A Model of Platelet Aggregation Involving Multiple Interactions of Thrombospondin-1, Fibrinogen, and GPIIbIIIa Receptor

Thrombospondin-1 (TSP) may, after secretion from platelet α granules, participate in platelet aggregation, but its mode of action is poorly understood. We evaluated the capacity of TSP to form inter-platelet cross-bridges through its interaction with fibrinogen (Fg), using either Fg-coated beads or Fg bound to the activated GPIIbIIIa integrin (GPIIbIIIa*) immobilized on beads or on activated fixed platelets (AFP), i.e. in a system free of platelet signaling and secretion mechanisms. Aggregation at physiological shear rates (100–2000 s−1) was studied in a microcouette device and monitored by flow cytometry. Soluble TSP bound to and induced aggregation of Fg-coated beads dose-dependently, which could be blocked by the amino-terminal heparin-binding domain of TSP, TSP18. Soluble TSP did not bind to GPIIbIIIa*-coated beads or AFP, unless they were preincubated with Fg. The interaction of soluble TSP with Fg-GPIIbIIIa*-coated beads or Fg-AFP resulted in the formation of aggregates via Fg-TSP-Fg cross-bridges, as demonstrated in a system where direct cross-bridges mediated by GPIIbIIIa*-Fg on one particle and free GPIIbIIIa* on a second particle were blocked by the RGD mimetic Ro 44–9883. Soluble TSP increased the efficiency of Fg-mediated aggregation of AFP by 30–110% over all shear rates and GPIIbIIIa* occupancies evaluated. Surprisingly, TSP binding to Fg already bound to its GPIIbIIIa* receptor appears to block the ability of this occupied Fg to recognize another GPIIbIIIa* receptor, but this TSP can indeed cross-bridge to another Fg molecule on a second platelet. Finally, TSP-coated beads could directly coaggregate at shear rates from 100 to 2000 s−1. Our studies provide a model for the contribution of secreted TSP in reinforcing inter-platelet interactions in flowing blood, through direct Fg-TSP-Fg andTSP-TSP cross-bridges. Thrombospondin-1 (TSP) may, after secretion from platelet α granules, participate in platelet aggregation, but its mode of action is poorly understood. We evaluated the capacity of TSP to form inter-platelet cross-bridges through its interaction with fibrinogen (Fg), using either Fg-coated beads or Fg bound to the activated GPIIbIIIa integrin (GPIIbIIIa*) immobilized on beads or on activated fixed platelets (AFP), i.e. in a system free of platelet signaling and secretion mechanisms. Aggregation at physiological shear rates (100–2000 s−1) was studied in a microcouette device and monitored by flow cytometry. Soluble TSP bound to and induced aggregation of Fg-coated beads dose-dependently, which could be blocked by the amino-terminal heparin-binding domain of TSP, TSP18. Soluble TSP did not bind to GPIIbIIIa*-coated beads or AFP, unless they were preincubated with Fg. The interaction of soluble TSP with Fg-GPIIbIIIa*-coated beads or Fg-AFP resulted in the formation of aggregates via Fg-TSP-Fg cross-bridges, as demonstrated in a system where direct cross-bridges mediated by GPIIbIIIa*-Fg on one particle and free GPIIbIIIa* on a second particle were blocked by the RGD mimetic Ro 44–9883. Soluble TSP increased the efficiency of Fg-mediated aggregation of AFP by 30–110% over all shear rates and GPIIbIIIa* occupancies evaluated. Surprisingly, TSP binding to Fg already bound to its GPIIbIIIa* receptor appears to block the ability of this occupied Fg to recognize another GPIIbIIIa* receptor, but this TSP can indeed cross-bridge to another Fg molecule on a second platelet. Finally, TSP-coated beads could directly coaggregate at shear rates from 100 to 2000 s−1. Our studies provide a model for the contribution of secreted TSP in reinforcing inter-platelet interactions in flowing blood, through direct Fg-TSP-Fg andTSP-TSP cross-bridges. thrombospondin-1 fibrinogen activated αIIbβ3 integrin activated fixed platelet fluorescein isothiocyanate bovine serum albumin FITC-labeled TSP FITC-labeled TSP18 FITC-labeled Fg Fg-coated bead TSP-coated bead BSA-coated bead GPIIbIIIa*-coated bead Thrombospondin-1 (TSP)1represents 20–30% of the glycoproteins stored in human platelet α-granules (1Baenziger N.L. Brodie G.N. Majerus P.W. J. Biol. Chem. 1972; 247: 273-2723Abstract Full Text PDF PubMed Google Scholar). Upon platelet activation and degranulation, TSP is released, and an important fraction is found associated with the platelet surface (2Phillips D.R. Jennings L.K. Prasanna H.R. J. Biol. Chem. 1980; 255: 11629-11632Abstract Full Text PDF PubMed Google Scholar, 3Rabhi-Sabile S. Pidard D. Lawler J. Renesto P. Chignard M. Legrand C. FEBS Lett. 1996; 386: 82-86Crossref PubMed Scopus (33) Google Scholar). Several putative receptors and ligands for TSP at the surface of activated platelets have been described, including fibrinogen (Fg) (4Tuszynski G.P. Srivastava S. Switalska H.I. Holt J.C. Cierniewski C.S. Niewiarowski S. J. Biol. Chem. 1985; 260: 12240-12245Abstract Full Text PDF PubMed Google Scholar, 5Bacon-Baguley T. Ogilvie M.L. Gartner T.K. Walz D.A. J. Biol. Chem. 1990; 265: 2317-2323Abstract Full Text PDF PubMed Google Scholar, 6Legrand C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar, 7Panetti T.S. Kudryk B.J. Mosher D.F. J. Biol. Chem. 1999; 274: 430-437Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar), sulfatides (8Roberts D.D. Lahav J. Thrombospondin. CRC Press, Boca Raton, FL1993: 73-90Google Scholar) glycoprotein IV (GPIV, CD36) (9Asch A.S. Silbiger S. Heimer E. Nachman R.L. Biochem. Biophys. Res. Commun. 1992; 182: 1208-1217Crossref PubMed Scopus (162) Google Scholar,10McGregor J.L. Catimel B. Parmentier S. Clezardin P. Dechavanne M. Leung L.L. J. Biol. Chem. 1989; 264: 501-506Abstract Full Text PDF PubMed Google Scholar), and integrin-associated protein (IAP/CD47) (11Gao A.G. Lindberg F.P. Finn M.B. Blystone S.D. Brown E.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). TSP with including and αIIbβ3 through its J. J. Biol. PubMed Scopus Google Scholar). the interaction of TSP with GPIIbIIIa is J. A. G.P. J. Biol. Chem. 1989; 264: Full Text PDF PubMed Google Scholar, G.P. Biochem. J. PubMed Scopus Google Scholar, P. Pidard D. D. V. Legrand C. Biophys. 1990; PubMed Scopus Google Scholar, Thromb. PubMed Scopus Google Scholar, E. PubMed Scopus Google of TSP in platelet aggregation been demonstrated by a of studies of platelet aggregation and by T.K. Walz D.A. M. Ogilvie M.L. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, L.L. J. PubMed Scopus Google Scholar, S. A. 1985; PubMed Scopus Google Scholar, Thromb. PubMed Scopus Google Scholar, C. V. V. B. Lawler J. 1992; PubMed Google Scholar, H. J.L. J. Biochem. PubMed Scopus Google Scholar) and or of TSP C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar, G.P. J. J. Biol. 1992; PubMed Scopus Google Scholar). Leung L.L. J. PubMed Scopus Google Scholar) the interaction of TSP with Fg on the surface of activated platelets the binding of Fg to its receptor, the activated integrin GPIIbIIIa with Fg in direct cross-bridges. studies TSP with the integrin-associated protein (IAP/CD47) (11Gao A.G. Lindberg F.P. Finn M.B. Blystone S.D. Brown E.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) and as a of platelet integrin GPIIbIIIa and J. A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Lindberg F.P. 1999; PubMed Google Scholar). direct for TSP as a of platelets interactions was by studies with platelet or activated fixed platelets Fg A. Thromb. PubMed Scopus Google Scholar, M. Arterioscler. Thromb. Biol. 1996; PubMed Scopus Google Scholar). in the of and of aggregation was not studies were 1985; PubMed Scopus Google Scholar) or in an A. Thromb. PubMed Scopus Google Scholar), i.e. not of the physiological flow and shear the using free of platelet and and the capacity of TSP to form and inter-platelet cross-bridges through its interactions with Fg or with TSP and the contribution of cross-bridges in the aggregation of platelets by studied the of TSP in platelet aggregation through its interaction with Fg bound to its receptor, We model either or or were to the surface of activated platelets but in the of signaling or secretion the of TSP and surface of TSP induced aggregation of dose-dependently, with a at and an aggregation efficiency of at a shear of s−1. Aggregation of by TSP after of the beads with Fg. Ro the RGD to block the cross-bridges GPIIbIIIa* bound Fg and free aggregation through Fg-TSP-Fg cross-bridges with α at to with at TSP surface with AFP aggregation by TSP at with Ro in the of with α for for the of Fg and TSP in this TSP can aggregation of beads or AFP by directly Fg on at a physiological shear of TSP, to the of platelet aggregation C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar), aggregation of by TSP but did not the is an for the of the amino-terminal of the TSP molecule in interactions and a interaction as in the binding of to where TSP18 was not to the bound but binding of not putative binding on Fg and TSP could or including on the (4Tuszynski G.P. Srivastava S. Switalska H.I. Holt J.C. Cierniewski C.S. Niewiarowski S. J. Biol. Chem. 1985; 260: 12240-12245Abstract Full Text PDF PubMed Google Scholar), and T. Ogilvie M.L. Gartner T.K. Walz D.A. J. Biol. Chem. 1990; 265: 2317-2323Abstract Full Text PDF PubMed Google and at on TSP C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar), the as TSP C. P. Clezardin P. J. Res. PubMed Scopus Google Scholar) and TSP J. J. Biol. Chem. Full Text PDF PubMed Google of with TSP did not the the binding of to GPIIbIIIa* immobilized on beads is in with the of and H. J.L. J. Biochem. PubMed Scopus Google Scholar) a platelet aggregation by of did not the of Fg binding to platelets with or Leung L.L. J. PubMed Scopus Google Scholar) TSP, by with Fg at a from its the of Fg for the on the an the of Fg binding to activated could a by the bound to TSP, the interactions by (9Asch A.S. Silbiger S. Heimer E. Nachman R.L. Biochem. Biophys. Res. Commun. 1992; 182: 1208-1217Crossref PubMed Scopus (162) Google Scholar, M. M. J. Biophys. PubMed Scopus Google Scholar, J. J. J. 1992; Google studies a Fg with TSP is of with another of of receptor with TSP the aggregation efficiency by this TSP of Fg a TSP a Fg molecule on an bead of the surface of Fg and TSP and is not by the system GPIIbIIIa* for Fg on a the efficiency of aggregation for Fg receptor as A. Legrand C. Biophys. J. Full Text Full Text PDF PubMed Scopus Google Scholar), the aggregation efficiency in the of TSP is to the aggregation efficiency be with Fg on to the of Fg occupied by the of TSP in the for platelet to immobilized Fg or after of with soluble TSP J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). Our the the of TSP is induced by the of the on Fg or for its platelet receptor, its by the of of TSP on the aggregation efficiency of AFP mediated by Fg and found an of 30–110% at all Fg receptor occupancies and all shear rates s−1) with of Fg by We on the surface the of aggregation aggregation by the of the which the surface for and the for the the of the and in platelet to platelet to Fg-TSP-Fg have interactions can participate in to particle aggregation at shear The beads at all shear with a in efficiency for a in shear to the for Fg-mediated aggregation of platelets by GPIIbIIIa*-Fg cross-bridges Biophys. J. 1994; Full Text PDF PubMed Scopus Google Scholar). The aggregation efficiency at was to for Fg-mediated aggregation of or platelets with GPIIbIIIa* A. Legrand C. Biophys. J. Full Text Full Text PDF PubMed Scopus Google and Biophys. J. 1994; Full Text PDF PubMed Scopus Google and this the direct contribution of TSP in reinforcing the inter-platelet interactions in physiological flow The of TSP is to be the of the platelet secretion of TSP at the of activated platelets with Fg already bound to a of cross-bridges in The cross-bridges cross-bridges with of TSP TSP cross-bridges TSP Fg in model platelets from with which have been to of TSP at the surface with aggregation in an H. J.L. J. Biochem. PubMed Scopus Google Scholar, M.L. J. PubMed Scopus Google Scholar). this with model from the of platelets in one by not be by M. A. D. Catimel B. Dechavanne M. J.L. Thromb. 1989; PubMed Scopus Google Scholar) and studies TSP was not on the platelet surface of one with and of TSP P. M. 1985; PubMed Google Scholar). is in of GPIIbIIIa TSP not be in an to platelet Our model of of is to as as and with the TSP found in for the of TSP in platelet aggregation mediated by of TSP Fg directly cross-bridges GPIIbIIIa* on platelets TSP could form cross-bridges Fg bound to either as a or TSP could platelets via receptors Fg bound to GPIIbIIIa* TSP could participate in and formation on and platelets model could with TSP in and cross-bridges The physiological of is by studies of TSP, and GPIIbIIIa in on the surface of activated platelets M. M. J. Biophys. PubMed Scopus Google Scholar, J. J. J. 1992; Google T.S. J. Google Scholar, A.S. Leung L.L. Nachman R.L. 1985; PubMed Google for TSP been in signaling in an of GPIIbIIIa J. A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We have demonstrated TSP an system of platelet aggregation via inter-platelet cross-bridges on the surface of activated which is by an of the platelet aggregation, be of in as a platelet with a surface activated or in flowing blood, is to be and studies be to at the of TSP in is TSP is to be as a for with the of Thrombospondin-1 (TSP)1represents 20–30% of the glycoproteins stored in human platelet α-granules (1Baenziger N.L. Brodie G.N. Majerus P.W. J. Biol. Chem. 1972; 247: 273-2723Abstract Full Text PDF PubMed Google Scholar). Upon platelet activation and degranulation, TSP is released, and an important fraction is found associated with the platelet surface (2Phillips D.R. Jennings L.K. Prasanna H.R. J. Biol. Chem. 1980; 255: 11629-11632Abstract Full Text PDF PubMed Google Scholar, 3Rabhi-Sabile S. Pidard D. Lawler J. Renesto P. Chignard M. Legrand C. FEBS Lett. 1996; 386: 82-86Crossref PubMed Scopus (33) Google Scholar). Several putative receptors and ligands for TSP at the surface of activated platelets have been described, including fibrinogen (Fg) (4Tuszynski G.P. Srivastava S. Switalska H.I. Holt J.C. Cierniewski C.S. Niewiarowski S. J. Biol. Chem. 1985; 260: 12240-12245Abstract Full Text PDF PubMed Google Scholar, 5Bacon-Baguley T. Ogilvie M.L. Gartner T.K. Walz D.A. J. Biol. Chem. 1990; 265: 2317-2323Abstract Full Text PDF PubMed Google Scholar, 6Legrand C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar, 7Panetti T.S. Kudryk B.J. Mosher D.F. J. Biol. Chem. 1999; 274: 430-437Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar), sulfatides (8Roberts D.D. Lahav J. Thrombospondin. CRC Press, Boca Raton, FL1993: 73-90Google Scholar) glycoprotein IV (GPIV, CD36) (9Asch A.S. Silbiger S. Heimer E. Nachman R.L. Biochem. Biophys. Res. Commun. 1992; 182: 1208-1217Crossref PubMed Scopus (162) Google Scholar,10McGregor J.L. Catimel B. Parmentier S. Clezardin P. Dechavanne M. Leung L.L. J. Biol. Chem. 1989; 264: 501-506Abstract Full Text PDF PubMed Google Scholar), and integrin-associated protein (IAP/CD47) (11Gao A.G. Lindberg F.P. Finn M.B. Blystone S.D. Brown E.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). TSP with including and αIIbβ3 through its J. J. Biol. PubMed Scopus Google Scholar). the interaction of TSP with GPIIbIIIa is J. A. G.P. J. Biol. Chem. 1989; 264: Full Text PDF PubMed Google Scholar, G.P. Biochem. J. PubMed Scopus Google Scholar, P. Pidard D. D. V. Legrand C. Biophys. 1990; PubMed Scopus Google Scholar, Thromb. PubMed Scopus Google Scholar, E. PubMed Scopus Google Scholar). The of TSP in platelet aggregation been demonstrated by a of studies of platelet aggregation and by T.K. Walz D.A. M. Ogilvie M.L. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, L.L. J. PubMed Scopus Google Scholar, S. A. 1985; PubMed Scopus Google Scholar, Thromb. PubMed Scopus Google Scholar, C. V. V. B. Lawler J. 1992; PubMed Google Scholar, H. J.L. J. Biochem. PubMed Scopus Google Scholar) and or of TSP C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar, G.P. J. J. Biol. 1992; PubMed Scopus Google Scholar). Leung L.L. J. PubMed Scopus Google Scholar) the interaction of TSP with Fg on the surface of activated platelets the binding of Fg to its receptor, the activated integrin GPIIbIIIa with Fg in direct cross-bridges. studies TSP with the integrin-associated protein (IAP/CD47) (11Gao A.G. Lindberg F.P. Finn M.B. Blystone S.D. Brown E.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) and as a of platelet integrin GPIIbIIIa and J. A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Lindberg F.P. 1999; PubMed Google Scholar). direct for TSP as a of platelets interactions was by studies with platelet or activated fixed platelets Fg A. Thromb. PubMed Scopus Google Scholar, M. Arterioscler. Thromb. Biol. 1996; PubMed Scopus Google Scholar). in the of and of aggregation was not studies were 1985; PubMed Scopus Google Scholar) or in an A. Thromb. PubMed Scopus Google Scholar), i.e. not of the physiological flow and shear the using free of platelet and and the capacity of TSP to form and inter-platelet cross-bridges through its interactions with Fg or with TSP and the contribution of cross-bridges in the aggregation of platelets by studied the of TSP in platelet aggregation through its interaction with Fg bound to its receptor, We model either or or were to the surface of activated platelets but in the of signaling or secretion the of TSP and surface of TSP induced aggregation of dose-dependently, with a at and an aggregation efficiency of at a shear of s−1. Aggregation of by TSP after of the beads with Fg. Ro the RGD to block the cross-bridges GPIIbIIIa* bound Fg and free aggregation through Fg-TSP-Fg cross-bridges with α at to with at TSP surface with AFP aggregation by TSP at with Ro in the of with α for for the of Fg and TSP in this TSP can aggregation of beads or AFP by directly Fg on at a physiological shear of TSP, to the of platelet aggregation C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar), aggregation of by TSP but did not the is an for the of the amino-terminal of the TSP molecule in interactions and a interaction as in the binding of to where TSP18 was not to the bound but binding of not putative binding on Fg and TSP could or including on the (4Tuszynski G.P. Srivastava S. Switalska H.I. Holt J.C. Cierniewski C.S. Niewiarowski S. J. Biol. Chem. 1985; 260: 12240-12245Abstract Full Text PDF PubMed Google Scholar), and T. Ogilvie M.L. Gartner T.K. Walz D.A. J. Biol. Chem. 1990; 265: 2317-2323Abstract Full Text PDF PubMed Google and at on TSP C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar), the as TSP C. P. Clezardin P. J. Res. PubMed Scopus Google Scholar) and TSP J. J. Biol. Chem. Full Text PDF PubMed Google of with TSP did not the the binding of to GPIIbIIIa* immobilized on beads is in with the of and H. J.L. J. Biochem. PubMed Scopus Google Scholar) a platelet aggregation by of did not the of Fg binding to platelets with or Leung L.L. J. PubMed Scopus Google Scholar) TSP, by with Fg at a from its the of Fg for the on the an the of Fg binding to activated could a by the bound to TSP, the interactions by (9Asch A.S. Silbiger S. Heimer E. Nachman R.L. Biochem. Biophys. Res. Commun. 1992; 182: 1208-1217Crossref PubMed Scopus (162) Google Scholar, M. M. J. Biophys. PubMed Scopus Google Scholar, J. J. J. 1992; Google studies a Fg with TSP is of with another of of receptor with TSP the aggregation efficiency by this TSP of Fg a TSP a Fg molecule on an bead of the surface of Fg and TSP and is not by the system GPIIbIIIa* for Fg on a the efficiency of aggregation for Fg receptor as A. Legrand C. Biophys. J. Full Text Full Text PDF PubMed Scopus Google Scholar), the aggregation efficiency in the of TSP is to the aggregation efficiency be with Fg on to the of Fg occupied by the of TSP in the for platelet to immobilized Fg or after of with soluble TSP J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). Our the the of TSP is induced by the of the on Fg or for its platelet receptor, its by the of of TSP on the aggregation efficiency of AFP mediated by Fg and found an of 30–110% at all Fg receptor occupancies and all shear rates s−1) with of Fg by We on the surface the of aggregation aggregation by the of the which the surface for and the for the the of the and in platelet to platelet to Fg-TSP-Fg have interactions can participate in to particle aggregation at shear The beads at all shear with a in efficiency for a in shear to the for Fg-mediated aggregation of platelets by GPIIbIIIa*-Fg cross-bridges Biophys. J. 1994; Full Text PDF PubMed Scopus Google Scholar). The aggregation efficiency at was to for Fg-mediated aggregation of or platelets with GPIIbIIIa* A. Legrand C. Biophys. J. Full Text Full Text PDF PubMed Scopus Google and Biophys. J. 1994; Full Text PDF PubMed Scopus Google and this the direct contribution of TSP in reinforcing the inter-platelet interactions in physiological flow The of TSP is to be the of the platelet secretion of TSP at the of activated platelets with Fg already bound to a of cross-bridges in The cross-bridges cross-bridges with of TSP TSP cross-bridges TSP Fg in model platelets from with which have been to of TSP at the surface with aggregation in an H. J.L. J. Biochem. PubMed Scopus Google Scholar, M.L. J. PubMed Scopus Google Scholar). this with model from the of platelets in one by not be by M. A. D. Catimel B. Dechavanne M. J.L. Thromb. 1989; PubMed Scopus Google Scholar) and studies TSP was not on the platelet surface of one with and of TSP P. M. 1985; PubMed Google Scholar). is in of GPIIbIIIa TSP not be in an to platelet Our model of of is to as as and with the TSP found in model could with TSP in and cross-bridges The physiological of is by studies of TSP, and GPIIbIIIa in on the surface of activated platelets M. M. J. Biophys. PubMed Scopus Google Scholar, J. J. J. 1992; Google T.S. J. Google Scholar, A.S. Leung L.L. Nachman R.L. 1985; PubMed Google for TSP been in signaling in an of GPIIbIIIa J. A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We have demonstrated TSP an system of platelet aggregation via inter-platelet cross-bridges on the surface of activated which is by an of the platelet aggregation, be of in as a platelet with a surface activated or in flowing blood, is to be and studies be to at the of TSP in is TSP is to be as a for with the of We studied the of TSP in platelet aggregation through its interaction with Fg bound to its receptor, We model either or or were to the surface of activated platelets but in the of signaling or secretion the of TSP and surface of Soluble TSP induced aggregation of dose-dependently, with a at and an aggregation efficiency of at a shear of s−1. Aggregation of by TSP after of the beads with Fg. Ro the RGD to block the cross-bridges GPIIbIIIa* bound Fg and free aggregation through Fg-TSP-Fg cross-bridges with α at to with at TSP surface with AFP aggregation by TSP at with Ro in the of with α for for the of Fg and TSP in this TSP can aggregation of beads or AFP by directly Fg on at a physiological shear of TSP, to the of platelet aggregation C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar), aggregation of by TSP but did not the is an for the of the amino-terminal of the TSP molecule in interactions and a interaction as in the binding of to where TSP18 was not to the bound but binding of not putative binding on Fg and TSP could or including on the (4Tuszynski G.P. Srivastava S. Switalska H.I. Holt J.C. Cierniewski C.S. Niewiarowski S. J. Biol. Chem. 1985; 260: 12240-12245Abstract Full Text PDF PubMed Google Scholar), and T. Ogilvie M.L. Gartner T.K. Walz D.A. J. Biol. Chem. 1990; 265: 2317-2323Abstract Full Text PDF PubMed Google and at on TSP C. Morandi V. Mendelovitz S. Shaked H. Hartman J.R. Panet A. Arterioscler. Thromb. 1994; 14: 1784-1791Crossref PubMed Google Scholar), the as TSP C. P. Clezardin P. J. Res. PubMed Scopus Google Scholar) and TSP J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of with TSP did not the the binding of to GPIIbIIIa* immobilized on beads is in with the of and H. J.L. J. Biochem. PubMed Scopus Google Scholar) a platelet aggregation by of did not the of Fg binding to platelets with or Leung L.L. J. PubMed Scopus Google Scholar) TSP, by with Fg at a from its the of Fg for the on the an the of Fg binding to activated could a by the bound to TSP, the interactions by (9Asch A.S. Silbiger S. Heimer E. Nachman R.L. Biochem. Biophys. Res. Commun. 1992; 182: 1208-1217Crossref PubMed Scopus (162) Google Scholar, M. M. J. Biophys. PubMed Scopus Google Scholar, J. J. J. 1992; Google Scholar). Surprisingly, studies a Fg with TSP is of with another of of receptor with TSP the aggregation efficiency by this TSP of Fg a TSP a Fg molecule on an bead of the surface of Fg and TSP and is not by the system GPIIbIIIa* for Fg on a the efficiency of aggregation for Fg receptor as A. Legrand C. Biophys. J. Full Text Full Text PDF PubMed Scopus Google Scholar), the aggregation efficiency in the of TSP is to the aggregation efficiency be with Fg on to the of Fg occupied by the of TSP in the for platelet to immobilized Fg or after of with soluble TSP J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). Our the the of TSP is induced by the of the on Fg or for its platelet receptor, its by the of of TSP on the aggregation efficiency of AFP mediated by Fg and found an of 30–110% at all Fg receptor occupancies and all shear rates s−1) with of Fg by We on the surface the of aggregation aggregation by the of the which the surface for and the for the the of the and in platelet to platelet to Fg-TSP-Fg have interactions can participate in to particle aggregation at shear The beads at all shear with a in efficiency for a in shear to the for Fg-mediated aggregation of platelets by GPIIbIIIa*-Fg cross-bridges Biophys. J. 1994; Full Text PDF PubMed Scopus Google Scholar). The aggregation efficiency at was to for Fg-mediated aggregation of or platelets with GPIIbIIIa* A. Legrand C. Biophys. J. Full Text Full Text PDF PubMed Scopus Google and Biophys. J. 1994; Full Text PDF PubMed Scopus Google and this Our the direct contribution of TSP in reinforcing the inter-platelet interactions in physiological flow The of TSP is to be the of the platelet secretion of TSP at the of activated platelets with Fg already bound to a of cross-bridges in The cross-bridges cross-bridges with of TSP TSP cross-bridges TSP Fg in model platelets from with which have been to of TSP at the surface with aggregation in an H. J.L. J. Biochem. PubMed Scopus Google Scholar, M.L. J. PubMed Scopus Google Scholar). this with model from the of platelets in one by not be by M. A. D. Catimel B. Dechavanne M. J.L. Thromb. 1989; PubMed Scopus Google Scholar) and studies TSP was not on the platelet surface of one with and of TSP P. M. 1985; PubMed Google Scholar). is in of GPIIbIIIa TSP not be in an to platelet Our model of of is to as as and with the TSP found in model could with TSP in and cross-bridges The physiological of is by studies of TSP, and GPIIbIIIa in on the surface of activated platelets M. M. J. Biophys. PubMed Scopus Google Scholar, J. J. J. 1992; Google T.S. J. Google Scholar, A.S. Leung L.L. Nachman R.L. 1985; PubMed Google Scholar). for TSP been in signaling in an of GPIIbIIIa J. A.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We have demonstrated TSP an system of platelet aggregation via inter-platelet cross-bridges on the surface of activated which is by an of the platelet aggregation, be of in as a platelet with a surface activated or in flowing blood, is to be and studies be to at the of TSP in is TSP is to be as a for with the of We and for and

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