP) and plasma-derived VWF concentrates are the primary therapies for spontaneous acute bleeding episodes and for preventing bleeding during invasive or surgical procedures. Pharmacokinetic (PK) models have been recently developed and applied to characterize VWD and AVWS, but these models cannot be calibrated from infusion tests data, and their calibration requires stressful 24-hours long tests to be carried out on subjects to achieve a satisfactory estimation of the individual haemostatic parameters. The objectives of this paper are: i) to present a new physiological model of VWD including exogenous infusion of plasma-derived VWF concentrates, suitable to describe AVWS; ii) to validate the newly proposed model from clinical data; iii) to quantify the information that can be obtained from clinical tests using different VWF concentrates by applying model-based design of experiments (MBDoE) techniques. Results show that the newly developed model calibrated from infusion data allows to estimate precisely the full set of haemostatic parameters for a subject affected by AVWS preserving the same level of information obtained from conventional tests. Most importantly, results demonstrate that the overall duration of infusion tests for the identification of key haemostatic parameters can significantly be reduced from 24 h to 2.5 h.

Impact of Anticoagulant Function By the Addition of Heparinoid in Vitro in the Plasmas from Patients with Hemophilia and Von Willebrand Disease

Background: Heparinoid (Hirudoid ®) is a local anticoagulant preparation as skin application that relieves pain and inflammation with addition to promoting healing in superficial thrombophlebitis and bruising. Heparinoid is mainly composed of chondroitin sulfate and has high moisturizing ability due to the large number of hydrophilic group. Thus, it is used as topical treatments for sebum deficiency in Japan. Since heparinoid has a structure similar to heparin, the package insert states the contraindication for hemorrhagic diseases such as hemophilia and von Willebrand disease (VWD) in Japan. Hemophilia A and B (HA/HB) are inherited bleeding disorders caused by a defect in factor (F) VIII and FIX coagulant protein, respectively. Based on its activity levels, the clinical severity is classified as severe (<1 IU/dL), moderate (1-5 IU/dL), and mild (>5-40 IU/dL). VWD is the common congenital bleeding disorders and is caused by a deficiency of von Willebrand factor (VWF). VWD is classified into partial deficiency (type 1), qualitative deficiency (type 2), and complete quantitative deficiency (type 3) of VWF, based on the VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) level. In the clinical practice, there are cases of hemorrhagic patients using heparinoid at the discretion of their families. However, the influence of heparinoid on coagulant function in human subjects remains to be investigated, and it is unclear if the patients with hemophilia and VWD can use heparinoid safely. Aim: To examine the impact of anticoagulant function of heparinoid in vitro in the plasmas from patients with hemophilia and VWD. Methods: The maximum blood concentration from absorbed heparinoid was estimated to be 2.5 µg/mL, based on the previous report, when heparinoid was applied to the skin as stated in package insert. Heparinoid (0-6.5 µg/mL) or unfractionated heparin (0-0.6 IU/mL) were added to normal plasma (NP), followed by measuring activated partial thromboplastin time (aPTT) by one-stage clotting assay. A modified clot waveform analysis (CWA) using an aPTT reagent were performed on the CS-2400™ (Sysmex), followed by measuring clotting time (CT) and adjusted maximum coagulation velocity (Ad|min1|). Heparinoid was also added to the patients' plasmas with HA, HB, or VWD, followed by CWA assessment. The CT and Ad|min1| of 20 healthy individuals were 31.1±0.1 sec and 6.90±0.05 (median±SEM). Results: aPTT and CT values in NP by the spike of heparinoid were prolonged and Ad|min1| was decreased dose-dependently. The addition of 2.5 µg/mL heparinoid showed that aPTT (34.3 sec; 1.2-fold of control (no heparinoid)), CT (36.3 sec; 1.2-fold of control), and Ad|min1| (9.5; 0.96-fold of control) were comparable to the effect of ~0.2 IU/mL heparin, suggesting that heparinoid exhibited slight anticoagulant effect for NP. To examine the effect of heparinoid on HA/HB plasmas, recombinant (r) FVIII or rFIX (0-50 IU/dL) were added to FVIII- or FIX-deficient plasmas (3 lots each) together with heparinoid (0-6.3 µg/mL), respectively. The addition of heparinoid had prolonged the CT and decreased the Ad|min1| at each concentration of FVIII and FIX dose-dependently. The addition of 2.5 µg/mL heparinoid showed modest anticoagulant effect for HA and HB at each concentration of FVIII and FIX (CT; 1.3- and 1.5-fold of control, Ad|min1|; 0.82- and 0.87-fold of control). Next, the effect of heparinoid on the plasma from one VWD patient each with type 1 (VWF:Ag/VWF:RCo 28 IU/dL/26 IU/dL), type 2 (20 IU/dL/9 IU/dL), and type 3 (<2 IU/dL/<3 IU/dL) was assessed. The addition of 2.5 µg/mL heparinoid showed slight anticoagulant effect for each type of VWD (CT; ~1.3-fold of control, Ad|min1|; ~0.91-fold of control). Conclusion: The presence of heparinoid demonstrated mild anticoagulant effect in vitro in the plasmas of patients with hemophilia and VWD. It might be possible to apply the heparinoid-contained product as skin treatment for these patients.

The Impacts of Genetic Polymorphisms on the Von Willebrand Factor Level in Type 1 Von Willebrand Disease

Background: von Willebrand disease (VWD) is the most common inherited bleeding disease, which results from deficiency or defect of von Willebrand factor (VWF). In type 1 VWD, there are only 53-81% patient whose mutations of VWF gene can be identified. Some studies reported that variants outside the VWF gene may also contribute to the VWF level. There are 7 genetic variants of single nucleotide polymorphism ( SNP ) reported to be associated with the variation of VWF levels, including CLEC4M, STXBP5, SCARA5, ABO, VWF, STAB2 and UFM1. The aims of this study were to explore the frequency of SNPs of the 7 genes among type 1 VWD patients and the effects of the 7 genetic variants on the VWF levels in type 1 VWD patients. Patients and methods: There were 62 patients ( the ratio of M/F: 1 ) with type 1 VWD enrolled in this study, including 35 (56.5%) patients with found mutations of VWF gene. Each patient's bleeding symptoms were assessed by the MCMDM-1 VWD bleeding score. The results of VWF levels: VWF:Ag and VWF activity ( VWF:ACL or VWF:RCo ) and FVIII: C at the VWD diagnosis were retrospectively collected, as shown in Table 1. Each enrolled patient's genomic DNA was extracted and the SNPs of the 7 gene were targeted by PCR amplification followed by direct sequencing. Results: There was high correlations between VWF:Ag and VWF activity ( r = 0.73, p < 0.0001 ) and between VWF:Ag and FVIII:C ( r = 0.60, p < 0.0001 ), respectively. The patients without variant ( A/A) of UFM1 has significantly lower median VWF:Ag of 33% than 44.7% of patients with heterozygous variant ( A/C ) type ( p = 0.033 ). Patients without variant (A/A ) of STXBP gene had both significantly lower median value of VWF:Ag ( 31.9% vs 46.1%, p = 0.017 ) and VWF activity (26.55% vs 30.4%, p = 0.0467 ) than those patients with heterozygous variant ( A/G ). Four alleles substitution of SNP of UFM1( C>A ) and STXBP genes ( G>A ) variant has remarkably lowest median VWF antigen level of 27.4%, which was significantly lower than 43.05% of the three alleles substitution ( p = 0.0014 ) and the 48.6% of the two alleles substitution ( p = 0.0279 ), as shown in Figure 1. Conclusions: Our study demonstrates that both C to A variant of UFM1 gene and G to A variant of STXBP5 gene were associated with lower VWF: Ag level than those without variant, respectively. The combination of four allelic variant of UFM1 and STXBP5 genes had the most reducing effect on VWF: Ag level.

A Propensity-Matched National Analysis of Transcatheter Aortic Valve Implantation Outcome in Patients With Gastrointestinal Bleeding

Gastrointestinal (GI) bleeding is often observed in severe aortic stenosis, which can be attributed to the presence of arteriovenous malformations and von Willebrand's factor deficiency. GI is one of the most common complications in patients who underwent transcatheter aortic valve implantation (TAVI). The outcome of the TAVI procedure with GI bleeding is unknown. We performed an International Classification of Diseases, Tenth Revision-based national cohort analysis using the national readmission database from 2016 to 2020. We compared cardiovascular outcomes, mortality, and readmission rates of patients with TAVI who developed GI bleeding compared with those who had no GI bleeding. A total of 320,353 hospitalizations with TAVI were identified from the year 2016 to 2020. Patients with TAVI with GI bleeding were 6,193.37 and without GI bleeding were 314,160. The median age of the patients with TAVI with GI or without GI bleeding was 80. GI bleed patients had statistically significantly higher readmission rates at 30, 90, and 180 days and they had higher odds of in-hospital mortality (adjusted odds ratio [aOR]=6.35; 95% confidence interval [CI]: 5.37 to 7.52; p<0.0001), acute kidney injury (aOR=5.22; 95% CI:4.75 to 5.74; p<0.0001), stroke (aOR=2.83; 95% CI 2.05 to 3.91 p:0.0001, postprocedural bleeding (aOR: 1.76; 95% CI: 1.35 to 2.30; p:0.0001), cardiac tamponade (aOR=2.54; 95% CI 1.86 to 3.49; p<0.0001), use of mechanical circulatory support (aOR: 5.33; 95% CI:4.13 to 6.86; p<0.0001), and heart failure (aOR:1.73; 95%CI: 1.54 to 1.94; p<0.0001). The total cost of hospitalization and length of stay was higher in the GI bleed group. Patients with TAVI with GI bleeding have worse clinical outcomes and higher in-hospital mortality and readmission rates compared with patients with no GI bleeding.

Shear-induced acquired von Willebrand syndrome: an accomplice of bleeding events in adults on extracorporeal membrane oxygenation support.

Extracorporeal membrane oxygenation (ECMO) is an increasingly acceptable life-saving mechanical assistance system that provides cardiac and/or respiratory support for several reversible or treatable diseases. Despite important advances in technology and clinical management, bleeding remains a significant and common complication associated with increased morbidity and mortality. Some studies suggest that acquired von Willebrand syndrome (AVWS) is one of the etiologies of bleeding. It is caused by shear-induced deficiency of von Willebrand factor (VWF). VWF is an important glycoprotein for hemostasis that acts as a linker at sites of vascular injury for platelet adhesion and aggregation under high shear stress. AVWS can usually be diagnosed within 24 h after initiation of ECMO and is always reversible after explantation. Nonetheless, the main mechanism for the defect in the VWF multimers under ECMO support and the association between AVWS and bleeding complications remains unknown. In this review, we specifically discuss the loss of VWF caused by shear induction in the context of ECMO support as well as the current diagnostic and management strategies for AVWS.

Acquired Von Willebrand Factor Deficiency at Patient-Prosthesis Mismatch after AVR Procedure-A Narrative Review.

Acquired von Willebrand factor deficiency has been described in patients with aortic valve stenosis due to high shear forces developed during passage through the narrowed valve orifice, which determines structural changes in this molecule. Similar flow conditions are present in patients with an aortic prosthesis that presents a patient-prosthesis mismatch. Patient-prosthesis mismatch is described by the smaller effective orifice area of the prosthesis than the native valve, which would probably determine similar changes in the molecules of the von Willebrand factor, leading to acquiring von Willebrand deficiency.

Phenotypic and genotypic (exon 28) characterization of patients diagnosed with von Willebrand disease type 1 in Eastern Saudi Arabia.

Von Willebrand factor (VWF) is a plasma glycoprotein that plays a key role in hemostasis. Mutations in this protein can result in von Willebrand disease (VWD), the most common form of bleeding disorder in humans. Patients with type 1 VWD have a quantitative plasmatic deficiency of normal structural and functional VWF. Our study aimed to investigate the phenotypic and genotypic characteristics of VWD type 1 patients in eastern Saudi Arabia, focusing on exon 28. We included patients previously diagnosed with WWD type 1 at the King Fahad teaching hospital in Al Khobar and their family members. The correlations between various phenotypic data and genotypic (exon 28) were analyzed using statistical software (SPSS) version 21. While these variants were generally considered benign with minor clinical effects, our analysis did identify two pathogenic variants that could lead to severe VWD symptoms. Specifically, we found these two pathogenic variants in three VWD patients from Saudi Arabia, providing essential insights into pathogenic VWD mutations in this population. Our study, therefore, sheds light on the prevalence of VWF variants in the eastern province of the Kingdom and highlights the need for continued research into the genetic causes of VWD in this region.

Von Willebrand factor levels in healthy blood donors and their association with blood group: A tertiary care hospital-based study.

von Willebrand disease is a common inherited bleeding disorder caused by the deficiency of von Willebrand factor (vWF).[1] The levels of vWF depend on several factors, including exercise, hormones, and ABO blood type.[2] This study was planned to evaluate plasma vWF levels and factor VIII (fVIII) levels in healthy blood donors and its association with the ABO blood group. The aim of this study was to evaluate plasma vWF levels and fVIII levels in healthy donors and its association with the ABO blood group. This study was done in 2016 healthy adult blood donors. Complete history and relevant examination were done along with ABO and Rh (D) blood group typing, complete blood count, prothrombin time, activated partial thromboplastin time, vWF antigen (Ag) level, fVIII coagulant assay, and other tests for hemostasis. Data were expressed in proportions and mean, median, and standard deviation, respectively. An appropriate test of significance was applied. P < 0.05 was considered statistically significant. vWF level of donors ranged from 24 to 186 IU/dL with a mean of 96.31 IU/dL. Low vWF Ag level (below 50 IU/dl) was found in 2.5% of donors while 0.1% (2/2016) had level <30 IU/dL. O Rh (D)-positive blood group donors had the lowest vWF level (87.85 IU/dL), while ARh (D)-negative donors had the highest vWF level (117.27 IU/dL). fVIII level of the donor population ranged from 22% to 174%, with a mean of 98.82%. About 2.48% of donors had fVIII levels below 50%. There was a statistically significant correlation between fVIII level and vWF level (P < 0.001).

The relative risk of ischemic cerebrovascular accident in patients with Von Willebrand disease.

Cerebrovascular accident (CVA) is one of the leading causes of death in the United States. Von Willebrand factor plays an important role in platelet activation and adhesion. It remains unclear whether Von Willebrand disease (vWD) is associated with a decreased risk of developing CVA. The study aimed to compare the relative risk (RR) of CVA in patients with and without vWD. We queried the National Inpatient Sample from 2009 to 2014 for discharge data and records for vWD and CVA using International Classification of Diseases, Ninth-Revision codes. The unadjusted and adjusted RR of CVA in patients with and without vWD were estimated using log-binomial model. Descriptive measures including means, medians, standard deviations, and range were presented based on normality test of continuous data. The prevalence of CVA was lower in patients with vWD than in those without vWD (1.31% vs 2.04%), with a RR of 0.64 (95% confidence interval (CI): 0.60-0.68). After adjusting for common CVA risk factors, the RR remained lower in vWD patients: 0.81 (95% CI: 0.76-0.86). vWD is associated with a lower RR of developing CVA. This suggests that deficiency of Von Willebrand factor is potentially protective against the development of CVA. To the best of our knowledge, this is the first study in humans to compare the RR of CVA in patients with and without vWD. Future studies are needed to explore causal relationships and therapeutic benefits.

Von Willebrand factor: from figurant to main character in the scene of inflammation

von Willebrand factor: from figurant to main character in the scene of inflammation

Von Willebrand factor neutralizing and non-neutralizing alloantibodies in 213 subjects with type 3 von Willebrand disease enrolled in 3WINTERS-IPS

BackgroundType 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions. ObjectiveThe objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS. MethodsAn indirect in-house enzyme-linked immunosorbent assay has been used to test all the alloantibodies against VWF. Neutralizing antibodies (inhibitors) have been tested with a Bethesda-based method by using a VWF collagen binding (VWF:CB) assay. Samples positive for anti-VWF antibodies were further tested with Bethesda-based methods by using the semiautomated gain-of-function glycoprotein-Ib binding (VWF:GPIbM) and a VWF antigen (VWF:Ag) enzyme-linked immunosorbent assay. ResultsIn total, 18 of the 213 (8.4%) subjects tested positive for anti-VWF antibodies and 13 of 213 (6%) had VWF:CB inhibitors. These 13 were among the 18 with anti-VWF antibodies. Of the 5 without VWF:CB inhibitors, 3 had non-neutralizing antibodies, 1 only inhibitor against VWF:GPIbM, and one could not be tested further. Ten of the 13 subjects with VWF:CB inhibitors also had VWF:GPIbM inhibitors, 6 of whom also had VWF:Ag inhibitors. Subjects with inhibitors were homozygous for VWF null alleles (11/14), homozygous for a missense variant (1/14), or partially characterized (2/14). ConclusionsAnti-VWF antibodies were found in 8.4% of subjects with type 3 VWD, whereas neutralizing VWF inhibitors were found in 6%, mainly in subjects homozygous for VWF null alleles. Because inhibitors may be directed toward different VWF epitopes, their detection is dependent on the assay used.

"Familial Multiple Coagulation Factor Deficiencies of FXI and FXII in an Asymptomatic Saudi Woman".

Factor XI deficiency (FXI) is the third most common coagulation factor deficiency after hemophilia A and B, ie, in the hierarchy after factors VIII and IX, taking into account von Willebrand's factor deficiency, as bleeding disorders are higher than in hemophilia C. Factor XII deficiency (FXII) is a congenital condition, inherited in the vast majority of cases in an autosomal recessive manner, more often associated with thromboembolic complications. A combination of both factor deficiencies has been found very rarely, and it can be familial multiple coagulation factor deficiency (FMCFD). This study reports the case of a 39-year-old woman from Saudi Arabia who had the combination of FXI and FXII deficiencies, known to be on treatment for hypothyroidism and was referred to a hematology clinic with an incidental finding of prolonged activated partial thromboplastin time (aPTT). Although there was no history of bleeding tendency, her siblings had a family history of an unknown type of bleeding disorder. On physical examination, the patient did not show any bruising, petechiae, or ecchymosis. The aPTT was 69 seconds (27-38) with normal use of other hemostatic agents and was corrected after a 50:50 mixing study. Intrinsic coagulation factors were evaluated, and they revealed severe FXI and moderate FXII deficiencies. Due to a strong family history, the patient was diagnosed with FMCFD. In conclusion, familial combined multiple clotting factor deficiency (FCMFD) is a rare condition that requires attention and reporting. The management strategy in such cases has not been well studied, especially in the long-term symptomatic patient with severe but asymptomatic combined FXI and FXII deficiencies, which is an area for review and further study.

Diagnostic pitfalls and conundrums in type 1 von Willebrand disease

Most people with von Willebrand disease (VWD) have a partial quantitative deficiency of plasma von Willebrand factor (VWF) or type 1 VWD. In contrast to type 2 and type 3 VWD, laboratory assays will not always establish the diagnosis in type 1 VWD. This is because plasma VWF levels in type 1 VWD, especially those with levels closer to 50 IU/dL, overlap with the general population. Assessment is further complicated by increased plasma VWF levels in response to physiologic stressors or aging. Diagnosis of those with type 1 VWD with plasma VWF levels 30 to 50 IU/dL (previously referred to as "low VWF") requires expert assessment of bleeding phenotype as well as an understanding of the limitations of both bleeding assessment tools (BATs) and laboratory testing. Using the available evidence and highlighting research gaps, we discuss common dilemmas facing providers relating to assessment of adolescents, transition from pediatrics to adult care, and older individuals with type 1 VWD.

Von Willebrand factor in diagnostics and treatment of cardiovascular disease: Recent advances and prospects.

Von Willebrand factor (VWF) is a large multimeric glycoprotein involved in hemostasis. It is essential for platelet adhesion to the subendothelium of the damaged endothelial layer at high shear rates. Such shear rates occur in small-diameter arteries, especially at stenotic sites. Moreover, VWF carries coagulation factor VIII and protects it from proteolysis in the bloodstream. Deficiency or dysfunction of VWF predisposes to bleeding. In contrast, an increase in the concentration of high molecular weight multimers (HMWM) of VWF is closely associated with arterial thrombotic events. Severe aortic stenosis (AS) or hypertrophic obstructive cardiomyopathy (HOCM) can deplete HMWM of VWF and lead to cryptogenic, gastrointestinal, subcutaneous, and mucosal bleeding. Considering that VWF facilitates primary hemostasis and a local inflammatory response at high shear rates, its dysfunction may contribute to the development of coronary artery disease (CAD) and its complications. However, current diagnostic methods do not allow for an in-depth analysis of this contribution. The development of novel diagnostic techniques, primarily microfluidic, is underway. Such methods can provide physiologically relevant assessments of VWF function at high shear rates; however, they have not been introduced into clinical practice. The development and use of agents targeting VWF interaction with the vessel wall and/or platelets may be reasonable in prevention of CAD and its complications, given the prominent role of VWF in arterial thrombosis.