Thromb Haemost 2009; 102(06): 1149-1156
DOI: 10.1160/TH09-05-0289
Review Article
Schattauer GmbH

Platelet response heterogeneity in thrombus formation

Imke C. A. Munnix*
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
Judith M. E. M. Cosemans*
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
Jocelyn M. Auger
2   Centre for Cardiovascular Sciences Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
,
Johan W. M. Heemskerk
1   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
› Author Affiliations
Financial support: This work was supported by the Netherlands Organization for Scientific Research (NWO, 11–400–0076).
Further Information

Publication History

Received: 06 May 2009

Accepted after minor revision: 09 July 2009

Publication Date:
28 November 2017 (online)

Summary

Vascular injury leads to formation of a structured thrombus as a consequence of platelet activation and aggregation, thrombin and fibrin formation, and trapping of leukocytes and red cells. This review summarises current evidence for heterogeneity of platelet responses and functions in the thrombus-forming process. Environmental factors contribute to response heterogeneity, as the platelets in a thrombus adhere to different substrates, and sense specific (ant)agonists and rheological conditions. Contraction of platelets and interaction with fibrin and other blood cells cause further response variation. On the other hand, response heterogeneity can also be due to intrinsic differences between platelets in age and in receptor and signalling proteins. As a result, at least three subpopulations of platelets are formed in a thrombus: aggregating platelets with (reversible) integrin activation, procoagulant (coated) platelets exposing phosphatidylserine and binding coagulation factors, and contracting platelets with cell-cell contacts. This recognition of thrombus heterogeneity has implications for the use and development of antiplatelet medication.

* These authors contributed equally.


 
  • References

  • 1 Van Gestel M, Heemskerk JWM, Slaaf DW. et al. 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: 534-543.
  • 2 Celi A, Merrill-Skoloff G, Gross P. et al. Thrombus formation: direct real-time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy. J Thromb Haemost 2003; 01: 60-68.
  • 3 Brass LF, Zhu L, Stalker TJ. Minding the gaps to promote thrombus growth and stability. J Clin Invest 2005; 115: 3385-3392.
  • 4 Jackson SP. The growing complexity of platelet aggregation. Blood 2007; 109: 5087-5095.
  • 5 Gibbins JM. Platelet adhesion signalling and the regulation of thrombus formation. J Cell Sci 2004; 117: 3415-3425.
  • 6 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94: 657-666.
  • 7 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-1234.
  • 8 Nesbitt WS, Kulkarni S, Giuliano S. et al. Distinct glycoprotein Ib/V/IX and integrin αIIbβ3-dependent calcium signals cooperatively regulate platelet adhesion under flow. J Biol Chem 2002; 277: 2965-2972.
  • 9 Reininger AJ, Heijnen HFG, Schumann H. et al. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress. Blood 2006; 107: 3537-3545.
  • 10 Maxwell MJ, Westein E, Nesbitt WS. et al. Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation. Blood 2007; 109: 566-576.
  • 11 Savage B, Sixma JJ, Ruggeri ZM. Functional selfassociation of von Willebrand factor during platelet adhesion under flow. Proc Natl Acad Sci USA 2002; 99: 425-430.
  • 12 Bergmeier W, Chauhan AK, Wagner DD. Glycoprotein Ibα and von Willebrand factor in primary platelet adhesion and thrombus formation: lessons from mice. Thromb Haemost 2008; 99: 264-270.
  • 13 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102: 449-461.
  • 14 Siljander PRM, Munnix ICA, Smethurst PA. et al. Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood. Blood 2004; 103: 1333-1341.
  • 15 Kuijpers MJE, Schulte V, Bergmeier W. et al. Complementary roles of glycoprotein VI and α2β1 integrin in collagen-induced thrombus formation in flowing whole blood ex vivo. FASEB J 2003; 17: 685-687.
  • 16 Chen H, Kahn ML. Reciprocal signaling by integrin and nonintegrin receptors during collagen activation of platelets. Mol Cell Biol 2003; 23: 4764-4777.
  • 17 Auger JM, Kuijpers MJE, Senis YA. et al. Adhesion of human and mouse platelets to collagen under shear: a unifying model. FASEB J 2005; 19: 825-827.
  • 18 Nieswandt B, Brakebusch C, Bergmeier W. et al. Glycoprotein VI but not α2β1 integrin is essential for platelet interaction with collagen. EMBO J 2001; 20: 2120-2130.
  • 19 Farndale RW, Sixma JJ, Barnes MJ. et al. The role of collagen in thrombosis and haemostasis. J Thromb Haemost 2004; 02: 561-573.
  • 20 Heemskerk JWM, Vuist WMJ, Feijge MAH. et al. Collagen but not fibrinogen surfaces induce bleb formation, exposure of phosphatidylserine, and procoagulant activity of adherent platelets: evidence for regulation by protein tyrosine kinase-dependent Ca2+ responses. Blood 1997; 90: 2615-2625.
  • 21 Patel D, Väänänen H, Jirousková M. et al. Dynamics of GPIIb/IIIa-mediated platelet-platelet interactions in platelet adhesion/thrombus formation on collagen in vitro as revealed by videomicroscopy. Blood 2003; 101: 929-936.
  • 22 Angelillo-Scherrer A, Garcia de Frutos P, Aparicio C. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nat Med 2001; 07: 215-221.
  • 23 Fung CYE, Cendana C, Farndale RW. et al. Primary and secondary agonists can use P2X1 receptors as a major pathway to increase intracellular Ca2+ in the human platelet. J Thromb Haemost 2007; 05: 910-917.
  • 24 Heemskerk JWM, Kuijpers MJE, Munnix ICA. et al. Platelet collagen receptors and coagulation. A characteristic platelet response as possible target for antithrombotic treatment. Trends Cardiovasc Med 2005; 15: 86-92.
  • 25 Cosemans JMEM, Iserbyt BF, Deckmyn H. et al. Multiple pathways to switch platelet integrins on and off. J Thromb Haemost 2008; 06: 1253-1261.
  • 26 Munnix ICA, Kuijpers MJE, Auger J. et al. Segregation of platelet aggregatory and procoagulant microdomains in thrombus formation: regulation by transient integrin activation. Arterioscler Thromb Vasc Biol 2007; 27: 2484-2490.
  • 27 Kulkarni S, Jackson SP. Platelet factor XIII and calpain negatively regulate integrin αIIbβ3 adhesive function and thrombus growth. J Biol Chem 2004; 279: 30697-30706.
  • 28 Fox JE, Austin CD, Reynolds CC. et al. Evidence that agonist-induced activation of calpain causes the shedding of procoagulant-containing microvesicles from the membrane of aggregating platelets. J Biol Chem 1991; 266: 13289-13295.
  • 29 Dachary-Prigent J, Pasquet JM, Freyssinet JM. et al. Calcium involvement in aminophospholipid exposure and microparticle formation during platelet activation, a study using Ca2+-ATPase inhibitors. Biochemistry 1995; 34: 11625-11634.
  • 30 Brass LF, Stalker TJ, Zhu L. et al. Boundary events: contact-dependent and contact-facilitated signaling between platelets. Sem Thromb Hemost 2004; 30: 399-410.
  • 31 Brass LF, Zhu L, Stalker TJ. Novel therapeutic targets at the platelet vascular interface. Arterioscler Thromb Vasc Biol 2008; 28: s43-s50.
  • 32 May AE, Langer H, Seizer P. et al. Platelet-leukocyte interactions in inflammation and atherothrombosis. Sem Thromb Hemost 2007; 33: 123-127.
  • 33 Kulkarni S, Woollard KJ, Thomas S. et al. Conversion of platelets from a proaggregatory to a proinflammatory adhesive phenotype: role of PAF in spatially regulating neutrophil adhesion and spreading. Blood 2007; 110: 1879-1886.
  • 34 Andrews RK, Karunakaran D, Gardiner EE. et al. Platelet receptor proteolysis. A mechanism for downregulating platelet reactivity. Arterioscler Thromb Vasc Biol 2007; 27: 1511-1520.
  • 35 Shim K, Anderson PJ, Tuley EA. et al. Platelet- VWF complexes are preferred substrates of ADAMTS-13 under fluid shear stress. Blood 2008; 111: 651-657.
  • 36 Reinhardt C, von Brühl ML, Manukyan D. et al. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J Clin Invest 2008; 118: 1110-1122.
  • 37 Cho J, Furie BC, Coughlin SR. et al. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. J Clin Invest 2008; 118: 1123-1131.
  • 38 Kuijpers MJE, Munnix ICA, Cosemans JMEM. et al. Platelet-dependent coagulation regulates arterial and venous thrombus formation in vivo. Microcirculation 2008; 15: 269-282.
  • 39 Zwaal RFA, Schroit AJ. Pathophysiological implications of membrane phospholipid asymmetry in blood cells. Blood 1997; 89: 1121-1132.
  • 40 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22: 1381-1389.
  • 41 Falati S, Liu Q, Gross P. et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197: 1585-1598.
  • 42 Mangin P, Yap CL, Nonne C. et al. Thrombin overcomes the thrombosis defect associated with platelet GPVI/RcRγ deficiency. Blood 2006; 107: 4346-4353.
  • 43 Dubois C, Panicot-Dubois L, Merrill-Skoloff G. et al. Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo. Blood 2006; 107: 3902-3906.
  • 44 Heemskerk JWM, Willems GM, Rook MB. et al. Ragged spiking in free calcium in ADP-stimulated platelets: regulation of puff-like calcium signal in vitro and ex vivo. J Physiol 2001; 535: 625-635.
  • 45 Albanyan AM, Murphy FM, Rasmussen JT. et al. Measurement of phosphatidylserine exposure during storage of platelet concentrates using the novel probe lactadherin: a comparison study with annexin V Transfusion. 2009; 49: 99-107.
  • 46 Heemskerk JWM, Bevers EM, Lindhout T. Platelet activation and blood coagulation. Thromb Haemost 2002; 88: 186-193.
  • 47 Thiagarajan P, Tait JF. Collagen-induced exposure of anionic phospholipids in platelets and platelet-derived microparticles. J Biol Chem 1991; 266: 24302-24307.
  • 48 Smeets EF, Heemskerk JWM, Comfurius P. et al. Thapsigargin amplifies the platelet procoagulant response caused by thrombin. Thromb Haemost 1993; 70: 1024-1029.
  • 49 Pasquet JM, Toti F, Nurden AT. et al. Procoagulant activity and active calpain in platelet-derived microparticles. Thromb Res 1996; 82: 509-522.
  • 50 Léon C, Alex M, Klocke A. et al. Platelet ADP receptors contribute to the initiation of intravascular coagulation. Blood 2004; 103: 594-600.
  • 51 Furihata K, Clemetson KJ, Deguchi H. et al. Variation in human platelet glycoprotein VI content modulates glycoprotein VI-specific prothrombinase activity. Arterioscler Thromb Vasc Biol 2001; 21: 1857-1863.
  • 52 London FS, Marcinkiewicz M, Walsh PN. A subpopulation of platelets responds to thrombin- or SFLLRN-stimulation with binding sites for factor IXa. J Biol Chem 2004; 279: 19854-19859.
  • 53 London FS, Marcinkiewicz M, Walsh PN. PAR1-stimulated factor IXa binding to a small platelet subpopulation requires a pronounced and sustained increase of cytoplasmic calcium. Biochemistry 2006; 45: 7289-7298.
  • 54 Panteleev MA, Ananyeva NM, Greco NJ. et al. Two subpopulations of thrombin-activated platelets differ in their binding of the components of the intrinsic factor Xa-activating complex. J Thromb Haemost 2005; 03: 2545-2553.
  • 55 Bachelot-Loza C, Badol P, Brohard-Bohn B. et al. Differential regulation of platelet aggregation and aminophospholipid exposure by calpain. Br J Haematol 2006; 133: 419-426.
  • 56 Dale GL, Friese P, Batar P. et al. Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Nature 2002; 415: 307-315.
  • 57 Dale GL. Coated-platelets: an emergic component of the procoagulant response. J Thromb Haemost 2005; 03: 2185-2192.
  • 58 Szasz R, Dale GL. Thrombospondin and fibrinogen bind serotonin-derivatized proteins on COAT platelets. Blood 2002; 100: 2827-2831.
  • 59 Alberio L, Safa O, Clemetson KJ. et al. Surface expression and functional characterization of α-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin. Blood 2000; 95: 1694-1702.
  • 60 Jobe SM, Leo L, Eastvold JS. et al. Role of FcRγ and factor XIIIa in coated platelet formation. Blood 2005; 106: 4146-4151.
  • 61 Jobe SM, Wilson KM, Leo L. et al. Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis. Blood 2008; 111: 1257-1265.
  • 62 Remenyi G, Szasz R, Frieze P. et al. Role of mitochondrial permeability transition pore in coated-platelet formation. Arterioscler Thromb Vasc Biol 2005; 25: 467-471.
  • 63 Bergmeier W, Oh-hora M, McCarl CA. et al. R93W mutation in Orai1 causes impaired calcium calcium influx in platelets. Blood 2009; 113: 675-678.
  • 64 Gilio K, Van Kruchten R, Braun A. et al. Role of platelet Orai1 and STIM1 in GPVI-dependent en GPVI-independent thrombus formation and procoagulant activity. J Thromb Haemost. 2009 07. (Suppl 2).
  • 65 Patel SR, Richardson JL, Schulze H. et al. Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes. Blood 2005; 106: 4076-4085.
  • 66 White JG, Keel S, Reyes M. et al. Alpha-delta platelet storage pool deficiency in three generations. Platelets 2007; 18: 1-10.
  • 67 Italiano JE, Richardson JL, Patel-Hett S. et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet α granules and differentially released. Blood 2009; 111: 1227-1233.
  • 68 Hardy AR, Conley PB, Luo J. et al. P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms. Blood 2005; 105: 3552-3560.
  • 69 Den Dekker E, van Abel M, van der Vuurst H. et al. Cell-to-cell variability in the differentiation program of human megakaryocytes. Biochim Biophys Acta 2003; 1643: 85-94.
  • 70 Mason KD, Carpinelli MR, Fletcher JI. et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128: 1173-1186.
  • 71 Hoffmeister KM, Felbinger TW, Falet H. et al. The clearance mechanism of chilled blood platelets. Cell 2003; 112: 87-97.
  • 72 Curvers J, van Pampus ECM, Feijge MAH. et al. Decreased responsiveness and development of activation markers of platelets stored in plasma. Transfusion 2004; 44: 49-58.
  • 73 Badlou BA, van der Meer PF, Akkerman JW. et al. Metabolic energy reduction by glucose deprivation and low gas exchange preserves platelet function after 48 h storage at 4 degrees C. Vox Sang 2007; 92: 311-318.
  • 74 Cauwenberghs S, van Pampus E, Curvers J. et al. Hemostatic and signaling functions of transfused platelets. Transfus Med Rev 2007; 21: 287-294.