Semin Thromb Hemost 2019; 45(08): 802-809
DOI: 10.1055/s-0039-1698829
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Platelets as Central Actors in Thrombosis—Reprising an Old Role and Defining a New Character

Hannah Stevens
1   Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, Australia
2   Department of Medicine, Monash University, Melbourne, Australia
3   Department of Clinical Haematology, Alfred Hospital, Melbourne, Australia
,
James D. McFadyen
1   Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, Australia
2   Department of Medicine, Monash University, Melbourne, Australia
3   Department of Clinical Haematology, Alfred Hospital, Melbourne, Australia
› Author Affiliations
Further Information

Publication History

Publication Date:
17 October 2019 (online)

Abstract

Platelets have long been considered simple anucleate cells that rapidly adhere and aggregate at sites of vascular injury. However, recent in vivo experimental data have shed new light on the platelet response to vascular injury. These data have unexpectedly revealed that platelet thrombus formation is a highly dynamic process and yields a platelet thrombus with a distinct hierarchical structure composed of a “core” of highly activated platelets and a “shell” of platelets in a low activation state. This has given rise to the concept that therapeutic targeting of the propagating thrombus shell may hold promise as a means to target thrombosis while sparing hemostasis. While platelets have been historically considered central to arterial thrombosis, they have been traditionally viewed as minor contributors to the formation of venous thrombosis. However, this concept has recently been challenged with the emergence of a large body of evidence highlighting the important proinflammatory function of platelets. The proinflammatory function of platelets is afforded by their ability to induce neutrophil extracellular trap formation, enhance leucocyte recruitment, and secrete granular contents such as high mobility group protein B1 and polyphosphate. These proinflammatory processes trigger coagulation, via the intrinsic pathway, and are central to the formation of venous thrombosis, a condition now appreciated to be a form of sterile inflammation. These data now place platelets at the center stage in orchestrating the thromboinflammatory response underpinning venous thrombosis and have provided new hope that novel platelet-targeted therapeutics may represent a safe and effective approach to prevent venous thrombosis.

 
  • References

  • 1 Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006; 133 (03) 251-258
  • 2 Brass LF, Diamond SL, Stalker TJ. Platelets and hemostasis: a new perspective on an old subject. Blood Adv 2016; 1 (01) 5-9
  • 3 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8 (11) 1227-1234
  • 4 Benjamin EJ, Muntner P, Alonso A. , et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: a report from the American Heart Association. Circulation 2019; 139 (10) e56-e528
  • 5 McFadyen JD, Jackson SP. Differentiating haemostasis from thrombosis for therapeutic benefit. Thromb Haemost 2013; 110 (05) 859-867
  • 6 Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011; 11 (04) 264-274
  • 7 McFadyen JD, Kaplan ZS. Platelets are not just for clots. Transfus Med Rev 2015; 29 (02) 110-119
  • 8 von Brühl ML, Stark K, Steinhart A. , et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
  • 9 Zahn F. Untersuchungen uber Thrombose: Bildung der Thromben. Virchows Arch A Pathol Anat Histol 1875; 61: 81-124
  • 10 Falk E. Coronary thrombosis: pathogenesis and clinical manifestations. Am J Cardiol 1991; 68 (07) 28B-35B
  • 11 Stalker TJ, Traxler EA, Wu J. , et al. Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood 2013; 121 (10) 1875-1885
  • 12 Nesbitt WS, Westein E, Tovar-Lopez FJ. , et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med 2009; 15 (06) 665-673
  • 13 Welsh JD, Stalker TJ, Voronov R. , et al. A systems approach to hemostasis: 1. The interdependence of thrombus architecture and agonist movements in the gaps between platelets. Blood 2014; 124 (11) 1808-1815
  • 14 Stalker TJ, Welsh JD, Tomaiuolo M. , et al. A systems approach to hemostasis: 3. Thrombus consolidation regulates intrathrombus solute transport and local thrombin activity. Blood 2014; 124 (11) 1824-1831
  • 15 McFadyen JD, Schaff M, Peter K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol 2018; 15 (03) 181-191
  • 16 Ju L, McFadyen JD, Al-Daher S. , et al. Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets. Nat Commun 2018; 9 (01) 1087
  • 17 Jackson SP. The growing complexity of platelet aggregation. Blood 2007; 109 (12) 5087-5095
  • 18 Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Haematol 2008; 143 (02) 180-190
  • 19 Sevitt S. The structure and growth of valve-pocket thrombi in femoral veins. J Clin Pathol 1974; 27 (07) 517-528
  • 20 Budnik I, Brill A. Immune factors in deep vein thrombosis initiation. Trends Immunol 2018; 39 (08) 610-623
  • 21 Zarbock A, Ley K, McEver RP, Hidalgo A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 2011; 118 (26) 6743-6751
  • 22 Brill A, Fuchs TA, Chauhan AK. , et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 2011; 117 (04) 1400-1407
  • 23 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
  • 24 Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 2012; 32 (08) 1777-1783
  • 25 Brinkmann V, Reichard U, Goosmann C. , et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663): 1532-1535
  • 26 Massberg S, Grahl L, von Bruehl ML. , et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (08) 887-896
  • 27 Tsai AW, Cushman M, Rosamond WD. , et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113 (08) 636-642
  • 28 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345 (8943): 152-155
  • 29 Chauhan AK, Kisucka J, Lamb CB, Bergmeier W, Wagner DD. von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins. Blood 2007; 109 (06) 2424-2429
  • 30 Astarita JL, Acton SE, Turley SJ. Podoplanin: emerging functions in development, the immune system, and cancer. Front Immunol 2012; 3: 283
  • 31 Uhrin P, Zaujec J, Breuss JM. , et al. Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 2010; 115 (19) 3997-4005
  • 32 Suzuki-Inoue K, Osada M, Ozaki Y. Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood. J Thromb Haemost 2017; 15 (02) 219-229
  • 33 Payne H, Ponomaryov T, Watson SP, Brill A. Mice with a deficiency in CLEC-2 are protected against deep vein thrombosis. Blood 2017; 129 (14) 2013-2020
  • 34 Simon DI, Chen Z, Xu H. , et al. Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192 (02) 193-204
  • 35 Wang Y, Gao H, Shi C. , et al. Corrigendum: leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat Commun 2017; 8: 16124
  • 36 André P, Hartwell D, Hrachovinová I, Saffaripour S, Wagner DD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci U S A 2000; 97 (25) 13835-13840
  • 37 Polgar J, Matuskova J, Wagner DD. The P-selectin, tissue factor, coagulation triad. J Thromb Haemost 2005; 3 (08) 1590-1596
  • 38 Wolberg AS, Rosendaal FR, Weitz JI. , et al. Venous thrombosis. Nat Rev Dis Primers 2015; 1: 15006
  • 39 Palabrica T, Lobb R, Furie BC. , et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359 (6398): 848-851
  • 40 Furie B, Furie BC. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 2004; 10 (04) 171-178
  • 41 Celi A, Pellegrini G, Lorenzet R. , et al. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A 1994; 91 (19) 8767-8771
  • 42 Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol 2018; 18 (02) 134-147
  • 43 Clark SR, Ma AC, Tavener SA. , et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13 (04) 463-469
  • 44 Etulain J, Martinod K, Wong SL, Cifuni SM, Schattner M, Wagner DD. P-selectin promotes neutrophil extracellular trap formation in mice. Blood 2015; 126 (02) 242-246
  • 45 Stark K, Philippi V, Stockhausen S. , et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 2016; 128 (20) 2435-2449
  • 46 Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5 (04) 331-342
  • 47 Vogel S, Bodenstein R, Chen Q. , et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J Clin Invest 2015; 125 (12) 4638-4654
  • 48 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
  • 49 Gould TJ, Vu TT, Swystun LL. , et al. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol 2014; 34 (09) 1977-1984
  • 50 Kornberg A, Rao NN, Ault-Riché D. Inorganic polyphosphate: a molecule of many functions. Annu Rev Biochem 1999; 68: 89-125
  • 51 Rao NN, Gómez-García MR, Kornberg A. Inorganic polyphosphate: essential for growth and survival. Annu Rev Biochem 2009; 78: 605-647
  • 52 Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem 2004; 279 (43) 44250-44257
  • 53 Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost 2015; 13 (Suppl. 01) S92-S97
  • 54 Müller F, Mutch NJ, Schenk WA. , et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139 (06) 1143-1156
  • 55 Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A 2006; 103 (04) 903-908
  • 56 Becattini C, Agnelli G, Schenone A. , et al; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366 (21) 1959-1967
  • 57 Brighton TA, Eikelboom JW, Mann K. , et al; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367 (21) 1979-1987
  • 58 Weitz JI, Lensing AWA, Prins MH. , et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
  • 59 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
  • 60 Stevens H, Tran H. Update on diagnosis and anticoagulant therapy for venous thromboembolism. Intern Med J 2018; 48 (10) 1175-1184
  • 61 Anderson DR, Dunbar M, Murnaghan J. , et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med 2018; 378 (08) 699-707
  • 62 Schwarz M, Meade G, Stoll P. , et al. Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ Res 2006; 99 (01) 25-33
  • 63 Stoll P, Bassler N, Hagemeyer CE. , et al. Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation. Arterioscler Thromb Vasc Biol 2007; 27 (05) 1206-1212
  • 64 Hanjaya-Putra D, Haller C, Wang X. , et al. Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis. JCI Insight 2018; 3 (15) 99329
  • 65 Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood 2014; 124 (22) 3183-3190
  • 66 Smith SA, Choi SH, Collins JN, Travers RJ, Cooley BC, Morrissey JH. Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation. Blood 2012; 120 (26) 5103-5110
  • 67 Labberton L, Kenne E, Long AT. , et al. Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 2016; 7: 12616
  • 68 Scully M, Minkue Mi Edou J, Callewaert F. Caplacizumab for acquired thrombotic thrombocytopenic purpura. Reply. N Engl J Med 2019; 380 (18) e32
  • 69 Plow EF, Wang Y, Simon DI. The search for new antithrombotic mechanisms and therapies that may spare hemostasis. Blood 2018; 131 (17) 1899-1902