• 1
    Brass LF, Zhu L, Stalker TJ. Minding the gaps to promote thrombus growth and stability. J Clin Invest 2005; 115: 338592.
  • 2
    Brass LF, Stalker TJ, Zhu L, Woulfe DS. Signal transduction during initiation, extension and perpetuation of platelet plug formation. In: MichelsonAD, ed. Platelets, 2nd edn. 31946. San Diego, CA: Academic Press, 2006.
  • 3
    Stegner D, Nieswandt B. Platelet receptor signaling in thrombus formation. J Mol Med 2011; 89: 10921.
  • 4
    Hantgan RR, Nichols WL, Ruggeri ZM. von Willebrand factor competes with fibrin for occupancy of GPIIb:IIIa on thrombin-stimulated platelets. Blood 1990; 75: 88994.
  • 5
    Hantgan RR, Hindriks G, Taylor RG, Sixma JJ, de Groot PG. Glycoprotein Ib, von Willebrand factor, and glycoprotein IIb:IIIa are all involved in platelet adhesion to fibrin in flowing whole blood. Blood 1990; 76: 34553.
  • 6
    Chen H, Locke D, Liu Y, Liu CD, Kahn ML. The platelet receptor GPVI mediates both adhesion and signaling responses to collagen in a receptor density-dependent fashion. J Biol Chem 2002; 277: 30119.
  • 7
    Clemetson JM, Polgar J, Magnenat E, Wells TNC, Clemetson KJ. The platelet collagen receptor glycoprotein VI is a member of the immunoglobulin superfamily closely related to FcalphaR and the natural killer receptors. J Biol Chem 1999; 274: 2901924.
  • 8
    Denis CV, Dubois C, Brass LF, Heemskerk JM, Lenting PJ. Towards standardization of in vivo thrombosis studies in mice. J Thromb Haemost 2011; doi: 10.1111/j.1538-7836.2011.04350.x.
  • 9
    Lee HS, Lim CJ, Puzon-McLaughlin W, Shattil SJ, Ginsberg MH. RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences. J Biol Chem 2009; 284: 511927.
  • 10
    Shattil SJ, Kim C, Ginsberg MH. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 2010; 11: 288300.
  • 11
    Watson SP, Auger JM, McCarty OJ, Pearce AC. GPVI and integrin alphaIIb beta3 signaling in platelets. J Thromb Haemost 2005; 3: 175262.
  • 12
    Waldo GL, Ricks TK, Hicks SN, Cheever ML, Kawano T, Tsuboi K, Wang X, Montell C, Kozasa T, Sondek J, Harden TK. Kinetic scaffolding mediated by a phospholipase C-beta and Gq signaling complex. Science 2010; 330: 97480.
  • 13
    Yang J, Wu J, Jiang H, Mortensen R, Austin S, Manning DR, Woulfe D, Brass LF. Signaling through Gi family members in platelets – redundancy and specificity in the regulation of adenylyl cyclase and other effectors. J Biol Chem 2002; 277: 4603542.
  • 14
    Jantzen HM, Milstone DS, Gousset L, Conley PB, Mortensen RM. Impaired activation of murine platelets lacking Galphai2. J Clin Invest 2001; 108: 47783.
  • 15
    Yang J, Wu J, Kowalska MA, Dalvi A, Prevost N, O’Brien PJ, Manning D, Poncz M, Lucki I, Blendy JA, Brass LF. Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs. Proc Natl Acad Sci U S A 2000; 97: 99849.
  • 16
    Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 2027.
  • 17
    Woulfe DS. Akt signaling in platelets and thrombosis. Expert Rev Hematol 2010; 3: 8191.
  • 18
    Woulfe D, Jiang H, Mortensen R, Yang J, Brass LF. Activation of Rap1B by Gi family members in platelets. J Biol Chem 2002; 277: 2338290.
  • 19
    Furlong B, Henderson AH, Lewis MJ, Smith JA. Endothelium-derived relaxing factor inhibits in vitro platelet aggregation. Br J Pharmacol 1987; 90: 68792.
  • 20
    Whittle BJ, Moncada S. Pharmacological interactions between prostacyclin and thromboxanes. Br Med Bull 1983; 39: 2328.
  • 21
    Weksler BB. Prostacyclin. Prog Hemost Thromb 1982; 6: 11338.
  • 22
    Yuhki K, Kojima F, Kashiwagi H, Kawabe J, Fujino T, Narumiya S, Ushikubi F. Roles of prostanoids in the pathogenesis of cardiovascular diseases: novel insights from knockout mouse studies. Pharmacol Ther 2011; 129: 195205.
  • 23
    Marcus AJ, Broekman MJ, Drosopoulos JHF, Islam N, Alyonycheva TN, Safier LB, Hajjar KA, Posnett DN, Schoenborn MA, Schooley KA, Gayle RB, Maliszewski CR. The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39. J Clin Invest 1997; 99: 135160.
  • 24
    Abramow-Newerly M, Roy AA, Nunn C, Chidiac P. RGS proteins have a signalling complex: interactions between RGS proteins and GPCRs, effectors, and auxiliary proteins. Cell Signal 2006; 18: 57991.
  • 25
    Ross EM, Wilkie TM. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 2000; 69: 795827.
  • 26
    Yowe D, Weich N, Prabhudas M, Poisson L, Errada P, Kapeller R, Yu K, Faron L, Shen MH, Cleary J, Wilkie TM, Gutierrez-Ramos C, Hodge MR. RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes. Biochem J 2001; 359: 10918.
  • 27
    Nagata Y, Oda M, Nakata H, Shozaki Y, Kozasa T, Todokoro K. A novel regulator of G-protein signaling bearing GAP activity for Galphai and Galphaq in megakaryocytes. Blood 2001; 97: 305160.
  • 28
    Kim SD, Sung HJ, Park SK, Kim TW, Park SC, Kim SK, Cho JY, Rhee MH. The expression patterns of RGS transcripts in platelets. Platelets 2006; 17: 4937.
  • 29
    Gagnon AW, Murray DL, Leadley RJ. Cloning and characterization of a novel regulator of G protein signalling in human platelets. Cell Signal 2002; 14: 595606.
  • 30
    Garcia A, Prabhakar S, Hughan S, Anderson TW, Brock CJ, Pearce AC, Dwek RA, Watson SP, Hebestreit HF, Zitzmann N. Differential proteome analysis of TRAP-activated platelets: involvement of DOK-2 and phosphorylation of RGS proteins. Blood 2004; 103: 208895.
  • 31
    Berthebaud M, Riviere C, Jarrier P, Foudi A, Zhang Y, Compagno D, Galy A, Vainchenker W, Louache F. RGS16 is a negative regulator of SDF-1-CXCR4 signaling in megakaryocytes. Blood 2005; 106: 29628.
  • 32
    Signarvic RS, Cierniewska A, Stalker TJ, Fong KP, Chatterjee MS, Hess PR, Ma P, Diamond SL, Neubig RR, Brass LF. RGS/Gi2alpha interactions modulate platelet accumulation and thrombus formation at sites of vascular injury. Blood 2010; 116: 6092100.
  • 33
    Huang X, Fu Y, Charbeneau RA, Saunders TL, Taylor DK, Hankenson KD, Russell MW, D’Alecy LG, Neubig RR. Pleiotropic phenotype of a genomic knock-in of an RGS-insensitive G184S Gnai2 allele. Mol Cell Biol 2006; 26: 68709.
  • 34
    Fu Y, Zhong H, Nanamori M, Mortensen RM, Huang X, Lan K, Neubig RR. RGS-insensitive G-protein mutations to study the role of endogenous RGS proteins. Methods Enzymol 2004; 389: 22943.
  • 35
    Allen PB, Ouimet CC, Greengard P. Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc Natl Acad Sci U S A 1997; 94: 995661.
  • 36
    Satoh A, Nakanishi H, Obaishi H, Wada M, Takahashi K, Satoh K, Hirao K, Nishioka H, Hata Y, Mizoguchi A, Takai Y. Neurabin-II/spinophilin. An actin filament-binding protein with one PDZ domain localized at cadherin-based cell-cell adhesion sites. J Biol Chem 1998; 273: 34705.
  • 37
    Smith FD, Oxford GS, Milgram SL. Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein. J Biol Chem 1999; 274: 19894900.
  • 38
    Richman JG, Brady AE, Wang Q, Hensel JL, Colbran RJ, Limbird LE. Agonist-regulated interaction between alpha2-adrenergic receptors and spinophilin. J Biol Chem 2001; 276: 150038.
  • 39
    Wang X, Zeng W, Kim MS, Allen PB, Greengard P, Muallem S. Spinophilin/neurabin reciprocally regulate signaling intensity by G protein-coupled receptors. EMBO J 2007; 26: 276876.
  • 40
    Bansal G, Druey KM, Xie Z. R4 RGS proteins: regulation of G-protein signaling and beyond. Pharmacol Ther 2007; 116: 47395.
  • 41
    Fujii S, Yamazoe G, Itoh M, Kubo Y, Saitoh O. Spinophilin inhibits the binding of RGS8 to M1-mAChR but enhances the regulatory function of RGS8. Biochem Biophys Res Commun 2008; 377: 2004.
  • 42
    Wang X, Zeng W, Soyombo AA, Tang W, Ross EM, Barnes AP, Milgram SL, Penninger JM, Allen PB, Greengard P, Muallem S. Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors. Nat Cell Biol 2005; 7: 40511.
  • 43
    Wang Q, Zhao J, Brady AE, Feng J, Allen PB, Lefkowitz RJ, Greengard P, Limbird LE. Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors. Science 2004; 304: 19404.
  • 44
    Ma P, Cierniewska A, Signarvic RS, Sinnamon A, Cieslak M, Stalker TJ, Brass LF. Discovery of a new signaling complex based on spinophilin that regulates platelet activation in vitro and in vivo. Blood 2010; 116: Abstract 161.
  • 45
    Shattil SJ. The beta3 integrin cytoplasmic tail: protein scaffold and control freak. J Thromb Haemost 2009; 7(Suppl. 1): 2103.
  • 46
    Prevost N, Kato H, Bodin L, Shattil SJ. Platelet integrin adhesive functions and signaling. Methods Enzymol 2007; 426: 10315.
  • 47
    Prevost N, Woulfe D, Tanaka T, Brass LF. Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred. Proc Natl Acad Sci U S A 2002; 99: 921924.
  • 48
    Prevost N, Woulfe DS, Tognolini M, Tanaka T, Jian W, Fortna RR, Jiang H, Brass LF. Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1. Blood 2004; 103: 134855.
  • 49
    Prevost N, Woulfe DS, Jiang H, Stalker TJ, Marchese P, Ruggeri ZM, Brass LF. Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets. Proc Natl Acad Sci U S A 2005; 102: 98205.
  • 50
    Pasterkamp RJ, Giger RJ. Semaphorin function in neural plasticity and disease. Curr Opin Neurobiol 2009; 19: 26374.
  • 51
    Roth L, Koncina E, Satkauskas S, Cremel G, Aunis D, Bagnard D. The many faces of semaphorins: from development to pathology. Cell Mol Life Sci 2009; 66: 64966.
  • 52
    Gherardi E, Love CA, Esnouf RM, Jones EY. The sema domain. Curr Opin Struct Biol 2004; 14: 66978.
  • 53
    Negishi M, Oinuma I, Katoh H. Plexins: axon guidance and signal transduction. Cell Mol Life Sci 2005; 62: 136371.
  • 54
    Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak M, Fan R, Boumsell L, Kumanogoh A, Kikutani H, Tamagnone L, Wagner DD, Milla ME, Brass LF. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci U S A 2007; 104: 16216.
  • 55
    Wannemacher KM, Zhu L, Jiang H, Fong KP, Stalker TJ, Lee D, Tran AN, Neeves KB, Maloney S, Kumanogoh A, Kikutani H, Hammer DA, Diamond SL, Brass LF. Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking semaphorin 4D. Blood 2010; 116: 570715.
  • 56
    Kumanogoh A, Watanabe C, Lee I, Wang X, Shi W, Araki H, Hirata H, Iwahori K, Uchida J, Yasui T, Matsumoto M, Yoshida K, Yakura H, Pan C, Parnes JR, Kikutani H. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 2000; 13: 62131.
  • 57
    Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 1999; 99: 7180.
  • 58
    Masuda K, Furuyama T, Takahara M, Fujioka S, Kurinami H, Inagaki S. Sema4D stimulates axonal outgrowth of embryonic DRG sensory neurones. Genes Cells 2004; 9: 8219.
  • 59
    Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol 2005; 25: 688998.
  • 60
    Lewandrowski U, Wortelkamp S, Lohrig K, Zahedi RP, Wolters DA, Walter U, Sickmann A. Platelet membrane proteomics: a novel repository for functional research. Blood 2009; 114: e109.
  • 61
    Fong KP, Barry C, Tran AN, Traxler EA, Wannemacher KM, Tang HY, Speicher KD, Blair IA, Speicher DW, Grosser T, Brass LF. Deciphering the human platelet sheddome. Blood 2011; 117: e1526.
  • 62
    Kashiwagi H, Shiraga M, Kato H, Kamae T, Yamamoto N, Tadokoro S, Kurata Y, Tomiyama Y, Kanakura Y. Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A. Blood 2005; 106: 91321.
  • 63
    Watkins NA, Gusnanto A, de Bono B, De S, Miranda-Saavedra D, Hardie DL, Angenent WG, Attwood AP, Ellis PD, Erber W, Foad NS, Garner SF, Isacke CM, Jolley J, Koch K, Macaulay IC, Morley SL, Rendon A, Rice KM, Taylor N, et al. A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood 2009; 113: e19.
  • 64
    Newman PJ, Newman DK. Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology. Arterioscler Thromb Vasc Biol 2003; 23: 95364.
  • 65
    Jackson DE, Kupcho KR, Newman PJ. Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of platelet/endothelial cell adhesion molecule-1 (PECAM-1) that are required for the cellular association and activation of the protein-tyrosine phosphatase, SHP-2. J Biol Chem 1997; 272: 2486875.
  • 66
    Moraes LA, Barrett NE, Jones CI, Holbrook LM, Spyridon M, Sage T, Newman DK, Gibbins JM. PECAM-1 regulates collagen-stimulated platelet function by modulating the association of PI3 Kinase with Gab1 and LAT. J Thromb Haemost 2010; 8: 253041.
  • 67
    Patil S, Newman DK, Newman PJ. Platelet endothelial cell adhesion molecule-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 2001; 97: 172732.
  • 68
    Falati S, Patil S, Gross PL, Stapleton M, Merrill-Skoloff G, Barrett NE, Pixton KL, Weiler H, Cooley B, Newman DK, Newman PJ, Furie BC, Furie B, Gibbins JM. Platelet PECAM-1 inhibits thrombus formation in vivo. Blood 2006; 107: 53541.
  • 69
    Huber M, Izzi L, Grondin P, Houde C, Kunath T, Veillette A, Beauchemin N. The carboxyl-terminal region of biliary glycoprotein controls its tyrosine phosphorylation and association with protein-tyrosine phosphatases SHP-1 and SHP-2 in epithelial cells. J Biol Chem 1999; 274: 33544.
  • 70
    Beauchemin N, Kunath T, Robitaille J, Chow B, Turbide C, Daniels E, Veillette A. Association of biliary glycoprotein with protein tyrosine phosphatase SHP-1 in malignant colon epithelial cells. Oncogene 1997; 14: 78390.
  • 71
    Wong C, Liu Y, Yip J, Chand R, Wee JL, Oates L, Nieswandt B, Reheman A, Ni H, Beauchemin N, Jackson DE. CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo. Blood 2009; 113: 181828.
  • 72
    Stalker TJ, Wu J, Morgans A, Traxler EA, Wang L, Chatterjee MS, Lee D, Quertermous T, Hall RA, Hammer DA, Diamond SL, Brass LF. Endothelial cell specific adhesion molecule (ESAM) localizes to platelet-platelet contacts and regulates thrombus formation in vivo. J Thromb Haemost 2009; 7: 188696.
  • 73
    Naik MU, Naik UP. Junctional adhesion molecule-A negatively regulates integrin αIIBβ3-dependent contractile signaling in platelets. J Thromb Haemost 2009; 7: OC-MO-046.
  • 74
    Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 2002; 3: 1518.
  • 75
    Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT, Chavakis T. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 2002; 196: 67991.
  • 76
    Dubois C, Panicot-Dubois L, Gainor JF, Furie BC, Furie B. Thrombin-initiated platelet activation in vivo is vWF independent during thrombus formation in a laser injury model. J Clin Invest 2007; 117: 95360.
  • 77
    Gross PL, Furie BC, Merrill-Skoloff G, Chou J, Furie B. Leukocyte-versus microparticle-mediated tissue factor transfer during arteriolar thrombus development. J Leukoc Biol 2005; 78: 131826.
  • 78
    Maxwell MJ, Westein E, Nesbitt WS, Giuliano S, Dopheide SM, Jackson SP. Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation. Blood 2007; 109: 56676.
  • 79
    van Gestel MA, Heemskerk JW, Slaaf DW, Heijnen VV, Sage SO, Reneman RS, oude Egbrink MG. Real-time detection of activation patterns in individual platelets during thromboembolism in vivo: differences between thrombus growth and embolus formation. J Vasc Res 2002; 39: 53443.
  • 80
    Vandendries ER, Hamilton JR, Coughlin SR, Furie B, Furie BC. PAR4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis. Proc Natl Acad Sci U S A 2007; 104: 28892.
  • 81
    Stalker TJ, Traxler EA, Diamond SL, Brass LF. Development of a stable thrombotic core with limited access to plasma proteins during thrombus formation in vivo. Blood 2010; 116: Abstract 2013.
  • 82
    Nesbitt WS, Westein E, Tovar-Lopez FJ, Tolouei E, Mitchell A, Fu J, Carberry J, Fouras A, Jackson SP. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med 2009; 15: 66573.
  • 83
    Maynard DM, Heijnen HF, Horne MK, White JG, Gahl WA. Proteomic analysis of platelet alpha-granules using mass spectrometry. J Thromb Haemost 2007; 5: 194555.
  • 84
    Calaminus SD, Auger JM, McCarty OJ, Wakelam MJ, Machesky LM, Watson SP. MyosinIIa contractility is required for maintenance of platelet structure during spreading on collagen and contributes to thrombus stability. J Thromb Haemost 2007; 5: 213645.
  • 85
    Leon C, Eckly A, Hechler B, Aleil B, Freund M, Ravanat C, Jourdain M, Nonne C, Weber J, Tiedt R, Gratacap MP, Severin S, Cazenave JP, Lanza F, Skoda R, Gachet C. Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion. Blood 2007; 110: 318391.
  • 86
    Ono A, Westein E, Hsiao S, Nesbitt WS, Hamilton JR, Schoenwaelder SM, Jackson SP. Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth. Blood 2008; 112: 909.