Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 2

Abstract

Platelet signal transduction is the focus of this review. While ‘classic’ platelet signaling through G protein–coupled receptors in response to fluid-phase agonists has been extensively studied, signaling mechanisms linking platelet adhesion receptors such as GPIb-IX-V, GPVI and α2β1 to the activation of αIIbβ3 are less well established. Moreover, ‘non-haemostatic’ pathways can also activate platelets in various settings, including platelet–immune or platelet–tumour cell interactions, platelet responses to neutrophil extracellular traps, or stimulation by microbial pathogens. Genetically determined integrin variants can modulate platelet function and increase thrombogenicity. A typical example is the Pro33 (HPA-1b) variant of αIIbβ3. Recent advances in the genotype–phenotype relation of this prothrombotic variant and its impact on outside-in signaling will be reviewed.

Zusammenfassung

Thrombozytäre Prozesse der Signaltransduktion stehen im Mittelpunkt von Teil II dieser Übersicht. Die 'klassische' Signalübertragung durch G-Protein-gekoppelte Rezeptoren bei Plättchenstimulation mit diffusiblen Agonisten ist intensiv erforscht. Bislang weniger gut untersucht sind hingegen Mechanismen, die Signale thrombozytärer Adhäsionsrezeptoren wie GPIb-IX-V, GPVI und α2β1 auf αIIbβ3 übertragen und zur Aktivierung dieses Integrins führen. Weiterhin existieren 'nicht-hämostatische' Signalwege, die ebenfalls eine Plättchenaktivierung auslösen können. Hierzu zählen Thrombozyteninteraktionen mit Immun- oder Tumorzellen, Reaktionen auf freigesetzte Zellkernkomponenten neutrophiler Granulozyten oder Stimulation durch pathogene Keime. Genetisch determinierte Integrinvarianten können die Plättchenfunktion modulieren und die Thrombogenität erhöhen. Musterbeispiel hierfür ist die Pro33 (HPA-1b)-Variante von αIIbβ3. Jüngste Erkenntnisse zur Genotyp-Phänotyp-Beziehung dieser prothrombotischen Rezeptorvariante mit Auswirkungen auf 'Outside-in'-Signalvorgänge werden besprochen.

Keywords

platelet signaling - integrin αIIbβ3 - G protein–coupled receptors - calcium mobilization

Schlüsselwörter

Thrombozytäre Signalübertrag - Integrin αIIbβ3 - G-Protein-gekoppelte Rezeptoren - Kalziummobilisierung

• References

• 1 Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res 2006; 99 (12) 1293-1304
• 2 Scharf RE, Reimers H-J, Schneider W. Die Rolle der Kalziumionen bei der Regulation der Thrombozytenfunktion. Hamostaseologie 1981; 1: 3-37
• 3 Sambrano GR, Weiss EJ, Zheng YW, Huang W, Coughlin SR. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 2001; 413 (6851): 74-78
• 4 Mazzucato M, Pradella P, Cozzi MR, De Marco L, Ruggeri ZM. Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibα mechanoreceptor. Blood 2002; 100 (08) 2793-2800
• 5 Mazzucato M, Cozzi MR, Pradella P, Ruggeri ZM, De Marco L. Distinct roles of ADP receptors in von Willebrand factor-mediated platelet signaling and activation under high flow. Blood 2004; 104 (10) 3221-3227
• 6 Mazzucato M, Cozzi MR, Battiston M. , et al. Distinct spatio-temporal Ca²⁺ signaling elicited by integrin α2β1 and glycoprotein VI under flow. Blood 2009; 114 (13) 2793-2801
• 7 Scharf RE. Drugs that affect platelet function. Semin Thromb Hemost 2012; 38 (08) 865-883
• 8 Shattil SJ, Newman PJ. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood 2004; 104 (06) 1606-1615
• 9 Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110 (06) 673-687
• 10 Shattil SJ, Kashiwagi H, Pampori N. Integrin signaling: the platelet paradigm. Blood 1998; 91 (08) 2645-2657
• 11 Coller BS, Shattil SJ. The GPIIb/IIIa (integrin αIIbβ3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood 2008; 112 (08) 3011-3025
• 12 Coller BS. αIIbβ3: structure and function. J Thromb Haemost 2015; 13 (Suppl. 01) S17-S25
• 13 Durrant TN, van den Bosch MT, Hers I. Integrin α_IIbβ₃ outside-in signaling. Blood 2017; 130 (14) 1607-1619
• 14 Stegner D, Nieswandt B. Platelet receptor signaling in thrombus formation. J Mol Med (Berl) 2011; 89 (02) 109-121
• 15 Zhang W, Deng W, Zhou L. , et al. Identification of a juxtamembrane mechanosensitive domain in the platelet mechanosensor glycoprotein Ib-IX complex. Blood 2015; 125 (03) 562-569
• 16 Ruggeri ZM, Mendolicchio GL. Interaction of von Willebrand factor with platelets and the vessel wall. Hamostaseologie 2015; 35 (03) 211-224
• 17 Kasirer-Friede A, Ware J, Leng L, Marchese P, Ruggeri ZM, Shattil SJ. Lateral clustering of platelet GP Ib-IX complexes leads to up-regulation of the adhesive function of integrin αIIbβ3. J Biol Chem 2002; 277 (14) 11949-11956
• 18 Kasirer-Friede A, Cozzi MR, Mazzucato M, De Marco L, Ruggeri ZM, Shattil SJ. Signaling through GP Ib-IX-V activates αIIbβ3 independently of other receptors. Blood 2004; 103 (09) 3403-3411
• 19 Watson SP, Asazuma N, Atkinson B. , et al. The role of ITAM- and ITIM-coupled receptors in platelet activation by collagen. Thromb Haemost 2001; 86 (01) 276-288
• 20 Clemetson JM, Polgar J, Magnenat E, Wells TN, 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 (41) 29019-29024
• 21 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102 (02) 449-461
• 22 Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol 2008; 28 (03) 403-412
• 23 Judd BA, Myung PS, Obergfell A. , et al. Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling. J Exp Med 2002; 195 (06) 705-717
• 24 Shattil SJ, Kim C, Ginsberg MH. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 2010; 11 (04) 288-300
• 25 Shattil SJ. Integrins and Src: dynamic duo of adhesion signaling. Trends Cell Biol 2005; 15 (08) 399-403
• 26 Wu Y, Span LM, Nygren P. , et al. The tyrosine kinase c-Src specifically binds to the active integrin αIIbβ3 to initiate outside-in signaling in platelets. J Biol Chem 2015; 290 (25) 15825-15834
• 27 Obergfell A, Eto K, Mocsai A. , et al. Coordinate interactions of Csk, Src, and Syk kinases with αIIbβ3 initiate integrin signaling to the cytoskeleton. J Cell Biol 2002; 157 (02) 265-275
• 28 Vidal C, Geny B, Melle J, Jandrot-Perrus M, Fontenay-Roupie M. Cdc42/Rac1-dependent activation of the p21-activated kinase (PAK) regulates human platelet lamellipodia spreading: implication of the cortical-actin binding protein cortactin. Blood 2002; 100 (13) 4462-4469
• 29 Schoenwaelder SM, Hughan SC, Boniface K. , et al. RhoA sustains integrin αIIbβ3 adhesion contacts under high shear. J Biol Chem 2002; 277 (17) 14738-14746
• 30 Law DA, DeGuzman FR, Heiser P, Ministri-Madrid K, Killeen N, Phillips DR. Integrin cytoplasmic tyrosine motif is required for outside-in αIIbβ3 signalling and platelet function. Nature 1999; 401 (6755): 808-811
• 31 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (04) 264-274
• 32 Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis, inflammation, and cancer. Blood 2015; 126 (05) 582-588
• 33 Pluskota E, Woody NM, Szpak D. , et al. Expression, activation, and function of integrin αMβ2 (Mac-1) on neutrophil-derived microparticles. Blood 2008; 112 (06) 2327-2335
• 34 Duchene J, von Hundelshausen P. Platelet-derived chemokines in atherosclerosis. Hamostaseologie 2015; 35 (02) 137-141
• 35 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123 (18) 2768-2776
• 36 Demers M, Wong SL, Martinod K. , et al. Priming of neutrophils toward NETosis promotes tumor growth. OncoImmunology 2016; 5 (05) e1134073
• 37 Fuchs TA, Brill A, Duerschmied D. , et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
• 38 Jiménez-Alcázar M, Rangaswamy C, Panda R. , et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 2017; 358 (6367): 1202-1206
• 39 Semeraro F, Ammollo CT, Morrissey JH. , et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118 (07) 1952-1961
• 40 Carestia A, Rivadeneyra L, Romaniuk MA, Fondevila C, Negrotto S, Schattner M. Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost 2013; 110 (05) 1035-1045
• 41 Zotz RB, Winkelmann BR, Nauck M. , et al. Polymorphism of platelet membrane glycoprotein IIIa: human platelet antigen 1b (HPA-1b/PlA2) is an inherited risk factor for premature myocardial infarction in coronary artery disease. Thromb Haemost 1998; 79 (04) 731-735
• 42 Zotz RB, Winkelmann BR, Müller C, Boehm BO, März W, Scharf RE. Association of polymorphisms of platelet membrane integrins αIIbβ3 (HPA-1b/Pl) and α2β1 (α2 807TT) with premature myocardial infarction. J Thromb Haemost 2005; 3 (07) 1522-1529
• 43 Zotz RB, Klein M, Dauben HP, Moser C, Gams E, Scharf RE. Prospective analysis after coronary-artery bypass grafting: platelet GP IIIa polymorphism (HPA-1b/PIA2) is a risk factor for bypass occlusion, myocardial infarction, and death. Thromb Haemost 2000; 83 (03) 404-407
• 44 Scharf RE, Zotz RB. Blood platelets and myocardial infarction: do hyperactive platelets really exist?. Transfus Med Hemother 2006; 33: 189-199
• 45 Loncar R, Stoldt V, Hellmig S, Zotz RB, Mihalj M, Scharf RE. HPA-1 polymorphism of αIIbβ3 modulates platelet adhesion onto immobilized fibrinogen in an in-vitro flow system. Thromb J 2007; 5: 2
• 46 Loncar R, Zotz RB, Sucker C, Vodovnik A, Mihalj M, Scharf RE. Platelet adhesion onto immobilized fibrinogen under arterial and venous in-vitro flow conditions does not significantly differ between men and women. Thromb J 2007; 5: 5
• 47 El Khattouti A, Stoldt VR, Scharf RE. The HPA-1b (Pro33) isoform of platelet integrin αIIbβ3 is a prothrombotic variant: characterization by fluorescence resonance energy transfer. Blood 2010; 116: 2018
• 48 El Khattouti A, Stoldt VR, Gyenes M, Huynh KC, Scharf RE. Variants of platelet integrin αIIbβ3 display different receptor activation. Blood 2011; 118: 1143
• 49 Scharf RE, Hasse M, Reiff E, Gyenes M, Stoldt VR. CD40 ligand (CD40L) increases thrombus stability and outside-in signaling through integrin αIIbβ3. J Thromb Haemost 2009; (07) (Suppl. 02) 060
• 50 Pagani G, Pereira JPV, Stoldt VR, Beck A, Scharf RE, Gohlke H. The human platelet antigen-1b (Pro³³) variant of α_IIbβ₃ allosterically shifts the dynamic conformational equilibrium of this integrin toward the active state. J Biol Chem 2018; 293 (13) 4830-4844
• 51 Gyenes M, Hasse M, Stoldt VR, El-Khattouti A, Huynh KC, Scharf RE. Enhanced outside-in signaling through the prothrombotic Pro33 variant of integrin αIIbβ3 in adherent platelets under static and flow dynamic conditions. Blood 2011; 118 (21) 2199
• 52 Gyenes M, Stoldt VR, Huynh KC, Scharf RE. The impact of shear stress on the interaction of human platelet integrin αIIbβ3 with fibrinogen. Blood 2012; 120 (21) 2167
• 53 Ye F, Liu J, Winkler H, Taylor KA. Integrin αIIbβ3 in a membrane environment remains the same height after Mn2+ activation when observed by cryoelectron tomography. J Mol Biol 2008; 378 (05) 976-986
• 54 Vijayan KV, Liu Y, Sun W, Ito M, Bray PF. The Pro33 isoform of integrin β3 enhances outside-in signaling in human platelets by regulating the activation of serine/threonine phosphatases. J Biol Chem 2005; 280 (23) 21756-21762
• 55 Feng S, Lu X, Reséndiz JC, Kroll MH. Pathological shear stress directly regulates platelet αIIbβ3 signaling. Am J Physiol Cell Physiol 2006; 291 (06) C1346-C1354
• 56 Gyenes M, Stoldt VR, Huynh KC, Scharf RE. Impact of the Leu33Pro polymorphism of αIIbβ3 on integrin-ligand interaction under abnormally high shear conditions. Blood 2014; 124 (21) 4156
• 57 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8 (11) 1227-1234
• 58 Balasubramanian V, Grabowski E, Bini A, Nemerson Y. Platelets, circulating tissue factor, and fibrin colocalize in ex vivo thrombi: real-time fluorescence images of thrombus formation and propagation under defined flow conditions. Blood 2002; 100 (08) 2787-2792
• 59 Bluestein D, Niu L, Schoephoerster RT, Dewanjee MK. Fluid mechanics of arterial stenosis: relationship to the development of mural thrombus. Ann Biomed Eng 1997; 25 (02) 344-356
• 60 Strony J, Beaudoin A, Brands D, Adelman B. Analysis of shear stress and hemodynamic factors in a model of coronary artery stenosis and thrombosis. Am J Physiol 1993; 265 (5, Pt 2): H1787-H1796
• 61 Bray PF. Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol 2000; 7 (05) 284-289
• 62 Kunicki TJ, Ruggeri ZM. Platelet collagen receptors and risk prediction in stroke and coronary artery disease. Circulation 2001; 104 (13) 1451-1453
• 63 Aslan JE, McCarty OJ. Rho GTPases in platelet function. J Thromb Haemost 2013; 11 (01) 35-46
• 64 Huveneers S, Danen EH. Adhesion signaling - crosstalk between integrins, Src and Rho. J Cell Sci 2009; 122 (Pt 8): 1059-1069