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Von Willebrand Factor and Cardiovascular Disease: From a Biochemical Marker to an Attractive Therapeutic Target
Abstract
Background:
Despite recent advances, there is still an unmet need in antithrombotic therapy. New drugs have to overcome old targets, looking for new complementary strategies to counteract thrombus formation and propagation. Since its initial recognition in the 50's, von Willebrand Factor (VWF) has proved to be a contributor in clot formation. The contribution of VWF to platelet adhesion and aggregation is pivotal at high shear rates (i.e. microcirculation and critical artery stenosis), where globular-inactive-VWF elongates in a long chain-active conformation. Particularly, at sites of plaque erosion/disruption the activation of VWF may contribute critically to post-stenotic thrombus formation. In this context, VWF is a potential target of antithrombotic therapies. The plasma concentration of VWF increases in high risk population and predicts cardiovascular (CV) outcome. VWF demonstrates an emerging role in different clinical settings; for example, in valvular heart disease where it has been recently proposed as a new fluido-dynamic marker of disease severity and a predictor of successful correction. Drugs used in daily clinical practice (LMWHs, statins, N-acetylcysteine, glycoprotein IIb/IIIa inhibitors) may have an unselective antagonism on the VWF-pathway. Recently, several "tailor-made" inhibitors of VWF have been investigated. In animal models and clinical studies monoclonal antibodies, aptamers and nanobodies have been demonstrated to directly interfere with the VWF pathway. These studies proved the powerful antithrombotic property and the acceptable level of safety of this strategy.
Conclusion:
We provide an overview of the drugs that a have a role in VWF-antagonism, illustrating how they might become a potential option to overcome current limitations of antithrombotic therapy.
... Binding a specific amino acid sequence in the A1-domain, heparin can interfere with VWF-GPIb interaction exerting an antiplatelet effect. 22 In patients with arterial thrombosis, low-molecular-weight heparins showed to, directly and indirectly, antagonize VWF with a positive impact on prognosis. 103 Beyond its anticoagulant activity, this anti-VWF effect may at least partly explain the therapeutic effect of heparin on VTE. ...
... N-acetylcysteine, GPIIb/IIIa inhibitors (tirofiban, eptifibatide, and abciximab), and colchicine may also exert anti-VWF effects; however, data on VTE for these drugs are lacking. 22,62,104 The unselective VWF antagonism of routinely used drugs may play a beneficial role in arterial and venous thrombosis. However, this effect is hard to measure in terms of benefit/ risk ratio, and definite conclusions cannot be drawn yet. ...
... To further clarify the potential advantage of the anti-VWF therapy in thrombotic disorders, selective antagonists have been tested in preclinical and clinical studies. 22,[105][106][107][108][109][110][111][112] ...
Venous thromboembolism (VTE) is a frequent cause of disability and mortality worldwide. Von Willebrand factor (VWF) is a major determinant of hemostasis and clot formation, in both arteries and veins. Although VWF is mainly known for its role in arterial thrombosis, several studies suggest a pathogenic role for VWF and its regulator ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in venous thrombosis. Nongenetic and genetic factors, including gene mutations and polymorphisms, aging, hormone status, ABO blood groups, and systemic inflammation, have been involved in the modulation of both VTE predisposition and plasma levels of VWF. In several clinical settings, including inflammatory disease and cancer, VWF and ADAMTS-13 are currently investigated as possible determinants of vein thrombosis. These data indicate VWF as a potential therapeutic target in the management of VTE. Several studies report unselective antagonism of VWF for drugs used in daily clinical practice, including heparin and statins. Selective inhibition of VWF pathway has recently been tested in animal models of arterial and venous thrombosis as a novel therapeutic strategy to prevent platelet aggregation and thrombosis, promote vein lumen recanalization, and improve vein valve competency with excellent safety profile. In this review, we summarize the role of VWF in VTE, focusing on clinical and potential therapeutic implications.
... Furthermore, increased exposure of procoagulant/proinflammatory factors on the atrial endocardium (i.e. von Willebrand factor [14][15][16] and tissue factor [10]) and reduced anticoagulant factors (i.e. thrombomodulin) [17] have been reported, suggesting the co-presence of local and systemic prothrombotic patterns [10,15]. ...
... von Willebrand factor [14][15][16] and tissue factor [10]) and reduced anticoagulant factors (i.e. thrombomodulin) [17] have been reported, suggesting the co-presence of local and systemic prothrombotic patterns [10,15]. A state of platelet hyper-reactivity and hypofibrinolysis has also been described, with increased levels of tissue plasminogen activator and plasminogen activator inhibitor-1, which are also associated with outcome [10]. ...
Major thromboembolic complications in patients with atrial fibrillation, secondary to thromboembolism from the left atrium or the left atrial appendage, are a major concern because of their burden of disabling stroke and mortality. To date, non-vitamin K antagonist oral anticoagulants (NOACs) are considered the first-line strategy in most patients with atrial fibrillation receiving chronic anticoagulation, as they have major advantages compared with vitamin K antagonists, including minimization of intracranial bleeding risk. Although several studies and post-hoc analyses have provided initial data on the use of NOACs in patients with documented atrial and/or left atrial appendage thrombosis, the benefit of NOACs in these patients has not been fully elucidated. In this review, we reappraise current evidence supporting the use of NOACs in patients with established atrial and/or left atrial appendage thrombosis, discussing potential mechanisms favouring the use of a NOAC-based strategy in this special setting.
... 25 In light of these features, vWF has recently been proposed as a new hemodynamic biomarker in patients with VHD, able to monitor real-time valve replacement (surgical or percutaneous) procedures. [26][27][28] von Willebrand Factor and AvWS in Aortic Valve Stenosis: Pathophysiological Basis ...
... 22 Enhanced clearance in HMW-vWF causes AvWS with impaired primary hemostasis due to the production of low-weight vWF molecules that are reduced in size and less hemostatically competent. 23,28 It has been reported that 20% to 70% of patients with moderate-to-severe AS have a significant reduction in the percentage of HMW-vWF multimers 30,31 and in up to 20% mucocutaneous and GI bleeding occurs. 32 In transcatheter aortic valve replacement (TAVR) cohorts, studies reported vWF abnormalities in 42% to 48% of patients. ...
von Willebrand Factor (vWF) is a well-known mediator of hemostasis and vascular inflammation. Its dynamic modulation in the bloodstream, according to hemodynamic conditions, makes it an appealing biomarker in patients with valvular heart disease (VHD). Recent studies highlight the close connection between vWF and VHD, with possible implications in the pathogenesis of VHD, promoting valve aging and calcification or favoring the development of infective endocarditis. Moreover, vWF has been recently proposed as a new diagnostic and prognostic tool in patients with valve stenosis or regurgitation, showing a strict correlation with severity of valve disease, outcome, and bleeding (Heyde syndrome). A novel role for vWF is also emerging in patients undergoing percutaneous or surgical valve repair/replacement to select and stratify patients, evaluate periprocedural bleeding risk, and detect procedural complications. We also report our single-center experience, suggesting, for the first time, possible clinical implications for vWF in percutaneous mitral valve repair (MitraClip). This review summarizes recent advances in the role of vWF in VHD with an updated overview going from bench to operating room.
... For instance, Mario et al. have shown that shearinduced platelet aggregation correlated with enhanced vWF concentration among AMI patients [37]. Rutten et al. observed a substantial increase in active vWF levels among individuals experiencing ST-elevation MI for the first time compared to controls (P < 0.0001), emphasizing the central role of vWF in the progression of thrombosis [38]. Moreover, Sergio et al. investigated the prognostic role of hemoglobin decline among patients with acute coronary syndrome (ACS). ...
Background
Acute myocardial infarction (AMI) is characterized by inflammation, oxidative stress, and atherosclerosis, contributing to increased mortality risk. High-density lipoprotein (HDL) takes a crucial part in mitigating atherosclerosis and inflammation through its diverse functionalities. Conversely, fibrinogen is implicated in the development of atherosclerotic plaques. However, the mortality risk predictive capacity of fibrinogen to HDL-cholesterol ratio (FHR) in AMI patients remains unexplored. This research aimed to evaluate the effectiveness of FHR for mortality risk prediction in relation to AMI.
Methods
A retrospective study involving 13,221 AMI patients from the Cardiorenal ImprovemeNt II cohort (NCT05050877) was conducted. Baseline FHR levels were used to categorize patients into quartiles. The assessment of survival disparities among various groups was conducted by employing Kaplan‒Meier diagram. Cox regression was performed for investigating the correlation between FHR and adverse clinical outcomes, while the Fine-Gray model was applied to evaluate the subdistribution hazard ratios for cardiovascular death.
Results
Over a median follow-up of 4.66 years, 2309 patients experienced all-cause death, with 1007 deaths attributed to cardiovascular disease (CVD). The hazard ratio (HR) and its 95% confidence interval (CI) for cardiac and all-cause death among individuals in the top quartile of FHR were 2.70 (1.99–3.65) and 1.48 (1.26–1.75), respectively, in comparison to ones in the first quartile, after covariate adjustment. Restricted cubic spline analysis revealed that FHR was linearly correlated with all-cause mortality, irrespective of whether models were adjusted or unadjusted (all P for nonlinearity > 0.05).
Conclusion
AMI patients with increased baseline FHR values had higher all-cause and cardiovascular mortality, regardless of established CVD risk factors. FHR holds promise as a valuable tool for evaluating mortality risk in AMI patients.
Trial registration
The Cardiorenal ImprovemeNt II registry NCT05050877.
... Furthermore, recent studies are suggesting hemostatic factors, including the Von Willebrand Factor (VWF), in the development, progression, and resolution of deep vein thrombosis (DVT), including UEDVT, which can include novels aspects to consider in the management of this condition [17,18]. Other acquired causes for thrombophilia, which we assessed in this study, can also contribute to this disorder including COVID-19 infection [19,20] or vaccinations [21,22], smoking [23], and repetitive muscle activity [24,25]. ...
Background
Effective treatment of upper extremity deep vein thrombosis (UEDVT) is crucial to prevent further complications. Various treatments, including percutaneous mechanical thrombectomy (PMT), catheter-directed thrombolysis (CDT), decompression surgery, and venoplasty are suggested for UEDVT. However, no prospective study has yet favored any of these treatments. This study presents a review of our experience with CDT followed by balloon venoplasty in patients with acute primary UEDVT.
Methods
We enrolled all patients diagnosed with acute UEDVT from January 2020 to June 2021. Subjects with UEDVT due to secondary causes like malignancies, indwelling catheters, or leads were excluded. CDT was performed through brachial vein access, using a perfusion catheter, and rt-PA administration. Balloon venoplasty was performed if the treated segment had remaining stenosis after CDT. Patients were followed up at the vein clinic for any signs and symptoms in the upper extremity and lifestyle changes. Follow-up ultrasonography was done 12 months after discharge.
Results
Twelve patients with a mean age of 41.08 ± 14.0 years were included in the study. The mean duration of CDT was 25.00 ± 10.56 h. After CDT, all patients had remaining occlusions, with seven having more than 50% remaining stenosis. However, after balloon venoplasty, no patient had significant (more than 50%) stenosis. There was no serious complication after both procedures. Patients were followed up for a mean duration of twelve months after their admission, with a mean time of maintenance anticoagulation was 10.73 ± 5.77 months. Only one patient had recurrent symptoms in his target limb which required a decompression surgery, while the rest were free of symptoms in their treated extremity. No subject developed pulmonary emboli (PE) during admission or the follow-up period. There was no evidence of hospital readmission for any reason. Upper extremity color-doppler sonography of the patients at twelve months after their procedure showed normal venous flow without any significant stenosis in 8 (66.7%), and partially normal flow with patent target vein in 4 (33.3%) patients.
Conclusions
CDT followed by balloon venoplasty may be an effective treatment for selected patients with acute primary UEDVT, providing desirable long-term results and potentially avoiding the need for decompression surgery in the short or long term.
... CRP and interleukin-8), which have been considered meaningful predictors of ASCVD development. 12,[24][25][26] The results of the Thrombotic RIsk Progression (TRIP) study demonstrated that a distinct pathophysiological state of heightened platelet function, hypercoagulability and inflammation marks the presence of unstable ASCVD requiring intervention. In this study, a significant relationship was found between two important biologic markers, PFCS and CRP, as well as between them and other biomarkers such as fibrinogen, von Willebrand factor, and plasminogen activator inhibitor (PAI)-1. ...
Aims:
Atherothrombotic events are influenced by systemic hypercoagulability and fibrinolytic activity. The present study evaluated thrombogenicity indices and their prognostic implications according to disease acuity.
Methods and results:
From the consecutive patients undergoing percutaneous coronary intervention (PCI), those with thrombogenicity indices (n = 2705) were grouped according to disease acuity [acute myocardial infarction (AMI) vs. non-AMI]. Thrombogenicity indices were measured by thromboelastography (TEG). Blood samples for TEG were obtained immediately after insertion of the PCI sheath, and TEG tracing was performed within 4 h post-sampling. Major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were evaluated for up to 4 years. Compared with non-AMI patients, AMI patients had higher platelet-fibrin clot strength [maximal amplitude (MA): 66.5 ± 7.8 vs. 65.3 ± 7.2 mm, P < 0.001] and lower fibrinolytic activity [clot lysis at 30 min (LY30): 0.9 ± 1.8% vs. 1.1 ± 1.9%, P < 0.001]. Index AMI presentation was associated with MA [per one-mm increase: odds ratio (OR): 1.024; 95% confidence interval (CI): 1.013-1.036; P < 0.001] and LY30 (per one% increase: OR: 0.934; 95% CI: 0.893-0.978; P = 0.004). The presence of high platelet-fibrin clot strength (MA ≥68 mm) and low fibrinolytic activity (LY30 < 0.2%) was synergistically associated with MACE occurrence. In the multivariable analysis, the combined phenotype of 'MA ≥ 68 mm' and 'LY30 < 0.2%' was a major predictor of post-PCI MACE in the AMI group [adjusted hazard ratio (HR): 1.744; 95% CI: 1.135-2.679; P = 0.011], but not in the non-AMI group (adjusted HR: 1.031; 95% CI: 0.499-2.129; P = 0.935).
Conclusion:
AMI occurrence is significantly associated with hypercoagulability and impaired fibrinolysis. Their combined phenotype increases the risk of post-PCI atherothrombotic event only in AMI patients. These observations may support individualized therapy that targets thrombogenicity for better outcomes in patients with AMI.
Clinical trial registration:
Gyeongsang National University Hospital (G-NUH) Registry, NCT04650529.
... Subsequently, the binding of plasma VWF to platelet GPIIb/IIIa on one side and to the exposed subendothelial collagen through its A3 domain on the other, contributes to thrombus growth [28]. This is particularly important for atherothrombosis, where arterial obstructions cause high blood flow velocity and shear [105]. ...
Platelets are the main effectors of the thrombotic events occurring at a ruptured atherosclerotic plaque and therefore antiplatelet agents are the mainstay of antithrombotic treatment for the prevention of myocardial infarction, atherotrombotic ischemic stroke and critical limb ischemia due to the thrombotic occlusion of the peripheral arteries. Despite great progress in antiplatelet agents over the last two decades, a number of important unmet medical needs still remain, like insufficient efficacy and a high incidence of hemorrhagic complications. Advances in the knowledge of the molecular mechanisms regulating platelet participation in hemostasis and in thrombosis and progress in pharmaceutical design have allowed to identify new drugs for established antiplatelet targets and novel targets for the development of new agents. Among the latter, several innovative approaches have already proceeded to clinical testing, like GPVI antagonism, PAR4 antagonism, PI3K inhibition, and some preliminary results seem promising. Here we review the pharmacologic approaches to platelet inhibition currently available and in development for their effects on platelet activation in vitro and on thrombosis in animal models and in humans. An ideal antithrombotic agent should selectively target events crucial for pathological thrombus formation without affecting hemostasis, an objective so far not achieved: if one or more of the novel agents in development will reach this goal this will represent a great step forward in the prevention of ischemic cardiovascular events.
... [33] Moreover, vWF levels are associated with CAD, according to the ECAT study and increased incidence of myocardial infarction. [34][35][36] In a pilot, case-control study, patients with chronic cerebrovascular disease had higher vWF levels. [37] Evidence also suggests patients with HF disease tend to have higher level of vWF. ...
Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial damage and inflammation. In addition, von Willebrand factor (vWF) has been discovered as a biomarker of endothelial dysfunction. Therefore, the study aims to investigate the association between vWF level and HFpEF. Moreover, we analyzed a potential correlation between vWF and inflammatory factors, such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-6.
We recruited altogether 272 hospitalized patients from The Fifth Affiliated Hospital of Xinjiang Medical University, 88 of whom were HFpEF patients, 88 were non-heart failure patients, and 96 were healthy controls from the medical examination center of the hospital. Enzyme-linked immunosorbent assay and double antibody sandwich immunochromatography were used for testing vWF, tissue plasminogen activator, galectin-3, nitric oxide, TNF-α, IL-6, and CRP.
The HFpEF group’s levels of vWF, IL-6, TNF-α, CRP, tissue plasminogen activator, galectin-3, and nitric oxide were statistically higher than those of non-heart failure and healthy control ones (F = 403.563, 21.825, 20.678, 39.609, 35.411, 86.407, 74.605; all P = .000). the highest level of vWF was observed in class IV (New York Heart Association) of HFpEF patients and the significant difference is <.05 (P < .001). An increasing level of vWF were shown in groups (CRP: CRP >3 mg/L group and CRP ≤3 mg/L group; IL-6: IL-6 <7.0 pg/mL group and IL-6 ≥7.0 pg/mL group; TNF-α: TNF-α <5.5 pg/mL group and TNF-α ≥5.5 pg/mL group) with higher level of IL-6, TNF-α, CRP. A multiple regression analysis regarding the relationship of vWF and inflammation markers was performed among the HFpEF patients. Further, statistical significance of the analysis remained after adjusting variables such as body mass index, low-density lipoprotein cholesterol, total cholesterol, coronary artery disease, and type 2 diabetes mellitus (β = 0.406, t = 4.579, P < .001; β = 0.323, t = 3.218, P < .001; β = 0.581, t = 6.922, P < .001).
Our study shows that elevated vWF levels are associated with HFpEF, and it may serve as a potential biomarker for HFpEF severity. We also found that increased vWF levels are positively correlated to IL-6, TNF-α, and CRP, which may provide a clue for further researching the pathogenesis of HFpEF.
... In particular, the fibrillating atrium and LAA present the so-called "rough" endocardium, typically edematous, inflamed, fibrotic and dotted with thrombotic formations, as a result of mechanical, oxidative and inflammatory stressors [17,18]. Moreover, a higher exposure of procoagulant/proinflammatory factors on the atrial endocardium (e.g., von Willebrand factor [19] and tissue factor [18]) to the flowing blood, and reduced anticoagulant factors (e.g., thrombomodulin) [20] have been described, suggesting the coexistence of both local and systemic prothrombotic patterns. Increased platelet reactivity and impaired endogenous fibrinolysis have also been reported in AF [18]. ...
Available evidence on left atrial (LA) thrombus dissolution in patients with atrial fibrillation (AF) largely refers to the use of vitamin K antagonist oral anticoagulants (VKAs), showing >50% thrombus resolution over a 4-week to 12-month treatment period. Available data on non-vitamin K antagonist anticoagulants (NOACs) in this setting are limited and derive from isolated case reports or observational small-sized investigations with dabigatran, rivaroxaban or apixaban. The aim of this study was to investigate the extent of thrombus resolution with edoxaban therapy in patients with AF and LA thrombosis. We conducted a prospective, observational, open-label pilot study in seven Italian institutions. We included a total of 25 patients with non-valvular AF and LA (or left atrial appendage (LAA)) thrombosis, documented by transesophageal echocardiography (TEE). All patients received edoxaban OD treatment (n = 23 on 60 mg daily; n = 2 on 30 mg daily) and underwent TEE examination after 4 weeks. The primary endpoint was the percentage of patients with complete thrombus resolution by TEE imaging at 4 weeks. The mean age of the study population was 68.3 ± 10.8 years with a female population of 16%. AF was permanent in all cases, with a mean arrhythmia duration of 4.3 ± 1.7 years. CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.5 and 1.9 ± 1.1, respectively. We were able to demonstrate a complete thrombus resolution in 14 patients (56%) at 4 weeks. In patients with residual atrial thrombosis (n = 11), we observed a 15.4 ± 14.9% reduction in the thrombus area from baseline. As compared with patients without thrombus dissolution, those with thrombus resolution had a numerically lower-indexed LA diameter (27.9 ± 9.3 vs 34.8 ± 16.1 mm/m2), a smaller maximum thrombus area at baseline (45.5 ± 44.6 vs 63.9 ± 43.5 mm2), a higher left ventricular ejection fraction (47.4 ± 21.0% vs 38.4 ± 20.6%) and higher maximum LAA flow velocities (26.3 ± 15.2 vs 19.3 ± 10.0 cm/s). Figures on the percentage of thrombus resolution in this study are comparable to those reported in the literature for the other OACs. We conclude that, in patients with AF, the use of edoxaban is associated with a >50% resolution of atrial thrombus at 4 weeks, similar to studies using VKAs and the other NOACs (ClinicalTrials.gov identifier number: NCT034899395).
... Increased levels of disintegrins and metalloproteases with a thrombospondin type 1 motif, member 13 (ADAMTS-13), and VWF are causative for cardiovascular events in SLE patients, as well as venous thrombosis. An increase in VWF concentration in high-risk population can predict cardiovascular (CV) outcomes [18][19][20]. In addition, dyslipidemia is of great significance in the atherosclerosis of SLE patients [21,22]. ...
Background:
To assess the value of peptidoglycan recognition protein 2 (PGLYRP2) in assessing the disease activity and lipid metabolism in patients with systemic lupus erythematosus (SLE).
Methods:
SLE patients with stable disease (n = 15), active lupus nephritis (LN) (n = 15) and neuropsychiatric systemic lupus erythematosus (NP-SLE) (n = 15) admitted to Northern Jiangsu People's Hospital (Jiangsu, China) in 2019-2020 were recruited. In addition, volunteers with matched age and sex (n = 15) were enrolled as controls. The level of PGLYRP2 in the serum and its expression in peripheral blood mononuclear cells (PBMCs) were measured. The link between PGLYRP2 level and clinical parameters (including lipid profile) was described.
Results:
Serum PGLYRP2 level in SLE cases exceeded that in healthy volunteers (3938.56 ± 576.07 pg/mL), and significantly higher in active LN (5152.93 ± 446.13 pg/mL) and NP-SLE patients (5141.52 ± 579.61 pg/mL). As shown by quantitative real-time PCR results, the expression of PGLYRP2 in PBMCs of SLE patients with active LN and NP-SLE surpassed that in healthy volunteers (P < 0.01). Receiver operating characteristic (ROC) curves demonstrated that PGLYRP2 was capable of distinguishing stable SLE from active LN (AUC = 0.841, 95%CI = 0.722-0.960, P = 0.000). PGLYRP2 level positively correlated with SLEDAI of SLE patients (r = 0.5783, P < 0.01). Moreover, its level varied with serological and renal function parameters (complement 3, complement 4, estimated glomerular filtration rate and 24-h urine protein) and immunoglobulin A (IgA) of SLE. A potential correlation between PGLYRP2 level and lipid profile (HLD-c, Apo-A1 and Apo B/A1) was determined in SLE patients. The linear regression analysis indicated SLEDAI as an independent factor of PGLYRP2 level, with a positive correlation in between (P < 0.05).
Conclusions:
Serum PGLYRP2 level significantly increases in SLE patients, and is positively correlated to SLEDAI. Moreover, serum PGLYRP2 level is correlated with renal damage parameters and the abnormal lipid profile of SLE. PGLYRP2 could be used to predict SLE activity, dyslipidemia and cardiovascular disease risks in SLE patients.
... The authors suggested that asprosin directly protects cardiomyocytes by improving mitochondrial respiration in response to hypoxia [28]. Moreover, it has been shown that other adipokines such as adiponectin, Von Willebrand factor and Lp(a) had relation with CAD [29][30][31]. ...
Background
Coronary artery disease (CAD) is considered as a multi-faceted chronic inflammatory disease involving reduced blood supply to the myocardium as a result of accumulating lipids in the atrial walls. Visceral adiposity with disrupted release of adipokines play a key role in its pathogenesis. Asprosin is a newly identified fasting-induced glucogenic adipokine that has been related with metabolic disorders such as type II diabetes mellitus and polycystic ovary syndrome. The preset study sought to assess circulating asprosin in context of CAD.
Methods
In this study, serum levels of asprosin were determined in 88 CAD patients and 88 non-CAD healthy controls. Serum IL-6, TNF-α, asprosin and adiponectin were assessed using ELISA kits.
Results: Serum asprosin was found to be higher in CAD patients when compared to non-CAD subjects (7.84 ± 2.08 versus 5.02 ± 1.29 μg/mL, p < 0.001). Similarly, serum TNF-α, and IL-6 elevated in CAD group significantly ( p < 0.001). However, circulating adiponectin diminished in CAD group when compared with non-CAD subjects ( p < 0.001). Moreover, serum asprosin levels directly correlated with BMI, FBG, HOMA-IR, TG and TC. Logistic regression analyses showed that asprosin levels were associated with increased risk of developing CAD (odds ratio: 3.01, 95% CI: 2.16, 4.20 and p < 0.001), after adjusting for potential confounders (age, sex and BMI).
Conclusions
The present study findings suggested a possible relation of serum asprosin with the pathogenesis of CAD, in particular through insulin resistance and dyslipidemia.
... Almost 100 years have passed since the discovery of diseases associated with the impaired metabolism of von Willebrand factor. Since that time it has been shown that this unique glycoprotein, which has many multimeric forms and varies among individuals with respect to glycosylation pattern and polymorphism, plays the crucial role in the normal functioning of an organism and in pathogenesis of many diseases [161]. The von Willebrand factor has been intensively studied over the past years. ...
—
Von Willebrand factor (vWF), the key component of hemostasis, is synthesized in endothelial cells and megakaryocytes and released into the blood as high molecular weight multimeric glycoproteins weighing up to 20 million Daltons. Blood plasma metalloprotease ADAMTS13 cleaves ultra-large vWF multimers to smaller multimeric and oligomeric molecules. The vWF molecules attach to the sites of damage at the surface of arterioles and capillaries and unfold under conditions of shear stress. On the unfolded vWF molecule, the regions interacting with receptors on the platelet membrane are exposed. After binding to the vWF filaments, platelets are activated; platelets circulating in the vessels are additionally attached to them, leading to thrombus formation, blocking of microvessels, and cessation of bleeding. This review describes the history of the discovery of vWF, presents data on the mechanisms of vWF secretion and its structure, and characterizes the processes of vWF metabolism in the body under normal and pathological conditions.
... 2,3 Of note vWF and ADAMTS13 play a key role in various other thrombotic conditions and in cardiovascular diseases. [4][5][6][7] ADAMTS13 deficiency can be secondary to mutations or polymorphisms of the ADAMTS13 gene (9q34) in hereditary TTP (Upshaw Schulman syndrome, Online Mendelian Inheritance in Man number, 274150) 8 or can be acquired through anti-ADAMTS13 antibodies in the majority of adult forms (immune TTP). 9 TTP is a rare disease with an incidence rate estimated as 1.5-6/million/year, affecting mostly young women. ...
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy secondary to a severely decreased A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats 13 (ADAMTS13) activity, resulting in the formation of widespread von Willebrand factor - and platelet-rich microthrombi. ADAMTS13 deficiency is mainly acquired through anti-ADAMTS13 autoantibodies in adults. With modern standards of care, unresponsive TTP has become rarer with a frequency of refractory/relapsing forms dropping from >40% to <10%. As patients with unresponsive TTP are at increased risk of mortality, prompt recognition and early therapeutic intensification are mandatory. Therapeutic options at the disposal of clinicians caring for patients with refractory TTP consist of increased ADAMTS13 supplementation, increased immunosuppression, and inhibition of von Willebrand factor adhesion to platelets. In this work, we focus on possible therapies for the management of patients with unresponsive TTP, and propose an algorithm for the management of these difficult cases.
... There are some unmeasured factors which may lead to residual bias, such as other biomarkers. For example, von Willebrand factor is associated with incident AF [38]. ...
Background
Frequent supraventricular arrhythmia is associated with increased incidence of atrial fibrillation. However, it is unknown whether the prognostic significance of supraventricular arrhythmia is modified by plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) or troponin T (TnT). This study examined the interrelationships between NT-proBNP, TnT levels and frequent supraventricular arrhythmia, and whether these biomarkers and a measure of frequent supraventricular arrhythmia could improve risk assessment for incidence of AF.
Methods
Supraventricular extrasystoles (SVEs) and supraventricular tachycardias were assessed from 24-h electrocardiograph recordings in 373 individuals initially without AF. Elevated NT-pro-BNP, TnT and SVEs was defined as a measurement in the top quartile of the study population distribution. Incident cases of AF were retrieved by linkage with the Swedish National Patient Register.
Results
During a mean follow-up of 15.4 years, 88 subjects had a diagnosis of AF. After multivariable adjustment, individuals with both elevated NT-proBNP and frequent SVEs had a significantly increased incidence of AF, compared to subjects without elevated NT-proBNP or frequent SVEs (hazard ratio (HR) 4.61, 95% confidence interval (CI) 2.45–8.69), and compared to individuals with either elevated NT-proBNP or frequent SVEs (both P < 0.05). HRs for frequent SVEs alone or elevated NT-proBNP alone were 2.32 (95% CI 1.33–4.06) and 1.52 (95% CI 0.76–3.05), respectively. The addition of NT-pro-BNP and SVEs to a validated risk prediction score for AF, CHARGE-AF, resulted in improved prediction (Harrell’s C 0.751 (95% CI 0.702–0.799) vs 0.720 (95% CI 0.669–0.771), P = 0.015).
Conclusion
Subjects with both elevated NT-proBNP and frequent SVEs have substantially increased risk of AF, and the use of these variables could improve long-term prediction of incident AF.
... VWF has been shown to have an important role in vascular inflammation and thrombus formation [34]. Considering its possible role in atherosclerosis, as well as in predicting cardiovascular events [34,35], increased vWF release could contribute, in particular, to exercise-induced pathological outcomes. Additionally, high-intensity exercise and stenotic arteries may lead to pathological shear stress on the endothelial wall resulting in attenuated nitric oxide production, endothelial dysfunction and a pro-coagulant microenvironment [36,37]. ...
Background
Both exercise and cold exposure increase blood coagulation potential but their combined effects are not known. The purpose of the present study was to assess blood coagulation factors in response to submaximal exercise in the cold environment among patients with stable coronary artery disease (CAD).
Methods
Sixteen men (61.1 ± 7.1 years) with stable CAD participated in three 30-min experimental conditions (seated rest in − 15 °C and exercise in both + 22 °C and − 15 °C) in random order. The employed exercise consisted of brisk walking (66–69% of maximal heart rate). Factor VII (FVII), fibrinogen, D-dimer and von Willebrand factor (vWF) were analyzed from blood samples obtained before, immediately and one hour after each experiment.
Results
On average, FVII activity (95% confidence interval, CI) was 123 (108–143) %, 123 (106–140) %, 121 (103–139) % (baseline, recovery 1, recovery 2), fibrinogen concentration (95% CI) 3.81 (3.49–4.12) g/l, 3.71 (3.34–4.08) g/l, 3.65 (3.26–4.05) g/l, D-dimer concentration (95% CI) 0.42 (0.28–0.56) µg/ml, 0.42 (0.29-.55) µg/ml and 0.39 (0.29–0.49) µg/ml, and vWF activity (95% CI) 184 (135–232) %, 170 (128–212) % and 173 (129–217) % after exercise in the cold. Average FVII activity varied from 122 to 123%, fibrinogen concentration from 3.71 to 3.75 g/l, D-dimer concentration from 0.35 to 0.51 µg/ml and von Willebrand factor activity from 168 to 175% immediately after each three experimental condition.
Conclusions
Our findings suggest that submaximal lower body exercise carried out in a cold environment does not significantly affect blood coagulation parameters among patients with stable CAD.
... To add to that, other studies show that elevated CRP and Lp-PLA2 levels correlate to increased circulating von Willebrand factor (vFW) [26]. vVF is an important regulator of systemic inflammation and thrombosis and its interplay with other inflammatory mediators like Lp-PLA2 may be of great significance in the progression of CAD [27,28]. Recent animal studies also show a favorable effect of darapladib on the preservation of retina-barrier, indicating novel possible treatment options for high risk populations (e.g. ...
Abstract Background Lipoprotein-associated Phospholipase A2 (Lp-PLA2), can exert proinflammatory as well as proatherogenic properties on the vascular wall. The current study sought to evaluate the influence of high Lp-PLA2 levels on indices of arterial wall properties in patients with stable coronary artery disease (CAD). Methods Three hundred seventy-four consecutive patients with stable CAD (mean age 61 ± 11 years, 89% males) were enrolled in this single-center cross-sectional study. Flow-mediated dilation (FMD) was used to assess endothelial function and augmentation index (AIx) of the central aortic pressure was used to assess reflected waves. ELISA was used to determine Lp-PLA2 serum levels. Results After dividing the participants in 3 equal groups based on the tertiles of circulating Lp-PLA2 values, no significant differences were demonstrated between those in the 3rd tertile with Lp-PLA2 values > 138 μg/L, in the 2nd tertile with Lp-PLA2 values between 101 and 138 μg/L and in the 1st tertile (Lp-PLA2 values
... In addition, SGLT2i could enhance lipoprotein clearance through heparan sulfate proteoglycans (HSPGs) and bile acid pathways [21], which could protect against atherosclerosis progression. Besides, vWF, involved in platelet adhesion and aggregation, could be a target of SGT2i [52], however, it needs further experiment validation. ...
Background
Several large clinical trials have confirmed the cardioprotective role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes. However, whether empagliflozin, as an SGLT2i, could alleviate atherosclerosis progression in non-diabetic states remain unknown.
Methods
ApoE-/- mice were fed a Western diet for 12 weeks to induce atherosclerosis. On the 7th week, a group of mice were treated with drinking water containing empagliflozin (10 mg/kg/day), while another group was given normal water. At the 12th week, the whole aortas of each group were harvested. Oil Red O, HE and Movat staining were performed for atherosclerotic lesion area and size. Mouse serum lipid profiles (total cholesterol [TC], triglyceride [TG], low-density lipoprotein-c [LDL], and high-density lipoprotein-c [HDL]), systemic inflammation levels (IL-1β, IL-6 and IL-10), renin-angiotensin-aldosterone system (RAAS) components and sympathetic activity (norepinephrine and neuropeptide Y) indicators were measured by ELISA.
Results
Empagliflozin reduced the atherosclerotic lesion burden (-8.6 %, P = 0.004) at aortic root in ApoE-/- mice. In addition, empagliflozin decreased body weight (-3.27 g, P = 0.002), lipid profiles (TC: [-15.3 mmol/L, P = 0.011]; TG: [-2.4 mmol/L, P < 0.001]; LDL: [-2.9 mmol/L, P = 0.010]), RAAS (renin [-9.3 ng/L, P = 0.047]; aldosterone [-16.7 ng/L, P < 0.001]) and sympathetic activity (norepinephrine [-8.9 ng/L, P = 0.019]; neuropeptide Y [-8.8 ng/L, P = 0.002]). However, the anti-inflammatory effect of empagliflozin was not significantly evident.
Conclusions
The early atherosclerotic lesion size was less visible in empagliflozin-treated mice. Empagliflozin could decrease lipid profiles and sympathetic activity in atherosclerosis.
... 11 VWF deficiency can be completely reversed after aortic valve replacement therapy 12 thus, vWF has been proposed as a new hemodynamic biomarker for monitoring surgical or percutaneous aortic valve replacement procedures. [13][14][15] It has been reported that defects of high-molecular-weight vWF multimers were resolved within minutes during transcatheter aortic valve replacement (TAVR) but not after ballon valvuloplasty procedures. 16 Similarly, the presence of AvWS has been described in patients with moderate to severe mitral valve dysfunction. 1 Blackshear et al. investigated a population of 53 patients with mild to severe mitral regurgitation and reported that more severe mitral valve regurgitation was associated with progressive worsening of vWF activity and bleeding tendency. ...
Background and Hypothesis
The acquired von Willebrand syndrome (AvWS), which predisposes to bleeding events, is often related to valvular heart diseases. We investigated possible implications of AvWS and factor VIII levels in patients with moderate to severe mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR).
Methods and Results
123 patients with moderate to severe MR were prospectively enrolled. Complete measurements of von Willebrand Factor activity (vWFAct), von Willebrand Factor antigen (vWFAg), and factor VIII expression before and 4 weeks after TMVR were available in 85 patients. At baseline, seven patients had a history of gastrointestinal bleeding, two patients suffered bleeding events during their hospital stay, and one patient had a bleeding 4 weeks after TMVR. Even though vWFAct, vWFAct/vWFAg ratio and vWFAg values did not change after TMVR, we observed a significantly lower vWFAct/vWFAg ratio in patients with primary MR as compared to patients with secondary MR both at baseline (p = 0.022) and 4 weeks following the TMVR procedure (p = 0.003). Additionally, patients with a mean mitral valve gradient ≥4 mmHg after TMVR had significantly lower vWFAct/vWFAg ratios as compared to patients with a mean mitral valve gradient <4 mmHg (p = 0.001).
Conclusions
MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, morphological changes leading to postprocedural transmitral gradients ≥4 mmHg were related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Alterations of the vWFAct/vWFAg ratio in turn did not translate into a greater risk for bleeding events.
... Consequently, an increase in VWF levels in the plasma is indicative of the possible occurrence of adverse cardiovascular, cerebrovascular, and peripheral vascular diseases [191,192]. Clinical studies have shown that aggregation of platelets is reversible and can be achieved through targeted VWF antagonist therapeutic tools [193]. Examples of commercially available antiplatelet drugs include aspirin, clopidogrel, and ticlopidine. ...
This chapter archives the state of the art concerning crucial drug delivery strategies aiding in cardiovascular therapies, including their benefits and associated challenges. The aspects which govern vascular transport and cardiovascular drug targeting have been reviewed, both from configuration and flow perspectives. In addition, the role of extracellular vesicles and exosomes, as well as the suitability of ultrasound and microbubble-mediated delivery, has been discussed. Current advancements made in the nanomedicine domain, with relevant applications pertaining to diverse categories, have been collated and discussed. A special focus has been laid on the applications of aptamers in cardiovascular drug targeting, particularly with respect to conjugation with specific coagulation factors and proteins. It also captures the potential and promises of the next generation of targeted strategies, with an eye on the foreseeable future.
... Pinto A et al. [25] observed that in ammatory markers, including TNF-α, IL-6 and von Willebrand factor (vWF), were predictors of new-onset IS in patients with chronic NVAF. Additionally, vWF has been shown to aggravate ischaemic injury by promoting thrombosis in the injured vessels, a nding that provides a new target for antithrombotic therapy [26][27]. In ammation has been con rmed to be associated with left atrial thrombosis in AF patients [28]. ...
Background: This study explored the relationships between the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and other clinical indicators and ischaemic stroke (IS) in patients with non-valvular atrial fibrillation (NVAF) in Xinjiang. The findings could provide a theoretical and therapeutic basis for NVAF patients.
Methods: NVAF patients who were admitted to 10 medical centres across Xinjiang were divided into stroke (798 patients) and control (2671 patients) groups according to the occurrence of first acute IS. Univariate and multivariate logistic regression analysis were used to examine the independent risk factors for IS in NVAF patients. Factor analysis and principal component regression analysis were used to analyse the main factors influencing IS. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of LDL-C/HDL-C for predicting the occurrence of IS.
Results: The stroke group had an average age of 71.64 ± 9.96 years and included 305 females (38.22%). The control group had a mean age of 67.30 ± 12.01 years and included 825 females (30.89%). Multivariate logistic regression showed that the risk of IS in the highest LDL-C/HDL-C quartile ( ≥2.73) was 16.23-fold that of the lowest quartile ( < 1.22); IS risk was 2.27-fold higher in obese patients than in normal-weight subjects; IS risk was 3.15-fold higher in smoking patients than in non-smoking patients. The area under the ROC curve of LDL-C/HDL-C was 0.76, the optimal critical value was 2.33, the sensitivity was 63.53%, and the specificity was 76.34%. Principal component regression analysis showed that LDL-C/HDL-C, age, smoking, drinking, LDL-C and hypertension were risk factors for IS in NVAF patients.
Conclusions: LDL-C/HDL-C >1.22, smoking, BMI ≥24 kg/m² and CHA2DS2-VASc score were independent risk factors for IS in NVAF patients; LDL-C/HDL-C was the main risk factor.
... Pinto A et al. [25] observed that in ammatory markers, including TNF-α, IL-6 and von Willebrand factor (vWF), were predictors of new-onset IS in patients with chronic NVAF. vWF aggravates ischaemic injury by promoting thrombosis in the injured vessels, a nding that provides a new target for antithrombotic therapy [26][27]. In ammation has been con rmed to be associated with left atrial thrombosis in AF patients [28]. ...
Background: This study explored the relationships between the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and other clinical indicators and ischaemic stroke (IS) in patients with non-valvular atrial fibrillation (NVAF) in Xinjiang. The findings could provide a theoretical and therapeutic basis for NVAF patients.
Methods: NVAF patients who were admitted to 10 medical centres across Xinjiang were divided into stroke (798 patients) and control (2671 patients) groups according to the occurrence of first acute IS occurred. Univariate and multivariate logistic regression analysis were used to examine the independent risk factors for IS in NVAF patients. Factor analysis and principal component regression analysis were used to analyse the main factors influencing IS. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of LDL-C/HDL-C for predicting the occurrence of IS.
Results: The stroke group had an average age of 71.64 ± 9.96 years and included 305 females (38.22%). The control group had a mean age of 67.30 ± 12.01 years and included 825 females (30.89%). Multivariate logistic regression showed that the risk of IS in the highest LDL-C/HDL-C quartile ( ≥2.73) was 16.23-fold that of the lowest quartile ( < 1.22); IS risk was 2.27-fold higher in obese patients than in normal-weight subjects; IS risk was 3.15-fold higher in smoking patients than in non-smoking patients. The area under the ROC curve of LDL-C/HDL-C was 0.76, the optimal critical value was 2.33, the sensitivity was 63.53%, and the specificity was 76.34%. Principal component regression analysis showed that LDL-C/HDL-C, age, smoking, drinking, LDL-C and hypertension were risk factors for IS in NVAF patients.
Conclusions: LDL-C/HDL-C >1.22, smoking, BMI ≥24 kg/m² and CHA2DS2-VASc score were independent risk factors for IS in NVAF patients; LDL-C/HDL-C was the main risk factor.
... Pinto A et al. [25] observed that inflammatory markers, including TNF-α, IL-6 and von Willebrand factor (vWF), were predictors of new-onset IS in patients with chronic NVAF. Additionally, vWF has been shown to aggravate ischaemic injury by promoting thrombosis in the injured vessels, a finding that provides a new target for antithrombotic therapy [26,27]. Inflammation has been confirmed to be associated with left atrial thrombosis in AF patients [28]. ...
Background:
This study explored the relationships between the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and other clinical indicators and ischaemic stroke (IS) in patients with non-valvular atrial fibrillation (NVAF) in Xinjiang. The findings could provide a theoretical and therapeutic basis for NVAF patients.
Methods:
NVAF patients who were admitted to 10 medical centres across Xinjiang were divided into stroke (798 patients) and control (2671 patients) groups according to the occurrence of first acute IS. Univariate and multivariate logistic regression analysis were used to examine the independent risk factors for IS in NVAF patients. Factor analysis and principal component regression analysis were used to analyse the main factors influencing IS. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of LDL-C/HDL-C for predicting the occurrence of IS.
Results:
The stroke group had an average age of 71.64 ± 9.96 years and included 305 females (38.22%). The control group had a mean age of 67.30 ± 12.01 years and included 825 females (30.89%). Multivariate logistic regression showed that the risk of IS in the highest LDL-C/HDL-C quartile (≥2.73) was 16.23-fold that of the lowest quartile (< 1.22); IS risk was 2.27-fold higher in obese patients than in normal-weight subjects; IS risk was 3.15-fold higher in smoking patients than in non-smoking patients. The area under the ROC curve of LDL-C/HDL-C was 0.76, the optimal critical value was 2.33, the sensitivity was 63.53%, and the specificity was 76.34%. Principal component regression analysis showed that LDL-C/HDL-C, age, smoking, drinking, LDL-C and hypertension were risk factors for IS in NVAF patients.
Conclusions:
LDL-C/HDL-C > 1.22, smoking, BMI ≥24 kg/m2 and CHA2DS2-VASc score were independent risk factors for IS in NVAF patients; LDL-C/HDL-C was the main risk factor.
... Some human studies have shown evidence of an inverse association between oleic acid and IL-6 concentration [27]. In addition, a diet rich in MUFA may also lower thrombotic factors, including the von Willebrand factor [28], the plasma levels of which are increased in high risk populations [29], and its release may be induced by IL-6 [30]. A growing body of evidence indicates that Lp-PLA 2 represents an independent risk factor for CVD. ...
Background:
The potential cardioprotective benefits of olive oil (OO) and canola oil (CO) consumption have been shown in some studies. The present study compared the effects of CO and OO on plasma lipids, some inflammatory cytokines, and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity in patients undergoing coronary angiography.
Methods:
The current randomized, controlled, parallel-arm, clinical trial involved 48 patients (44 men and 4 women, aged 57.63 ± 6.34 years) with at least one classic cardiovascular risk factor (hypertension, dyslipidemia, or diabetes) who referred for coronary angiography. Patients were randomly divided into two groups and received 25 mL/day refined olive oil (n = 24) or canola oil (n = 24) for 6 weeks. Plasma lipids, some selected inflammatory markers, and Lp-PLA2 levels were measured at baseline and after the intervention.
Results:
CO consumption produced a significant reduction in plasma Lp-PLA2 mass (- 0.97 ± 1.84 vs. 0.34 ± 1.57 ng/mL, p = 0.008 for CO and OO, respectively), whereas the mean changes in interleukine-6 concentration were significantly lower after OO consumption compared with CO (- 9.46 ± 9.46 vs. -0.90 ± 6.80 pg/mL, p = 0.008 for OO and CO, respectively). After 6 weeks of intervention, no significant changes were observed in plasma Lp-PLA2 activity, complement C3, C4, or lipid profiles in the two intervention groups.
Conclusions:
Comparing the two vegetable oils in subjects with cardiovascular risk factors showed that the consumption of olive oil is more effective in reducing the level of inflammatory cytokine interleukine-6, whereas canola oil was more effective in lowering Lp-PLA2 levels; however, this finding should be interpreted with caution, because Lp-PLA2 activity did not change significantly.
Trial registration:
IRCT20160702028742N5 at www.irct.ir (04/19/2019).
... Some human studies have shown evidence of an inverse association between oleic acid and IL-6 concentration [27]. In addition, a diet rich in MUFA may also lower thrombotic factors, including the von Willebrand factor [28], the plasma levels of which are increased in high risk populations [29], and its release may be induced by IL-6 [30]. ...
Background: The potential cardioprotective benefits of olive oil (OO) and canola oil (CO) consumption have been shown in some studies. The present study compared the effects of CO and OO on plasma lipids, some inflammatory cytokines, and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity in patients undergoing coronary angiography.
Methods: The current randomized, controlled, parallel-arm, clinical trial involved 48 patients (44 men and 4 women, aged 57.63 ± 6.34 years) with at least one classic cardiovascular risk factor (hypertension, dyslipidemia, or diabetes) who referred for coronary angiography. Patients were randomly divided into two groups and received 25 mL/day refined olive oil (n=24) or canola oil (n=24) for 6 weeks. Plasma lipids, some selected inflammatory markers, and Lp-PLA2 levels were measured at baseline and after the intervention.
Results: CO consumption produced a significant reduction in plasma Lp-PLA2 mass (-0.97 ± 1.84 vs. 0.34 ± 1.57 ng/mL, p = 0.008 for CO and OO, respectively), whereas the mean changes in interleukine-6 concentration were significantly lower after OO consumption compared with CO (-9.46 ± 9.46 vs. -0.90 ± 6.80 pg/mL, p = 0.008 for OO and CO, respectively). After 6 weeks of intervention, no significant changes were observed in plasma Lp-PLA2 activity, complement C3, C4, or lipid profiles in the two intervention groups.
Conclusions: Comparing the two vegetable oils in subjects with cardiovascular risk factors showed that the consumption of olive oil is more effective in reducing the level of inflammatory cytokine interleukine-6, whereas canola oil was more effective in lowering Lp-PLA2 levels; however, this finding should be interpreted with caution, because Lp-PLA2 activity did not change significantly.
Trial registration: IRCT20160702028742N5 at www.irct.ir (04/19/2019)
... • General down-stream markers of inflammation: High-sensitivity C-reactive protein (hs-CRP) (14) and glycoprotein 130 (gp130, a member of the interleukine-6 receptor family) (15). • Markers of vascular inflammation, calcification, and endothelial function: Pentraxin 3 (PTX3) (16), osteoprotegerin (OPG) (17), and von Willebrand factor (vWF) (18). • Markers related to fibrosis and extracellular matrix (ECM) remodeling: Galectin 3 (19) and Cathepsin S (20). ...
Background
Cardiovascular disease (CVD) is a major cause of premature death in patients with psychotic disorders, where dyslipidemia occurs frequently. In the pathogenesis of these serious mental disorders, a low-grade inflammation seems to be a possible contributor. Concurrently, systemic inflammation and its interplay with dyslipidemia is a central driver in the pathogenesis of CVD. We hypothesize that evaluation of atherogenic lipid ratios together with inflammatory markers reflecting different inflammatory pathways with relevance for atherogenesis, could give novel information on immune-related mechanisms involved in early CVD risk in patients with psychotic disorders.
Methods
As a measure for CVD risk we calculated atherogenic lipid ratios using established sex-specific cut-offs: Total cholesterol/high-density lipoprotein; HDL-c (TC/HDL) and triglyceride/HDL-c (TG/HDL) were evaluated in 571 schizophrenia (SCZ) and 247 bipolar disorder (BD) patients, and in 99 healthy controls (HC). In addition, as a measure of low-grade inflammation, we measured fasting plasma levels of nine stable atherogenic inflammatory markers in patients (SCZ, BD) and in HC. The elevated inflammatory markers and CVD risk in patients, as reflected by TC/HDL and TG/HDL, were further assessed in multivariable analyses adjusting for comorbid cardio-metabolic risk factors.
Results
A markedly higher proportion (26%–31%) of patients had increased TC/HDL and TG/HDL ratios compared with HC. Plasma levels of high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO) were higher (p<0.05, p<0.001) in patients with psychotic disorders than in HC, and hs-CRP and MPO were independently associated with atherogenic lipid ratios in the multivariable analyses.
Conclusions
Our findings suggest that low-grade inflammation and abnormal neutrophil activation may cause increased CVD risk in patients with psychotic disorders. These mechanisms should be further examined to determine the potential for development of novel risk evaluation strategies.
... 2,3 In the last decades, numerous prognostic factors have been investigated. 2,4 Hyperhomocysteinaemia, defined as elevation of plasma homocysteine concentration, has been associated with stroke and arrhythmias and proposed as an independent cardiovascular disease risk factor. 5 The C677T polymorphism for the MTHFR gene is associated with reduced enzyme activity and increased homocysteine levels. ...
... 35 Translation of the above-mentioned pathophysiology to clinic may reveal both the predicting value of high plasma levels of vWf as an independent risk factor for cardiovascular diseases 36 and the possibility of vWfantagonization in overcoming some limitations in the treatment of thromotic events. 37 In line with other studies, we showed more serum vWf levels in USAP patients. The 1-year follow-up of the French population enrolled in the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events)trial demonstrated that the combined evaluation of vWf and troponin I during the first 48 hours provides useful information on long-term prognosis of these patients with USAP. ...
Unstable angina pectoris (USAP) is a complex condition in which widespread coronary inflammatory processes have important implications for clearer understanding of its pathogenesis and also its treatment. This study aimed at evaluating the diagnostic as well as prognostic value of serum inflammatory markers of pentraxin-3 (PTX-3), Von Willebrand Factor (vWf) and C-X-C Motif Chemokine Ligand 13 (CXCL13) in such patients. Out of sixty-nine patients, thirty-nine had USAP, thirty had stable angina pectoris (SAP), and thirty-nine were healthy controls. For all participants, serum PTX-3, vWf and CXCL13 levels were measured using ELISA. For each patient with USAP, the Thrombolysis in Myocardial Infarction (TIMI) and the scores of Global Registry of Acute Coronary Events (GRACE) were calculated to determine the severity of the disease. We, then, analyzed the relation of PTX-3, vWf and CXCL13 levels with TIMI and GRACE scores in patients with USAP. Serum PTX-3, vWf and CXCL13 levels were significantly higher in USAP group than those in either SAP or control groups (p˂0.001). Strong correlation was observed between CXCL13 level and TIMI risk score (p=0.019). In receiver operating characteristic (ROC) curves, area under the curve (AUC) values of PTX3, vWf and CXCL13 for detection of USAP were 0.755, 0.751, and 0.906, respectively. The levels of serum PTX3, vWf and CXCL13 increased in patients with USAP. The notable correlation implied that CXCL13 might be a sensitive and specific biomarker for the diagnosis of USAP as well as its severity. It might also show additional diagnostic values when measured in combination with vWf.
... These novel drugs have been reported to safely exert powerful antithrombotic effects. [34] To assess the effectiveness of these new drugs on coronary atherosclerosis, large-scale, prospective and randomized clinical trials are required. ...
High von Willebrand factor (VWF) levels have been reported to be associated with an increased risk of cardiovascular events. However, the relationship between VWF levels and coronary atherosclerosis in patients with coronary artery disease (CAD) who have already received stain treatment is still unclear. We examined the association between VWF levels and coronary plaque as assessed by intravascular ultrasound (IVUS) in CAD patients treated with statins. Ninety-one CAD patients who underwent percutaneous coronary intervention under IVUS guidance, and who were already receiving statin treatment based on Japanese guidelines, were included. An IVUS examination was performed for the culprit lesion, and plasma VWF antigen levels were measured using enzyme-linked immuno sorbent assay. In all of the patients, the low-density lipoprotein cholesterol levels just before the IVUS examination were low (86 ± 26 mg/dL). The VWF levels were positively correlated with the plaque burden expressed as percent atheroma volume (PAV) (r = 0.39, P = .001), while there was no significant association between VWF and plaque composition. Multivariate stepwise regression analysis showed that higher VWF levels were independently associated with increased PAV (β=0.26, P = .01). In CAD patients who had already been treated with statins, higher VWF levels were associated with a higher coronary plaque burden, suggesting that a high VWF level may be a marker of the residual cardiovascular risk after statin treatment.
... The residual cardiovascular risk is multifactorial, and well-known risk factors (including smoking habit, hypertension, and diabetes mellitus) have to be well-controlled according to guideline recommendations, with a fully comprehensive approach to cardiovascular health and prevention [42]. Evaluation of old and novel factors regulating disease progression and regression in the setting of LDL-C depletion is necessary to identify pathogenic mechanisms and propose new therapeutic strategies against atherosclerosis [78][79][80][81][82]. ...
Despite recent therapeutic advances, there is an unmet need in cardiovascular disease prevention. Clinical trials and meta-analyses have established that LDL-C lowering, particularly by statin therapy, reduces the progression of coronary atherosclerosis and the risk of coronary events. Insufficient LDL-C reduction and high residual risk in a significant proportion of statin-treated patients signify that additional therapies are required to deliver more effective coronary care. Pharmacological inhibition of cholesterol absorption (with ezetimibe) and PCSK9 activity (with evolocumab or alirocumab) provides potentially useful approaches for the therapeutic modulation of LDL-C metabolism in statin-treated patients. In recent trials, combination strategies involving a statin and a non-statin agent (ezetimibe or evolocumab) have been shown to promote coronary atherosclerosis regression and improve cardiovascular outcomes in patients with moderate-to-high cardiovascular risk. This review summarizes recent evidence on the effects of dual lipid-lowering therapy on coronary atherosclerosis.
... Clinical Studies. VWF and ADAMTS13 have been proposed as useful biomarkers and predictors of prognosis in patients with cardiovascular and metabolic disease [75]. In diabetic patients, VWF and ADAMTS13 activities correlate with CV outcome and risk of chronic complications and may predict a response to therapies [30,76]. ...
Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation. Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis. The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions. Moreover, VWF and ADAMTS13 have been recently proposed as prognostic biomarkers in cardiovascular, metabolic, and inflammatory diseases, such as diabetes, stroke, myocardial infarction, and sepsis. All these features make VWF an attractive therapeutic target in thromboinflammation. Several lines of research have recently investigated “tailor-made” inhibitors of VWF. Results from animal models and clinical studies support the potent anti-inflammatory and antithrombotic effect of VWF antagonism, providing reassuring data on its safety profile. This review describes the role of VWF in vascular inflammation “from bench to bedside” and provides an updated overview of the drugs that can directly interfere with the VWF/ADAMTS13 axis.
Background
To observe the correlation of osteoprotegerin, soluble receptor activator of nuclear factor‐κB ligand (sRANKL), inflammatory factors and epicardial adipose tissue volume (EATV) with the severity of coronary heart disease (CHD).
Methods
We studied 390 patients who were admitted to the Department of Cardiology of our hospital because of chest pain and underwent coronary angiography (CAG) from August 2018 to December 2019. According to CAG, 209 patients had non‐CHD and 181 patients had CHD. Demographic data, biochemical indicators including low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), total cholesterol (TC), lipoprotein a (Lp(a)), apolipoprotein B (apoB), apolipoprotein AI (apoAI), creatine kinase isoenzyme (CK‐MB), osteoprotegerin, sRANKL, inflammatory factors (hs‐CRP, FIB and IL‐6), and EATV were collected.
Results
The number of males, age, diabetes and hypertension in the CHD group was higher than those in the non‐CHD group (P < 0.05). LDL‐C, TC and apoB in the two groups were not significantly different (P > 0.05); HDL‐C and apoAI in the CHD group were lower than those in the non‐CHD group, and Lp(a) and CK‐MB were higher than those in the control group (P < 0.05). Osteoprotegerin, IL‐6, hs‐CRP, EATV and FIB in the CHD group were higher than those in the non‐CHD group, while sRANKL was lower than that in the control group (P < 0.05). Pearson correlation analysis showed that osteoprotegerin, sRANKL, inflammatory factors (hs‐CRP, FIB and IL‐6) and EATV were correlated with the severity of CHD (P < 0.05). Multivariate logistic regression analysis showed that CK‐MB, osteoprotegerin, sRANKL, inflammatory factors (hs‐CRP, FIB and IL‐6) and EATV were risk factors for CHD, while HDL‐C, Lp(a), apoAI were protective factors.
Conclusion
Osteoprotegerin, sRANKL, inflammatory factors and EATV were positively correlated with the severity of CHD, which had certain value for the diagnosis of CHD.
Background: Previous studies had shown that aspartate aminotransferase to alanine aminotransferase (AST/ALT ratio) plays a role in cardiovascular disease. Peripheral artery disease (PAD) is an important risk factor for cardiovascular disease. However, there are a little research on the association between the AST/ALT ratio and Peripheral artery disease (PAD).
Methods: A total of 10, 900 hypertensive patients from the Chinese Hypertension Registry Study were included in the final analysis. The association between AST / ALT and peripheral arterial disease (PAD), which was defined as ABI ≤ 0.9 in either leg, was estimated by a multivariate logistic regression model.
Results: Overall, the prevalence of PAD was 3.21%. After adjusting for potential confounders, AST / ALT ratio was independently and positively associated with the risk of PAD (OR: 1.31, 95% CI: 1.13 to 1.59), and a statistically significant increased risk of PAD for the third tertile (T3) of AST / ALT ratio compared to the first tertile (T1) (OR:1.49, 95% CI: 1.09 to 2.04, P-trend= 0.005) was found. Moreover, when the T1-T2 group was combined into one group and used it as a reference group, the risk of PAD increased with the increase of AST/ALT and the risk ratio was 1.52 (95% CI :1.20 to 1.95).
Conclusion: A higher AST/ALT ratio (≥1.65) was associated with PAD risk in Chinese adults with hypertension. The presented results suggested that AST / ALT may help us highlight patients who are at high risk of vascular endpoints.
Trial registration: CHICTR, CHiCTR1800017274. Registered 20 July 2018.
Von Willebrand factor has a pivotal role in primary hemostasis. Its role in thrombotic microangiopathies (TMA), as well as cardiovascular disease, has been demonstrated. Thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy, is a life-threatening condition with a high mortality rate if untreated. Current management strategies comprise plasma exchange to remove autoantibodies and replenish ADAMTS13, along with immunosuppressive agents in immune TTP. This review focuses on novel antiplatelet strategies that target VWF and GPIb. The benefits of the nanobody caplacizumab in achieving faster normalization of platelet count, as well as reduced thromboembolic events were shown through TITAN and HERCULES trials, and these findings have been practice changing. The use of caplacizumab in patients with immune TTP (iTTP) has now become well established. Potential benefits of ARC1779 and N-acetylcysteine have also been shown on a small scale in iTTP, however these lack evidence through larger randomized controlled trials. Further therapies, some in early phase, others in clinical practice, target platelet aggregation within arteries and their utility is presented with cerebrovascular disorders.
We recently identified ABO(H) blood group structures in Asn-linked sugar chains of human von Willebrand factor (vWF) purified from factor VIII concentrates (J Biol Chem 267:8723, 1992). We surveyed plasma glycoproteins carrying ABO(H) blood group antigens by Western blotting analysis and sandwich enzyme-linked immunosorbent assay using blood group-specific monoclonal antibodies (MoAbs) and a lectin. Two major plasma proteins showing apparent molecular weight of about 180 Kd and 270 Kd by sodium dodecyl sulfate polyacrylamide gel electrophoresis reacted with blood group-specific MoAbs and Ulex europaeus lectin I in accordance with donor blood group. Direct sequence analysis of the protein bands showed their identity with the N-terminal sequences of alpha 2-macroglobulin (alpha 2M) and vWF, respectively. The two bands also reacted with anti-alpha 2M and anti-vWF antibodies. The alpha 2M and vWF prepared from plasma by immunoprecipitation showed the appropriate blood group antigenicity. After incubation with endoglycosidase F, both alpha 2M and vWF lost almost all reactivity with anti-blood group reagents. About 90% of plasma vWF, but only approximately 10% of alpha 2M, was immunoprecipitated with anti-blood group antibody. These results indicate that at least two plasma glycoproteins, vWF and alpha 2M, possess Asn-linked ABO(H) blood group antigens in normal individuals with corresponding ABO phenotype. Therefore, ABO(H) blood group antigens in plasma glycoproteins should be considered during preparation of plasma materials for therapeutic use.
Interest in arterial stiffness has been fueled by the scientific and clinical implications of its “vicious cycle” relationship with aging and systolic blood pressure. In physical terms, stiffness is the slope of the relationship between an artery’s distending pressure and its cross-sectional area or volume. Pulse wave velocity (PWV, in m/s), the most common arterial stiffness indicator, is usually measured by the foot-to-foot time and distance method and is proportional to [stiffness × area (or volume)]1/2 at a given pressure. Its intrinsic pressure dependency and other flaws in current PWV methods limit its utility. In contrast, the arterial stiffness–arterial pressure relationship is near-linear, with a slope β, the exponent of the curvilinear arterial pressure–arterial volume relationship. The concept of arterial stiffening is related to β and describes a more functionally relevant aspect of arterial behavior: the change in stiffness for a given change in pressure. Arterial stiffening can be estimated from the variability of within-individual BP measurements (24-h ambulatory, home BP, or BP measured at different arm heights) and can be expressed as the pulse stiffening ratio (PSR) = [systolic stiffness]/[diastolic stiffness] or the ambulatory arterial stiffness index (AASI or its symmetric form, sAASI). High arterial stiffness (PWV) and stiffening (β, stiffness index, cardio-ankle vascular index, AASI, and PSR) are associated with increased cardiovascular disease risk, but it remains unclear whether these indicators are useful in improving medical care quality; the standard of care remains stringent BP control.
The main goal of ischemic stroke treatment is rapid recanalization of the occluded blood vessel to limit brain injury and to salvage threatened cerebral tissue. To achieve early vessel recanalization, thrombolysis using recombinant tissue-type plasminogen activator is currently the only approved pharmacological intervention. Only recently, endovascular therapy has made its way into the clinic extending the therapeutic time-window and increasing reperfusion rates. However, despite fast restoration of blood vessel patency, progressive stroke still develops in many patients, which has led to the concept of reperfusion injury. During the past decades, many studies have been addressing the mechanisms underlying ischemic stroke damage and cerebral reperfusion injury, but the picture remains far from complete.1 It has become clear that both thrombotic and inflammatory pathways are important pathophysiologic contributors to ischemic brain damage. At ischemic vascular lesions, blood platelets adhere and become activated, increasing the risk of secondary thrombotic events.2 At the same time, cerebral ischemia elicits a strong inflammatory response involving upregulation of cell adhesion molecules and cytokines as well as adhesion, activation, and transmigration of several subsets of leukocytes.3 Interestingly, emerging insights indicate an important link between these thrombotic and inflammatory pathways in stroke, which led to the concept of thromboinflammation in stroke pathology. In this review, we focus on recently discovered thromboinflammatory pathways of ischemic stroke and discuss the clinical potential of targeting thromboinflammation as a novel treatment strategy in stroke management. An overview of the key components is given in Tables I to III in the online-only Data Supplement.
Collagen, von Willebrand factor (vWF), and platelet glycoprotein (GP) Ib together form an important axis that is crucial for initial platelet adhesion at sites of vascular injury.4 On exposure of the subendothelial matrix, platelets are able to adhere to exposed collagen via their collagen receptors GP …
The ability of von Willebrand factor (VWF) to initiate platelet adhesion depends on the number of monomers in individual VWF multimers and on the self-association of individual VWF multimers into larger structures. VWF self-association is accelerated by shear stress. We observed that VWF self-association occurs during adsorption of VWF onto surfaces, assembly of secreted VWF into hyperadhesive VWF strings on the endothelial surface, and incorporation of fluid-phase VWF into VWF fibers. VWF adsorption under static conditions increased with increased VWF purity and was prevented by a component of plasma. We identified that component as high-density lipoprotein (HDL) and its major apolipoprotein ApoA-I. HDL and ApoA-I also prevented VWF on the endothelium from self-associating into longer strands and inhibited the attachment of fluid-phase VWF onto vessel wall strands. Platelet adhesion to VWF fibers was reduced in proportion to the reduction in self-associated VWF. In a mouse model of thrombotic microangiopathy, HDL also largely prevented the thrombocytopenia induced by injection of high doses of human VWF. Finally, a potential role for ApoA-I in microvascular occlusion associated with thrombotic thrombocytopenic purpura and sepsis was revealed by the inverse relationship between the concentration of ApoA-I and that of hyperadhesive VWF. These results suggest that interference with VWF self-association would be a new approach to treating thrombotic disorders.
Introduction: Increased plasma levels of von Willebrand factor Antigen (vWF:Ag) are associated with high risk of coronary artery disease. The effect of statin therapy on vWF:Ag levels remains uncertain. Therefore the aim of this meta-analysis was to evaluate the effect of statin therapy on vWF:Ag Levels.
Methods: A systematic multiple-database search was carried out to identify RCTs that investigated the effect of statins on plasma vWF:Ag levels.
Results: Random-effect meta-analysis of 21 treatment arms revealed a significant decrease in plasma vWF:Ag levels following statin therapy (SMD:-0.54, 95%CI: -0.87, -0.21, p=0.001). In subgroup analyses, the greatest effect was observed with simvastatin (SMD:-1.54, 95%CI: -2.92, -0.17, p=0.028) and pravastatin (SMD:-0.61, 95%CI: -1.18, -0.04, p=0.035), but not with fluvastatin (SMD:-0.34, 95%CI: -0.69, 0.02, p=0.065), atorvastatin (SMD:-0.23, 95%CI: -0.57, 0.11, p=0.179) and rosuvastatin (SMD:-0.20, 95% CI: -0.71, 0.30, p=0.431). The lowering effect of statins on plasma vWF:Ag levels was greater in the subset of studies lasting ≥12 weeks (SMD:-0.70, 95%CI: -1.19, -0.22, p=0.005) compared with that of studies lasting <12 weeks (SMD:-0.34, 95%CI: -0.67, 0.003, p=0.052). Finally, low-intensity statin therapy was not associated with a significant reduction in vWF:Ag levels (SMD:-0.28, 95%CI: -0.82, 0.27, p=0.320), but a significant effect was observed in high-intensity statin trials (SMD:-0.66, 95%CI: -1.07, -0.24, p=0.002).
Conclusions: This meta-analysis of available RCTs demonstrates a significant reduction in plasma vWF:Ag levels following statin therapy.
Key Points
Low ADAMTS13 activity is associated with ischemic stroke. ADAMTS13 activity improved the accuracy of ischemic stroke risk predictions beyond the traditional risk factors.
Background
Arterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chronic immune activation.Methods
We reviewed the Dutch National HIV registry database for HIV infected patients in Rotterdam with a history of arterial or venous thrombosis and calculated the incidence. We collected samples from patients with and without thrombosis to compare plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and von Willebrand Factor antigen level (vWF). ResultsDuring a 10-year period, a total of 60 documented events in 14,026 person years of observation (PYO) occurred, resulting in an incidence rate of 2.50, 2.21 and 4.28 for arterial, venous and combined thrombotic events per 1000 PYO, respectively. The vWF was elevated in the majority of study subjects (mean 2,36 SD±0.88 IU/ml); we found a significant difference when comparing venous cases to controls (mean 2.68 SD±0.82 IU/ml vs 2.20 SD±0.77 IU/ml; p=0.024). This difference remained significant for recurrent events (mean 2.78 SD±0.75p=0,043).). sCD14 was positively correlated with LPS (r=0.255; p=0.01).Conclusion
The incidence of venous thrombosis was twofold higher in HIV infected patients compared to age-adjusted data from general population cohort studies. We couldn't find a clear association between immune activation markers to either arterial or venous thrombotic events. We observed a marked increase in vWF levels and observed a correlation of vWF to first and recurrent venous thrombo-embolic events.These findings suggest that HIV infection is an independent risk factor for coagulation abnormalities and could contribute to the observed high incidence in venous thrombosis. This could be a reason to prolong anti-thrombotic treatment in HIV patients with a history of thrombosis.
To 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.Above 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.RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, p
Several systemic diseases, including thrombotic thrombocytopenic purpura, manifest much of their pathology through activation of endothelium and thrombotic occlusion of small blood vessels, often leading to multi-organ failure and death. Modelling these diseases is hampered by the complex three-dimensional architecture and flow patterns of the microvasculature. Here, we employ engineered microvessels of complex geometry to examine the pathological responses to endothelial activation. Our most striking finding is the capacity of endothelial-secreted von Willebrand factor (VWF) to assemble into thick bundles or complex meshes, depending on the vessel geometry and flow characteristics. Assembly is greatest in vessels of diameter ≤300 μm, with high shear stress or strong flow acceleration, and with sharp turns. VWF bundles and webs bind platelets, leukocytes and erythrocytes, obstructing blood flow and sometimes shearing passing erythrocytes. Our findings uncover the biophysical requirements for initiating microvascular thrombosis and suggest mechanisms for the onset and progression of microvascular diseases.
A system-level identification of drug-target direct interactions is vital to drug repositioning and discovery. However, the biological means on a large scale remains challenging and expensive even nowadays. The available computational models mainly focus on predicting indirect interactions or direct interactions on a small scale. To address these problems, in this work, a novel algorithm termed weighted ensemble similarity (WES) has been developed to identify drug direct targets based on a large-scale of 98,327 drug-target relationships. WES includes: (1) identifying the key ligand structural features that are highly-related to the pharmacological properties in a framework of ensemble; (2) determining a drug's affiliation of a target by evaluation of the overall similarity (ensemble) rather than a single ligand judgment; and (3) integrating the standardized ensemble similarities (Z score) by Bayesian network and multi-variate kernel approach to make predictions. All these lead WES to predict drug direct targets with external and experimental test accuracies of 70% and 71%, respectively. This shows that the WES method provides a potential in silico model for drug repositioning and discovery.
While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required.
Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Hemostasis and pathological thrombus formation are dynamic processes that require multiple adhesive receptor-ligand interactions, with blood platelets at the heart of such events. Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury. This review will recapitulate our current knowledge on the subject from the rheological aspect to the spatio-temporal development of thrombus formation. We will also discuss the signaling events generated by VWF/GPIb-IX-V interaction, leading to platelet activation. Additionally, we will review the growing body of evidence gathered from the recent development of pathological mouse models suggesting that VWF binding to GPIb-IX-V is a promising target in arterial and venous pathological thrombosis. Finally, the pathological aspects of VWF and its impact on platelets will be addressed.
Background and Purpose
In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD).
Methods
A case–control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA.
Results
Patients with CCD (158±46%) had significantly higher VWF levels than HV (113±36%, P<0.001), but lower levels than AIS/TIA patients (200±95%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05).
Conclusions
VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation.
In diabetics, impaired ADAMTS13 proteolysis of highly-thrombogenic VWF multimers may accelerate renal and cardiovascular complications. Restoring physiological VWF handling might contribute to ACE inhibitors (ACEi) reno- and cardioprotective effects.To assess how Pro618Ala ADAMTS13 variants and related proteolytic activity interact with ACEi therapy in predicting renal and cardiovascular complications, we genotyped 1163 normoalbuminuric type 2 diabetics from the BENEDICT trial. Interaction between Pro618Ala and ACEi was significant in predicting both renal and combined renal and cardiovascular events. The risk [HR(95%CI)] for renal or combined events vs reference Ala carriers on ACEi progressively increased from Pro/Pro homozygotes on ACEi [2.80(0.849-9.216) and 1.58(0.737-3.379), respectively], to Pro/Pro homozygotes on non-ACEi [4.77(1.484-15.357) and 1.99(0.944-4.187)], to Ala carriers on non-ACEi [8.50(2.416-29.962) and 4.00(1.739-9.207)]. In a sub-study, serum ADAMTS13 activity was significantly lower in Ala carriers than in Pro/Pro homozygotes and in cases with renal, cardiovascular or combined events than in uneventful diabetic controls. ADAMTS13 activity significantly and negatively correlated with all outcomes.In diabetics, ADAMTS13 618Ala variant associated with less proteolytic activity, higher risk of chronic complications and better response to ACEi therapy. Screening for Pro618Ala polymorphism may help identifying diabetics at highest risk who may benefit the most from early reno- and cardioprotective therapy.
Pharmacologically, vasoactive agents targeting endothelial and/or smooth muscle cells (SMC) are known to cause acute drug-induced vascular injury (DIVI) and the resulting pathology is due to endothelial cell (EC) perturbation, activation, and/or injury. Alteration in EC structure and/or function may be a critical event in vascular injury and, therefore, evaluation of the circulatory kinetic profile and secretory pattern of EC-specific proteins such as VWF and VWFpp could serve as acute vascular injury biomarkers. In rat and dog models of DIVI, this profile was determined using pharmacologically diverse agents associated with functional stimulation/perturbation (DDAVP), pathological activation (lipopolysaccharide [LPS]/endotoxin), and structural damage (fenoldopam [FD], dopamine [DA], and potassium channel opener (PCO) ZD6169). In rats, FD caused moderate DIVI and time-related increase in plasma VWF levels ∼33% while in control rats VWF increased ∼5%. In dogs, VWF levels transiently increased ∼30% when there was morphologic evidence of DIVI by DA or ZD6169. However, in dogs, VWFpp increased >60-fold (LPS) and >6-fold (DDAVP), respectively. This was in comparison to smaller dynamic 1.38-fold (LPS) and 0.54-fold (DDAVP) increases seen in plasma VWF. Furthermore, DA was associated with a dose-dependent increase in plasma VWFpp. In summary, VWF and VWFpp can discriminate between physiological and pathological perturbation, activation, and injury to ECs.
The von Willebrand factor (vWF) is an acute stroke response protein involved in platelet aggregation, adhesion, inflammation, and thrombus formation, responses that occur following an ischemic stroke. We hypothesize that administration of an anti-vWF antibody (anti-vWF-Ab) may be used as adjunctive therapy with tissue plasminogen activator (tPA) to promote behavioral improvement following an embolic stroke. In this proof-of-concept study, which used a blinded and randomized design, we studied delayed treatment with the anti-vWF-Ab, AJW200 (0.30 mg/kg), alone or in combination with a rabbit low-dose of tPA (0.9 mg/kg) using the rabbit small clot embolic stroke model (RSCEM) with behavioral function as the primary clinically relevant endpoint. To evaluate the quantitative relationship between clot burden in brain and clinical scores, so that an effective stroke dose (P50) could be calculated, logistic sigmoidal quantal analysis curves were constructed. A beneficial treatment significantly increases P50 compared to control. The effect of antibody administration, either alone or with low dose tPA was compared to a "positive control", a standard rabbit optimized dose of tPA (3.3 mg/kg), as a measure of the maximum improvement potential in the RSCEM. The anti-vWF-Ab, AJW200, or control IgG were administered IV 1 hour following embolization, and behavior was measured 48 hours later. AJW200 plus low-dose tPA significantly increased the P50 value by 74% (p<0.05, t=2.612) and 81% (p<0.05, t=2.519) compared to low dose tPA or IgG, respectively, but not the AJW200 group (p>0.05). AJW200 increased the P50 value by 28%, (p>0.05) compared to the control IgG-treated group. Standard dose tPA increased the P50 value by 154% (p<0.05). Statistically, the combination response for AJW200 plus low-dose tPA was not significantly different from standard dose tPA (p=0.26). This study shows that the concomitant administration of the anti-vWF-Ab AJW200 with low dose tPA is synergistic and results in significantly improved behavioral function following embolic stroke. We postulate that neutralization of vWF may suppress or attenuate one or more aspects of the acute phase stroke cascade response including suppression of inflammatory response and reduced leukocyte adhesion.
Introduction
The reader will find here a concise summary of established notions on the structure and function of von Willebrand factor (vWF), followed by a brief discussion of selected recent advances that illustrate how this molecule supports platelet function in hemostasis and thrombosis. A comprehensive review of the topic is beyond the scope of this chapter and may be found elsewhere.1-3
Background
Postprocedural aortic regurgitation occurs in 10 to 20% of patients undergoing transcatheter aortic-valve replacement (TAVR) for aortic stenosis. We hypothesized that assessment of defects in high-molecular-weight (HMW) multimers of von Willebrand factor or point-of-care assessment of hemostasis could be used to monitor aortic regurgitation during TAVR.
Methods
We enrolled 183 patients undergoing TAVR. Patients with aortic regurgitation after the initial implantation, as identified by means of transesophageal echocardiography, underwent additional balloon dilation to correct aortic regurgitation. HMW multimers and the closure time with adenosine diphosphate (CT-ADP), a point-of-care measure of hemostasis, were assessed at baseline and 5 minutes after each step of the procedure. Mortality was evaluated at 1 year. A second cohort (201 patients) was studied to validate the use of CT-ADP in order to identify patients with aortic regurgitation.
Results
After the initial implantation, HMW multimers normalized in patients without aortic regurgitation (137 patients). Among the 46 patients with aortic regurgitation, normalization occurred in 20 patients in whom additional balloon dilation was successful but did not occur in the 26 patients with persistent aortic regurgitation. A similar sequence of changes was observed with CT-ADP. A CT-ADP value of more than 180 seconds had sensitivity, specificity, and negative predictive value of 92.3%, 92.4%, and 98.6%, respectively, for aortic regurgitation, with similar results in the validation cohort. Multivariable analyses showed that the values for HMW multimers and CT-ADP at the end of TAVR were each associated with mortality at 1 year.
Conclusions
The presence of HMW-multimer defects and a high value for a point-of-care hemostatic test, the CT-ADP, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure. (Funded by Lille 2 University and others; ClinicalTrials.gov number, NCT02628509.)
Portal vein thrombosis (PVT) dramatically changes the prognosis of cirrhotic patients, especially those waiting for liver transplantation. However, the possible contribution to PVT of von Willebrand factor (VWF) and ADAMTS-13 is poorly documented. The aim of our study was to assess the presence of alterations of VWF and ADAMTS-13 serum levels in cirrhotic patients with PVT. Twenty-four patients with PVT (group PVT) and 60 without PVT (group without PVT) were enrolled. A comprehensive analysis of biochemical and hemostatic parameters was performed. ADAMTS-13 activity was significantly lower in group A (median 16.8 vs. 69.1 %, p = 0.0047). Group PVT, compared to group without PVT, showed a significantly higher VWF:act, (median 308.4 vs 203.3 %, p = 0.032), whereas no difference was observed for VWF:Ag, FVIII level and the presence of risk factors for venous thromboembolism. No correlation was found between the Child–Pugh score and ADAMTS-13 activity. In multivariable logistic regression analysis performed on data concerning both group PVT and without PVT, only the ADAMTS-13 activity (p = 0.007) was independently and inversely associated with PVT. In conclusion, ADAMTS-13 activity is independently associated with PVT in cirrhotic patients.
Thrombotic thrombocytopenic purpura (TTP), a rare thrombotic microangiopathy, is defined by a mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia due to systemic platelet-rich microthrombi. Specifically in TTP microthrombi, von Willebrand factor, not fibrinogen, is the protein that binds to platelets.(1) Von Willebrand factor is a multimeric glycoprotein that is crucial for physiologic platelet adhesion and aggregation at high shear rates of blood flow, and the largest von Willebrand factor multimers are the most adhesive. The hemostatic power of von Willebrand factor is regulated by a specific cleaving metalloprotease named ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, . . .
Background
Acquired thrombotic thrombocytopenic purpura (TTP) is caused by aggregation of platelets on ultralarge von Willebrand factor multimers. This microvascular thrombosis causes multiorgan ischemia with potentially life-threatening complications. Daily plasma exchange and immunosuppressive therapies induce remission, but mortality and morbidity due to microthrombosis remain high.
Methods
Caplacizumab, an anti–von Willebrand factor humanized single-variable-domain immunoglobulin (Nanobody), inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. In this phase 2, controlled study, we randomly assigned patients with acquired TTP to subcutaneous caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 days afterward. The primary end point was the time to a response, defined as confirmed normalization of the platelet count. Major secondary end points included exacerbations and relapses.
Results
Seventy-five patients underwent randomization (36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P=0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group.
Conclusions
Caplacizumab induced a faster resolution of the acute TTP episode than did placebo. The platelet-protective effect of caplacizumab was maintained during the treatment period. Caplacizumab was associated with an increased tendency toward bleeding, as compared with placebo. (Funded by Ablynx; ClinicalTrials.gov number, NCT01151423.)
In this issue of Blood , [Chung and colleagues][1] demonstrate in vitro and in an animal model that von Willebrand factor (VWF) self-association under shear stress can be modulated by the high-density lipoprotein and apolipoprotein A-I (HDL/ApoA-I) complex, with significant reduction in the length
The success of a primary percutaneous intervention (PCI) in the setting of ST elevation myocardial infarction depends on the functional and structural integrity of coronary microcirculation. Coronary microvascular dysfunction and obstruction (CMVO) occurs in up to half of patients submitted to apparently successful primary PCI and is associated to a much worse outcome. The current review summarizes the complex mechanisms responsible for CMVO, including pre-existing coronary microvascular dysfunction, and highlights the current limitations in the assessment of microvascular function. More importantly, at the light of the substantial failure of trials hitherto published on the treatment of CMVO, this review proposes a novel integrated therapeutic approach, which should overcome the limitations of previous studies.
During percutaneous coronary intervention (PCI), trauma occurs in the arterial endothelium, resulting in platelet activation and aggregation. As platelet aggregation may lead to coronary thrombosis, antiplatelet agents are essential adjunctive therapies in patients undergoing PCI. The aim of this study was to determine the effect of the intracoronary administration of high-dose N-acetylcysteine (NAC) for the evaluation of its antiplatelet effects in human subjects. In this triple-blind trial, 147 patients undergoing primary PCI were enrolled. Finally, 100 patients were randomized to receive high-dose intracoronary NAC (100 mg/kg bolus, followed by 10 mg·kg·h intracoronary continued intravenously for 12 hours) (n = 50) or dextrose solution (n = 50). Platelet activation biomarkers were measured before and 24 hours after the procedure. Secondary end points, comprising all-cause death, reinfarction, and target-vessel revascularization, were assessed at 30 days and 2 years. In comparison with the placebo, NAC could not reduce the level of platelet activation biomarkers within a 24-hour period after its prescription. Major adverse clinical events at 30 days and 2 years were infrequent and not statistically different between the 2 groups. Our results revealed that NAC, compared with the placebo, did not provide an additional clinical benefit as an effective antiplatelet agent after PCI.
Patients with bleeding complications during left ventricular assist device (LVAD) support often require a reduction in the recommended warfarin plus aspirin regimen. To characterize those who can be safely managed with a reduced anti-thrombotic strategy, the TRACE (STudy of Reduced Anti-Coagulation/Anti-platelEt Therapy in Patients with the HeartMate II LVAS) study was initiated in the United States (U.S.) and Europe.
The TRACE U.S. arm enrolled HeartMate II (HMII; Thoratec) outpatients on a regimen of reduced anti-thrombotic therapy (RT), defined as vitamin K antagonist (warfarin) only, aspirin only, or no anti-thrombotic agent. The indication for RT, changes in anti-thrombotic therapies, and patient outcomes after RT were documented. Results for patients reaching 12 months or outcome are presented here.
Between April 2012 and June 2013, 100 HMII outpatients (85% men) on RT (median age 64.5 [interquartile range, 32, 82] years, 61% with ischemic etiology, 69% destination therapy) were enrolled from 9 U.S. sites. The primary reason for RT initiation was in response to a bleeding event (82%). Pharmacotherapy at RT initiation included warfarin only (38%), aspirin only (28%), or no anti-thrombotic agent (34%). Freedom from ischemic stroke at 1 year was 93.8% ± 2.5%, and freedom from device thrombosis was 92.7% ± 2.7%. Despite RT, a subsequent bleeding event occurred in 52%.
Reducing anti-thrombotic therapies in response to bleeding among HMII patients was achievable but may be associated with a higher risk for device thrombosis. Furthermore, despite an RT strategy, bleeding often will persist in those prone to such events.
Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Low levels of ADAMTS13 have been repeatedly associated with an increased risk of ischemic stroke but results for risk of myocardial infarction (MI) are inconclusive.
To perform an individual patient data meta-analysis from observational studies investigating the association between ADAMTS13 levels and MI.
A one step meta-analytic approach with random treatment effects was used to estimate pooled odds ratios (OR) and corresponding 95% confidence intervals (CI) adjusted for confounding. Analyses were based on dichotomous exposures, with the 5(th) and 1(st) percentile of ADAMTS13 antigen levels as cut off values. Quartile analyses, with the highest quartile as a reference category, were used to assess a graded association between levels and risk ('dose' relationship). Additionally, we assessed the risk of the combined presence of low ADAMTS13 and high von Willebrand Factor (VWF) levels.
Five studies were included, yielding individual data on 1501 cases and 2258 controls (mean age 49 years). Low levels of ADAMTS13 were associated with myocardial infarction risk, with an OR of 1.89 (95% CI 1.15-3.12) for values below the 5(th) percentile versus above, and an OR of 4.21 (95% CI 1.73-10.21) for values below the 1(st) percentile versus above. Risk appeared restricted to these extreme levels, as there was no graded association between levels of ADAMTS13 and MI risk over quartiles. Finally, there was only a minor synergistic effect for the combination of low ADAMTS13 and high VWF levels.
Low levels of ADAMTS13 are associated with an increased risk of MI. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
The interaction between platelet glycoprotein Ib and von Willebrand factor (vWF) plays a crucial role in platelet-mediated thrombus formation under high-shear-stress conditions. The aim of this study was to investigate the antiplatelet profile of a humanized anti-vWF monoclonal antibody, AJW200. In vitro studies were performed with a modified cone-and-plate viscometer and human platelets. AJW200 inhibited high-shear-stress-induced platelet adhesion, aggregation, and thrombin generation, but it did not have such effects under low-shear-stress conditions. Although abciximab inhibited platelet aggregation under both shear stress conditions, it did not inhibit platelet adhesion and thrombin generation. In addition, the pharmacokinetics and pharmacodynamics of AJW200 were evaluated in cynomolgus monkeys. Sustained inhibition of ristocetin-induced platelet aggregation was observed over 24 hours, 6 days, and 2 weeks after a single bolus injection of 0.3, 1, and 3 mg/kg, respectively. Moderate prolongation of the bleeding time was observed at the doses of 1 and 3 mg/kg. Abciximab markedly prolonged the bleeding time at 0.4 mg/kg, at which concentration complete inhibition of ADP-induced platelet aggregation was observed. These results suggest that glycoprotein Ib-vWF blockade with AJW200 results in a sustained antiplatelet effect without extensive prolongation of the bleeding time, probably due to a shear-stress-dependent inhibitory action.
Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurological deficits. It is characterized by a deficiency of the Von Willebrand Factor (VWF) cleaving enzyme, ADAMTS13, resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There is limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.
Copyright © 2015 American Society of Hematology.
Aortic valve stenosis (AVS) can be complicated by bleeding associated with acquired type 2A von Willebrand syndrome. The association of AVS and gastrointestinal bleeding from angiodysplasia is defined as Heyde syndrome. We sought to evaluate the effect of transcutaneous aortic valve implantation (TAVI) on hemostasis disorders and to assess its effectiveness to treat Heyde syndrome.
We prospectively enrolled 49 consecutive patients with severe AVS addressed for TAVI at our institution. Biological hemostasis parameters involving von Willebrand factor (vWF) were assessed at baseline and 1 week after the procedure.
At baseline, a significant link between vWF abnormalities and the severity of AVS was evidenced: mean aortic transvalvular gradient was negatively correlated with the levels of vWF antigen (vWF:Ag) (r = -0.29; P < 0.05), vWF ristocetin cofactor activity (r = -0.402; P = 0.006), and vWF collagen-binding activity (vWF:CB; r = -0.441; P = 0.005). One week after the procedure, a significant increase of vWF:Ag, vWF ristocetin cofactor activity, and vWF:CB was evidenced in the whole cohort (respectively, 3.32 vs 2.29 IU/mL, P < 0.001; 2.98 vs 1.86 IU/mL, P < 0.001; and 3.16 vs 2.16 IU/mL, P < 0.001). Patients with pre-TAVI vWF abnormalities consistent with a type 2A vWF syndrome (ratio vWF:CB/vWF:Ag < 0.7) preferentially improved their vWF function with respect to patients with a normal ratio (relative increase of vWF:CB of 63.8% vs 3.5%).
Hemostasis parameters involving vWF are improved after TAVI, especially in patients with pre-existing abnormalities consistent with acquired type 2A von Willebrand syndrome.
Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Rationale:
Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis. Residual gradient and residual aortic regurgitation are major predictors of midterm and long-term outcome after percutaneous aortic valve procedures. We hypothesized that (1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor defect could be instantaneous after acute changes in blood flow, (2) a bedside point-of-care assay (platelet function analyzer-closure time adenine DI-phosphate [PFA-CADP]), reflecting HMW multimers changes, could be used to monitor in real-time percutaneous aortic valve procedures.
Objective:
To investigate the time course of HMW multimers changes in models and patients with instantaneous induction/reversal of pathological high shear and its related bedside assessment.
Methods and results:
We investigated the time course of the induction/recovery of HMW multimers defects under instantaneous changes in shear stress in an aortic stenosis rabbit model and in patients undergoing implantation of a continuous flow left ventricular assist device. We further investigated the recovery of HMW multimers and monitored these changes with PFA-CADP in aortic stenosis patients undergoing transcatheter aortic valve implantation or balloon valvuloplasty. Experiments in the aortic stenosis rabbit model and in left ventricular assist device patients demonstrated that induction/recovery of HMW multimers occurs within 5 minutes. Transcatheter aortic valve implantation patients experienced an acute decrease in shear stress and a recovery of HMW multimers within minutes of implantation which was sustained overtime. In patients with residual high shear or with residual aortic regurgitation, no recovery of HMW multimers was observed. PFA-CADP profiles mimicked HMW multimers recovery both in transcatheter aortic valve implantation patients without aortic regurgitation (correction) and transcatheter aortic valve implantation patients with aortic regurgitation or balloon valvuloplasty patients (no correction).
Conclusions:
These results demonstrate that variations in von Willebrand factor multimeric pattern are highly dynamic, occurring within minutes after changes in blood flow. It also demonstrates that PFA-CADP can evaluate in real time the results of transcatheter aortic valve procedures.
Aptamers are oligonucleotides targeting protein-protein interactions with pharmacokinetic profiles and activity reversal options. Although P-selectin and von Willebrand factor (vWF) have been implicated in the development of venous thrombosis (VT), no studies have directly compared aptamer efficacy with standard of care in VT. In this study, ARC5692, an anti-P-selectin aptamer, and ARC15105, an anti-vWF aptamer, were compared with low-molecular-weight heparin, enoxaparin, to test the efficacy of P-selectin or vWF inhibition in promoting thrombus resolution and preventing vein wall fibrosis, in a baboon model of VT.
Groups were as follows: treatment arm: animals received P-selectin or vWF aptamer inhibitors or enoxaparin (n=3 per group). Controls received no treatment (n=3). Prophylactic arm: animals received P-selectin inhibitor (n=4) or vWF inhibitor (n=3). Treatment arm: P-selectin-inhibitor demonstrated a significant improvement in vein recanalization by magnetic resonance venography (73% at day 21), and significantly decreased vein wall collagen, compared with all groups. Anti-P-selectin equaled enoxaparin in maintaining valve competency by ultrasound. All control animals had compromised valve competency post thrombosis. Prophylactic arm: animals receiving P-selectin and vWF inhibitors demonstrated improved vein recanalization by magnetic resonance venography versus controls (80% and 85%, respectively, at day 21). Anti-P-selectin protected iliac valve function better than anti-vWF, and both improved valve function versus controls. No adverse bleeding events were observed.
The P-selectin inhibitor aptamer promoted iliac vein recanalization, preserved valve competency, and decreased vein wall fibrosis. The results of this work suggest that P-selectin inhibition maybe an ideal target in the treatment and prophylaxis of deep VT, warranting clinical trials.
© 2015 American Heart Association, Inc.
Platelets are involved in life-sustaining processes such as hemostasis, wound healing, atherothrombosis and angiogenesis. Mechanical trauma to blood vessels causes platelet activation resulting in their adherence and clot formation at the damaged site, culminating in clot retraction and tissue repair. Two of the major players underlying this process are the cytoskeleton, i.e., actin and microtubules, and the membrane integrin receptors. Rare congenital bleeding disorders such as Glanzmann thrombasthenia and Bernard-Soulier syndrome are associated with genetic alterations of platelet surface receptors, also affecting the platelet cytoskeletal structure. In this review, we summarize the current knowledge about platelet structure and adhesion, and delve into the mechanical aspects of platelet function. Platelets lack a nucleus, and can thus provide a minimal model of a biological cell. New biophysical tools may help to scrutinize platelets anew and to extend the existing knowledge on cell biology.
High von Willebrand factor (VWF) plasma levels are associated with an increased risk of coronary artery disease. It has been suggested that the increase of VWF levels is partly due to endothelial dysfunction and atherosclerosis. Our aim was to investigate the association between coronary plaque burden, the presence of high-risk coronary lesions as measured by intravascular ultrasound virtual histology (IVUS-VH) and VWF levels. In addition, we studied the association between VWF levels and one-year cardiovascular outcome. Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography for acute coronary syndrome (ACS) (n= 318) or stable angina pectoris (SAP) (n= 263). Arterial blood was sampled prior to the coronary angiography. VWF antigen (VWF:Ag) levels were measured using ELISA (n= 577). Patients with ACS had significantly higher VWF:Ag levels than SAP patients (median 1.73 IU/ml [IQR 1.27-2.31] vs 1.26 IU/ml [0.93-1.63], p< 0.001). High coronary plaque burden was associated with higher VWF:Ag levels (β= 0.12, p=0.027) in SAP patients, but not in ACS patients. In ACS patients, VWF:Ag levels were associated with 1-year MACE (HR 4.14 per SD increase of lnVWF:Ag, 95 % CI 1.47-11.6), whereas in SAP patients VWF:Ag levels predicted 1-year all-cause death and hospitalisation for ACS (HR 7.07 95 % CI 1.40-35.6). In conclusion, coronary plaque burden was associated with VWF:Ag levels in SAP patients undergoing coronary angiography. In ACS and SAP patients, high VWF levels are predictive of adverse cardiovascular outcome and death during one-year follow-up.
Background
Gastrointestinal hemorrhage is considered a severe complication of von Willebrand disease. Optimal therapy for acquired von Willebrand syndrome and severe gastrointestinal bleeding with hypertrophic cardiomyopathy is undefined.Patients/Methods
Seventy seven patients, median, (IQR) age 67, (56-75) years, 49% women with hypertrophic cardiomyopathy underwent von Willebrand factor multimer testing and acquisition of bleeding history. Bleeding was detected in 27 (36%), median, (IQR) age 74, (66-76) years, 74% women, 20 with gastrointestinal bleeding, including 11 women with transfusion dependence. In these 11 women, median, IQR duration of transfusion dependency was 36, (18-44) months, and median, IQR number of transfusions required was 25, (20-38). Two patients had had bowel resections for bleeding, one twice. Seven patients demonstrated angiodysplasia, and the remainder had no endoscopic lesion. Bleeding recurred after bowel surgery or endoscopic intervention and medical therapy for hypertrophic cardiomyopathy in 10/11 patients. Two patients had septal myectomy, and 6 patients underwent alcohol septal ablation. With the exception of one patient in whom a significant gradient persisted after septal ablation, after the peri-procedural period, patients post-septal reduction therapy remained free of recurrent bleeding and need for transfusions.Conclusion
Acquired von Willebrand syndrome is common in hypertrophic cardiomyopathy. Gastrointestinal bleeding often recurs after endoscopic therapy, but may be relieved by structural cardiac repair.This article is protected by copyright. All rights reserved.
Background
Mitral valve regurgitation is associated with an acquired hemostatic defect.Objective
We sought to assess the prevalence and severity of acquired von Willebrand syndrome in native valve mitral regurgitation (MR).Patients/Methods
Fifty-three patients were prospectively observed with bleeding questionnaires and laboratory tests when undergoing an echocardiographic assessment of MR. In patients referred for mitral valve surgery, testing was repeated post-operatively.ResultsEchocardiography identified 13 patients with mild MR, 14 with moderate MR, and 26 patients with severe MR. In mild, moderate, or severe MR, loss of the highest molecular weight von Willebrand factor (VWF) multimers occurred in 8%, 64%, and 85% respectively, while median (interquartile range, IQR) platelet function analyzer adenosine diphosphate closure time (PFA-CADP) was 84 sec (73-96 sec), 156 sec (104-181 sec), and 190 sec (157-279 sec) respectively, and the ratio of VWF latex activity to antigen, was 0.92 (0.83-0.97), 0.85 (0.76-0.89), and 0.79 (0.75-0.82) respectively, all p<0.001. Nine patients reported clinically significant bleeding, and 7 had intestinal angiodysplasia and transfusion dependent gastrointestinal bleeding (Heyde syndrome), with median (IQR) number of transfusions required 20 (10, 33), range 4-50. In patients who underwent mitral valve repair (n=13) or replacement (n=7), all measures of VWF function reported above significantly improved.Conclusion
The high shear environment of moderate to severe MR is sufficient to produce prevalent perturbations in VWF activity. Acquired von Willebrand syndrome may occur in this setting, and appears to be reversible with mitral valve surgery.This article is protected by copyright. All rights reserved.
When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that like characters in Star Wars who learn to use the Force to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended thread-like in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables post-secretion regulation of VWF length. Mutations in VWF in von Willebrand disease (VWD) contribute to and are illuminated by VWF biology. I attempt to integrate classic studies on the physiology of hemostatic plug formation into modern molecular understanding, and point out what remains to be learned.
Von Willebrand disease (VWD), the most common genetic bleeding disorder, is characterised by a quantitative or qualitative defect of von Willebrand factor (VWF). Patients with VWD suffer from mucocutaneous bleeding, of severity usually proportional to the degree of VWF defect. In particular, gastrointestinal bleeding associated with angiodysplasia is often a severe symptom of difficult management. This review focuses on the pathophysiology, diagnosis and treatment of VWD-associated gastrointestinal angiodysplasia and related bleeding.
Von Willebrand factor (VWF), a key player in hemostasis and thrombosis, is released from endothelial cells during inflammation. Upon release, VWF is processed by ADAMTS13 into an inactive conformation. The aim of our study was to investigate whether plasma levels of active VWF, total VWF, ADAMTS13, osteoprotegerin (OPG) and the ratios between VWF and ADAMTS13 are risk factors for first ST-segment elevation myocardial infarction (STEMI).
We assessed 1026 patients with confirmed first STEMI and 652 control subjects from China, Italy and Scotland, within six hours after their cardiovascular event. Median plasma levels of total VWF, active VWF, OPG and ratios VWF/ADAMTS13 were increased, while plasma levels of ADAMTS13 were decreased in patients compared to controls. The odds ratio (OR) of STEMI in patients with high plasma levels of active VWF was 2.3 (interquartile range (IQR): 1.8-2.9), total VWF was 1.8 (1.4-2.3), ADAMTS13 was 0.6 (05-0.8), OPG was 1.6 (1.2-2.0) and high VWF/ADAMTS13 ratios was 1.5 (1.2-2.0). The OR for total VWF, active VWF and ratios VWF/ADAMTS13 remained significant after adjustment for established risk factors, medical treatment, C-reactive protein, total VWF, ADAMTS13 and OPG. When we adjusted for levels of active VWF, the significance of the OR for VWF and ratios VWF/ADAMTS13 disappeared while the OR for active VWF remained significant.
We found evidence that plasma levels of active VWF are an independent risk factor for first STEMI in patients from three different ethnic groups. Our findings confirm the presence of VWF abnormalities in patients with STEMI and may be used to develop new therapeutic approaches.
The term systems pharmacology describes a field of study that uses computational and experimental approaches to broaden the view of drug actions rooted in molecular interactions and advance the process of drug discovery. The aim of this work is to stick out the role that the systems pharmacology plays across the multi-target drug discovery from natural products for cardiovascular diseases (CVDs). Firstly, based on network pharmacology methods, we reconstructed the drug-target and target-target networks to determine the putative protein target set of multi-target drugs for CVDs treatment. Secondly, we reintegrated a compound dataset of natural products and then obtained a multi-target compounds subset by virtual-screening process. Thirdly, a drug-likeness evaluation was applied to find the ADME-favorable compounds in this subset. Finally, we conducted in vitro experiments to evaluate the reliability of the selected chemicals and targets. We found that four of the five randomly selected natural molecules can effectively act on the target set for CVDs, indicating the reasonability of our systems-based method. This strategy may serve as a new model for multi-target drug discovery of complex diseases.
In patients with diabetes, impaired ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) proteolysis of highly thrombogenic von Willebrand factor (VWF) multimers may accelerate renal and cardiovascular complications. Restoring physiological VWF handling might contribute to ACE inhibitors' (ACEi) reno- and cardioprotective effects. To assess how Pro618Ala ADAMTS13 variants and related proteolytic activity interact with ACEi therapy in predicting renal and cardiovascular complications, we genotyped 1,163 normoalbuminuric type 2 diabetic patients from BErgamo NEphrologic DIabetes Complications Trial (BENEDICT). Interaction between Pro618Ala and ACEi was significant in predicting both renal and combined renal and cardiovascular events. The risk for renal or combined events versus reference Ala carriers on ACEi progressively increased from Pro/Pro homozygotes on ACEi (hazard ratio 2.80 [95% CI 0.849-9.216] and 1.58 [0.737-3.379], respectively) to Pro/Pro homozygotes on non-ACEi (4.77 [1.484-15.357] and 1.99 [0.944-4.187]) to Ala carriers on non-ACEi (8.50 [2.416-29.962] and 4.00 [1.739-9.207]). In a substudy, serum ADAMTS13 activity was significantly lower in Ala carriers than in Pro/Pro homozygotes and in case subjects with renal, cardiovascular, or combined events than in diabetic control subjects without events. ADAMTS13 activity significantly and negatively correlated with all outcomes. In patients with diabetes, ADAMTS13 618Ala variant associated with less proteolytic activity, higher risk of chronic complications, and better response to ACEi therapy. Screening for Pro618Ala polymorphism may help identify patients with diabetes at highest risk who may benefit the most from early reno- and cardioprotective therapy.
There is evidence indicating that statins (3-hydroxy-methylglutaryl coenzyme A reductase inhibitors) may produce several cholesterol-independent antithrombotic effects. In this review, we provide an update on the current understanding of the interactions between statins and blood coagulation and their potential relevance to the prevention of venous thromboembolism (VTE). Anticoagulant properties of statins reported in experimental and clinical studies involve decreased tissue factor expression resulting in reduced thrombin generation and attenuation of pro-coagulant reactions catalysed by thrombin, such as fibrinogen cleavage, factor V and factor XIII activation, as well as enhanced endothelial thrombomodulin expression, resulting in increased protein C activation and factor Va inactivation. Observational studies and one randomized trial have shown reduced VTE risk in subjects receiving statins, although their findings still generate much controversy and suggest that the most potent statin rosuvastatin exerts the largest effect.
Factors explaining the association between impaired kidney function and venous thrombosis have not been identified so far. The aim of our study was to determine whether the association between impaired kidney function and venous thrombosis can be explained by the concurrent presence of genetic or acquired venous thrombosis risk factors.
The glomerular filtration rate was estimated (eGFR) in 2473 venous thrombosis patients and 2936 controls from a population-based case-control study. Kidney function was grouped into 6 categories based on percentiles of the eGFR in the controls (>50th percentile [reference], 10th-50th percentile, 5th-10th percentile, 2.5th-5th percentile, 1st-2.5th percentile, and <1st percentile). Several hemostatic factors showed a procoagulant shift with decreasing kidney function in controls, most notably factor VIII and von Willebrand factor (VWF). As compared with eGFR> 50th percentile, factor VIII levels (adjusted mean difference of 60 IU/dl for the <1st eGFR percentile category) and VWF levels (adjusted mean difference of 60 IU/dl for the <1st eGFR percentile category) increased with each percentile category. The ORs for venous thrombosis similarly increased across the categories from 1.1 (95%CI,0.9-1.3) for the 10th-50th percentile to 3.7 (95%CI,2.4-5.7) for the <1st percentile category. Adjustment for factor VIII or von Willebrand factor attenuated these ORs indicating an effect of eGFR on thrombosis through these factors. Adjustments for other risk factors for venous thrombosis did not affect the ORs.
Impaired kidney function affects venous thrombosis risk via concurrently raised factor VIII and von Willebrand factor levels.