Role Of Von Willebrand Factor Research Articles

Coronary microthrombi in the failing human heart: the role of von Willebrand factor and PECAM-1.

The recognition of microthrombi in the heart microcirculation has recently emerged from studies in COVID-19 decedents. The present study investigated the ultrastructure of coronary microthrombi in heart failure (HF) due to cardiomyopathies that are unrelated to COVID-19 infection. In addition, we have investigated the role of von Willebrand factor (VWF) and PECAM-1 in microthrombus formation. We used electron microscopy to investigate the occurrence of microthrombi in patients with HF due to dilated (DCM, n = 7), inflammatory (MYO, n = 6) and ischemic (ICM, n = 7) cardiomyopathy and 4 control patients. VWF and PECAM-1 was studied by quantitative immunohistochemistry and Western blot. In comparison to control, the number of microthrombi was increased 7-9 times in HF. This was associated with a 3.5-fold increase in the number of Weibel-Palade bodies (WPb) in DCM and MYO compared to control. A fivefold increase in WPb in ICM was significantly different from control, DCM and MYO. In Western blot, VWF was increased twofold in DCM and MYO, and more than threefold in ICM. The difference between ICM and DCM and MYO was statistically significant. These results were confirmed by quantitative immunohistochemistry. Compared to control, PECAM-1 was by approximatively threefold increased in all groups of patients. This is the first study to demonstrate the occurrence of microthrombi in the failing human heart. The occurrence of microthrombi is associated with increased expression of VWF and the number of WPb, being more pronounced in ICM. These changes are likely not compensated by increases in PECAM-1 expression.

Investigation of the role of von Willebrand factor in shear-induced platelet activation and functional alteration under high non-physiological shear stress.

von Willebrand factor (vWF) plays a crucial role in physiological hemostasis through platelet and subendothelial collagen adhesion. However, its role in shear-induced platelet activation and functional alteration under non-physiological conditions common to blood-contacting medical devices (BCMDs) is not well investigated. Fresh healthy human blood was treated with an anti-vWF antibody to block vWF-GPIbα interaction. Untreated blood was used as a control. They were exposed to three levels of non-physiological shear stress (NPSS) (75, 125, and 175 Pa) through a shearing device with an exposure time of 0.5 s to mimic typical shear conditions in BCMDs. Flow cytometric assays were used to measure the expression levels of PAC-1 and P-Selectin and platelet aggregates for platelet activation and the expression levels of GPIbα, GPIIb/IIIa, and GPVI for receptor shedding. Collagen/ristocetin-induced platelet aggregation capacity was characterized by aggregometry. The levels of platelet activation and aggregates increased with increasing NPSS in the untreated blood. More receptors were lost with increasing NPSS, resulting in a decreased capacity of collagen/ristocetin-induced platelet aggregation. In contrast, the increase in platelet activation and aggregates after exposure to NPSS, even at the highest level of NPSS, was significantly lower in treated blood. Nevertheless, there was no notable difference in receptor shedding, especially for GPIIb/IIIa and GPVI, between the two blood groups at the same level of NPSS. The block of vWF exacerbated the decreased capacity of collagen/ristocetin-induced platelet aggregation. High NPSS activates platelets mainly by enhancing the vWF-GPIbα interaction. Platelet activation and receptor shedding induced by high NPSS likely occur through different pathways.

The role of platelets and von Willebrand factor in the procoagulant phenotype of inflammatory bowel disease.

Although the risk for thrombosis is well documented for inflammatory bowel disease (IBD) patients, the underlying pathological mechanism seems to be different from other thrombotic conditions. Deciphering the actors responsible for the increased risk of thrombosis in IBD would help to improve management of this frequent complication. We studied the interplay between platelets, coagulation, and von Willebrand factor (VWF) in 193 IBD patients and in experimental models (acute and chronic) of colitis in wild-type and VWF-deficient mice. We found a platelet-dependent increase in thrombin generation in IBD patients and in our mouse model of colitis. Agglutinated platelets were present in the blood of patients and mice. Interestingly, we observed not only a significant increase in total VWF antigen, but we were able to detect the presence of active VWF (VWF in its platelet-binding conformation; 3.2±2.7µg/ml) in the plasma of 30% of all IBD patients. In healthy controls, active VWF levels were below 0.3µg/ml. This led us to further explore experimental colitis in VWF-deficient mice and we observed that these mice were protected against the procoagulant state triggered by the colitis. Unexpectedly, these mice also manifested a significant worsening of colitis severity both in acute and chronic models. Platelets and VWF (including its active form) appear to be central players in the procoagulant phenotype in IBD. We observed that the role of VWF in hemostasis differs from its role in colic tissue healing, potentially opening new therapeutic avenues for a life-threatening complication in IBD patients.

Von Willebrand factor modulates immune complexes and the recall response against factor VIII in a murine hemophilia A model

AbstractAchieving tolerance toward factor VIII (FVIII) remains an important goal of hemophilia treatment. Up to 40% of patients with severe hemophilia A (HA) develop neutralizing antibodies against FVIII, and the only proven treatment to achieve tolerance is infusion of FVIII over prolonged periods in the context of immune tolerance induction. Here, we addressed the role of von Willebrand factor (VWF) as a modulator of anti-FVIII antibody effector functions and the FVIII-specific recall response in an HA mouse model. Analytical ultracentrifugation was used to demonstrate formation of FVIII-containing immune complexes (FVIII-ICs). VWF did not fully prevent FVIII-IC formation but was rather incorporated into larger macromolecular complexes. VWF prevented binding of FVIII-ICs to complement C1q, most efficiently when it was preincubated with FVIII before the addition of antibodies. It also prevented binding to immobilized Fc-γ receptor and to bone marrow–derived dendritic cells. An in vitro model of the anti-FVIII recall response demonstrated that addition of VWF to FVIII abolished the proliferation of FVIII-specific antibody-secreting cells. After adoptive transfer of sensitized splenocytes into immunocompetent HA mice, the FVIII recall response was diminished by VWF. In summary, these data indicate that VWF modulates the formation and effector functions of FVIII-ICs and attenuates the secondary immune response to FVIII in HA mice.

The role of von Willebrand factor in thrombotic post-transplantation complications

The role of von Willebrand factor in thrombotic post-transplantation complications

Role of von Willebrand Factor, Fibrinogen, C Reactive Protein, Complete Blood Count and ABO blood type in monitoring ABO –typed Cardiovascular Disease patients attending University of Calabar Teaching Hospital, Calabar, Nigeria

Introduction: Cardiovascular disease is known to be the leading cause of death globally and it is responsible for one third of all global deaths.The research was conducted to assess some complete blood count, von Willebrand factor, fibrinogen, C reactive protein and ABO blood group that could serve as a biomarker for the diagnosis and management of cardiovascular disease. Materials and Methods: Three hundred and sixty persons were studied, comprising 200 CVD subjects and 160 apparently healthy persons as controls, between 35-82 years of age. Fifty-nine percent of the CVD subjects were male while female constituted 41%. Questionnaires and folders were used to obtain information. Data was analyzed by SPSS version 22. ABO blood group was determined by standard tube method. Complete Blood Count was carried out with Sysmex counter, von Willebrand factor, Fibrinogen levels and C reactive protein were determined by Enzyme-Link Immuno-sorbent Assay methods, while plasma glucose and lipid profile were determined by colorimetric method. Systolic Blood Pressure and Diastolic Blood Pressure of the participants were determined. Results: Significantly higher value were observed for SBP, DBP, vWf, WBC, RDW-CV, FPG, CRP and MPV among CVD subjects, when compared to control group, While significant lower level of platelet count were recorded among CVD subjects (200.43±70.45/l) compared to control group (234.91±48.85). CVD subjects on treatment recorded significant lower value of vWf (p=0.000) and FPG (p=0.000), compared with untreated subjects. Classification of subjects based on ABO blood type revealed that group O had significantly lower vwf (p=0.000), Group A had significant higher value of plasma glucose compared to other groups. Group A also recorded significant higher value of LDL than other blood groups. CVD subjects who smoke cigarettes had significant raised glucose levels (p=0.005) than non-smokers. Significantly lower level of CRP (4.63±3.77mg/L) was seen in female subjects compared to the male (6.41±4.35mg/L). Conclusion: It concludes that CBC, vWf, SBP, and DBP showed mild significant increase in their plasma level in CVD subjects and their assay should form part of the markers for routine diagnosis of CVD in UCTH and can be useful for monitoring of treatment.

Early lyophilized cryoprecipitate enhances the ADAMTS13/VWF ratio to reduce systemic endotheliopathy and lessen lung injury in a mouse multiple-trauma hemorrhage model.

Recent studies in severely injured patients suggest an important role of von Willebrand Factor (VWF) and ADAMTS13 in the endotheliopathy of trauma (EoT). We hypothesized that the early use of cryoprecipitate would be effective as an endothelial protector by supplementing physiologic VWF and ADAMTS13 to reverse the EoT. We tested a pathogen-reduced lyophilized cryoprecipitate (LPRC) that could expedite the early administration of cryoprecipitate in the battlefield. A mouse multiple-trauma model with uncontrolled hemorrhage (UCH) from liver injury was utilized followed by hypotensive resuscitation (mean arterial pressure, 55-60) × 3 hours with lactated Ringer's (LR), fresh frozen plasma (FFP), conventional pathogen-reduced cryoprecipitate (CC), and LPRC. Blood was collected for measurement of syndecan-1, VWF, and ADAMTS13 by ELISA. Lungs were stained for histopathologic injury and syndecan-1 and bronchial alveolar lavage (BAL) fluid harvested for protein as an indicator of permeability. Statistical analysis was by ANOVA followed by Bonferroni correction. Following multiple trauma and UCH, blood loss was similar across groups. Mean volume of resuscitation was higher in the LR group compared with the other resuscitation groups. Lung histopathologic injury, syndecan-1 immunostaining and BAL protein were higher with LR compared with resuscitation with FFP and CC, while LPRC further reduced BAL compared with FFP and CC. The ADAMTS13/VWF ratio was significantly lower in LR but improved with FFP and CC, comparable to shams while LPRC further increased this ratio. The protective effects of CC and LPRC were comparable to FFP in ameliorating the EoT in our murine multiple trauma and UCH model. Lyophilized cryoprecipitate may also provide additional benefit by enhancing the ADAMTS13/VWF ratio. These data provide evidence of the safety and efficacy of LPRC and warrants further investigation for its potential application in military settings once approved for human administration.

Association of Genetic and Allelic Variants of Von Willebrand Factor (VWF), Glutathione S-Transferase and Tumor Necrosis Factor Alpha with Ischemic Stroke Susceptibility and Progression in the Saudi Population.

Stroke is a key cerebrovascular disease and important cause of death and disability worldwide, including in the kingdom of Saudi Arabia (KSA). It has a large economic burden and serious socioeconomic impacts on patients, their families and the community. The incidence of ischemic stroke is probably increased by the interaction of GSTT1 and GSTM1 null genotypes with high blood pressure, diabetes and cigarette smoking. The roles of VWF, GSTs and TNF-alpha gene variations in the induction of stroke are still uncertain and require further examination. In the current study, we studied the associations of SNPs in the genes VWF, GSTs and TNF-alpha with stroke in the Saudi population. Genotyping was performed using the ARMS -PCR for TNF-alpha, AS-PCR for VWF and multiplex PCR for GSTs. The study included 210 study subjects: 100 stroke cases and 110 healthy controls. We obtained significant distributions of VWF rs61748511 T > C, TNF-alpha rs1800629 G > A and GST rs4025935 and rs71748309 genotypes between stroke cases and the healthy controls (p < 0.05). The results also indicated that the TNF-alpha A allele was associated with risk of stroke with odd ratio (OR) = 2.22 and risk ratio = RR 2.47, p < 0.05. Similarly, the VWF-TC genotype and C allele were strongly linked with stroke with OR = 8.12 and RR 4.7, p < 0.05. In addition, GSTT1 and GSTT1 null genotype was strongly associated with stroke predisposition with OR = 8.30 and RR = 2.25, p < 0.0001. We conclude that there is a possible strong association between the VWF-T > C, TNF-alpha G > A, GSTT1 gene variants and ischemic stroke susceptibility in the Saudi population. However, future well-designed and large-scale case-control studies on protein-protein interactions and protein functional studies are required to verify these findings and examine the effects of these SNPs on these proteins.

Hidden behind thromboinflammation: revealing the roles of von Willebrand factor in sickle cell disease pathophysiology.

This review provides an update on the pathophysiology of sickle cell disease (SCD) with a particular focus on the dysregulation of the von Willebrand factor (VWF) - ADAMTS13 axis that contributes to its pathogenesis. In discussing recent developments, we hope to encourage new and ongoing discussions surrounding therapeutic targets for SCD. Within the last 5 years, the role of VWF in the pathophysiology of SCD has been further elucidated and is now a target of study in ongoing clinical trials. The pathophysiology of SCD is multifaceted, as it involves systemwide vascular activation, altered blood rheology, and the activation of immune responses and coagulative pathways. The presence of VWF in excess in SCD, particularly in its largest multimeric form, greatly contributes to its pathogenesis. Understanding the molecular mechanisms that underly the presence of large VWF multimers in SCD will provide further insight into the pathogenesis of SCD and provide specific targets for therapy.

Spatiotemporal profile of neutrophil extracellular trap formation in a mouse model of ischemic stroke

BackgroundThromboinflammatory processes modulate the complex pathophysiology of cerebral ischemia-reperfusion (I/R) injury in ischemic stroke, but the exact underlying mechanisms remain poorly understood. Emerging evidence indicates that neutrophil extracellular traps (NETs) might play an important role in the thromboinflammatory cascade. In addition, the link between von Willebrand factor (VWF) and neutrophil recruitment in the ischemic brain might promote thromboinflammation, possibly by the formation of NETs. ObjectivesTo study NET formation in a murine model of cerebral I/R injury in ischemic stroke. MethodsThe filament–induced transient middle cerebral artery occlusion model was used to induce 60 minutes of focal cerebral ischemia after which reperfusion was allowed. At different time points postischemia, NETs were identified in the ischemic mouse brain using quantitative immunofluorescence microscopy. ResultsNETs could be identified in the ipsilateral brain hemisphere. Interestingly, NETs could already be detected at 6 hours poststroke. Their presence increased at 12 hours, was highest at 24 hours, and decreased again 48 hours postischemia. Remarkably, NETs were predominantly localized within the brain vasculature postischemia, suggesting that NETs play a role in secondary microthrombosis. Strikingly, NET formation was significantly decreased in VWF–deficient mice compared to littermate wild-type mice 24 hours postischemia, indicating a possible role for VWF in promoting NETosis in the ischemic brain. ConclusionThis study identified the spatiotemporal profile of NET formation in a mouse model of cerebral I/R injury in ischemic stroke. NETs, potentially in combination with VWF, might be attractive targets for the development of novel therapeutic strategies in ischemic stroke treatment.

The mechanistic and structural role of von Willebrand factor in endotoxemia-enhanced deep vein thrombosis in mice

BackgroundAlthough the concept of immunothrombosis has established a link between inflammation and thrombosis, the role of inflammation in the pathogenesis of deep vein thrombosis remains to be fully elucidated. Further, although various constituents of venous thrombi have been identified, their localizations and cellular and molecular interactions are yet to be combined in a single, multiplexed analysis. ObjectivesThe objective of this study was to investigate the role of the von Willebrand factor (VWF) in inflammation-associated venous thrombosis. We also performed a proof-of-concept study of imaging mass cytometry to quantitatively and simultaneously analyze the localizations and interactions of 10 venous thrombus constituents. MethodsWe combined the murine inferior vena cava stenosis model of deep vein thrombosis with the lipopolysaccharide model of endotoxemia. We also performed a proof-of-concept study of imaging mass cytometry to assess the feasibility of this approach in analyzing the structural composition of thrombi. ResultsWe found that lipopolysaccharide-treated mice had significantly higher incidences of venous thrombosis, an effect that was mitigated when VWF was inhibited using inhibitory αVWF antibodies. Our detailed structural analysis also showed that most thrombus components are localized in the white thrombus regardless of endotoxemia. Moreover, although endotoxemia modulated the relative representation and interactions of VWF with other thrombus constituents, the scaffolding network, comprised VWF, fibrin, and neutrophil extracellular traps, remained largely unaffected. ConclusionsWe observe a key role for VWF in the pathogenesis of inflammation-associated venous thrombosis while providing a more comprehensive insight into the molecular interactions that constitute the architecture of venous thrombi.

Investigating the Role of Von Willebrand Factor (VWF) in Modulating In Vivo angiogenesis in VWF-Deficient Mice

Background: Previous studies have demonstrated the negative regulatory role of von Willebrand Factor (VWF) in angiogenesis involving extracellular and intracellular pathways that promote vascular endothelial growth factor (VEGF) signaling. These findings have provided direct evidence for the longstanding association between inherited and acquired abnormalities of VWF and the formation of angiodysplastic lesions, which continue to remain a major challenge. Understanding the role of VWF in angiogenesis could reveal new therapeutic targets that may lead to improved patient management strategies. Aim: To examine the impact and mechanisms of localized VWF replacement on in vivo angiogenesis in a VWF-deficient mouse model. Methods: Three separate experiments were carried out in 10 to 12-week old C57Bl/6 VWF-/- mice of both sexes. In all experiments plugs were excised after seven days of incubation and processed for hematoxylin and eosin (H&E) and immunohistochemical staining (IHC) to assess vessel formation and vascular permeability/maturity, except for the directed in vivo angiogenesis assay (DIVAA) where there was technical difficulty in obtaining histological sections. In the first experiment, DIVAA was employed to decrease inter-assay variability. Angioreactors containing Matrigel mixed with fibroblast growth factor (FGF), VEGF and varying doses of recombinant VWF (rVWF, VONVENDI®) were implanted subcutaneously in the right back flank of mice. Similar angioreactors without rVWF were implanted in the left back flank of mice as a control (N=15, 3 per dose group). In the second experiment the in vivo Matrigel plug assay was used to enable histological evaluation of plugs. 300 μL of Matrigel mixed with FGF, VEGF and rVWF at 0.5IU/ml and 10.0IU/ml, was injected subcutaneously in the right back flank of each mouse based on dose group. In the left back flank, an equal volume of Matrigel without rVWF was injected as a control (N=12, 6 per dose group of rVWF). The setup of the last experiment was similar to the second, however, Matrigel was supplemented with normal endothelial-colony-forming cells (ECFCs) as the source of localized VWF in place of rVWF, in a titration curve of cell numbers (1 x 105, 5 x 105, 1 x 106 cells; N=15, 3 per dose group). Results: Generally, there was a dose response gradient across all three experiments, with higher doses of rVWF or ECFC titres yielding more pronounced effects. In comparison to the lightly coloured angioreactors from the experimental group (supplemented with rVWF), those from the control group were dark red in colour indicating the presence of more vessels and erythrocytes in the Matrigel. No clear differences were observed between plugs that received rVWF at 0.5 IU/ml and those that did not, both grossly and histologically. Most plugs with 10 IU/ml of rVWF appeared lighter in colour compared to those without rVWF. A similar pattern was observed on H&E staining with sections from plugs supplemented with rVWF showing fewer capillaries and red cells, compared with plugs that had only growth factors (Figure 1A). In line with these observations, IHC quantitation of endothelial cells (ECs), pericytes and smooth muscle cells showed a decrease in capillary formation and vessel maturity in rVWF supplemented plugs, although this did not reach significance (Figure 1B). Compared to plugs that had ECFCs, those without ECFCs were dark red in colour, indicating the presence of more mature vessels with red cells. H&E staining of control plugs showed increased cellular infiltrate and capillary formation compared to those supplemented with ECFCs. Immunostaining of control Matrigel plugs also showed increased vascularization and maturity of vessels as evidenced by higher signals for neural/glial antigen 2 (NG2) stain for pericytes and alpha-smooth muscle actin (ASMA) which stains smooth muscle, compared to plugs with ECFCs across all groups. Conclusion: Despite clear differences observed in the gross images of plugs, no significant differences were seen following microscopic quantitation. This was possibly due to the small sample size per group and the marked variability between data points. However, considering the data reported above, the findings appear to highlight a potential inhibitory role of VWF in angiogenesis. Further experimentation is required to establish whether localized VWF can reverse the proangiogenic phenotype observed in VWF-deficient mice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Von Willebrand factor and cancer: Another piece of the puzzle

Von Willebrand factor and cancer: Another piece of the puzzle

Determining the role of von Willebrand factor in thrombotic post transplantation complications using ex vivo lung perfusion system

Background and Aims : A major complication of lung transplantation is thrombosis, which may lead to allograft failure. Increased production of procoagulant molecules, such as von Willebrand factor (VWF), is a significant risk factor for thrombus formation. VWF is a pro-coagulant glycoprotein expressed only in endothelial cells and megakaryocytes, which mediates adhesion of platelets to the endothelium/sub-endothelium. External stimuli, including hypoxia can upregulate VWF. Since during organ-transplantation donor organs are under hypoxic conditions, we explored whether this may lead to alterations in VWF expression, and whether ex vivo lung perfusion (EVLP) as an innovative method for organ preservation prior transplantation can moderate the effect of VWF upregulation and its thrombogenic consequences.

Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) has a high morbidity and mortality rate worldwide, and its growth and metastasis require angiogenesis. The density of microvessels in LUAD is positively correlated with metastasis and recurrence. Von Willebrand factor (VWF) is a multifunctional glycoprotein in blood plasma. Recent evidence shows that VWF inhibits angiogenesis through regulation of angiopoietin-2 (Ang-2) and integrin αvβ3. LUAD patients exhibit an increase in the plasma VWF/ADAMTS-13 ratio. Gene expression profiles of LUAD tissues indicate that VWF is differentially expressed in LUAD tissues compared to normal tissues. GATA binding protein 3 (GATA3) transcription factor may mediate VWF expression in LUAD. In this review, we summarize the role of VWF in LUAD and its regulatory mechanisms. We also discuss the potential of VWF as a diagnostic indicator and therapeutic target of LUAD.

The Role of Von Willebrand Factor in the Pathogenesis of Pulmonary Vascular Thrombosis in COVID-19.

The increased plasma levels of von Willebrand factor (VWF) in patients with COVID-19 was reported in many studies, and its correlation with disease severity and mortality suggest its important role in the pathogenesis of thrombosis in COVID-19. We performed histological and immunohistochemical studies of the lungs of 29 patients who died from COVID-19. We found a significant increase in the intensity of immunohistochemical reaction for VWF in the pulmonary vascular endothelium when the disease duration was more than 10 days. In the patients who had thrombotic complications, the VWF immunostaining in the pulmonary vascular endothelium was significantly more intense than in nonsurvivors without thrombotic complications. Duration of disease and thrombotic complications were found to be independent predictors of increased VWF immunostaining in the endothelium of pulmonary vessels. We also revealed that bacterial pneumonia was associated with increased VWF staining intensity in pulmonary arterial, arteriolar, and venular endothelium, while lung ventilation was an independent predictor of increased VWF immunostaining in arterial endothelium. The results of the study demonstrated an important role of endothelial VWF in the pathogenesis of thrombus formation in COVID-19.

Investigation of the Role of Von Willebrand Factor in Shear-Induced Platelet Activation and Functional Alternation Under High Non-Physiological Shear Stress

Investigation of the Role of Von Willebrand Factor in Shear-Induced Platelet Activation and Functional Alternation Under High Non-Physiological Shear Stress

What is the role of Von Willebrand factor in chronic hepatitis B virus infection to hepatocellular carcinoma: a review article

Von Willebrand factor (VWF) is a glycoprotein synthesized and secreted by vascular endothelial cells and megakaryocytes, found on plasma surface, endothelial cells, and α-granule of platelets. VWF can be interacted with collagen and platelet membrane glycoproteins GPIb and GPIb-IIa and play an important role in platelet adhesion and aggregation. Growing research evidence suggests that VWF also mediates the prevention or protesting of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients from several clinical studies. While the mechanism of VWF in HCC protection or protest is still unclear, further study is required. This article aims to rationalize the role of VWF in the development of HCC, and the functional domain of VWF in cancer as well as cross-talking with platelets and miRNAs. This article also looks forward to the future development and challenges of VWF research.

Relationship between the D-dimer and von Willebrand factor levels and the development of gastrointestinal bleeding in patients with stable coronary artery disease: data from the registry of long-term antithrombotic therapy REGATTA-1

Aim. To study the role of von Willebrand factor (VWF) and D-dimer (DD) as predictors of upper gastrointestinal bleeding (GIB) in patients with stable coronary artery disease (CAD).Material and methods. The study included patients with stable CAD who are members of the prospective registry of long-term antithrombotic therapy (REGATTA-1) (ClinicalTrials.gov Identifier: NCT04347200). The primary endpoints were actionable GIBs (Bleeding Academic Research Consortium type 2-5). Cut-off points for DD and VWF were determined by ROC analysis. The predictive significance of an increase in VWF and DD was assessed by the logistic regression.Results. The study included 408 patients (men, 77,5%; mean age, 61,3±10,8 years). The median follow-up period was 2,5 [1,1-14,7] years. DD was determined in all patients, including 36 patients with GIB, while VWF — in 169 patients (28 patients with GIB). An increase in DD &gt;928 ng/ml was an independent predictor of GIB, including taking into account clinical risk factors (odds ratio (OR), 3,26 [95% confidence interval (CI), 1,43-7,42] (p=0,0047), or the previously developed REGATTA scale score (OR, 3,73, 95% CI: 1,65-8,43 (p=0,0015)). VWF &gt;105% was also an independent predictor of GIB (OR, 14,02; 95% CI: 1,41-139,42 (p=0,023)); in the REGATTA scale model — OR 11,3, 95% CI: 1,43-88,83 (p=0,021). The increase in both markers was most unfavorable, since the proportion of those with GIB was 41,4%, while among patients with normal DD and increased VWF — 14,9%, and with low values of both markers — 0%. OR of GIB in patients with an increase in both markers was 4,1 (95% CI: 1,6-10,3 (p=0,003)).Conclusion. In patients with stable CAD, an increase in VWF and DD was associated with an increase in GIB risk regardless of the presence of clinical risk factors.

Association of von Willebrand factor Ag-to-ADAMTS13 ratio with early sepsis-related mortality

IntroductionSepsis is a highly complex syndrome with highly heterogeneous clinical manifestations, which makes it difficult to detect and treat. Von Willebrand factor (vWF) functions differently depending on its multimeric size and adhesive properties, which are regulated by ADAMTS 13. Thus, a decrease in ADAMTS 13 activity results in the persistence of ultralarge vWF and the formation of microvascular thrombi, ischaemia, and organ failure. The aim of the study was to identify the role of von Willebrand factor antigen-to-ADAMTS 13 ratio in predicting early sepsis-related mortality.Material and methodsThis is a cohort of 70 sequentially selected adults with sepsis. The patients were classified into two groups: A (survivors) and B (non-survivors) based upon their survival within 7 days of hospital admission.ResultsVWF Ag, ADAMTS13, and vWF/ADAMTS13 ratio were significant predictors of early hospital mortality. For vWF Ag at a cut-off level of ≥ 3560 ng/l, sensitivity was 76% and specificity was 88.9%. For ADAMTS at a cut-off level of ≤ 210 ng/l, sensitivity was 84% and specificity was reported as 68.9%. For vWF/ADAMTS ratio at a cut off level of ≥ 17, sensitivity was 80% and specificity was 84.4%. There was a statistically highly significant positive correlation between non-survival and levels of vWF and vWF/ADAMTS 13 ratio, and there was a statistically highly significant negative correlation between non-survival and ADAMTS 13 level.ConclusionsHigh vWF/Ag and vWF/Ag/ADAMTS13 ratios on day 1 of admission are associated with increased early (7 days) sepsis-related mortality.