Dynamic analysis of platelet deposition to resolve platelet adhesion receptor activity in whole blood at arterial shear rate

Pugh, Nicholas; Bihan, Dominique; Perry, David J.; Farndale, Richard W.

doi:10.3109/09537104.2014.893289

Cited by 15 publications

(25 citation statements)

References 7 publications

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“…A separate measure of the absolute height of the thrombus, ZV50, was calculated as the Z‐height at which thrombus volume was half‐maximal. Platelet rolling measurements were taken as previously described using the SC calculated for each image during the time course, subtracted from a duplicated single frame offset image to yield the change in surface distribution with time (dSD/dT) as previously described . dSD/dT expressed relative to SC of the corresponding, unprocessed frame produces dSD/dT/SC; a measurement of the rate of change of platelet capture ranging from a numerical value of 1 for 100% rolling and 0 for static, adherent platelets.…”

Section: Methodsmentioning

confidence: 99%

“…Platelet rolling measurements were taken as previously described using the SC calculated for each image during the time course, subtracted from a duplicated single frame offset image to yield the change in surface distribution with time (dSD/dT) as previously described. 24 dSD/dT expressed relative to SC of the corresponding, unprocessed frame produces dSD/dT/SC; a measurement of the rate of change of platelet capture ranging from F I G U R E 1 Cleavage of von Willebrand factor (VWF) by matrix metalloproteinase-13 (MMP-13). A, SDS-PAGE of cleaved VWF samples.…”

Section: Whole Blood Perfusion Experimentsmentioning

confidence: 99%

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Cleavage by MMP‐13 renders VWF unable to bind to collagen but increases its platelet reactivity

Howes

Knäuper

Malcor

et al. 2020

Journal of Thrombosis and Haemostasis

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Background Atherosclerotic plaque rupture and subsequent thrombosis underpin thrombotic syndromes. Under inflammatory conditions in the unstable plaque, perturbed endothelial cells secrete von Willebrand Factor (VWF) which, via its interaction with GpIbα, enables platelet rolling across and adherence to the damaged endothelium. Following plaque rupture, VWF and platelets are exposed to subendothelial collagen, which supports stable platelet adhesion, activation, and aggregation. Plaque‐derived matrix metalloproteinase (MMP)‐13 is also released into the surrounding lumen where it may interact with VWF, collagen, and platelets. Objectives We sought to discover whether MMP‐13 can cleave VWF and whether this might regulate its interaction with both collagen and platelets. Methods We have used platelet adhesion assays and whole blood flow experiments to assess the effects of VWF cleavage by MMP‐13 on platelet adhesion and thrombus formation. Results Unlike the shear‐dependent cleavage of VWF by a disintegrin and metalloprotease with thrombospondin motif member 13 (ADAMTS13), MMP‐13 is able to cleave VWF under static conditions. Following cleavage by MMP‐13, immobilized VWF cannot bind to collagen but interacts more strongly with platelets, supporting slower platelet rolling in whole blood under shear. Compared with intact VWF, the interaction of cleaved VWF with platelets results in greater GpIbα upregulation and P‐selectin expression, and the thrombi formed on cleaved VWF–collagen co‐coatings are larger and more contractile than platelet aggregates on intact VWF‐collagen co‐coatings or on collagen alone. Conclusions Our data suggest a VWF‐mediated role for MMP‐13 in the recruitment of platelets to the site of vascular injury and may provide new insights into the association of MMP‐13 in atherothrombotic and stroke pathologies.

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Section: Methodsmentioning

confidence: 99%

Section: Whole Blood Perfusion Experimentsmentioning

confidence: 99%

Cleavage by MMP‐13 renders VWF unable to bind to collagen but increases its platelet reactivity

Howes

Knäuper

Malcor

et al. 2020

Journal of Thrombosis and Haemostasis

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“…7H). 21,22 On CRP/GFOGER, 50 mM TPEN reduced ZV 50 from 3.6 AE 0.3 mm to 1.2 AE 0.2 mm, whilst on CRP/GFOGER/ VWF-III, ZV 50 was reduced from 3.2 AE 0.3 mm to 1.4 AE 0.2 mm. On VWF-III/CRP, ZV 50 was reduced from 3.5 AE 1.3 mm to 1.3 AE 0.1 mm.…”

Section: Tpen Inhibits Platelet Activation Induced By Multiple Agonistsmentioning

confidence: 98%

Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner

et al. 2016

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Following platelet adhesion and primary activation at sites of vascular injury, secondary platelet activation is induced by soluble platelet agonists, such as ADP, ATP, thrombin and thromboxane. Zinc ions are also released from platelets and damaged cells and have been shown to act as a platelet agonist. However, the mechanism of zinc-induced platelet activation is not well understood. Here we show that exogenous zinc gains access to the platelet cytosol and induces full platelet aggregation that is dependent on platelet protein tyrosine phosphorylation, PKC and integrin αIIbβ3 activity and is mediated by granule release and secondary signalling. ZnSO4 increased the binding affinity of GpVI, but not integrin α2β1. Low concentrations of ZnSO4 potentiated platelet aggregation by collagen-related peptide (CRP-XL), thrombin and adrenaline. Chelation of intracellular zinc reduced platelet aggregation induced by a number of different agonists, inhibited zinc-induced tyrosine phosphorylation and inhibited platelet activation in whole blood under physiologically relevant flow conditions. Our data are consistent with a transmembrane signalling role for zinc in platelet activation during thrombus formation.

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“…While biochemical factors including cell surface receptors and vessel wall composition have been extensively characterized [5, 6], the roles of biophysical components is less characterized in part due to the failure to reproduce physiological fluid shear in many in vitro assays. Traditional parallel plate flow chambers and newer microfluidic devices have emerged as a promising technology to fill this gap.…”

Section: Introductionmentioning

confidence: 99%

Application of microfluidic devices in studies of thrombosis and hemostasis

Zhang

Neelamegham

2017

Platelets

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Due to the importance of fluid flow during thrombotic episodes, it is quite appropriate to study clotting and bleeding processes in devices that have well-defined fluid shear environments. Two common devices for applying these defined shear stresses include the cone-and-plate viscometer and parallel-plate flow chamber. While such tools have many salient features, they require large amounts of blood or other protein components. With growth in the area of microfluidics over the last two decades, it has become feasible to miniaturize such flow devices. Such miniaturization not only enables saving of precious samples but also increases the throughput of fluid shear devices, thus, enabling the design of combinatorial experiments and making the technique more accessible to the larger scientific community. In addition to simple flows that are common in traditional flow apparatus, more complex geometries that mimic stenosed arteries and the human microvasculature can also be generated. The composition of the microfluidics cell substrate can also be varied for diverse basic science investigations, and clinical investigations that aim to assay either individual patient coagulopathy or response to anti-coagulation treatment. This review summarizes the current state of the art for such microfluidic devices and their applications in the field of thrombosis and hemostasis.

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Dynamic analysis of platelet deposition to resolve platelet adhesion receptor activity in whole blood at arterial shear rate

Cited by 15 publications

References 7 publications

Cleavage by MMP‐13 renders VWF unable to bind to collagen but increases its platelet reactivity

Cleavage by MMP‐13 renders VWF unable to bind to collagen but increases its platelet reactivity

Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner

Application of microfluidic devices in studies of thrombosis and hemostasis

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