Levels of von Willebrand factor and ADAMTS13 determine clinical outcome after cardioversion for atrial fibrillation

2011 ◽  
Vol 105 (03) ◽  
pp. 435-443 ◽  
Author(s):  
Veronika Bruno ◽  
Rudolf Jarai ◽  
Susanne Gruber ◽  
Thomas Höchtl ◽  
Ivan Brozovic ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Independent Predictor ◽  
Thrombus Formation ◽  
Critical Role ◽  
Inverse Correlation ◽  
Von Willebrand ◽  
Rhythm Stability ◽  
Willebrand Factor

SummaryVon Willebrand factor (vWF) plays an essential role in platelet adhesion and thrombus formation. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 antigen levels compared to controls. Little is known about vWF and ADAMTS13 in AF patients treated with cardioversion (CV). Thus we investigated the alterations of plasma vWF and ADAMTS13 after CV and evaluated the predictive value of these parameters for recurrence of AF. In this observational study we determined plasma levels of vWF and ADAMTS13 in 77 patients before and immediately after CV, as well as 24 hours (h) and six weeks thereafter, by means of commercially available assays. The vWF/ ADAMTS13-ratio was significantly elevated immediately after CV (p=0.02) and 24 h after CV (p=0.002) as compared to baseline levels. ADAMTS13, 24 h after CV, exhibited a significant association with recurrence of AF (HR: 0.97; p=0.037). Accordingly, tertiles of ADAMTS13 showed a stepwise inverse correlation with the risk of recurrent AF (HR: 0.50; p=0.009). After adjustment for confounders, ADAMTS13 remained significant as an independent predictor of recurrent AF (HR: 0.61; p=0.047). Similarly, the vWF/ADAMTS13-ratio, 24 h after CV, was associated with rhythm stability and remained an independent predictor of recurrent AF (HR: 1.88; p=0.028). The regulation of vWF and its cleaving protease ADAMTS13 after CV might play a critical role in producing a pro-thrombotic milieu immediately after CV for AF. Since ADAMTS13 plasma concentration and the vWF/ADAMTS13-ratio are independently associated with rhythm stability, these indexes might be used for prediction of recurrence of AF.

Abstract 2641: Plasma Von Willebrand Factor and ADAMTS13 Concentrations in Atrial Fibrillation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Takashi Uemura ◽  
Koichi Kaikita ◽  
Hiroshige Yamabe ◽  
Masakazu Matsukawa ◽  
Kenji Soejima ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Von Willebrand Factor ◽  
Left Atrial ◽  
Thrombus Formation ◽  
Significant Negative Correlation ◽  
Platelet Surface ◽  
Control Subjects ◽  
Number Of Patients ◽  
Von Willebrand ◽  
Willebrand Factor

Background : Von Willebrand factor (VWF) is released from damaged endothelium, and has a role in platelet aggregation through a receptor on the platelet surface. A metalloprotease that cleaves VWF multimers has been identified, namely, ADAMTS13. We recently reported that the serial changes in plasma VWF and ADAMTS13 antigen levels in patients with acute myocardial infarction (AMI), and that the VWF/ADAMTS13 ratio was a useful prognostic indicator of long-term thrombotic events after AMI. Although previous studies have shown raised plasma VWF in patients with atrial fibrillation (AF), little is known about the role of ADAMTS13 in the pathogenesis of AF. In the present study, we examined the relation between VWF and ADAMTS13 in AF patients. Methods and Results : We measured the plasma VWF and ADAMTS13 antigen levels by ELISA in 45 AF patients and 49 control subjects, and also performed echocardiography to examine the relations between these markers and left atrial or ventricular functions. The plasma VWF antigen levels were significantly higher in AF patients compared with controls (2017±749 vs. 1504±497 mU/ml, P=0.0002). In contrast, the plasma ADAMTS13 antigen levels were significantly lower in AF patients compared with controls (825±181 vs. 911±193 mU/ml, P=0.03). The VWF/ADAMTS13 ratio was significantly higher in AF patients compared with controls (2.59±1.20 vs. 1.75±0.76, P<0.0001). The number of patients who received aspirin and warfarin was significantly higher in AF group than control subjects, however, those medical therapy did not affect the VWF and ADAMTS13 antigen levels. There was significant positive correlation between VWF antigen levels and the left atrial dimension (n=128, r=0.228, P=0.0095). Furthermore, there was significant negative correlation between VWF antigen levels and the left atrial appendage peak flow velocity measured by transesophageal echocardiography (n=23, r=-0.611, p=0.0015). Conclusions : These findings suggest that the balance between VWF and ADAMTS13 levels may play an important role in the intra-atrial thrombus formation in AF patients. The present results would open a new therapeutic target for prevention of thromboembolic complications in AF.

Endothelial CD40 Mediates Microvascular von Willebrand Factor-Dependent Platelet Adhesion Inducing Inflammatory Venothrombosis in ADAMTS13 Knockout Mice

2020 ◽  
Vol 120 (03) ◽  
pp. 466-476
Author(s):  
Sibgha Tahir ◽  
Andreas H. Wagner ◽  
Steffen Dietzel ◽  
Hanna Mannell ◽  
Joachim Pircher ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Knockout Mice ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Cd40 Ligand ◽  
Inflammatory Conditions ◽  
String Formation ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background von Willebrand factor (vWF) plays an important role in platelet activation. CD40–CD40 ligand (CD40L) induced vWF release has been described in large vessels and cultured endothelium, but its role in the microcirculation is not known. Here, we studied whether CD40 is expressed in murine microvessels in vivo, whether CD40L induces platelet adhesion and leukocyte activation, and how deficiency of the vWF cleaving enzyme ADAMTS13 affects these processes. Methods and Results The role of CD40L in the formation of beaded platelet strings reflecting their adhesion to ultralarge vWF fibers (ULVWF) was analyzed in the murine cremaster microcirculation in vivo. Expression of CD40 and vWF was studied by immunohistochemistry in isolated and fixed cremasters. Microvascular CD40 was only expressed under inflammatory conditions and exclusively in venous endothelium. We demonstrate that CD40L treatment augmented the number of platelet strings, reflecting ULVWF multimer formation exclusively in venules and small veins. In ADAMTS13 knockout mice, the number of platelet strings further increased to a significant extent. As a consequence extensive thrombus formation was induced in venules of ADAMTS13 knockout mice. In addition, circulating leukocytes showed primary and rapid adherence to these platelet strings followed by preferential extravasation in these areas. Conclusion CD40L is an important stimulus of microvascular endothelial ULVWF release, subsequent platelet string formation and leukocyte extravasation but only in venous vessels under inflammatory conditions. Here, the lack of ADAMTS13 leads to severe thrombus formation. The results identify CD40 expression and ADAMTS13 activity as important targets to prevent microvascular inflammatory thrombosis.

The role of platelet von Willebrand factor in platelet adhesion and thrombus formation: a study of 34 patients with various subtypes of type I von Willebrand disease

1994 ◽  
Vol 86 (2) ◽  
pp. 327-332 ◽  
Author(s):  
Edith Fressinaud ◽  
Augusto B. Federici ◽  
Giancarlo Castaman ◽  
Chantal Rothschild ◽  
Francesco Rodeghiero ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Von Willebrand Disease ◽  
Type I ◽  
Von Willebrand ◽  
Willebrand Factor

Glycoprotein Ibα and von Willebrand factor in primary platelet adhesion and thrombus formation: Lessons from mutant mice

2008 ◽  
Vol 99 (02) ◽  
pp. 264-270 ◽  
Author(s):  
Anil K. Chauhan ◽  
Denisa D. Wagner ◽  
Wolfgang Bergmeier
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Mutant Mice ◽  
Receptor Complex ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Primary Platelet ◽  
Adhesion Process ◽  
Main Ligand

SummaryThe von Willebrand factor (VWF) receptor complex, glycoprotein (GP)Ib-V-IX, and its main ligand VWF play a key role in the adhesion process of platelets to sites of vascular injury. Recent studies in mutant mice have shed new light on the importance of either molecule for the development of arterial and venous thrombosis. In this review, we summarize the most important aspects from these studies.

Von Willebrand factor C1C2 domain is involved in platelet adhesion to polymerized fibrin at high shear rate

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1741-1746 ◽  
Author(s):  
Jeffrey F. W. Keuren ◽  
Dominique Baruch ◽  
Paulette Legendre ◽  
Cécile V. Denis ◽  
Peter J. Lenting ◽  
...  
Keyword(s):  
Shear Rate ◽  
Binding Site ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
High Shear Rate ◽  
High Shear ◽  
Perfusion Studies ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractFibrin is actively involved in platelet reactions essential for thrombus growth, in which von Willebrand factor (VWF) might be an important mediator. The aim of this study was to localize VWF domains that bind to fibrin and to determine their relevance in platelet adhesion. VWF binds specifically to fibrin with an apparent Kd of 2.2 μg/mL. Competition in the presence of 2 complementary fragments, SpIII (residues 1-1365) and SpII (residues 1366-2050), indicated that the high affinity binding site for fibrin is located in the C-terminal part, thus distinct from the A domains. Comparison of 2 deleted rVWF (ΔD4B-rVWF, ΔC1C2-rVWF) suggested that the C1C2 domains contained a fibrin binding site. This site is distinct from RGD, as shown by binding of D1746G-rVWF to fibrin. Perfusion studies at high shear rate demonstrated that C1C2 domains were required for optimal platelet adhesion to fibrin. With the use of a VWF-deficient mouse model, it was found that plasma VWF is critical for platelet tethering and adhesion to fibrin. These results suggest a dual role of fibrin-bound VWF in thrombus formation: first, fibrin-bound VWF is critical in the recruitment of platelets by way of glycoprotein (GP) Ib, and, second, it contributes to stationary platelet adhesion by way of binding to activated αIIbβ3.

scholarly journals Glycoprotein Ib, von Willebrand factor, and glycoprotein IIb:IIIa are all involved in platelet adhesion to fibrin in flowing whole blood

Blood ◽  
1990 ◽  
Vol 76 (2) ◽  
pp. 345-353 ◽  
Author(s):  
RR Hantgan ◽  
G Hindriks ◽  
RG Taylor ◽  
JJ Sixma ◽  
PG de Groot
Keyword(s):  
Platelet Aggregation ◽  
Shear Rate ◽  
Von Willebrand Factor ◽  
Whole Blood ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Shear Rates ◽  
Wall Shear ◽  
Von Willebrand ◽  
Willebrand Factor

We have investigated the molecular basis of thrombus formation by measuring the extent of platelet deposition from flowing whole blood onto fibrin-coated glass coverslips under well-defined shear conditions in a rectangular perfusion chamber. Platelets readily and specifically adhered to fibrin-coated coverslips in 5 minute perfusion experiments done at either low (300 s-1) or high (1,300 s-1) wall shear rates. Scanning electron microscopic examination of fibrin-coated coverslips after perfusions showed surface coverage by a monolayer of adherent, partly spread platelets. Platelet adhesion to fibrin was effectively inhibited by a monoclonal antibody (MoAb) specific for glycoprotein (GP) IIb:IIIa. The dose-response curve for inhibition of adhesion by anti-GPIIb:IIIa at both shear rates paralleled that for inhibition of platelet aggregation. Platelet aggregation and adhesion to fibrin were also blocked by low concentrations of prostacyclin. In contrast, anti- GPIb reduced adhesion by 40% at 300 s-1 and by 70% at 1,300 s-1. A similar pattern of shear rate-dependent, incomplete inhibition resulted with a MoAb specific for the GPIb-recognition region of von Willebrand factor (vWF). Platelets from an individual with severe von Willebrand's disease, whose plasma and platelets contained essentially no vWF, exhibited defective adhesion to fibrin, especially at the higher shear rate. Addition of purified vWF restored adhesion to normal values. These results are consistent with a two-site model for platelet adhesion to fibrin, in which the GPIIb:IIIa complex is the primary receptor, with GPIb:vWF providing a secondary adhesion pathway that is especially important at high wall shear rates.

The Role of Platelet Adhesion Receptor GPIb α Far Exceeds That of Its Main Ligand von Willebrand Factor in Arterial Thrombosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1797-1797 ◽  
Author(s):  
Wolfgang Bergmeier ◽  
Crystal L. Piffath ◽  
Tobias Goerge ◽  
Stephen M. Cifuni ◽  
Zaverio M. Ruggeri ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Arterial Thrombosis ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Interleukin 4 ◽  
Arterial Thrombus ◽  
A Site ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract GPIbα binding to von Willebrand factor (VWF) exposed at a site of vascular injury is thought to be the first step in the formation of a hemostatic plug. However, our previous studies in VWF-deficient mice demonstrated delayed but not absent arterial thrombus formation suggesting that, under these conditions, GPIbα may bind other ligands or that a receptor other than GPIbα can mediate platelet adhesion. Here we studied thrombus formation in transgenic mice expressing GPIbα in which the extracellular domain was replaced by that of the human interleukin-4 receptor (IL4Rα/GPIbα-tg mice). Platelet adhesion to ferric chloride-treated mesenteric arterioles in IL4Rα/GPIbα-tg mice was virtually absent in contrast to avid adhesion in wild-type (WT) mice. As a consequence, arterial thrombus formation was completely inhibited in the mutant mice. Our studies further show that, when infused into WT recipient mice, IL4Rα/GPIbα-tg platelets or WT platelets lacking the 45 kD N-terminal domain of GPIbα failed to incorporate into growing arterial thrombi, even if the platelets were activated prior to infusion. Surprisingly, platelets lacking β3 integrins, which are unable to form thrombi on their own, incorporated efficiently into WT thrombi. Our studies provide in vivo evidence that GPIbα is absolutely required for recruitment of platelets to both exposed subendothelium and thrombi under arterial flow conditions. Thus, GPIbα contributes to arterial thrombosis by important adhesion mechanisms independent of the binding to VWF.

scholarly journals Synthetic Partially Reduced Human Neutrophil Peptide (HNP)-1 Inhibits Platelet Adhesion and Aggregation on Von Willebrand Factor-Collagen Surfaces Under Arterial Shear Stress through a Disulfide Bond Reduction Mechanism

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3722-3722
Author(s):  
Jenny K. McDaniel ◽  
Khalil Bdeir ◽  
Douglas B. Cines ◽  
X. Long Zheng
Keyword(s):  
Mass Spectrometry ◽  
Disulfide Bond ◽  
Von Willebrand Factor ◽  
Whole Blood ◽  
Human Neutrophil ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Reduction Mechanism ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Human neutrophil peptides (HNPs) are small cationic proteins primarily released from activated and degranulated neutrophils. HNPs have antimicrobial activity against diverse bacteria, viruses, fungi, and parasites. Additionally, HNPs exhibit prothrombotic properties by enhancing platelet aggregation and fibrin formation and by inhibiting proteolytic cleavage of von Willebrand factor (VWF) by ADAMTS13. However, the role of HNPs in thrombus formation under more physiological conditions (i.e. under flow) has not been determined. Objective: To investigate the effects of HNPs on platelet adhesion/aggregation on VWF/collagen surfaces under arterial shears. Design/Method: Whole blood was obtained from C57/BL6 wild type and Adamts13-/-mice, anticoagulated with a potent thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK) and prostaglandin-E1 (PGE1), and platelets were labeled with FITC anti-mouse CD41 IgG. After incubation with varying concentrations of native HNPs and synthetic partially reduced HNP1 (sHNP1) for 30 minutes, the whole blood samples were perfused through a fibrillar collagen-coated surface in a microfluidic system at 100 dyne/cm² for 180 seconds. The rate and extent of accumulation of fluorescein-labeled platelets were determined under an inverted fluorescent microscope at 4-second intervals. The images were analyzed off-line with Montage to evaluate the area of platelet coverage over time. This process was repeated with the addition of N-ethylmaleimide (NEM) alone or NEM-treated sHNP1 to the samples to probe the effect of free cysteine residues. In addition, samples of native HNPs and sHNP1 incubated with NEM were analyzed via LC-mass spectrometry for NEM incorporation. Results: Purified native HNPs at final concentrations of 15 μM and 30 μM exhibited no or little effect on the adhesion and aggregation of murine platelets on VWF/collagen surfaces under arterial shears (100 dyne/cm2). Surprisingly, sHNP1 at the same concentrations (15 and 30 μM) dramatically reduced the rate and surface coverage of platelets from WT (Fig. 1A) and, more profoundly, from Adamts13-/- mice (Fig. 1B) on VWF/collagen surfaces under the same conditions. This inhibitory activity of sHNP1 was abolished upon pretreatment with NEM, which reacts with free thiols (-SH) (not shown). Aliphatic HNP1 with all 6 cysteine residues chemically modified also did not inhibit the adhesion and aggregation of murine platelets on VWF/collagen surfaces under shear (not shown). Analysis of samples by LC-mass spectrometry confirmed the NEM-labeling of free thiols present in sHNP1, but not in native HNPs. Conclusion: These results suggest that high concentrations of locally released native HNPs may be required to inhibit ADAMTS13 activity in vivo. However, the findings from this study indicate that HNPs differentially affect thrombus formation depending on how its redox state is modified by its biological milieu. Somewhat unexpectedly, synthetic and partially reduced HNP1 may be a potent antithrombotic agent by reducing platelet interactions with VWF under arterial shear via a disulfide bond reduction mechanism. Disclosures Zheng: Alexion: Research Funding; Ablynx: Consultancy.

scholarly journals Analysis of the Involvement of the von Willebrand Factor–Glycoprotein Ib Interaction in Platelet Adhesion to a Collagen-Coated Surface Under Flow Conditions

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4413-4424 ◽  
Author(s):  
Masaaki Moroi ◽  
Stephanie M. Jung ◽  
Shosaku Nomura ◽  
Sadayoshi Sekiguchi ◽  
Antonio Ordinas ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Initial Reaction ◽  
Adhesion Assay ◽  
Flow Conditions ◽  
Coated Surface ◽  
Von Willebrand ◽  
Willebrand Factor

The requisite initial reaction for in vivo thrombus formation in flowing blood is platelet adhesion to the exposed surface of the extracellular matrix. The contribution of von Willebrand factor (vWF ) in plasma and glycoprotein (GP) Ib on the platelet membrane to platelet adhesion has been well-documented. We have recently developed a procedure (the “flow adhesion assay”) for measuring platelet adhesion under flow conditions that allowed us to characterize platelet adhesion to a collagen-coated surface. Here, we apply our method to analyze platelet adhesion to a vWF-coated surface to determine how this might differ from adhesion to a collagen-coated surface. Platelet adhesion to the vWF-coated surface was monitored as the linear increase in the area occupied by adherent platelets. The fluorescence image showed that platelets adhering to the vWF surface were mainly single platelets, and if any were present, the platelet aggregates were small, this being the primary difference from the adhesion to a collagen surface, where adherent platelets were mostly in aggregates. The flow adhesion assay detected the movement of platelets on the vWF surface, suggesting the reversible binding of vWF with platelets. The velocity of the platelets increased at higher shear rates or at lower vWF densities on the surface. Treatment of the vWF-coated surface with the aggregating agent botrocetin before initiation of blood flow increased platelet adhesion while dramatically decreasing the velocity of platelet movement. The present observations on the adhesion of platelets to the vWF-pretreated collagen surface and measurements of the velocity of platelets moving on the collagen surface suggest that the first interaction on the collagen-coated surface is the binding of vWF molecules to the collagen surface. This small number of vWF molecules would serve to attract and slow platelets flowing near the surface. This would facilitate the actual adhesion to the collagen surface that is mainly generated by the interaction between platelet collagen receptors, including GP Ia/IIa and GP VI, with collagen.

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