Mechanobiology of Platelets: Techniques to Study the Role of Fluid Flow and Platelet Retraction Forces at the Micro- and Nano-Scale

Feghhi, Shirin; Sniadecki, Nathan J.

doi:10.3390/ijms12129009

Cited by 32 publications

(27 citation statements)

References 153 publications

(157 reference statements)

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“…These larger, more amalgamated thrombi translated into an overall increased mean particle size and correspondingly lower particle count. GpIb‐V‐IX and αIIbβ3 are known to have a large role in platelet mechanobiology; the adhesion of VWF to GpIbα can trigger mechanotransduction and platelet activation by enhancing the drag force applied on the cell‐surface receptor and both receptors work together to mediate platelet shape change and contraction during activation and aggregation . We hypothesized that these more dense thrombi, likely to contain a larger proportion of active platelets, may result in a greater degree of clot contraction in the latter stages of thrombus formation.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…As a clot is formed, clot retraction initiated by platelets occurs and changes the structure and composition of the clot remarkably as it ages over time (Fox and Phillips 1983; Feghhi and Sniadecki 2011). In the clot retraction process, the fibrin network shrinks and effectively increases fibrin density per unit of clot volume and/or decreasing plasminogen concentration, and results in lower porosity and reduced permeability (Carr and Hardin 1987; Blinc et al 1994; Kirchhof et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Histotripsy Thrombolysis on Retracted Clots

Owens

Cain

et al. 2016

Ultrasound in Medicine & Biology

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Retracted blood clots have been previously recognized to be more resistant to drug-based thrombolysis methods, even with ultrasound and microbubble enhancements. Microtripsy, a new histotripsy approach, has been investigated as a non-invasive, drug-free, and image-guided method that uses ultrasound to break up clots with improved treatment accuracy and a lower risk of vessel damage when compared to the traditional histotripsy thrombolysis approach. Unlike drug-mediated thrombolysis, which is dependent on the permeation of the thrombolytic agents into the clot, microtripsy controls acoustic cavitation to fractionate clots. We hypothesize that microtripsy thrombolysis is effective on retracted clots and that the treatment efficacy can be enhanced using strategies incorporating electronic focal steering. To test our hypothesis, retracted clots were prepared in vitro and the mechanical properties were quantitatively characterized. Microtripsy thrombolysis was applied on the retracted clots in an in vitro flow model using three different strategies: single-focus, electronically-steered multi-focus, and a dual-pass multi-focus strategy. Results show that microtripsy was used to successfully generate a flow channel through the retracted clot and the flow was restored. The multi-focus and the dual-pass treatments incorporating the electronic focal steering significantly increased the recanalized flow channel size compared to the single-focus treatments. The dual-pass treatments achieved a restored flow rate up to 324 mL/min without cavitation contacting the vessel wall. The clot debris particles generated from microtripsy thrombolysis remained within the safe range. The results in this study show the potential of microtripsy thrombolysis for retracted clot recanalization with the enhancement of electronic focal steering.

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“…65,66 Platelets can affect the clot structure by secreting polyphosphate 67 and platelet factor 4, 68 but the most dramatic platelet-mediated effect is the manifold densification of the fibrin network referred to as clot retraction. 69 Other intravascular and extravascular cells (leukocytes, fibroblasts, endothelium, etc.) have effects on the fibrin formed in their vicinity, including those expressing tissue factor, and thus promote local thrombin generation.…”

Section: Fibrin Polymerization and Clinical Implications 1715mentioning

confidence: 99%

Mechanisms of fibrin polymerization and clinical implications

Weisel

Litvinov

2013

Blood

412

363

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Research on all stages of fibrin polymerization, using a variety of approaches including naturally occurring and recombinant variants of fibrinogen, x-ray crystallography, electron and light microscopy, and other biophysical approaches, has revealed aspects of the molecular mechanisms involved. The ordered sequence of fibrinopeptide release is essential for the knob-hole interactions that initiate oligomer formation and the subsequent formation of 2-stranded protofibrils. Calcium ions bound both strongly and weakly to fibrin(ogen) have been localized, and some aspects of their roles are beginning to be discovered. Much less is known about the mechanisms of the lateral aggregation of protofibrils and the subsequent branching to yield a 3-dimensional network, although the aC region and B:b knob-hole binding seem to enhance lateral aggregation. Much information now exists about variations in clot structure and properties because of genetic and acquired molecular variants, environmental factors, effects of various intravascular and extravascular cells, hydrodynamic flow, and some functional consequences. The mechanical and chemical stability of clots and thrombi are affected by both the structure of the fibrin network and cross-linking by plasma transglutaminase. There are important clinical consequences to all of these new findings that are relevant for the pathogenesis of diseases, prophylaxis, diagnosis, and treatment. (Blood. 2013;121(10):1712-1719 IntroductionFibrin polymer is an end product of the enzymatic cascade of blood clotting. In vivo formation of the polymeric fibrin network, along with platelet adhesion and aggregation, are the key events in salutary stopping of bleeding at the site of injury (hemostasis) as well as in pathological vascular occlusion (thrombosis). Fibrin polymerization comprises a number of consecutive reactions, each affecting the ultimate structure and properties of the fibrin scaffold. These properties determine the development and outcomes of various diseases, such as heart attack, ischemic stroke, cancers, trauma, surgical and obstetrical complications, hereditary and acquired coagulopathies, and thrombocytopathies. In addition to providing a better understanding of the pathogenesis of such disorders, the knowledge of the molecular mechanisms of fibrin formation provides a foundation for new diagnostic tools and therapeutic approaches. Fibrinopeptide releaseFibrinogen is 45 nm-long and made up of 6 paired polypeptide chains (Aa Bb g) 2 held together by 29 disulfide bonds. There are now crystal structures of large parts of fibrinogen, including the g-and b-nodules, the coiled coil, and the central nodule.1 Still missing in the crystal structures are the flexible NH 2 -terminal (N-terminal) ends of the Aa-chains and the carboxyl-terminal (C-terminal) portion of the Aa-chain, but modern simulation techniques make possible partial computational reconstructions of these parts of fibrin(ogen) (Figure 1).Fibrin polymerization is initiated by the thrombin cleavage of fibrinopeptides A (...

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Mechanobiology of Platelets: Techniques to Study the Role of Fluid Flow and Platelet Retraction Forces at the Micro- and Nano-Scale

Cited by 32 publications

References 153 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

Histotripsy Thrombolysis on Retracted Clots

Mechanisms of fibrin polymerization and clinical implications

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