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Thromb Haemost 2013; 110(05): 859-867
DOI: 10.1160/TH13-05-0379
Theme Issue Article
Schattauer GmbH

Differentiating haemostasis from thrombosis for therapeutic benefit

James D. McFadyen
1   Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
,
Shaun P. Jackson
1   Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
› Author Affiliations
Further Information

Publication History

Received: 08 May 2013

Accepted after major revision: 18 July 2013

Publication Date:
01 December 2017 (online)

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Summary

The central role of platelets in the formation of the primary haemostatic plug as well as in the development of arterial thrombosis is well defined. In general, the molecular events underpinning these processes are broadly similar. Whilst it has long been known that disturbances in blood flow, changes in platelet reactivity and enhanced coagulation reactions facilitate pathological thrombus formation, the precise details underlying these events remain incompletely understood. Intravital microscopy studies have highlighted the dynamic and heterogeneous nature of thrombus development and demonstrated that there are considerable spatiotemporal differences in the activation states of platelets within a forming thrombus. In this review we will consider the factors regulating the activation state of platelets in a developing thrombus and discuss how specific prothrombotic factors may influence this process, leading to excessive thrombus propagation. We will also discuss some potentially novel therapeutic approaches that may reduce excess thrombus development whilst minimising bleeding risk.

Keywords

Thrombosis - atherothrombosis - antiplatelet agents
 

  • References

  • 1 Ross R. Atherosclerosis–an inflammatory disease. New Engl J Med 1999; 340: 115-126.
    CrossrefPubMedGoogle Scholar
  • 2 Goyal A, Bhatt DL, Steg PG. et al. Attained educational level and incident atherothrombotic events in low- and middle-income compared with high-income countries. Circulation 2010; 122: 1167-1175.
    CrossrefPubMedGoogle Scholar
  • 3 Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nature Rev Drug Discov 2010; 9: 154-169.
    CrossrefPubMedGoogle Scholar
  • 4 Sellers MB, Tricoci P, Harrington RA. A new generation of antiplatelet agents. Curr Opin Cardiol 2009; 24: 307-312.
    CrossrefPubMedGoogle Scholar
  • 5 Patrono C, Baigent C, Hirsh J. et al. American College of Chest P. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. (8th Edition) Chest 2008; 133 (Suppl. 06) 199S-233S.
    CrossrefPubMedGoogle Scholar
  • 6 Anderson JL, Adams CD, Antman EM. et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Acadaemic Emergency Medicine. Circulation 2007; 116: e148-304.
    CrossrefPubMedGoogle Scholar
  • 7 Kushner FG, Hand M, Smith Jr. SC. et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120: 2271-2306.
    CrossrefPubMedGoogle Scholar
  • 8 Fisher M, Loscalzo J. The perils of combination antithrombotic therapy and potential resolutions. Circulation 2011; 123: 232-235.
    CrossrefPubMedGoogle Scholar
  • 9 Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983; 50: 127-134.
    CrossrefPubMedGoogle Scholar
  • 10 Jackson SP. The growing complexity of platelet aggregation. Blood 2007; 109: 5087-5095.
    CrossrefPubMedGoogle Scholar
  • 11 Denis CV, Wagner DD. Platelet adhesion receptors and their ligands in mouse models of thrombosis. Arterioscl Thromb Vasc Biol 2007; 27: 728-739.
    CrossrefPubMedGoogle Scholar
  • 12 Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor?. Blood 2003; 102: 449-461.
    CrossrefPubMedGoogle Scholar
  • 13 Ruggeri ZM. Platelet adhesion under flow. Microcirculation 2009; 16: 58-83.
    CrossrefPubMedGoogle Scholar
  • 14 Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289-297.
    CrossrefPubMedGoogle Scholar
  • 15 Ruggeri ZM. Structure and function of von Willebrand factor. Thromb Haemost 1999; 82: 576-584.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 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.
    CrossrefPubMedGoogle Scholar
  • 17 Siedlecki CA, Lestini BJ, Kottke-Marchant KK. et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood 1996; 88: 2939-2950.
    PubMedGoogle Scholar
  • 18 Jin J, Daniel JL, Kunapuli SP. Molecular basis for ADP-induced platelet activation.II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem 1998; 273: 2030-2034.
    CrossrefPubMedGoogle Scholar
  • 19 Huang JS, Ramamurthy SK, Lin X. et al. Cell signalling through thromboxane A2 receptors. Cell Signal 2004; 16: 521-533.
    CrossrefPubMedGoogle Scholar
  • 20 Hollopeter G, Jantzen HM, Vincent D. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
    CrossrefPubMedGoogle Scholar
  • 21 Shattil SJ. Signaling through platelet integrin alpha IIb beta 3: inside-out, outside-in, and sideways. Thromb Haemost 1999; 82: 318-325.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Coller BS, Peerschke EI, Scudder LE. et al. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 1983; 72: 325-338.
    CrossrefPubMedGoogle Scholar
  • 23 Wright RS, Anderson JL, Adams CD. et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123: 2022-2060.
    CrossrefPubMedGoogle Scholar
  • 24 Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci USA 1999; 96: 11023-11027.
    CrossrefPubMedGoogle Scholar
  • 25 Furie B, Furie BC. Mechanisms of thrombus formation. New Engl J Med 2008; 359: 938-949.
    CrossrefPubMedGoogle Scholar
  • 26 Gailani D, Renne T. Intrinsic pathway of coagulation and arterial thrombosis. Arterioscl Thromb Vasc Biol 2007; 27: 2507-2513.
    CrossrefPubMedGoogle Scholar
  • 27 Heemskerk JW, Mattheij NJ, Cosemans JM. Platelet-based coagulation: different populations, different functions. Journal of thrombosis and haemostasis :. J Thromb Haemost 2013; 11: 2-16.
    CrossrefPubMedGoogle Scholar
  • 28 Nesbitt WS, Westein E, Tovar-Lopez FJ. et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nature Med 2009; 15: 665-673.
    CrossrefPubMedGoogle Scholar
  • 29 Stalker TJ, Traxler EA, Wu J, Wannemacher KM. et al. Hierarchical organization in the haemostatic response and its relationship to the platelet-signaling network. Blood 2013; 121: 1875-1885.
    CrossrefPubMedGoogle Scholar
  • 30 Nishimura S, Manabe I, Nagasaki M. et al. In vivo imaging visualizes discoid platelet aggregations without endothelium disruption and implicates contribution of inflammatory cytokine and integrin signaling. Blood 2012; 119: e45-56.
    CrossrefPubMedGoogle Scholar
  • 31 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: 953-960.
    CrossrefPubMedGoogle Scholar
  • 32 Gross PL, Furie BC, Merrill-Skoloff G. et al. Leukocyte-versus microparticle-mediated tissue factor transfer during arteriolar thrombus development. J Leukocyte Biol 2005; 78: 1318-1326.
    CrossrefPubMedGoogle Scholar
  • 33 Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005; 115: 3355-3362.
    CrossrefPubMedGoogle Scholar
  • 34 Sachs UJ, Nieswandt B. In vivo thrombus formation in murine models. Circulation Res 2007; 100: 979-991.
    CrossrefPubMedGoogle Scholar
  • 35 Mailhac A, Badimon JJ, Fallon JT. et al. Effect of an eccentric severe stenosis on fibrin(ogen) deposition on severely damaged vessel wall in arterial thrombosis. Relative contribution of fibrin(ogen) and platelets. Circulation 1994; 90: 988-996.
    PubMedGoogle Scholar
  • 36 Wootton DM, Ku DN. Fluid mechanics of vascular systems, diseases, and thrombosis. Ann Rev Biomed Engin 1999; 1: 299-329.
    PubMedGoogle Scholar
  • 37 Einav S, Bluestein D. Dynamics of blood flow and platelet transport in pathological vessels. Ann NY Acad Sci 2004; 1015: 351-366.
    CrossrefPubMedGoogle Scholar
  • 38 Lowe GD. Blood rheology in arterial disease. Clin Sci 1986; 71: 137-146.
    CrossrefPubMedGoogle Scholar
  • 39 Ruggeri ZM, Orje JN, Habermann R. et al. Activation-independent platelet adhesion and aggregation under elevated shear stress. Blood 2006; 108: 1903-1910.
    CrossrefPubMedGoogle Scholar
  • 40 Dopheide SM, Maxwell MJ, Jackson SP. Shear-dependent tether formation during platelet translocation on von Willebrand factor. Blood 2002; 99: 159-167.
    CrossrefPubMedGoogle Scholar
  • 41 Ikeda Y, Handa M, Kawano K. et al. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest 1991; 87: 1234-1240.
    CrossrefPubMedGoogle Scholar
  • 42 Lopez JA, Dong JF. Structure and function of the glycoprotein Ib-IX-V complex. Curr Opin Hematol 1997; 4: 323-329.
    CrossrefPubMedGoogle Scholar
  • 43 Mazzucato M, Pradella P, Cozzi MR. et al. Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibalpha mechanoreceptor. Blood 2002; 100: 2793-2800.
    CrossrefPubMedGoogle Scholar
  • 44 Nesbitt WS, Giuliano S, Kulkarni S. et al. Intercellular calcium communication regulates platelet aggregation and thrombus growth. J Cell Biol 2003; 160: 1151-1161.
    CrossrefPubMedGoogle Scholar
  • 45 Goncalves I, Nesbitt WS, Yuan Y. et al. Importance of temporal flow gradients and integrin alphaIIbbeta3 mechanotransduction for shear activation of platelets. J Biol Chem 2005; 280: 15430-15437.
    CrossrefPubMedGoogle Scholar
  • 46 Gillespie PG, Walker RG. Molecular basis of mechanosensory transduction. Nature 2001; 413: 194-202.
    CrossrefPubMedGoogle Scholar
  • 47 Nesbitt WS, Kulkarni S, Giuliano S. et al. Distinct glycoprotein Ib/V/IX and integrin alpha IIbbeta 3-dependent calcium signals cooperatively regulate platelet adhesion under flow. J Biol Chem 2002; 277: 2965-2972.
    CrossrefPubMedGoogle Scholar
  • 48 Marshall SJ, Senis YA, Auger JM. et al. GPIb-dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP-dependent kinase. Blood 2004; 103: 2601-2609.
    CrossrefPubMedGoogle Scholar
  • 49 Jackson SP, Schoenwaelder SM, Goncalves I. et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nature Med 2005; 11: 507-514.
    CrossrefPubMedGoogle Scholar
  • 50 Rathbone RL, Ardlie NG, Schwartz CJ. Platelet aggregation and thrombus formation in Diabetes Mellitus: an in vitro study. Pathology 1970; 2: 307-316.
    CrossrefPubMedGoogle Scholar
  • 51 Opper C, Clement C, Schwarz H. et al. Increased number of high sensitive platelets in hypercholesterolemia, cardiovascular diseases, and after incubation with cholesterol. Atherosclerosis 1995; 113: 211-217.
    CrossrefPubMedGoogle Scholar
  • 52 Terres W, Becker P, Rosenberg A. Changes in cardiovascular risk profile during the cessation of smoking. Am J Med 1994; 97: 242-249.
    CrossrefPubMedGoogle Scholar
  • 53 Hamet P, Skuherska R, Pang SC. et al. Abnormalities of platelet function in hypertension and diabetes. Hypertension 1985; 7: II135-142.
    PubMedGoogle Scholar
  • 54 Calkin AC, Drew BG, Ono A. et al. Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux. Circulation 2009; 120: 2095-2104.
    CrossrefPubMedGoogle Scholar
  • 55 Podrez EA, Byzova TV, Febbraio M. et al. Platelet CD36 links hyperlipidaemia, oxidant stress and a prothrombotic phenotype. Nature Med 2007; 13: 1086-1095.
    CrossrefPubMedGoogle Scholar
  • 56 Ma Y, Ashraf MZ, Podrez EA. Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidaemia. Blood 2010; 116: 1932-1941.
    CrossrefPubMedGoogle Scholar
  • 57 Zhu W, Li W, Silverstein RL. Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36. Blood 2012; 119: 6136-6144.
    CrossrefPubMedGoogle Scholar
  • 58 Renne T, Schmaier AH, Nickel KF. et al. In vivo roles of factor XII. Blood 2012; 120: 4296-4303.
    CrossrefPubMedGoogle Scholar
  • 59 Renne T, Pozgajova M, Gruner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-281.
    CrossrefPubMedGoogle Scholar
  • 60 Rosen ED, Gailani D, Castellino FJ. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thromb Haemost 2002; 87: 774-776.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Muller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
    CrossrefPubMedGoogle Scholar
  • 62 Suzuki J, Umeda M, Sims PJ. et al. Calcium-dependent phospholipid scrambling by TMEM16F. Nature 2010; 468: 834-838.
    CrossrefPubMedGoogle Scholar
  • 63 Jackson SP, Schoenwaelder SM. Procoagulant platelets: are they necrotic?. Blood 2010; 116: 2011-2018.
    CrossrefPubMedGoogle Scholar
  • 64 Schoenwaelder SM, Yuan Y, Josefsson EC. et al. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 2009; 114: 663-666.
    CrossrefPubMedGoogle Scholar
  • 65 Zong WX, Thompson CB. Necrotic death as a cell fate. Genes Develop 2006; 20: 1-15.
    CrossrefPubMedGoogle Scholar
  • 66 Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis, a well-orchestrated form of cell daemise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 2006; 1757: 1371-1387.
    CrossrefPubMedGoogle Scholar
  • 67 Mason KD, Carpinelli MR, Fletcher JI. et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128: 1173-1186.
    CrossrefPubMedGoogle Scholar
  • 68 Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nature Rev Mol Cell Biol 2008; 9: 231-241.
    CrossrefPubMedGoogle Scholar
  • 69 Yousuf O, Bhatt DL. The evolution of antiplatelet therapy in cardiovascular disease. Nature Rev Cardiol 2011; 8: 547-559.
    CrossrefPubMedGoogle Scholar
  • 70 Zhang H, Lowenberg EC, Crosby JR. et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692.
    CrossrefPubMedGoogle Scholar
  • 71 Schumacher WA, Luettgen JM, Quan ML. et al. Inhibition of factor XIa as a new approach to anticoagulation. Arterioscl Thromb Vasc Biol 2010; 30: 388-392.
    CrossrefPubMedGoogle Scholar
  • 72 Hagedorn I, Schmidbauer S, Pleines I. et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 2010; 121: 1510-1517.
    CrossrefPubMedGoogle Scholar
  • 73 Smith SA, Choi SH, Collins JN. et al. Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation. Blood 2012; 120: 5103-5110.
    CrossrefPubMedGoogle Scholar
  • 74 Ghosh A, Li W, Febbraio M. et al. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice. J Clin Invest 2008; 118: 1934-1943.
    PubMedGoogle Scholar
  • 75 Armstrong PC, Peter K. GPIIb/IIIa inhibitors: from bench to bedside and back to bench again. Thromb Haemost 2012; 107: 808-814.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Schwarz M, Meade G, Stoll P, Ylanne J, Bassler N, Chen YC. et al. Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circulation Res 2006; 99: 25-33.
    CrossrefPubMedGoogle Scholar
  • 77 De Meyer SF, Stoll G, Wagner DD. et al. von Willebrand factor: an emerging target in stroke therapy. Stroke 2012; 43: 599-606.
    CrossrefPubMedGoogle Scholar
  • 78 Diener JL, Daniel Lagasse HA, Duerschmied D. et al. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J Thromb Haemost 2009; 7: 1155-1162.
    CrossrefPubMedGoogle Scholar
  • 79 Nylander S, Kull B, Bjorkman JA. et al. Human target validation of phosphoinositide 3-kinase (PI3K)beta: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kbeta inhibitor. J Thromb Haemost 2012; 10: 2127-2136.
    CrossrefPubMedGoogle Scholar
  • 80 Yap CL, Anderson KE, Hughan SC. et al. Essential role for phosphoinositide 3-kinase in shear-dependent signaling between platelet glycoprotein Ib/V/IX and integrin alpha(IIb)beta(3). Blood 2002; 99: 151-158.
    CrossrefPubMedGoogle Scholar