Increased Levels Of Von Willebrand Factor Research Articles

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.

Aging Is Associated With Organ-Specific Alterations in the Level and Expression Pattern of von Willebrand Factor.

VWF (von Willebrand factor) is an endothelial-specific procoagulant protein with a major role in thrombosis. Aging is associated with increased circulating levels of VWF, which presents a risk factor for thrombus formation. Circulating plasma, cellular protein, and mRNA levels of VWF were determined and compared in young and aged mice. Major organs were subjected to immunofluorescence analyses to determine the vascular pattern of VWF expression and the presence of platelet aggregates. An in vitro model of aging, using extended culture time of endothelial cells, was used to explore the mechanism of age-associated increased VWF levels. Increased circulating plasma levels of VWF with elevated levels of larger multimers, indicative of VWF functional activity, were observed in aged mice. VWF mRNA and cellular protein levels were significantly increased in the brains, lungs, and livers but not in the kidneys and hearts of aged mice. Higher proportion of small vessels in brains, lungs, and livers of aged mice exhibited VWF expression compared with young, and this was concomitant with increased platelet aggregate formation. Prolonged culture of endothelial cells resulted in increased cell senescence that correlated with increased VWF expression; VWF expression was specifically detected in senescent cultured endothelial cells and abolished in response to p53 knockdown. A significantly higher proportion of VWF expressing endothelial cells in vivo exhibited senescence markers SA-β-Gal (senescence-associated β-galactosidase) and p53 in aged mouse brains compared with that of the young. Aging elicits a heterogenic response in endothelial cells with regard to VWF expression, leading to organ-specific increase in VWF levels and alterations in vascular tree pattern of expression. This is concomitant with increased platelet aggregate formation. The age-associated increase in VWF expression may be modulated through the process of cell senescence, and p53 transcription factor contributes to its regulation.

Small interfering RNA–mediated allele-selective silencing of von Willebrand factor in vitro and in vivo

AbstractAn imbalance in von Willebrand factor (VWF) may either lead to bleeding (von Willebrand disease, VWD) or thrombosis. Both disorders have shortcomings in the currently available treatments. VWF itself could be a potential therapeutic target because of its role in both bleeding and thrombosis. Inhibiting VWF gene expression through allele-selective silencing of VWF with small interfering RNAs (siRNAs) could be a personalized approach to specifically inhibit mutant VWF in VWD or to normalize increased VWF levels in thrombotic disorders without complete VWF knockdown. Therefore, we investigated a method to allele-selectively silence the VWF gene in mice as a therapeutic strategy. Fourteen candidate siRNAs targeting murine Vwf of either the C57BL/6J (B6) or the 129S1/SvImJ (129S) strain were tested in vitro in cells expressing B6- and 129S-Vwf for inhibitory effect and allele-selective potential. Together with a nonselective siVwf, 2 lead candidate siRNAs, siVwf.B6 and siVwf.129S, were further tested in vivo in B6 and 129S mice. Efficient endothelial siRNA delivery was achieved by siRNA encapsulation into 7C1 oligomeric lipid nanoparticles. Treatment with the nonselective siVwf resulted in dose-dependent inhibition of up to 80% of both lung messenger RNA and plasma VWF protein in both mouse strains. In contrast, the allele-selective siVwf.B6 and siVwf.129S were shown to be effective in and selective solely for their corresponding mouse strain. To conclude, we showed efficient endothelial delivery of siRNAs that are highly effective in allele-selective inhibition of Vwf in mice, which constitutes an in vivo proof of principle of allele-selective VWF silencing as a therapeutic approach.

Abstract TMP4: BB-031 Reduces Platelet Reactivity And Attenuates Von Willebrand Factor Levels In A Large Vessel Occlusion Stroke Model

Introduction: Acute ischemic strokes (AIS) are a leading cause of death and long-term disability worldwide. Von Willebrand Factor (VWF) is an attractive target for anti-thrombotic therapeutics as it plays a pivotal role in platelet adhesion, activation, and aggregation with large vessel occlusion (LVO) stroke. VWF is stored in an ultra large form in platelet α-granules and Weibel-Palade bodies of endothelial cells from where it is released during injury or inflammation. BB-031 is an RNA aptamer that binds and inhibits VWF, and both prevents and lyses an occlusive thrombus. Hypothesis: We hypothesize BB-031 treatment will inhibit VWF thereby reducing platelet reactivity and attenuating the increase in VWF levels in a canine model of LVO stroke. Methods: A canine embolic MCAO model was used to assess BB-031 efficacy of VWF inhibition and platelet activity compared to placebo. After 6 hours of LVO with an autologous clot, intravenous treatment was initiated with placebo (n=7), or 0.5 (n=8), 1.0 (n=4), and 5.0 (n=4) mg/kg BB-031. Whole blood was collected at baseline, 6 hours after occlusion then at 10, 15, 20, 25, 30, 60 min after treatment and lastly, at time of sacrifice 9 hours after MCAO induction. Enzyme-linked immunosorbent assay (ELISA) was used to measure circulating VWF and platelet function analysis (PFA-100 Siemens) was utilized to determine platelet reactivity. Results: VWF levels immediately after LVO in vehicle control were significantly attenuated within 10 minutes of administration with all BB-031 concentrations (p<0.05). Within 15 minutes after vehicle treatment, VWF levels increased by 3.102 ± .382 ng/ml whereas BB-031 administration of 0.5, 1.0, and 5.0 mg/kg reduced VWF levels by 0.223 ± .154 ng/ml, 0.269 ± .304 ng/ml and 1.053 ± .267 ng/ml respectively. Platelet reactivity to ADP/Collagen (PFA-100) revealed significantly increased platelet closing time in all BB-031 treated canines from immediately after administration through 60 minutes. (p<0.05). Conclusion: BB-031 treatment demonstrated significant VWF inhibition and reduced platelet reactivity in a canine AIS LVO model compared to placebo. These findings indicate that BB-031 may offer a superior therapeutic treatment paradigm for ischemic stroke.

Von Willebrand factor and cancer: Another piece of the puzzle

Von Willebrand factor and cancer: Another piece of the puzzle

The von Willebrand factor–binding aptamer rondaptivon pegol as a treatment for severe and nonsevere hemophilia A

AbstractFactor VIII (FVIII) circulates in a noncovalent complex with von Willebrand Factor (VWF), the latter determining FVIII half-life. The VWF-binding aptamer rondaptivon pegol (BT200) increases plasma levels of VWF/FVIII in healthy volunteers. This trial assessed its safety, pharmacokinetics, and pharmacodynamics in hemophilia A. Nineteen adult patients (ages 20-62 years, 4 women) with hemophilia A (8 mild, 2 moderate, and 9 severe) received subcutaneous injections of rondaptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2 to 9 mg until day 28. Severe hemophilia A patients underwent sparse-sampling population pharmacokinetics individual profiling after the final dose of rondaptivon pegol. Adverse events, pharmacokinetics, and pharmacodynamics were assessed. FVIII activity and VWF levels were measured. All patients tolerated rondaptivon pegol well. The geometric mean half-life of rondaptivon pegol was 5.4 days and rondaptivon pegol significantly increased VWF levels. In severe hemophilia A, 6 doses of rondaptivon pegol increased the half-lives of 5 different FVIII products from a median of 10.4 hours to 31.1 hours (range, 20.8-56.0 hours). Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondaptivon pegol is a first-in-class prohemostatic molecule that extended the half-life of substituted FVIII approximately 3-fold and increased endogenous FVIII levels approximately 2-fold in hemophilia patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.

Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease

Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)-induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.

Von Willebrand disease and von Willebrand factor.

In 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. For 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. With 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.

Effects of Inflammation on Hemostasis in Acutely Ill Patients with Liver Disease.

Patients with liver diseases are in a rebalanced state of hemostasis, due to simultaneous decline in pro- and anticoagulant factors. This balance seems to remain even in the sickest patients, but is less stable and might destabilize when patients develop disease complications. Patients with acute decompensation of cirrhosis, acute-on-chronic liver failure, or acute liver failure often develop complications associated with changes in the hemostatic system, such as systemic inflammation. Systemic inflammation causes hemostatic alterations by adhesion and aggregation of platelets, release of von Willebrand factor (VWF), enhanced expression of tissue factor, inhibition of natural anticoagulant pathways, and inhibition of fibrinolysis. Laboratory tests of hemostasis in acutely-ill liver patients may indicate a hypocoagulable state (decreased platelet count, prolongations in prothrombin time and activated partial thromboplastin time, decreased fibrinogen levels) due to decreased synthetic liver capacity or consumption, or a hypercoagulable state (increased VWF levels, hypofibrinolysis in global tests). Whether these changes are clinically relevant and should be corrected with antithrombotic drugs or blood products is incompletely understood. Inflammation and activation of coagulation may cause local ischemia, progression of liver disease, and multiorgan failure. Anti-inflammatory treatment in acutely-ill liver patients may be of potential interest to prevent thrombotic or bleeding complications and halt progression of liver disease.

The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

Age-Associated Increase in Thrombogenicity and Its Correlation with von Willebrand Factor.

Endothelial cells that cover the lumen of all blood vessels have the inherent capacity to express both pro and anticoagulant molecules. However, under normal physiological condition, they generally function to maintain a non-thrombogenic surface for unobstructed blood flow. In response to injury, certain stimuli, or as a result of dysfunction, endothelial cells release a highly adhesive procoagulant protein, von Willebrand factor (VWF), which plays a central role in formation of platelet aggregates and thrombus generation. Since VWF expression is highly restricted to endothelial cells, regulation of its levels is among the most important functions of endothelial cells for maintaining hemostasis. However, with aging, there is a significant increase in VWF levels, which is concomitant with a significant rise in thrombotic events. It is not yet clear why and how aging results in increased VWF levels. In this review, we have aimed to discuss the age-related increase in VWF, its potential mechanisms, and associated coagulopathies as probable consequences.

ПОКАЗАТЕЛИ КОАГУЛЯЦИОННОГО РАВНОВЕСИЯ И АГРЕГАЦИИ ТРОМБОЦИТОВ У ПАЦИЕНТОВ С ИНФЕКЦИЕЙ COVID-19

Objective. To determine changes in coagulation balance and platelet aggregation in patient during the treatment of COVID-19 infection. Methods. A pilot non-randomized prospective clinical study of coagulation balance and platelet aggregation in patients admitted to the intensive care unit with acute respiratory distress syndrome and the diagnosis of COVID-19 (n=50) was performed. Out of 50 patients, 19 patients died, 31 patients were transferred to the therapeutic department. The study of indicators of coagulation balance and platelet aggregation was carried out once in 1-3 days starting from the patient’s admission to the hospital using coagulation analyzer ACL 10000 (Instrumentation Laboratory, USA) and platelet aggregation analyzer AP 2110 (ZAO “SOLAR”, Republic of Belarus). Results. In 45 (90%) patients with COVID-19, there is a significant increase of von Willebrand factor activity 350 (244.5; 480) %. There were no statistically significant differences in the level of von Willebrand factor activity among the deceased and surviving patients: 450.0 (338.8; 530.5) % in deceased patients and 342.0 (188.8; 480.0) % in survivors. At von Willebrand factor activity level of up to 250%, the mortality rate was 8.3%, at a level of 250-400% - 31.3%, at a level of more than 400% - 59.1%. Significantly above the normal range in most patients were fibrinogen (above normal in 68% of patients, 4.63 (3.49; 5.87) g/L) and D-dimers (above normal in 88% of patients, 0.73 (0,31; 1.4) μg/ml). Antithrombin III was below normal in 56% of patients (82 (67.1; 97.2) %). The degree of platelet aggregation has a strong direct correlation with the von Willebrand factor level: with an ADP inducer 0.3 μg/ml (R=0.71, р=0.003); ADP 0.6 μg/ml (R=0.74, р=0.0001); ADP 1.25 μg/ml (R=0.53, р=0.01). Conclusion. Analysis and evaluation of coagulation balance and platelet aggregation should be an integral part in the treatment of patients with COVID-19 infection. What this paper adds For the first time, the indicators of coagulation balance and platelet aggregation have been assessed in the treatment of COVID-19 infection. It has been found that 90% of patients had the increasedlevels ofvon Willebrand factor(VWF) - 350 (244.5; 480)%. In addition to an increase of von Willebrand factor activity, 56% of patients show a reduction of antithrombin III levels, and 88% and 68% of patients have an increasing D-dimers and fibrinogen, respectively. Analysis and assessment of coagulation balance and platelet aggregation indicators should be integral components of the treatment of patients with COVID-19 infection.

VWF/ADAMTS13 Imbalance, But Not Global Coagulation or Fibrinolysis, Is Associated With Outcome and Bleeding in Acute Liver Failure.

Background and AimsRecent studies of acute liver failure (ALF) in man and animals have suggested that rebalanced hemostasis occurs, with distinct hypercoagulable features clinically evidenced by a low risk of bleeding. Rodent models have shown a link between intrahepatic microthrombus formation and progression of ALF. We sought to confirm these earlier findings in a large series of patients with well‐characterized ALF from the Acute Liver Failure Study Group.Approach and ResultsCitrated plasma samples taken on admission from 676 patients with ALF or acute liver injury (international normalized ratio ≥2.0 without hepatic encephalopathy) were used to determine levels of von Willebrand factor (VWF), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity, thrombomodulin‐modified thrombin generation, and clot lysis time (CLT) and compared with the levels in 40 healthy controls. Patients had 3‐fold increased VWF levels, 4‐fold decreased ADAMTS13 activity, similar thrombin generating capacity, and 2.4‐fold increased CLT, compared with controls. Increasing disease severity was associated with progressively more elevated VWF levels as well as hypofibrinolysis. Patients who died or underwent liver transplantation within 21 days of admission had higher VWF levels, lower ADAMTS13 activity, but similar thrombin generation and a similar proportion of patients with severe hypofibrinolysis, when compared with transplant‐free survivors. Likewise, patients with bleeding complications had higher VWF levels and lower ADAMTS13 activity compared to those without bleeding. Thrombin generation and CLT did not differ significantly between bleeding and nonbleeding patients.ConclusionsRebalanced hemostatic status was confirmed in a large cohort of patients with acute liver injury/ALF, demonstrating that VWF/ADAMTS13 imbalance is associated with poor outcome and bleeding. The association between VWF/ADAMTS13 imbalance and bleeding suggests that bleeding in ALF relates more to systemic inflammation than a primary coagulopathy.

Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells

Thrombomodulin (TM) is a thrombin receptor on endothelial cells that is involved in promoting activation of the anticoagulant protein C pathway during blood coagulation. TM also exerts protective anti-inflammatory properties through a poorly understood mechanism. In this study, we investigated the importance of TM signaling to cellular functions by deleting it from endothelial cells by CRISPR-Cas9 technology and analyzed the resultant phenotype of TM-deficient (TM-/- ) cells. Deficiency of TM in endothelial cells resulted in increased basal permeability and hyperpermeability when stimulated by thrombin and TNF-α. The loss of the basal barrier permeability function was accompanied by increased tyrosine phosphorylation of VE-cadherin and reduced polymerization of F-actin filaments at cellular junctions. A significant increase in basal NF-κB signaling and expression of inflammatory cell adhesion molecules was observed in TM-/- cells that resulted in enhanced adhesion of leukocytes to TM-/- cells in flow chamber experiments. There was also a marked increase in expression, storage, and release of the von Willebrand factor (VWF) and decreased storage and release of angiopoietin-2 in TM-/- cells. In a flow chamber assay, isolated platelets adhered to TM-/- cells, forming characteristic VWF-platelet strings. Increased VWF levels and inflammatory foci were also observed in the lungs of tamoxifen-treated ERcre-TMf/f mice. Reexpression of the TM construct in TM-/- cells, but not treatment with soluble TM, normalized the cellular phenotype. Based on these results, we postulate cell-bound TM endows a quiescent cellular phenotype by tightly regulating expression of procoagulant, proinflammatory, and angiogenic molecules in vascular endothelial cells.

The impact of ABO blood type on the prevalence of portal vein thrombosis in patients with advanced chronic liver disease.

Background and aimsNon‐O blood type (BT) is a risk factor for thromboses, which has been attributed to its effects on von Willebrand factor (VWF)/factor VIII (FVIII) levels. Although high VWF/FVIII may be risk factors for portal vein thrombosis (PVT) in patients with advanced chronic liver disease (ACLD), the impact of BT on PVT is unknown. We aimed to assess (I) whether non‐O‐BT is a risk factor for PVT and (II) whether non‐O‐BT impacts VWF/factor VIII in patients with ACLD.MethodsRetrospective analysis comprising two cohorts: (I) “US” including all adult liver transplantations in the US in the MELD era and (II) “Vienna” comprising patients with a hepatic venous pressure gradient (HVPG) ≥6 mmHg.Results(I) The “US cohort” included 84 947 patients (non‐O: 55.43%). The prevalence of PVT at the time of listing (4.37% vs 4.56%; P = .1762) and at liver transplantation (9.56% vs 9.33%; P = .2546) was similar in patients with O‐ and non‐O‐BT. (II) 411 patients were included in the “Vienna cohort” (non‐O: 64%). Mean HVPG was 18(9) mmHg and 90% had an HVPG ≥10 mmHg. Patients with non‐O‐BT had slightly increased VWF levels (318(164)% vs 309(176)%; P = .048; increase of 23.8%‐23.9% in adjusted analyses), but this difference was driven by patients with less advanced disease. However, non‐O‐BT explained only 1% of the variation in VWF and had no effect on FVIII.ConclusionsAlthough non‐O‐BT impacts VWF in patients with early stage ACLD, its contribution to VWF variation is considerably smaller than in the general population. Moreover, non‐O‐BT had no impact on FVIII. These findings may explain the absence of an association between non‐O‐BT and PVT in patients with advanced cirrhosis.

Increased von Willebrand factor levels in polycythemia vera and phenotypic differences with essential thrombocythemia

BackgroundAcquired von Willebrand factor (VWF) deficiency was described in Philadelphia‐negative myeloproliferative neoplasms, especially in essential thrombocythemia (ET). VWF phenotype in contemporary patients with polycythemia vera (PV) remains less explored. ObjectivesTo characterize the VWF phenotype in PV and to compare VWF phenotype in PV with matched healthy subjects and ET patients. Patients/MethodsWe studied 48 PV patients, treated according to current recommendations (hematocrit ≤ 45%, on low‐dose aspirin prophylaxis); 48 healthy and 41 subjects with ET, all sex, age, and blood group matched. We measured VWF antigen, activity, multimeric pattern, ADAMTS‐13, and factor VIII (FVIII) antigen. ResultsIn patients with PV, VWF antigen and activity were significantly higher than in healthy subjects (antigen: 119[96‐137] vs 93[79‐107] IU/dL; activity: 114[95‐128] vs 90[79‐107] IU/dL, respectively, medians and interquartile, P < 0.01), with normal multimeric distribution. ADAMTS‐13 levels were similar between patients with PV and healthy subjects. FVIII levels were higher in PV than in healthy subjects (141[119‐169] versus 98[88‐123] IU/dL, respectively, P < 0.01). By multivariable analysis, JAK2‐p.V617F allelic burden, erythrocyte count, and male sex significantly predicted VWF antigen and activity levels. As compared to patients with ET, patients with PV showed similar VWF antigen levels but approximately 40% higher activity (79[49‐104] vs 112[93‐125] IU/dL, respectively, P < 0.01). ConclusionsPatients with PV show increased VWF and FVIII levels, predicted by JAK2‐p.V617F burden and erythrocyte count. At variance with ET, acquired VWF defect was not observed in PV. High VWF/FVIII levels may sustain the thrombotic diathesis of PV and may be investigated as biomarkers for risk stratification.

Effect of Von Willebrand Antigen on Mortality and Major Adverse Cardiac Events in Diabetic and Non-diabetic Patients with Anterior ST Elevated Myocardial Infarction

Background: Coronary artery disease (CAD) is one of the main causes of mortality in the world. The role of Von Willebrand Factor (VWF) is very important in platelet adhesion, microcirculation, and acute stenosis and it contributes to the development of atherothrombotic processes. Objectives: We decided to evaluate the level of VWF in diabetic and non-diabetic patients as an effective factor in CAD. Methods: This study was performed on 65 patients (32 diabetic patients and 33 non-diabetic patients), who referred to an Echocardiography and Angiography Department. They were evaluated for the VWF level, blood group, and fasting blood glucose. Patients underwent echocardiography, angiography, and, if necessary, percutaneous coronary intervention (PCI) during the hospitalization. They also underwent coronary artery bypass grafting (CABG) if they needed the surgery. After 40 days, we evaluated the anterior ST-elevation myocardial infarction (STEMI), mortality, major adverse cardiac events (MACE), heart failure, and limb ischemia. Results: The VWF level was significantly higher in diabetic patients (P < 0.0001). Also, the increased VWF levels were significantly more frequent in diabetic patients under CABG than in non-diabetic patients under CABG (P = 0.013). There was a significant relationship between positive MACE and increased VWF levels. Conclusions: The level of VWF in diabetic patients increases cardiovascular problems. Therefore, it seems that these patients can benefit from VWF-reducing drugs. Clinical research can be promising in this field.

The role of ADAMTS‐13 and von Willebrand factor in cancer patients: Results from the Vienna Cancer and Thrombosis Study

Unlabelled Box BackgroundCancer‐associated venous thromboembolism (VTE) is an important complication in the course of a malignant disease. Low ADAMTS‐13 (a disintegrin‐like and metalloproteinase with thrombospondin type 1 motif 13) and increased von Willebrand Factor (VWF) levels in cancer patients have been described numerously. ObjectivesInvestigation of the influence of ADAMTS‐13 and VWF on the probability of VTE and survival in malignancy. Patients/MethodsIn the framework of the ongoing prospective Cancer and Thrombosis Study (CATS) ADAMTS‐13 activity and VWF antigen levels were investigated in cancer patients. ResultsIn total, 795 patients with various tumor types (364 female/431 male, median age 62 years) were included; of those, 56 developed VTE and 359 patients died during a median follow‐up time of 730 days. The hazard ratio (HR) of VTE per doubling of VWF level was 1.56 (95% confidence interval [CI] 1.13‐2.16) in multivariable competing risk analysis. ADAMTS‐13 levels showed no correlation with the incidence of VTE in univariate competing risk analysis. The HR of mortality per doubling of VWF level was 1.46 (95% CI 1.28‐1.66) and per SD increment of ADAMTS‐13was 0.90 (95% CI 0.81‐1.00) in multivariable Cox regression analysis. Patients with VWF >75th percentile and concomitant low (<25th percentile) or medium (25‐75th percentile) ADAMTS‐13 values had the highest probability of mortality (HR 4.31 and 4.75, respectively). ConclusionsHigh VWF levels were significantly associated with the risk of developing VTE in cancer patients, whereas ADAMTS‐13 was not. Low ADAMTS‐13 and increased VWF levels were independently associated with worse overall survival.

The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13–von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13–VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted β −23.4%, 95% CI −30.9– −15.1%, p<0.001) and increased VWF levels (β +75.5%, 95% CI 44.8–113%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identified a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13–VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13–VWF axis in CTEPH pathobiology.

Expression Profile of VEGF and VEGFR2 in the Female Reproductive Tract at the Time of Placentation in a Porcine Model of Von Willebrand Disease Type 1

Objectives: Clinical studies showed that women affected by von Willebrand disease (VWD) trend towards higher rates of miscarriages, but the underlying pathomechanisms remain unclear. Several in vitro studies demonstrated an influence of von Willebrand factor (VWF) on angiogenesis, which seems to be partly mediated via VEGF. Since angiogenesis in the reproductive organs is essential to establish and maintain pregnancy, we aimed to investigate gene expression of VWF, VEGF, and its receptor VEGFR2 in non-pregnant and pregnant individuals, using a porcine model of VWD type 1.Methods: Tissue samples of uterus, oviduct and ovary were harvested from eight female pigs of which four were pregnant on day 30 (time of placentation) and four were non-pregnant and in estrus. Of each group, two were affected by VWD type 1 and two were wildtype (WT) individuals. The gene expression of VWF, VEGF, and VEGFR2 was measured by qRT-PCR and relatively quantified against the endothelial specific housekeeping genes PROCR and CD31 using the ΔΔCT method and calculating the respective x-fold changes. The gene expression differences were compared between both genotypes as well as between both reproductive states Mean differences were taken into account, if the divergences were consistent in both individuals of each group and not within the range of the group they were compared to.Results: Regarding the non-pregnant sows, VWF expression was lower in uterus and ovary of the VWD type 1 animals. This difference was not seen comparing the pregnant animals of each genotype, but the VWD type 1 animals showed higher VEGF expression in oviduct and higher VEGF and VEGFR2 expression in the ovary. The expression of VEGFR2 was reduced in the uterus. Comparing the non-pregnant with the pregnant animals within each genotype, the following results were found: the pregnant WT pigs showed increased expression of VEGFR2 in uterus and ovary, but decreased expression of VEGF in the uterus. For the pregnant VWD type 1 animals increased expression was found for VWF and VEGFR2 in the ovary, and decreased expression for VEGF in uterus and oviduct and VEGFR2 in the uterus.Discussion and Conclusion: Comparison of the different groups revealed differences of gene expression in the female reproductive tract during early pregnancy. The expectedly lower expression of VWF in the VWD type 1 animals was not found for the pregnant animals. Apparently, there is an increase of VWF levels during pregnancy as seen in women. While VEGFR2 expression in the uterus increases during placentation in the WT animals, it decreases in the VWD type 1 animals. This suggests altered regulation of early angiogenesis, which is essential during placentation. Expression of VEGF and VEGFR2 was increased in the ovaries of the VWD type 1 animals. This points to an enhanced involvement of this pathway during conversion of the ruptured follicles to sufficient corpora lutea graviditates, which may affect this process. Enhanced angiogenesis via the VEGF/VEGFR2-pathway due to lack of VWF was already shown in vitro. Our study shows that the expression of VEGF and VEGFR2 differs during early pregnancy in VWD type 1 compared to wildtype sows. Therefore, this pathway may influence angiogenesis in the reproductive tract. DisclosuresNo relevant conflicts of interest to declare.