Association of von Willebrand factor deficiency with prevalent cardiovascular disease and asymptomatic carotid atherosclerosis: The Atherosclerosis Risk in Communities Study.
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ABSTRACT:
SUBMITTER: Seaman CD
PROVIDER: S-EPMC5339890 | biostudies-literature | 2016 Aug
REPOSITORIES: biostudies-literature
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Association of von Willebrand factor deficiency with prevalent cardiovascular disease and asymptomatic carotid atherosclerosis: The Atherosclerosis Risk in Communities Study.
Seaman Craig D CD George Kristen M KM Ragni Margaret M Folsom Aaron R AR
Thrombosis research 20160602
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Project description:Atherosclerosis is an inflammatory disease of the vessel wall, with cholesterol crystal (CC) deposition being a hallmark of the disease. As evidence for a cross-talk between complement activation and hemostasis on CC surfaces has been limited to in vitro data, the aim of this study was to demonstrate the presence of C1q-vWF complexes in human atherosclerosis ex vivo. We used immunofluorescence staining and a proximity ligation assay (PLA, Duolink®) to examine the presence, localization, and co-localization of C1q and vWF in frozen sections of human carotid arteries with atherosclerosis or without atherosclerotic changes as well as material from thrombendarteriectomy. We observed significantly higher levels of C1q and vWF in healthy tissue compared to diseased material and greater co-localization in the PLA in healthy samples than in diseased samples. In diseased samples, fluorescence signals were highest in locations encompassing atheroma and foam cells. While there was overall reduced signal in areas with CCs, the staining was spotty, and there was evidence of co-localization on individual CCs. Thus, we demonstrate the presence of C1q-vWF complexes in human carotid arteries ex vivo, which was most abundant in healthy endothelial and subendothelial space and reduced in diseased tissue. C1q-vWF interaction can also be demonstrated on the CC surface.
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Project description:Use of animal models of inherited and induced von Willebrand factor (VWF) deficiency continues to advance the knowledge of VWF-related diseases: von Willebrand disease (VWD), thrombotic thrombocytopenic purpura (TTP), and coronary artery thrombosis. First, in humans, pigs, and dogs, VWF is essential for normal hemostasis; without VWF bleeding events are severe and can be fatal. Second, the ADAMTS13 cleavage site is preserved in all three species suggesting all use this mechanism for normal VWF multimer processing and that all are susceptible to TTP when ADAMTS13 function is reduced. Third, while the role of VWF in atherogenesis is debated, arterial thrombosis complicating atherosclerosis appears to be VWF-dependent. The differences in the VWF gene and protein between humans, pigs, and dogs are relatively few but important to consider in the design of VWF-focused experiments. These homologies and differences are reviewed in detail and their implications for research projects are discussed. The current status of porcine and canine VWD are also reviewed as well as their potential role in future studies of VWF-related disorders of hemostasis and thrombosis.
| S-EPMC3211078 | biostudies-literature
Project description:Progress in both basic and translational research into the molecular mechanisms of VWD can be seen in multiple fields.Genetics of vwdIn the past several decades, knowledge of the underlying pathogenesis of von Willebrand disease (VWD) has increased tremendously, thanks in no small part to detailed genetic mapping of the von Willebrand Factor (VWF) gene and advances in genetic and bioinformatic technology. However, these advances do not always easily translate into improved management for patients with VWD and low-VWF levels.Vwd and pregnancyFor example, the treatment of pregnant women with VWD both pre- and postpartum can be complicated. While knowledge of the VWF genotype at some amino acid positions can aid in knowledge of who may be at increased risk of thrombocytopenia or insufficient increase in VWF levels during pregnancy, in many cases, VWF levels and bleeding severity is highly heterogeneous, making monitoring recommended during pregnancy to optimize treatment strategies. VWF AND COVID-19: New challenges related to the consequences of dysregulation of hemostasis continue to be discovered. The ongoing COVID-19 pandemic has highlighted that VWF has additional biological roles in the regulation of inflammatory disorders and angiogenesis, disruption of which may contribute to COVID-19 induced vasculopathy. Increased endothelial cell activation and Weibel-Palade body exocytosis in severe COVID-19 lead to markedly increased plasma VWF levels. Coupled with impairment of normal ADAMTS13 multimer regulation, these data suggest a role for VWF in the pathogenesis underlying pulmonary microvascular angiopathy in severe COVID-19.ConclusionWith the increased affordability and availability of next-generation sequencing techniques, as well as a push towards a multi-omic approach and personalized medicine in human genetics, there is hope that translational research will improve VWD patient outcomes.
| S-EPMC9094051 | biostudies-literature
Project description:Liver diseases are associated with complex changes in the hemostatic system and elevated levels of the platelet-adhesive protein Von Willebrand factor (VWF) are reported in patients with acute and chronic liver damage. Although elevated levels of VWF are associated with fibrosis in the general population, the role of VWF in acute and chronic liver injury has not been examined in depth in experimental settings. We tested the hypothesis that VWF deficiency inhibits experimental liver injury and fibrosis. Wild-type (WT) and VWF-deficient mice were challenged with carbon tetrachloride (CCl4) and the impact of VWF deficiency on acute liver injury and chronic liver fibrosis was determined. VWF deficiency did not significantly affect acute CCl4-induced hepatocellular necrosis in mice. Chronic CCl4 challenge, twice weekly for 6weeks, significantly increased hepatic stellate cell activation and collagen deposition in livers of WT mice. Interestingly, hepatic induction of several profibrogenic and stellate cell activation genes was attenuated in VWF-deficient mice. Moreover, birefringent sirius red staining (indicating type I and III collagens) and type I collagen immunofluorescence indicated a reduction in hepatic collagen deposition in CCl4-exposed VWF-deficient mice compared to CCl4-exposed WT mice. The results indicate that VWF deficiency attenuates chronic CCl4-induced liver fibrosis without affecting acute hepatocellular necrosis. The results are the first to demonstrate that VWF deficiency reduces the progression of liver fibrosis, suggesting a mechanistic role of elevated plasma VWF levels in cirrhosis.
| S-EPMC5516268 | biostudies-literature
Project description:BackgroundTo evaluate association between von Willebrand factor (vWF) activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA) and low cardiovascular risk.MethodsAbove mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3±10.0 vs. 45.2±9.8 years). Intima-media thickness (IMT) was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%), none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately.ResultsRA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, p<0.05). Predictive value of vWF activity for subclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP), modified Health Assessment Questionnaire (p<0.01 for all), duration of smoking, number of cigarettes/day, rheumatoid factor concentration (p<0.05 for all), and anti-CCP antibodies (p<0.01). In the entire study population, vWF activity was higher in participants with subclinical atherosclerosis (130±68% vs. 97±38%, p<0.05) or atherosclerotic plaques (123±57% vs. 99±45%, p<0.05) than in those without. Duration of smoking was significantly associated with vWF activity (β 0.026, p = 0.039).ConclusionsWe demonstrated association of vWF activity and subclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of early atherosclerosis in RA patients.
| S-EPMC4527675 | biostudies-literature
Project description:AbstractLong-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.
| S-EPMC10950830 | biostudies-literature
Project description:Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P).
| S-EPMC7948283 | biostudies-literature
Project description:This study used in vivo molecular imaging to characterize endotheliall activation attributable to von Willebrand factor (vWF)-mediated platelet adhesion in atherosclerosis. In atherosclerotic mice lacking the low-density lipoprotein receptor on Western diet, the additional genetic deletion of the ADAMTS13, which cleaves endothelial-associated vWF, produced greater aortic molecular imaging signal for not only vWF and platelets, but also for endothelial adhesion molecules VCAM1 and P-selectin, larger plaque size, and lower aortic distensibility. Sustained ADAMTS13 therapy reduced signal for all 4 molecular targets and plaque size. We conclude that excess endothelial-associated vWF contributes to not only platelet adhesion, but also to up-regulation of endothelial cell adhesion molecules.
| S-EPMC7591934 | biostudies-literature
Project description:Backgroundvon Willebrand factor (VWF) variant c.2771G>A; p.R924Q has been described as a benign polymorphism or a possible marker for a null allele and been associated with mild bleeding phenotypes. It was identified in several patients in recent type 1 von Willebrand disease (VWD) studies.ObjectivesTo determine whether the p.R924Q allele contributes to reduced VWF levels and type 1 VWD.MethodsOne thousand one hundred and fifteen healthy controls and 148 index cases from the MCMDM-1VWD study were genotyped for c.2771G>A; VWF and FVIII levels were analyzed in ABO blood group stratified individuals and the p.R924Q variant was expressed in 293 EBNA cells.Resultsc.2771G>A was present in six index cases, five of whom had a second VWF variant which probably contributed to the phenotype. A common core haplotype identified in families, which included the rare G allele of c.5843-8C>G, was present in the majority of 35 c.2771G>A heterozygous controls. c.2771G>A contributed about 10% variance in VWF and FVIII levels in controls and 35% variance when co-inherited with blood group O. Recombinant p.R924Q VWF had no effect on in vitro expression and heterozygous family members had normal VWF-FVIII binding and normal clearance of VWF and FVIII.ConclusionsThe allele bearing c.2771A leads to reductions in VWF and FVIII levels particularly in combination with blood group O. Its inheritance alone may be insufficient for VWD diagnosis, but it appears to be associated with a further VWF level reduction in individuals with a second VWF mutation and it contributes to population variance in VWF and FVIII levels.
| S-EPMC3856360 | biostudies-literature