Elevated Plasma von Willebrand Factor Antigen and Activity Levels Are Associated With the Severity of Coronary Stenosis

von Willebrand factor (VWF) acts as a bridge between platelets and the subendothelial matrix following vessel damage and plays a vital role in coronary artery disease (CAD). The aim of this study was to investigate the association between VWF and the severity of coronary stenosis quantified by the Gensini score in acute myocardial infarction (AMI), the most dangerous complication of CAD. Plasma VWF antigen (VWF: Ag) and VWF-collagen binding (VWF: CB) in normal controls (n = 123) and in patients with AMI (n = 205) were tested, and then the patients were divided based on Gensini scores. The levels of VWF: Ag and VWF: CB in patients with AMI were significantly higher than those in the control group ( P < .001). Plasma levels of VWF: Ag and VWF: CB were positively correlated with both Gensini score and the number of affected vessels. Both VWF: Ag and VWF: CB were independent factors for coronary stenosis, adjusting confounding factors. Thus, the levels of VWF: Ag and VWF: CB were positively correlated with the severity of coronary stenosis. Screening of VWF at time of AMI may have prognostic value in terms of the severity of coronary stenosis.

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Comparative analysis of prothrombotic activity in patients with myocardial infarction with non-obstructive and obstructive atherosclerotic lesions of the coronary arteries

European Heart Journal Acute Cardiovascular Care ◽

10.1093/ehjacc/zuab020.140 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

Author(s):

VV Ryabov ◽

D Vorobyeva ◽

YUG Lugacheva ◽

IV Kulagina

Keyword(s):

Myocardial Infarction ◽

Coronary Arteries ◽

Von Willebrand Factor ◽

Protein C ◽

Control Group ◽

Moderate Correlation ◽

Blood Tests ◽

Group A ◽

Von Willebrand ◽

Willebrand Factor

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The reported study was funded by RFBR, project number №19-315-90106 Aim To compare indicators of blood prothrombotic activity in patients with myocardial infarction with and without coronary arteries obstruction Material and methods. The study included 40 patients with AMI (19 patients in the main group and 21 patients in the control group). Three patients (15.7%) with acute myocarditis were excluded from the analysis. Hemostasiological and hematological blood tests were studied upon admission, on the 2nd, 4th, 7th days from hospitalization. Blood samples for protein C, antithrombin, von Willebrand factor (WF), plasminogen, homocysteine were performed on 4th ± 1 day from hospitalization. To determine the IgG / IgM antibodies to cardiolipin and β2-glycoprotein for the diagnosis of APS, the ORGENTEC Anti-β2-Glycoprotein I IgG / IgM ELISA enzyme immunoassay was used. Blood tests for lupus anticoagulant were performed using an ACL-Top 700 analyzer (Werfen) with HemosIL SynthASil dRVVT screen reagents / dRVVT confirm and with a SCT screen / SCT confirm quartz activator. Results In patients with MINOCA a statistically higher level of homocysteine (p = 0.03) and a lower level of plasminogen (p = 0.007) are determined. Protein C, antithrombin, WF the presence of lupus anticoagulant, antibodies to cardiolipin and β2-glycoprotein no differences between the groups were detected, p >0.05. MINOCA patients have a statistically higher platelet level on the 2nd and 4th day of AMI (p = 0.046 and p = 0.01 ) however the level of hemoglobin and hematocrit was statistically lower on the 4th day of AMI, (p = 0.008). In the main group, a moderate correlation was found between protein C and antithrombin (r = 0.65, p = 0.0001), antithrombin and von Willebrand factor (r = 0.54, p = 0.0001), between protein C and platelet level by 4th day (r = - 0.49, p = 0.04). In MINOCA patients a moderate negative correlation was found between homocysteine and plasminogen (r = -0.69, p = 0.002). In the control group, a high correlation was found between protein C and antithrombin (r = 0.96, p = 0.0001), a moderate correlation between protein C and plasminogen (r = 0.47, p = 0.03). In addition, a relationship was revealed between the presence of thrombosis according to ICAG data and the level of ejection fraction (r = 0.46, p = 0.04) in the control group, as well as between the presence of thrombosis and the level of fibrinogen upon admission (r = 0.55, p = 0.008). Conclusions Patients with MINOCA have a higher level of homocysteine and a lower level of plasminogen. For such indicators as protein C, antithrombin III, WF the presence of antibodies on the APS is not defined differences between groups. According to laboratory data patients with MINOCA showed higher levels of platelets but lower levels of hemoglobin and hematocrit in the early post-infarction period.

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Regulation of plasma von Willebrand factor

F1000Research ◽

10.12688/f1000research.13056.1 ◽

2018 ◽

Vol 7 ◽

pp. 96 ◽

Cited By ~ 6

Author(s):

Karl C Desch

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Coagulation Factor ◽

Vascular Wall ◽

Healthy Human ◽

Venous Thromboembolic ◽

Artery Disease ◽

Von Willebrand ◽

Willebrand Factor

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a central role in the initiation of blood coagulation. Through interactions between its specific functional domains, the vascular wall, coagulation factor VIII, and platelet receptors, VWF maintains hemostasis by binding to platelets and delivering factor VIII to the sites of vascular injury. In the healthy human population, plasma VWF levels vary widely. The important role of VWF is illustrated by individuals at the extremes of the normal distribution of plasma VWF concentrations where individuals with low VWF levels are more likely to present with mucocutaneous bleeding. Conversely, people with high VWF levels are at higher risk for venous thromboembolic disease, stroke, and coronary artery disease. This report will summarize recent advances in our understanding of environmental influences and the genetic control of VWF plasma variation in healthy and symptomatic populations and will also highlight the unanswered questions that are currently driving this field of study.

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Population Pharmacokinetic Modeling of von Willebrand Factor Activity in von Willebrand Disease Patients after Desmopressin Administration

Thrombosis and Haemostasis ◽

10.1055/s-0040-1714349 ◽

2020 ◽

Vol 120 (10) ◽

pp. 1407-1416

Author(s):

Nico C. B. de Jager ◽

Jessica M. Heijdra ◽

Quincy Kieboom ◽

Marieke J. H. A. Kruip ◽

Frank W. G. Leebeek ◽

...

Keyword(s):

Von Willebrand Factor ◽

Time Profile ◽

Von Willebrand Disease ◽

Activity Level ◽

Population Pharmacokinetic ◽

Activity Levels ◽

Interpatient Variability ◽

Starting Point ◽

Von Willebrand ◽

Willebrand Factor

Abstract Objective Most von Willebrand disease (VWD) patients can be treated with desmopressin during bleeding or surgery. Large interpatient variability is observed in von Willebrand factor (VWF) activity levels after desmopressin administration. The aim of this study was to develop a pharmacokinetic (PK) model to describe, quantify, and explain this variability. Methods Patients with either VWD or low VWF, receiving an intravenous desmopressin test dose of 0.3 µg kg−1, were included. A PK model was derived on the basis of the individual time profiles of VWF activity. Since no VWF was administered, the VWF dose was arbitrarily set to unity. Interpatient variability in bioavailability (F), volume of distribution (V), and clearance (Cl) was estimated. Results The PK model was developed using 951 VWF activity level measurements from 207 patients diagnosed with a VWD type. Median age was 28 years (range: 5–76), median predose VWF activity was 0.37 IU/mL (range: 0.06–1.13), and median VWF activity response at peak level was 0.64 IU/mL (range: 0.04–4.04). The observed PK profiles were best described using a one-compartment model with allometric scaling. While F increased with age, Cl was dependent on VWD type and sex. Inclusion resulted in a drop in interpatient variability in F and Cl of 81.7 to 60.5% and 92.8 to 76.5%, respectively. Conclusion A PK model was developed, describing VWF activity versus time profile after desmopressin administration in patients with VWD or low VWF. Interpatient variability in response was quantified and partially explained. This model is a starting point toward more accurate prediction of desmopressin dosing effects in VWD.

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Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site

Blood ◽

10.1182/blood-2009-01-195461 ◽

2009 ◽

Vol 114 (8) ◽

pp. 1666-1674 ◽

Cited By ~ 71

Author(s):

Thomas J. Raife ◽

Wenjing Cao ◽

Bonnie S. Atkinson ◽

Bruce Bedell ◽

Robert R. Montgomery ◽

...

Keyword(s):

Von Willebrand Factor ◽

Hot Spot ◽

Peptide Bond ◽

Cathepsin G ◽

Human Neutrophils ◽

Activity Levels ◽

Activated Neutrophils ◽

Von Willebrand ◽

Willebrand Factor

Abstract The function of von Willebrand factor (VWF) is regulated by proteolysis, which limits its multimeric size and ability to tether platelets. The importance of ADAMTS13 metalloprotease in VWF regulation is demonstrated by the association between severe deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura (TTP). However, ADAMTS13 activity levels do not always correlate with the clinical course of TTP, suggesting that other proteases could be important in regulating VWF. We identified 4 leukocyte proteases that cleave the synthetic VWF substrate FRETS-VWF73 and multimeric VWF. Elastase and proteinase 3 (PR3) cleave multimeric VWF and FRETS-VWF73 at the V1607-T1608 peptide bond; cathepsin G and matrix metalloprotease 9 cleave VWF substrates at the Y1605-M1606 and M1606-V1607 bonds, respectively. Isolated intact human neutrophils cleave FRETS-VWF73 at the V1607-T1608 peptide bond, suggesting that elastase or PR3 expressed on leukocyte surfaces might cleave VWF. In the presence of normal or ADAMTS13-deficient plasma, cleavage of FRETS-VWF73 by resting neutrophils is abolished. However, activated neutrophils retain proteolytic activity toward FRETS-VWF73 in the presence of plasma. Although the in vivo relevance remains to be established, these studies suggest the existence of a “hot spot” of VWF proteolysis in the VWF A2 domain, and support the possibility that activated leukocytes may participate in the proteolytic regulation of VWF.

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Changes in von Willebrand factor during cardiac surgery: effect of desmopressin acetate

Blood ◽

10.1182/blood.v71.6.1648.1648 ◽

1988 ◽

Vol 71 (6) ◽

pp. 1648-1655 ◽

Cited By ~ 83

Author(s):

M Weinstein ◽

JA Ware ◽

J Troll ◽

E Salzman

Keyword(s):

Cardiopulmonary Bypass ◽

Blood Loss ◽

Drug Treatment ◽

Von Willebrand Factor ◽

Drug Induced ◽

Before And After ◽

Artery Disease ◽

Von Willebrand ◽

The Relationship ◽

Willebrand Factor

Abstract Patients who receive desmopressin acetate (dDAVP) after cardiopulmonary bypass bleed less during operation and in the first 24 hours after operation than do patients who receive a placebo. To study the mechanism of improved hemostasis in bypass patients, we examined the relationship between von Willebrand factor (vWF) and blood loss in 70 cardiopulmonary bypass patients, one-half of whom received desmopressin intraoperatively. vWF concentration and multimeric composition were analyzed before and after bypass, after drug treatment, and 24 hours after operation. Before operation, patients with valvular disease had lower percentages of vWF high-mol-wt multimers (HMWMs) than did healthy subjects or patients with coronary artery disease, but subsequent blood loss, vWF activity, and bleeding times were not related to this finding. Irrespective of drug treatment, patients who had low preoperative vWF and who had a net loss of the protein during bypass bled more after bypass than did similar patients who had a net increase of vWF during bypass. HMWMs rose to above normal levels after bypass regardless of desmopressin infusion. Differences in the concentration of vWF between desmopressin and placebo patients after receipt of the drug, although small, were better correlated with reduced blood loss than were differences in HMWM distribution. We conclude that the beneficial effect of desmopressin on hemostasis following cardiopulmonary bypass cannot be attributed to a drug-induced change in HMWM distribution but may be related to an increase in overall vWF concentration.

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Evaluation of von Willebrand factor in COPD patients

Jornal Brasileiro de Pneumologia ◽

10.1590/s1806-37132014000400004 ◽

2014 ◽

Vol 40 (4) ◽

pp. 373-379 ◽

Cited By ~ 4

Author(s):

Thiago Prudente Bártholo ◽

Cláudia Henrique da Costa ◽

Rogério Rufino

Keyword(s):

Von Willebrand Factor ◽

Medical Research Council ◽

Control Group ◽

X Rays ◽

Copd Patients ◽

Never Smokers ◽

Von Willebrand ◽

And Control ◽

Willebrand Factor ◽

Selection Phase

OBJECTIVE: To compare the absolute serum von Willebrand factor (vWF) levels and relative serum vWF activity in patients with clinically stable COPD, smokers without airway obstruction, and healthy never-smokers. METHODS: The study included 57 subjects, in three groups: COPD (n = 36); smoker (n = 12); and control (n = 9). During the selection phase, all participants underwent chest X-rays, spirometry, and blood testing. Absolute serum vWF levels and relative serum vWF activity were obtained by turbidimetry and ELISA, respectively. The modified Medical Research Council scale (cut-off score = 2) was used in order to classify COPD patients as symptomatic or mildly symptomatic/asymptomatic. RESULTS: Absolute vWF levels were significantly lower in the control group than in the smoker and COPD groups: 989 ± 436 pg/mL vs. 2,220 ± 746 pg/mL (p < 0.001) and 1,865 ± 592 pg/mL (p < 0.01). Relative serum vWF activity was significantly higher in the COPD group than in the smoker group (136.7 ± 46.0% vs. 92.8 ± 34.0%; p < 0.05), as well as being significantly higher in the symptomatic COPD subgroup than in the mildly symptomatic/asymptomatic COPD subgroup (154 ± 48% vs. 119 ± 8%; p < 0.05). In all three groups, there was a negative correlation between FEV1 (% of predicted) and relative serum vWF activity (r2 = −0.13; p = 0.009). CONCLUSIONS: Our results suggest that increases in vWF levels and activity contribute to the persistence of systemic inflammation, as well as increasing cardiovascular risk, in COPD patients.

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Early Increase of von Willebrand Factor Predicts Adverse Outcome in Unstable Coronary Artery Disease

Circulation ◽

10.1161/01.cir.98.4.294 ◽

1998 ◽

Vol 98 (4) ◽

pp. 294-299 ◽

Cited By ~ 150

Author(s):

Gilles Montalescot ◽

François Philippe ◽

Annick Ankri ◽

Eric Vicaut ◽

Etienne Bearez ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Von Willebrand Factor ◽

Adverse Outcome ◽

Unstable Coronary Artery Disease ◽

Early Increase ◽

Artery Disease ◽

Von Willebrand ◽

Willebrand Factor

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The Role Of High Von Willebrand Factor and Low ADAMTS13 Levels In The Risk Of Venous Thromboembolism

Blood ◽

10.1182/blood.v122.21.1128.1128 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1128-1128 ◽

Cited By ~ 2

Author(s):

Christiane Pereira Gouvea ◽

Sandra Satiko Matsuda ◽

Rodrigo Vaez ◽

Patrícia Nunes Bezerra Pinheiro ◽

Maria Aparecida Eiko Noguti ◽

...

Keyword(s):

Venous Thromboembolism ◽

Von Willebrand Factor ◽

Control Group ◽

Exclusion Criteria ◽

Reference Category ◽

Gender And Age ◽

History Of ◽

Von Willebrand ◽

Willebrand Factor

Abstract Background Venous thromboembolism (VTE) is a common multicausal disease in the general population. von Willebrand factor (VWF) has been associated with VTE in epidemiological studies and recently VWF-mediated platelet adhesion has been shown to be critical for deep vein thrombosis (DVT) in mouse models. The large VWF multimers are cleaved by ADAMTS13 into smaller, less active multimers. Because of the key role of ADAMTS13, VWF and factor VIII (FVIII) in hemostasis and their close biological relationship, we aimed at investigating in the same population the effect of these proteins on VTE risk. Materials and Methods We included consecutive patients admitted to our anticoagulation clinic with a first objectively confirmed VTE event between January 2007 and July 2011. The study included only patients with DVT of the lower limbs and/or pulmonary embolism aged between 18-70 years, and without medical history of overt malignancy, arterial thrombosis, liver cirrhosis, renal failure on hemodialysis, connective tissue disease and other conditions characterized by chronic inflammation. Blood was collected at least 1 month after stopping anticoagulation and ≥ 6 months after VTE. Controls were recruited from friends or partners of patients, had no personal history of VTE and were matched to patients by gender and age. The other exclusion criteria for controls were the same as for patients, and in both groups pregnant or postpartum women at blood collection were excluded. ADAMTS13 and VWF antigens were determined by commercial ELISA and FVIII activity was measured using FVIII deficient plasma. High VWF (>150%) and FVIII (>150%) were defined by plasma levels of these proteins exceeding the 88th and 94th percentiles of the control group, respectively. To define low ADAMTS13 levels we used the 10th percentile of the controls (≤0.64 μg/ml). Odds ratios (OR) and 95% confidence intervals (CI) were presented adjusted for gender and age and medians with interquartile variation (25th-75th percentiles). Results 358 patients with a first objectively confirmed VTE event were admitted to our clinic, of whom 282 did not participate in the study due to the exclusion criteria (n= 249) and loss of follow-up or refusal (n= 33). Therefore, we included 76 patients (53 women, 70%) with a median age of 43 years (33-55 years) and 96 controls (66 women, 69%), with a median age of 42 years (31-52 years). In controls, there was a negative albeit weak correlation between ADAMTS13 levels and VWF (rs= -0.213 by Spearman coefficient, p= 0.037) and FVIII (rs= -0.251, p= 0.014). As expected, VTE was associated with high levels of VWF (OR 2.80, 95% CI 1.20-6.54) and FVIII (OR 3.02, 95% CI 1.08-8.43). Low ADAMTS13 levels were detected in 12 patients and 9 controls (OR 1.76, 95% CI 0.70-4.46). The population was dichotomized according to the 88th percentile of VWF of the controls. Median ADAMTS13 was lower in the group with VWF >p88 compared to the group with VWF ≤p88 in controls (0.80μg/ml, 0.63-0.94μg/ml vs. 0.98μg/ml, 0.81-1.23μg/ml, p= 0.051) and in patients (0.75μg/ml, 0.53-0.95μg/ml vs. 0.95μg/ml, 0.81-1.14μg/ml, p= 0.001). Next the population was categorized into subjects with VWF ≤p88 and ADAMTS13 >p10 (reference category: 52 patients, 79 controls), VWF ≤p88 and ADAMTS13 ≤p10 (4 patients, 6 controls), VWF >p88 and ADAMTS13 >p10 (12 patients, 8 controls) and VWF >p88 and ADAMTS13 ≤p10 (8 patients, 3 controls). The combination of high VWF and low ADAMTS13 increased VTE risk when compared to the reference category (OR 4.14; 95% CI 1.03-16.71). The risk did not substantially change with adjustment for acute phase proteins and ABO group, and it was attenuated when further adjusted for high FVIII (OR 3.41, 95% CI 0.80-14.70). No correlation was found between the time since the VTE event and levels of VWF, FVIII and ADAMTS13 (p>0.05). Conclusions our data suggest a potential effect of high VWF and low ADAMTS13 on VTE risk. An unbalance between these two interconnected proteins might have a role in the pathophysiology of VTE. Results should be interpreted with caution due to the wide 95% CI and to the attenuation of VTE risk with further adjustment for FVIII. In order to better explain our results studies with larger sample size are warranted. Disclosures: No relevant conflicts of interest to declare.

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Inhibition of von Willebrand factor–platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons

Blood ◽

10.1182/blood-2012-04-421248 ◽

2012 ◽

Vol 120 (17) ◽

pp. 3611-3614 ◽

Cited By ~ 29

Author(s):

Hendrik B. Feys ◽

Jan Roodt ◽

Nele Vandeputte ◽

Inge Pareyn ◽

Harald Mottl ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Von Willebrand Factor ◽

Platelet Glycoprotein ◽

Control Group ◽

Severe Thrombocytopenia ◽

Thrombocytopenic Purpura ◽

Platelet Aggregates ◽

New Treatment ◽

Von Willebrand ◽

Willebrand Factor

Abstract The pathophysiology of thrombotic thrombocytopenic purpura (TTP) can be explained by the absence of active ADAMTS13, leading to ultra-large von Willebrand factor (UL-VWF) multimers spontaneously interacting with platelets. Preventing the formation of UL-VWF–platelet aggregates therefore is an attractive new treatment strategy. Here, we demonstrate that simultaneous administration of the inhibitory anti-VWF monoclonal antibody GBR600 and the inhibitory anti-ADAMTS13 antibody 3H9 to baboons (prevention group) precluded TTP onset as severe thrombocytopenia and hemolytic anemia were absent in these animals. In addition, partial VWF inhibition was not enough to prevent thrombocytopenia, demonstrating the specificity of this therapeutic strategy. GBR600 treatment of baboons during acute TTP (treatment group) resulted in a rapid recovery of severe thrombocytopenia similar to the platelet count increases observed in TTP patients treated by plasma exchange. Baboons in the control group only injected with 3H9 developed early stages of TTP as previously described. Hence, inhibiting VWF-GPIb interactions is an effective way to prevent and treat the early symptoms of acquired TTP in baboons.

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