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Molecular basis of clot retraction and its role in wound healing

      Highlights

      • Clot retraction stabilizes thrombi by αIIbβ3-dependent interactions with fibrin and myosin-mediated contractile forces.
      • Activated platelets provide a surface for thrombin generation and are a source of proteins active in tissue repair.
      • Altered mechanosensitive properties of platelets within the clot influence thrombosis as in stroke and Covid-19 pathologies.

      Abstract

      Clot retraction is important for the prevention of bleeding, in the manifestations of thrombosis and for tissue repair. The molecular mechanisms behind clot formation are complex. Platelet involvement begins with adhesion at sites of vessel injury followed by platelet aggregation, thrombin generation and fibrin production. Other blood cells incorporate into a fibrin mesh that is consolidated by FXIIIa-mediated crosslinking and platelet contractile activity. The latter results in the asymmetric redistribution of erythrocytes into a tighter central mass providing the clot with stability and resistance to fibrinolysis. Integrin αIIbβ3 on platelets is the key player in these events, bridging fibrin and the platelet cytoskeleton. Glycoprotein VI participates in thrombus formation but not in the retraction. Rheological and environmental factors influence clot construction with retraction driven by the platelet cytoskeleton with actomyosin acting as the motor. Activated platelets provide procoagulant activity stimulating thrombin generation together with the release of a plethora of biologically active proteins and substances from storage pools; many form chemotactic gradients within the fibrin or the underlying matrix. Also released are newly synthesized metabolites and lipid-rich vesicles that circulate within the vasculature and mimic platelet functions. Platelets and their released elements play key roles in wound healing. This includes promoting stem cell and mesenchymal stromal cell recruitment, fibroblast and endothelial cell migration, angiogenesis and matrix formation. These properties have led to the use of autologous clots in therapies designed to accelerate tissue repair while offering the potential for genetic manipulation in both inherited and acquired diseases.

      Keywords

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      References

        • George J.N.
        • Nurden A.T.
        • Phillips D.R.
        Molecular defects in interactions of platelets with the vessel wall.
        New Engl. J. Med. 1984; 311: 1084-1098
        • Nieswandt B.
        • Watson S.P.
        Platelet-collagen interaction: is GPVI the central receptor?.
        Blood. 2003; 102: 449-461
        • Coller B.S.
        • Shattil S.J.
        The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns and even a bend.
        Blood. 2008; 112: 3011-3025
        • Mosesson M.W.
        Fibrinogen and fibrin structure and functions.
        J. Thromb. Haemost. 2005; 3: 1894-1904
        • Furie B.
        • Furie B.C.
        The molecular basis of blood coagulation.
        Cell. 1988; 53: 505-518
        • Weisel J.W.
        • Litvinov R.I.
        Fibrin formation, structure and properties.
        Subcell. Biol. 2017; 82: 405-456
        • Mammadova-Bach E.
        • Ollivier V.
        • Loyau S.
        • Schaff M.
        • Dumont B.
        • Favier R.
        • Freyburger G.
        • Latger-Cannard V.
        • Nieswandt B.
        • Gachet C.
        • Mangin P.H.
        • Jandrot-Perrus M.
        Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation.
        Blood. 2015; 126: 683-691
        • Choo H.-J.
        • Kholmukhamedov A.
        • Zhou C.
        • Jobe S.
        Apoptotic and agonist-initiated phosphatidylserine externalization in platelets.
        Arterioscler. Thromb. Vasc. Biol. 2017; 37: 1503-1512
        • Swieringa F.
        • Baaten C.C.
        • Verdoold R.
        • Mastenbroek T.G.
        • Rijnveld N.
        • van der Laan K.O.
        • Breel E.J.
        • Collins P.W.
        • Lancé M.D.
        • Henskens Y.M.
        • Cosemans J.M.
        • Heemskerk J.W.
        • van der Meijden P.E.J.
        Platelet control of fibrin distribution and microelasticity in thrombus formation under flow.
        Arterioscler. Thromb. Vasc. Biol. 2016; 36: 692-699
        • Bender M.
        • Palankar R.
        Platelet shape changes during thrombus formation: role of actin-based protrusions.
        Hamostaseologie. 2021; 41: 14-21
        • Xiao T.
        • Takagi J.
        • Coller B.S.
        • Wang J.H.
        • Springer T.A.
        Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics.
        Nature. 2004; 432: 59-67
        • Xiong J.-P.
        • Mahalingham B.
        • Alonso J.L.
        • Borrelli L.A.
        • Rui X.
        • Anand S.
        • Hyman B.T.
        • Rysiok T.
        • Müller-Pompala D.
        • Goodman S.L.
        • Arnaout M.A.
        Crystal structure of the complete integrin alphaVbeta3 ectodomain plus an alpha/beta transmembrane domain fragment.
        J. Cell Biol. 2009; 186: 589-600
        • Zhu J.
        • Zhu J.
        • Springer T.A.
        Complete integrin headpiece opening in eight steps.
        J. Cell Biol. 2013; 201: 1053-1068
        • Wang Y.
        • Reheman A.
        • Spring C.M.
        • Kalantari J.
        • Marshall A.H.
        • Wolberg A.S.
        • Gross P.L.
        • Weitz J.L.
        • Rand M.L.
        • Mosher D.F.
        • Freedman J.
        • Ni H.
        Plasma fibronectin supports hemostasis and regulates thrombosis.
        J. Clin. Invest. 2014; 124: 4281-4293
        • Springer T.A.
        • Zhu J.
        • Xiao T.
        Structural basis for distinctive recognition of fibrinogen γC peptide by the integrin αIIbβ3.
        J. Cell Biol. 2008; 182: 791-800
        • Nurden A.
        Profiling the genetic and molecular characteristics of Glanzmann thrombasthenia: can it guide current and future therapies?.
        Blood Med. 2021; 12: 581-599
        • Mor-Cohen R.
        • Rosenberg N.
        • Landau M.
        • Lahav J.
        • Seligsohn U.
        Specific cysteines in beta3 are involved in disulfide bond exchange-dependent and -independent activation of alphaIIbbeta3.
        J. Biol. Chem. 2008; 283: 19235-19244
        • Mor-Cohen R.
        • Rosenberg N.
        • Averbukh Y.
        • Seligsohn U.
        • Lahav J.
        Disulfide bond exchanges in integrins αIIbβ3 and αvβ3 are required for activation and post-ligation signaling during clot retraction.
        Thromb. Res. 2014; 133: 826-836
        • Lahav J.
        • Jurk K.
        • Hess O.
        • Barnes M.J.
        • Farndale R.W.
        • Luboshitz J.
        • Kehrel B.E.
        Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange.
        Blood. 2002; 100: 2472-2478
        • Podolnikova N.P.
        • Yakovlev S.
        • Yakubenko V.P.
        • Wang X.
        • Gorkun O.V.
        • Ugarova T.P.
        The interaction of integrin αIIbβ3 with fibrin occurs through multiple binding sites in the αIIb β-propeller domain.
        J. Biol. Chem. 2014; 289: 2371-2383
        • Litvinov R.I.
        • Farrell D.H.
        • Weisel J.W.
        • Bennett J.S.
        The platelet integrin αIIbβ3 differentially interacts with fibrin versus fibrinogen.
        J. Biol. Chem. 2016; 291: 7858-7867
        • Buitrago L.
        • Lefkowitz S.
        • Bentur O.
        • Padovan J.
        • Coller B.
        Platelet binding to polymerizing fibrin is avidity driven and requires activated αIIbβ3 but not fibrin cross-linking.
        Blood Adv. 2021; 5: 3986-4002
        • Komatsuya K.
        • Kaneko K.
        • Kasahara K.
        Function of platelet glycosphingolipid microdomains/lipid rafts.
        Int. J. Mol. Sci. 2020 Aug 2; 21: 5539https://doi.org/10.3390/ijms21155539
        • Brass L.F.
        • Zhu L.
        • Stalker T.J.
        Minding the gaps to promote thrombus growth and stability.
        J. Clin. Invest. 2005; 115: 3385-3392
        • Alshehri O.M.
        • Hughes C.E.
        • Montague S.
        • Watson S.K.
        • Frampton J.
        • Bender M.
        • Watson S.P.
        Fibrin activates GPVI in human and mouse platelets.
        Blood. 2015; 126: 1601-1608
        • Induruwa I.
        • Kempster C.
        • Thomas H.
        • Batista J.
        • Bonna A.
        • Bumanlag-Amis E.
        • Rehnstrom K.
        • Ashford S.
        • Soejima K.
        • Ouwehand W.
        • Farndale R.
        • Downes K.
        • Warburton E.
        • Moroi M.
        • Jung S.
        • McKinney H.
        • Malcor J.-D.S.
        • McGee J.
        Platelet surface receptor glycoprotein VI-dimer is overexpressed in stroke: the glycoprotein VI in stroke (GYPSIE) study results.
        PLoS One. 2022; 17 (Jan 18) (eCollection)e026269Shttps://doi.org/10.1371/journal.pone.0262955
        • Bender M.
        • Hagedorn I.
        • Nieswandt B.
        Genetic and antibody-induced glycoprotein VI deficiency equally proitects mice from mechanically and FeCl3-induced thrombosis.
        J. Thromb. Haemost. 2011; 9: 1423-1426
        • Mangin P.H.
        • Onsalaer M.-B.
        • Receveur N.
        • Le Lay N.
        • Hardy A.T.
        • Wilson C.
        • Sanchez X.
        • Loyau S.
        • Dupuis A.
        • Babar A.K.
        • Miller J.L.C.
        • Philippou H.
        • Hughes C.E.
        • Hert A.B.
        • Ariens R.A.S.
        • Mezzano D.
        • Jandrot-Perrus M.
        • Gachet C.
        • Watson S.P.
        Immobilized fibrinogen activates human platelets through GPVI.
        Haematologica. 2018; 103: 898-907
        • Perrella G.
        • Huang J.
        • Provenzale I.
        • Swieringa F.
        • Heubel-Moenen F.C.
        • Farndale R.W.
        • van der Meijden P.E.
        • Thomas M.
        • Ariens R.A.
        • Jandrot-Perrus M.
        • Watson S.P.
        • JWM Heemskerk
        • RoestM
        Nonredundant roles of platelet glycoprotein VI and integrin αIIbβ3 in fibrin-mediated microthrombus formation.
        Arterioscler Thromb Vasc Biol. 2021; 41: e97-e111
        • Nurden A.T.
        Clinical significance of altered collagen-receptor functioning in platelets with emphasis on glycoprotein VI.
        Blood Rev. 2019; 38 (jun 11)100592
        • Nurden P.
        • Stritt S.
        • Favier R.
        • Nurden A.T.
        Inherited platelet diseases with normal platelet count : phenotypes, genotypes and diagnostic strategy.
        Haematologica. 2021; 106: 337-350
        • Montague S.J.
        • Hicks S.M.
        • Lee C.S.-M.
        • Coupland L.A.
        • Parish C.R.
        • Lee W.M.
        • Andrews R.K.
        • Gardiner E.E.
        Fibrin exposure triggers αIIbβ3-independent platelet aggregate formation, ADAM10 activity and glycoprotein VI shedding in a charge-dependent manner.
        J. Thromb. Haemost. 2020; 18: 1447-1458
        • He L.
        • Pappan L.K.
        • Grenache D.G.
        • Li Z.
        • Tollefsen D.M.
        • Santoro S.A.
        • Zutter M.M.
        The contributions of the alpha2beta1 integrin to vascular thrombosis in vivo.
        Blood. 2003; 102: 3652-3657
        • Siljander P.R.-M.
        • Munnix I.C.A.
        • Smethurst P.A.
        • Deckmyn H.
        • Lindhout T.
        • Ouwehand W.H.
        • Farndale R.W.
        • Heemskerk J.W.M.
        Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood.
        Blood. 2004; 103: 1333-1341
        • Grover S.P.
        • Bergmeier W.
        • Mackman N.
        Platelet signaling pathways and new inhibitors.
        Arterioscler. Thromb. Vasc. Biol. 2018; 38: e28-e35
        • Hollopeter G.
        • Jantzen H.M.
        • Vincent D.
        • Li G.
        • England L.
        • Ramakrishnan V.
        • Yang R.B.
        • Nurden P.
        • Nurden A.
        • Julius D.
        • Conley P.B.
        Identification of the platelet ADP receptor targeted by anti-thrombotic drugs.
        Nature. 2001; 409: 202-207
        • Moser M.
        • Legate K.R.
        • Fassler R.
        The tail of integrins, talin, and kindlins.
        Science. 2009; 324: 895-899
        • Stefanini L.
        • Paul D.S.
        • Robledo R.G.
        • Chan E.R.
        • Getz T.M.
        • Campbell R.A.
        • Kechele D.O.
        • Casari C.
        • Platt R.
        • Caron K.M.
        • Mackman N.
        • Weyrich A.S.
        • Parrott M.C.
        • Boulaftali Y.
        • Adams M.D.
        • Peters L.L.
        • Bergmeier W.
        RASA3 is a critical inhibitor of RAP1-dependent platelet activation.
        J. Clin. Invest. 2015; 125: 1419-1432
        • Wegener K.L.
        • Partridge A.W.
        • Han J.
        • Pickford A.R.
        • Liddington R.C.
        • Ginsberg M.H.
        • Cambell I.D.
        Structural basis for integrin activation by.
        Cell. 2007; 128: 171-182
        • Calderwood D.A.
        • Campbell I.D.
        • Critchley D.R.
        Talins and kindlins: partners in integrin -mediated adhesion.
        Nat. Rev. Mol. Cell Biol. 2013; 14: 503-517
        • Haling J.R.
        • Monkley S.J.
        • Critchley D.R.
        • Petrich B.G.
        Talin-dependent integrin activation is required for fibrin clot retraction by platelets.
        Blood. 2011; 117: 1719-1722
        • Rosa J.P.
        • Raslova H.
        • Bryckaert M.
        Filamin a: a key actor in platelet biology.
        Blood. 2019; 134: 1270-1288
        • Gong H.
        • Shen B.
        • Flevaris P.
        • Chow C.
        • Lam S.C.
        • Voyno-Yasenetskaya T.A.
        • Kozasa T.
        • Du X.
        G protein subunit Gα13 binds to integrin αIIbβ3 and mediates integrin ‘outside-in’ signaling.
        Science. 2010; 327: 340-343
        • Law D.A.
        • DeGuzman F.R.
        • Heiser P.
        • Ministri-Madrid K.
        • Killeen N.
        • Phillips D.R.
        Integrin cytosplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signaling and platelet function.
        Nature. 1999; 401: 808-811
        • Osdoit S.
        • Rosa J.-P.
        Fibrin clot retraction by human platelets correlates with αIIbβ3 integrin-dependent protein tyrosine dephosphorylation.
        J. Biol. Chem. 2001; 276: 6703-6710
        • Martin V.
        • Guillermet-Guibert J.
        • Chicanne G.
        • Cabou C.
        • Jandrot-Perrus M.
        • Plantavid M.
        • Vanhaesebroeck B.
        • Payrastre B.
        • Gratacap M.
        Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo.
        Blood. 2010; 115: 2008-2013
        • Flevaris P.
        • Li Z.
        • Zhang G.
        • Zheng Y.
        • Liu J.
        • Du X.
        Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway.
        Blood. 2009; 113: 893-901
        • Yago T.
        • Lou J.
        • Wu T.
        • Yang J.
        • Miner J.J.
        • Coburn L.
        • Lopez J.A.
        • Cruz M.A.
        • Dong J.-F.
        • McIntyre L.V.
        • McEver R.P.
        • Zhu C.
        Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF.
        J. Clin. Invest. 2008; 118: 3195-3207
        • Qiu Y.
        • Brown A.C.
        • Myers D.R.
        • Sakurai Y.
        • Mannino R.G.
        • Tran R.
        • Ahn B.
        • Hardy E.T.
        • Kee M.F.
        • Kumar S.
        • Bao G.
        • Barker T.H.
        • Lam W.A.
        Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation.
        Proc. Natl. Acad. Sci. U. S. A. 2014; 111: 14430-14435
        • Gingras R.
        • Ginsberg M.H.
        Signal transduction: physical deformation of the membrane activates integrins.
        Curr. Biol. 2020; 30: R397-R400
        • Kim J.
        • Lee J.
        • Jang J.
        • Ye F.
        • Hong S.J.
        • Petrich B.G.
        • Ulmer T.S.
        • Kim C.
        Topological adaptation of transmembrane domains to the force-modulated lipid bilayer is a basis of sensing mechanical force.
        Curr. Biol. 2020; 30: 1614-1625
        • Falet H.
        Anatomy of the platelet cytoskeleton.
        in: Gresele P. Kleiman N.S. Lopez J.A. Page C.P. Platelets in Thrombotic and Non-thrombotic Disorders. Pathophysiology, Pharmacology, Therapeutics: An update. Springer International Publishing, 2017: 139-156
        • Myers D.R.
        • Qiu Y.
        • Fay M.E.
        • Tennenbaum M.
        • Chester D.
        • Cuadrado J.
        • Sakurai Y.
        • Baek J.
        • Tran R.
        • Ciciliano J.C.
        • Ahn B.
        • Mannino R.G.
        • Bunting S.T.
        • Bennett C.
        • Vriones M.
        • Fernandez-Nieves A.
        • Smith M.L.
        • Brown A.C.
        • Sulchek T.
        • Lam W.A.
        Single-platelet nanomechanics measured by high-throughput cytometry.
        Nat. Mater. 2017; 16: 230-235
        • Falet H.
        • Hoffmeister K.M.
        • Italiano Neujhar R.
        • Jr J.E.
        • Stossel T.P.
        • Southwick F.S.
        • Hartwig J.H.
        Importance of free actin filament barbed ends for Arp 2/3 complex function in platelets and fibroblasts.
        Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16782-16787
        • Kim O.V.
        • Litvinov R.I.
        • Alber M.S.
        • Weisel J.W.
        Quantitative structural mechanobiology of platelet-driven blood clot contraction.
        Nat. Commun. 2017; 8: 1274https://doi.org/10.1038/s41467-017-00885-x
        • Flevaris P.
        • Stojanovic A.
        • Gong H.
        • Chishti A.
        • Welch E.
        • Du X.
        A molecular switch that controls cell spreading and retraction.
        J. Cell Biol. 2007; 179: 553-565
        • Fong K.P.
        • Molnar K.S.
        • Agard N.
        • Litinov R.I.
        • Kim O.V.
        • Wells J.A.
        • Weisel J.W.
        • DeGrado W.F.
        • Bennett J.S.
        Cleavage of talin by calpain promotes platelet-mediated fibrin clot contraction.
        Blood Adv. 2021; 5: 4901-4909
        • Ilkan Z.
        • Wright J.R.
        • Goodall A.H.
        • Gibbins J.M.
        • Jones C.I.
        • Mahaut-Smith M.P.
        Evidence for shear-mediated Ca2+ entry through mechanosensitive cation channels in human platelets and a megakaryocytic cell line.
        J. Biol. Chem. 2017; 292: 9204-9217
        • Weyrich A.S.
        • Denis M.M.
        • Schwertz H.
        • Tolley N.D.
        • Foulks J.
        • Spencer E.
        • Kraiss L.W.
        • Albertine K.H.
        • McIntyre T.M.
        • Zimmerman G.A.
        mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets.
        Blood. 2007; 109: 1975-1983
        • Keuren J.F.W.
        • Baruch D.
        • Legendre P.
        • Denis C.V.
        • Lenting P.J.
        • Girma J.-P.
        • Lindhout T.
        Von Willebrand factor C1C2 domain is involved in platelet adhesion to polymerized fibrin at high shear rate.
        Blood. 2004; 103: 1741-1746
        • Janus-Bell E.
        • Yakusheva A.
        • Scandola C.
        • Receveur N.
        • Muhammed-Usman A.
        • Mouriaux C.
        • Bourdon C.
        • Loubière C.
        • Eckly A.
        • Senis Y.A.
        • Panteleev M.A.
        • Gachet C.
        • Mangin P.H.
        Characterization of the role of integrin α5β1 in platelet function, hemostasis and experimental thrombosis.
        Thromb. Haemost. 2022; 122: 767-776
        • Bale M.D.
        • Mosher D.F.
        Effects of thrombospondin on fibrin polymerization and structure.
        J. Biol. Chem. 1986; 261: 862-868
        • Suzuki J.
        • Umeda M.
        • Sims P.J.
        • Nagata S.
        Calcium-dependent phospholipid scambling by TMEM16F.
        Nature. 2010; 468: 634-638
        • Kasahara K.
        • Kaneda M.
        • Miki T.
        • Lida K.
        • Sekino-Suzuki N.
        • Kawashima I.
        • Suzuki H.
        • Shimonaka M.
        • Arai M.
        • Ohno-Iwashita Y.
        • Kojima S.
        • Abe M.
        • Kobayashi T.
        • Okazaki T.
        • Souri M.
        • Ichinose A.
        • Yamamoto N.
        Clot retraction is mediated by factor XIII-dependent fibrin- αIIbβ3-myosin axis in platelet sphingomyelin-rich membrane rafts.
        Blood. 2013; 122: 3340-3348
        • Stalker T.J.
        • Traxler E.A.
        • Wu J.
        • Wannemacher K.M.
        • Cermignano S.L.
        • Voronov R.
        • Diamond S.L.
        • Brass L.F.
        Hierarchical organization in the hemostatic response and its relationship to the platelet signaling network.
        Blood. 2013; 121 (1875-1775)
        • Morrissey J.H.
        • Smith S.A.
        Polyphosphate as modulator of hemostasis, thrombosis and hemostasis.
        J. Thromb. Haemost. 2015; 13: 592-597
        • Mutch N.J.
        • Engel R.
        • Uitte de Willige S.
        • Philippou H.
        • Ariens R.A.S.
        Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin.
        Blood. 2010; 115: 3980-3988
        • Aleman M.M.
        • Byrnes J.R.
        • Wang J.-G.
        • Tran R.
        • Lam W.A.
        • Di Paola J.
        • Mackman N.
        • Degen J.L.
        • Flick M.J.
        • Wolberg A.S.
        Factor XIII activity mediates red blood cell retention in venous thrombi.
        J. Clin. Invest. 2014; 124: 3590-3600
        • Mitchell J.L.
        • Lionikiene A.S.
        • Fraser S.R.
        • Whyte C.S.
        • Booth N.A.
        • Mutch N.J.
        Functional factor XIII-A is exposed on the stimulated platelet surface.
        Blood. 2014; 124: 3982-3990
        • Dale G.L.
        • Friese B.
        • Batar P.
        • Hamilton S.F.
        • Reed G.L.
        • Jackson K.W.
        • Clemetson K.J.
        • Alberio L.
        Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface.
        Nature. 2002; 415: 175-179
        • Abaeva A.A.
        • Canault M.
        • Kotova Y.N.
        • Obydennyy S.I.
        • Yakimenko A.O.
        • Podoplelova N.A.
        • Kolyadko V.N.
        • Chambost H.
        • Mazurov A.V.
        • Ataullakhanov F.I.
        • Nurden A.T.
        • Alessi M.-C.
        • Panteleev M.A.
        Procoagulant platelets form an α-granule protein-covered “cap” on their surface that promotes their attachment to aggregates.
        J. Biol. Chem. 2013; 288: 29621-29632
        • Mattheij N.J.A.
        • Swieringa F.
        • Mastenbroek T.G.
        • Berny-Lang M.A.
        • May F.
        • Baaten C.C.F.M.J.
        • van der Meijden P.E.J.
        • Henskens Y.M.C.
        • Beckers E.A.M.
        • Suylen D.P.L.
        • Noite M.W.
        • Hackeng T.M.
        • McCarty O.J.
        • Heemskerk J.W.M.
        • Cosemans J.M.E.M.
        Coated platelet function in platelet-dependent fibrin formation via integrin αIIbβ3 and transglutaminase factor XIII.
        Haematologica. 2016; 101: 427-436
        • Agbani E.O.
        • van den Bosch M.T.J.
        • Brown E.
        • Williams C.M.
        • Mattheij N.J.A.
        • Cosemans J.M.E.M.
        • Collins P.W.
        • Heemskerk J.W.M.
        • Hers I.
        • Poole A.W.
        Coordinated membrane ballooning and procoagulant spreading in human platelets.
        Circulation. 2015; 132: 1414-1424
        • Boilard E.
        • Duchez A.C.
        • Brisson A.
        The diversity of platelet microparticles.
        Curr. Opin. Haematol. 2015; 22: 437-444
        • Zubairova L.D.
        • Nabiullina R.M.
        • Nagaswami C.
        • Zuev Y.F.
        • Mustafin I.G.
        • Litinov R.I.
        • Weisel J.W.
        Circulating microparticles alter formation, structure, and properties of fibrin clots.
        Sci Rep. 2015; 5 (Dec 4): 17611https://doi.org/10.1038/srep17611
        • Tutwiler V.
        • Litinov R.I.
        • Lozhkin A.P.
        • Peshkova A.D.
        • Lebedeva T.
        • Ataullakhanov F.I.
        • Spiller K.L.
        • Cines D.B.
        • Weisel J.W.
        Kinetics and mechanics of clot retraction are governed by the molecular and cellular composition of the blood.
        Blood. 2016; 127: 149-159
        • Cines D.B.
        • Lebedeva T.
        • Nagaswami C.
        • Hayes V.
        • Massefski W.
        • Litvinov R.I.
        • Rauova L.
        • Lowery T.J.
        • Weisel J.W.
        Clot retraction: compression of erythrocytes into tightly packed polyhedral and redistribution of platelets and fibrin.
        Blood. 2014; 123: 1596-1603
        • Chernysh I.N.
        • Nagaswarni C.
        • Kosolapova S.
        • Peshkova A.D.
        • Cuker A.
        • Cines D.B.
        • Cambor C.L.
        • Litvinov R.I.
        • Weisel J.W.
        The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli.
        Sci. Rep. 2020; 10 (Mar 20): 5112https://doi.org/10.1038/s41598-020-50526-x
        • Noubouossie D.F.
        • Whelihan M.F.
        • Yu Y.B.
        • Sparkenbaugh E.
        • Pawlinski R.
        • Monroe D.M.
        • Key N.S.
        In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps.
        Blood. 2017; 129: 1021-1029
        • Longstaff C.
        • Varju I.
        • Sotonyi P.
        • Szabo L.
        • Krumrey M.
        • Hoeli A.
        • Bota A.
        • Varga Z.
        • Komorowicz E.
        • Kolev K.
        Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones.
        J. Biol. Chem. 2013; 288: 6946-6956
        • Fuchs T.A.
        • Brill A.
        • Duerschmied D.
        • Schatzberg D.
        • Monestier M.
        • Myers D.D.
        • Wrobleski S.K.
        • Wakefield T.W.
        • Hartwig J.H.
        • Wagner D.D.
        Extracellular DNA traps promote thrombosis.
        Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 15880-15885
        • Tutwiler V.
        • Peshkova A.D.
        • Andrianova I.A.
        • Khasanova D.R.
        • Weisel J.W.
        • Litvinov R.I.
        Contraction of blood clots is impaired in actute ischemic stroke.
        Arterioscler. Thromb. Vasc. Biol. 2017; 37: 271-279
        • Braun A.
        • Anders H.-J.
        • Gudermann T.
        • Mammadova-Bach E.
        Platelet-cancer interplay: molecular mechanisms and new therapeutic avenues.
        Front. Oncol. 2021; 11 (Jul 12) (doi: 3389/fonc.2021.665534. eCollection 2021)665534
        • Martinod K.
        • Deppermann C.
        Immunothrombosis and thromboinflammation in host and disease.
        Platelets. 2021; 32: 314-324
        • Gomez R.M.
        • Lopez Ortiz A.O.
        • Schattner M.
        New roles of platelets in inflammation.
        Curr. Opin. Physiol. 2021; 19: 99-104
        • Peshkova A.D.
        • Malyasyov D.V.
        • Bredikhin R.A.
        • Le Min G.
        • Andrianova I.A.
        • Tutwiler V.
        • Nagaswami C.
        • Weisel J.W.
        • Litvinov R.I.
        Reduced contraction of blood clots in venous thromboembolism is a potential thrombogenic and embologenic mechanism.
        Thomb. Haemost. Open. 2018; 2: e104-e115
        • Peshkova A.D.
        • Le Minh G.
        • Tutwiler V.
        • Andrianova I.A.
        • Weisel J.W.
        • Litvinov R.I.
        Activated monocytes enhance platelet-driven clots via tissue factor expression.
        Sci. Rep. 2017; 7: 5149https://doi.org/10.1038/s41598-017-05601-9
        • Padilla S.
        • Nurden A.T.
        • Prado R.
        • Nurden P.
        • Anitua E.
        Healing through the lens of immunothrombosis: biology-inspired, evolution-tailored, and human-engineered biomimetic therapies.
        Biomaterials. 2021; 279 (Dec) (Epub 2021 Oct 21)121205https://doi.org/10.1016/J.biomaterials.2021.121205
        • Nurden A.T.
        The biology of the platelet with special reference to inflammation, wound healing and immunity.
        Front. Biosci. (Landmark Ed.). 2018 Jan 1; 23: 726-751
        • Ley K.
        • Rivera-Nieves J.
        • Sandborn W.J.
        • Shattil S.
        Integrin-based therapeutics: biological basis, clinical use and new drugs.
        Nat. Rev. Drugs Discov. 2016; 15: 173-183
        • Chen Y.-P.
        • O’Toole T.E.
        • Leong L.
        • Liu B.-O.
        • Diaz-Gonzalez F.
        • Ginsberg M.H.
        β3 integrin-mediated clot retraction by nucleated cells: differing behaviour of αIIbβ3 and αvβ3.
        Blood. 1995; 86: 2606-2615
        • Martin K.
        • Reimann A.
        • Fritz R.D.
        • Ryu H.
        • Jeon N.L.
        • Pertz O.
        Spatio-temporal co-ordination of RhoA, Rac1 and Cdc42 activation during prototypical edge protrusion and retraction dynamics.
        Sci. Rep. 2016 Feb; 25: 21901https://doi.org/10.1038/srep21901
        • Jasuja R.
        • Furie B.
        • Furie B.C.
        Endothelium-derived but not platelet-derived protein disulfide isomerase is required for thrombus formation in vivo.
        Blood. 2010; 116: 4665-4674
        • Levi M.
        • Thatchil J.
        • Iba T.
        • Levy J.H.
        Coagulation abnormalities and thrombosis in patients with severe Covid-19.
        Lancet Haematol. 2020; 7: E438-E440
        • Wygrecka M.
        • Birnhuber A.
        • Seeliger B.
        • Michalick L.
        • Pak O.
        • Schulz A.-S.
        • Schramm F.
        • Zacharias M.
        • Gorkiewicz G.
        • David S.
        • Welte T.
        • Schmidt J.J.
        • Weissmann N.
        • Schermuly R.T.
        • Barreto G.
        • Schaefer L.
        • Markart P.
        • Brack M.C.
        • Hippenstiel S.
        • Kurth F.
        • Sander L.E.
        • Witzenrath M.
        • Kuebler W.M.
        • Kwapiszewska G.
        • Preissner K.T.
        Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19.
        Blood Adv. 2022; 6: 1074-1097
        • Veras F.P.
        • Pontelli M.C.
        • Silva C.M.
        • Toller-Kawahisa J.E.
        • De Lima M.
        • Nascimento D.C.
        • Schneider A.H.
        • Caetite D.
        • Tavares L.A.
        • Paiva I.M.
        • Rosales R.
        • Colon D.
        • Martins R.
        • Castro I.A.
        • Almeida G.M.
        • Fernandes Lopes M.I.
        • Benatti M.N.
        • Bonjorno L.P.
        • Giannini M.C.
        • Luppino-Assas R.
        • Almeida S.L.
        • Vilar F.
        • Santana R.
        • Bollela V.R.
        • Auxiliadora-Martins M.
        • Borges M.
        • Miranda C.H.
        • Pazin-Filho A.
        • LLP Da Silva
        • Dias Cunha L.
        • Zamboni D.S.
        • Dal-Pizzol F.
        • Leira L.O.
        • Siyuan L.
        • Batah S.
        • Fabro A.
        • Mauad T.
        • Dolhnikoff M.
        • Duarte-Neto A.
        • Saldiva P.
        • Mattar Cunha T.
        • Alves-Filho J.C.
        • Arruda E.
        • Louzada-Junior P.
        • Oliviera R.D.
        • Cunha F.Q.
        SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology.
        J Exp Med. 2020; 217e20201129https://doi.org/10.1084/jem.20201129
        • Coste B.
        • Mathur J.
        • Schmidt M.
        • Earley T.J.
        • Ranade S.
        • Petrus M.J.
        • Dubin A.E.
        • Patapoutian A.
        Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.
        Science. 2010; 330: 55-60
        • Zhu W.
        • Guo S.
        • Homilius M.
        • Nsubaga C.
        • Wright S.H.
        • Quan D.
        • Kc A.
        • Eddy S.S.
        • Victorio R.A.
        • Beerens M.
        • Flaumenhaft R.
        • Deo R.C.
        • CA MacRae
        PIEZO1 mediates a mechanothrombotic pathway in diabetes.
        Sci. Transl. Med. 2022; 14 (Jan 5) (Epub 2022)eabk1707https://doi.org/10.1126/scitranslmed.abk1707
        • Luyendyk J.P.
        • Schoenecker J.G.
        • Flick M.J.
        The multifaceted role of fibrinogen in tissue injury and inflammation.
        Blood. 2019; 133: 511-520
        • Carmeliet P.
        Angiogenesis in health and disease.
        Nat. Med. 2003; 9: 653-660
        • Kearney K.J.
        • Ariens R.A.S.
        • Macrae F.L.
        The role of fibrin(ogen) in wound healing and infection control.
        Semin. Thromb. Hemost. 2022; 48: 174-187
        • Anitua E.
        • Andia I.
        • Ardanza B.
        • Nurden P.
        • Nurden A.T.
        Autologous platelets as a source of proteins for healing and tissue regeration.
        Thromb. Heamost. 2004; 91: 4-15
        • Blair P.
        • Flaumenhaft R.
        Platelet alpha-granules: basic biology and clinical correlates.
        Blood Rev. 2009; 23: 177-189
        • Lindemann S.
        • Tolley N.D.
        • Dixon D.A.
        • McIntyre T.M.
        • Prescott S.M.
        • Zimmerman G.A.
        • Weyrich A.S.
        Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis.
        J. Cell Biol. 2001; 154: 485-490
        • Amelot A.A.
        • Taqzirt M.
        • Ducouret G.
        • Kuen R.L.
        • Le Bonniec B.F.
        Platelet factor 4 (CXCL4) seals blood clots by altering the structure of fibrin.
        J. Biol. Chem. 2007; 282: 710-720
        • Welsh J.D.
        • Muthard R.W.
        • Stalker T.J.
        • Taliaferro J.P.
        • Diamond S.L.
        • Brass L.F.
        A systems approach to hemostais: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature.
        Blood. 2016; 127: 1598-1605
        • Grover S.P.
        • Mackman N.
        Tissue factor. An essential mediator of haemostasis and trigger of thrombosis.
        Arterioscler. Thromb. Vasc. Viol. 2018; 38: 709-725
        • Laurens N.
        • Koolwijk P.
        • De Maat M.P.M.
        Fibrin structure and wound healing.
        J. Thromb. Haemost. 2006; 4: 932-939
        • Hu M.S.
        • Borrelli M.R.
        • Lorenz P.
        • Longaker M.T.
        • Wan D.C.
        Mesenchymal stromal cells and cutaneous wound healing: a comprehensive review of the background, role and therapeutic potential.
        Stem Cells Int. 2018; https://doi.org/10.1155/2018/6901983
        • Florian J.A.
        • Kosky J.R.
        • Ainslie K.
        • Pang Z.
        • Dull R.O.
        • Tarbell J.M.
        Heparan sulfate proteoglycan is a mechanosensor on endothelial cells.
        Circulation Res. 2003; 93: e136-e142
        • Tapper H.
        • Herwald H.
        Modulation of hemostatic mechanisms in bacterial infectious diseases.
        Blood. 2000; 96: 2329-2337
        • Yeaman M.R.
        Platelets: at the nexus of antimicrobial defence.
        Nat. Rev. Microbiol. 2014; 12: 426-437
        • D’Atri L.P.
        • Schattner M.
        Platelet toll-like receptors in thromboinflammation.
        Front. Biosci. (Landmark Ed.). 2017; 22: 1867-1883
        • Nicolai L.
        • Gaertner S.
        • Massberg S.
        Platelets in host defence: experimental and clinical insights.
        Trends Immunol. 2019; 40: 922-938
        • Gaertner F.
        • Ahmad Z.
        • Rosenberger G.
        • Fan S.
        • Nicolai L.
        • Busch B.
        • Yavuz G.
        • Luckner M.
        • Ishikawa-Ankerhold H.
        • Hennel R.
        • Benechet A.
        • Lorenz M.
        • Chandraratne S.
        • Schubert I.
        • Helmer S.
        • Striednig B.
        • Stark K.
        • Janko M.
        • Bottcher R.T.
        • Verschoor A.
        • Leon C.
        • Gachet C.
        • Guderman T.
        • Zachary Pincus Z.
        • Iannacone M.
        • Haas R.
        • Wanner G.
        • Lauber K.
        • Sixt M.
        • Massberg S.
        • Mederos Y.
        • Schnitzler M.
        Migrating platelets are mechano-scavengers that collect and bundle bacteria.
        Cell. 2017; 171 (1368.e23–1382.e23)
        • Burnouf T.
        • Goubran H.A.
        • Chen T.M.
        • Ou K.L.
        • El-Ekiaby M.
        • Radosevic M.
        Blood-derived biomaterials and platelet growth factors in regenerative medicine.
        Blood Rev. 2013; 27: 77-89
        • Anitua E.
        • Nurden P.
        • Prado R.
        • Nurden A.T.
        Padilla S autologous fibrin scaffolds: when platelet- and plasma-derived biomolecules meet fibrin.
        Biomaterials. 2018; 192: 440-460
        • Fox J.M.
        • Kausar F.
        • Day A.
        • Osborne M.
        • Hussain K.
        • Mueller A.
        • Lin J.
        • Tsuchiya T.
        • Kanegasaki S.
        • Pease J.E.
        CXCL4/platelet factor 4 is an agonist of CCR1 and drives human monocyte migration.
        Sci. Rep. 2018; 8: 9466https://doi.org/10.1038/s41598-018-27710-9
        • Frangogiannis N.G.
        Transforming growth factor-β in tissue fibrosis.
        J. Exp. Med. 2020; 217e20190103
        • Fan Q.
        • Ma Q.
        • Bai J.
        • Xu J.
        • Fei Z.
        • Dong Z.
        • Maruyama A.
        • Leong K.W.
        • Liu Z.
        • Wang C.
        An implantable blood clot based immune niche for enhanced cancer vaccination.
        Sci. Adv. 2020; 6eabb4639
        • Wilcox D.A.
        Megakaryocyte and megakaryocyte precursor-related gene therapies.
        Blood. 2016; 127: 1260-1268
        • Du L.M.
        • Nurden P.
        • Nurden A.T.
        • Nichols T.C.
        • Bellinger D.A.
        • Jensen E.S.
        • Haberichter S.L.
        • Merricks E.
        • Raymer R.A.
        • Fang J.
        • Koukouritaki S.B.
        • Jacobi P.M.
        • Hawkins T.B.
        • Cornetta K.
        • Shi Q.
        • Wilcox D.A.
        Platelet targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A.
        Nat. Commun. 2013; 4: 2773https://doi.org/10.1038/ncomms3773
        • Huang J.
        • Swieringa F.
        • Solari F.A.
        • Provenzale I.
        • Grassi L.
        • De Simone I.
        • CCFM Baaten
        • Cavill R.
        • Sickmann A.
        • Frontini M.
        • JWM Heemskerk
        Assessment of a complete and classified platelet proteome from genome-wide transcripts of human platelets and megakaryocytes covering platelet functions.
        Sci Rep. 2021; 11 (jun 11): 12358https://doi.org/10.1038/s41598-021-91661-x