Catheter thrombosis and percutaneous coronary intervention: fundamental perspectives on blood, artificial surfaces and antithrombotic drugs

  • Mark Y. Chan
  • Jeffrey I. Weitz
  • Yahye Merhi
  • Robert A. Harrington
  • Richard C. Becker
Article

Abstract

Recent reports of catheter thrombosis among patients undergoing percutaneous coronary intervention (PCI) have had a significant impact on the development of new antithrombotic therapies. The overall incidence of this complication is unknown, mainly because of underreporting in contemporary clinical trials of coronary intervention. The etiology and pathophysiology of catheter thrombosis is also poorly understood. Introduction of a catheter or guidewire may not provoke the intense thrombotic response that follows angioplasty or stenting, but factors such as catheter materials and device size, equipment surface properties, flow conditions, procedural time and complexity, as well as the antiplatelet and anticoagulant drugs administered during the procedure influence the likelihood, rate and clinical impact of thrombosis. The crucial role of cellular interactions involving tissue-factor bearing cells and platelets in the process of thrombosis also needs to be critically explored when considering blood contact with an exogenous material. Focusing on the inherently prothrombotic environment of percutaneous coronary intervention, we review the physiologic underpinnings of catheter and guidewire thrombosis, and explore the effect of antithrombotic drugs at the interface between blood and material surfaces. We also propose a clinical classification for the diagnosis and investigation of catheter thrombosis in clinical trials of anticoagulant therapy and PCI.

Keywords

Device Anticoagulant Thrombosis Angioplasty Stenting 

Notes

Acknowledgements

We would like to thank Leslie M. Eibest from the Duke Department of Biology for her assistance with the environmental SEM imaging. Dr. Mark Y. Chan receives salary support from the National Medical Research Council, Singapore, Singapore and the National University Heart Centre. Singapore, Singapore, and tuition fee and research support from the Montreal Heart Institute, Montreal, QC. This work was partially funded by a research grant from The Snyderman Foundation, Durham, NC.

Conflicts of interest statement

Mark Y. Chan––research support from Regado Biosciences, Inc, Eli-Lilly, Daichii-Sankyo and Sanofi-Aventis, Jeffrey I. Weitz––consultant for Daiichi-Sankyo, Sanofi-Aventis and The Medicines Company, Yahya Mehri––research support from Archemix Inc., Robert A. Harrington––Dr. Harrington’s conflicts of interest can be found at http://www.dcri.duke.edu/research/coi.jsp, Richard C. Becker––research support from Regado Biosciences, The Medicines Company, Bristol-Myers Squibb, AstraZeneca, and Bayer.

References

  1. 1.
    King SB 3rd, Smith SC Jr, Hirshfeld JW Jr et al (2008) 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of cardiology/american heart association task force on practice guidelines: 2007 writing group to review new evidence and update the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention, writing on behalf of the 2005 writing committee. Circulation 117:261–295PubMedCrossRefGoogle Scholar
  2. 2.
    Yusuf S, Mehta SR, Chrolavicius S et al (2006) Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 295:1519–1530PubMedCrossRefGoogle Scholar
  3. 3.
    Yusuf S, Mehta SR, Chrolavicius S et al (2006) Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 354:1464–1476PubMedCrossRefGoogle Scholar
  4. 4.
    Formanek G, Frech RS, Amplatz K (1970) Arterial thrombus formation during clinical percutaneous catheterization. Circulation 41:833–839PubMedGoogle Scholar
  5. 5.
    Hoffman M, Monroe DM 3rd (2001) A cell-based model of hemostasis. Thromb Haemost 85:958–965PubMedGoogle Scholar
  6. 6.
    Monroe DM, Hoffman M, Roberts HR (1996) Transmission of a procoagulant signal from tissue factor-bearing cell to platelets. Blood Coagul Fibrinolysis 7:459–464PubMedCrossRefGoogle Scholar
  7. 7.
    Myles T, Yun TH, Hall SW et al (2001) An extensive interaction interface between thrombin and factor V is required for factor V activation. J Biol Chem 276:25143–25149PubMedCrossRefGoogle Scholar
  8. 8.
    Colman RW, Schmaier AH (1997) Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 90:3819–3843PubMedGoogle Scholar
  9. 9.
    Monroe DM, Hoffman M (2006) What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 26:41–48PubMedCrossRefGoogle Scholar
  10. 10.
    Gorbet MB, Sefton MV (2004) Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 25:5681–5703PubMedCrossRefGoogle Scholar
  11. 11.
    Gailani D, Renne T (2007) Intrinsic pathway of coagulation and arterial thrombosis. Arterioscler Thromb Vasc Biol 27:2507–2513PubMedCrossRefGoogle Scholar
  12. 12.
    Kleinschnitz C, Stoll G, Bendszus M et al (2006) Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 203:513–518PubMedCrossRefGoogle Scholar
  13. 13.
    Keeley EC, Grines CL (1998) Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1, 000 cases. J Am Coll Cardiol 32:1861–1865PubMedCrossRefGoogle Scholar
  14. 14.
    van der Kamp KW, van Oeveren W (1994) Factor XII fragment and kallikrein generation in plasma during incubation with biomaterials. J Biomed Mater Res 28:349–352PubMedCrossRefGoogle Scholar
  15. 15.
    Cornelius RM, Brash JL (1993) Identification of proteins absorbed to hemodialyser membranes from heparinized plasma. J Biomater Sci Polym Ed 4:291–304PubMedCrossRefGoogle Scholar
  16. 16.
    van der Kamp KW, Hauch KD, Feijen J et al (1995) Contact activation during incubation of five different polyurethanes or glass in plasma. J Biomed Mater Res 29:1303–1306PubMedCrossRefGoogle Scholar
  17. 17.
    Blezer R, Willems GM, Cahalan PT et al (1998) Initiation and propagation of blood coagulation at artificial surfaces studied in a capillary flow reactor. Thromb Haemost 79:296–301PubMedGoogle Scholar
  18. 18.
    Burman JF, Chung HI, Lane DA et al (1994) Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass. Lancet 344:1192–1193PubMedCrossRefGoogle Scholar
  19. 19.
    Hong J, Nilsson Ekdahl K, Reynolds H et al (1999) A new in vitro model to study interaction between whole blood and biomaterials Studies of platelet and coagulation activation and the effect of aspirin. Biomaterials 20:603–611PubMedCrossRefGoogle Scholar
  20. 20.
    Gemmell CH (1998) Platelet adhesion onto artificial surfaces: inhibition by benzamidine, pentamidine, and pyridoxal-5-phosphate as demonstrated by flow cytometric quantification of platelet adhesion to microspheres. J Lab Clin Med 131:84–92PubMedCrossRefGoogle Scholar
  21. 21.
    Palabrica T, Lobb R, Furie BC et al (1992) Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 359:848–851PubMedCrossRefGoogle Scholar
  22. 22.
    Llanos GR, Sefton MV (1993) Immobilization of poly(ethylene glycol) onto a poly(vinyl alcohol) hydrogel: 2 evaluation of thrombogenicity. J Biomed Mater Res 27:1383–1391PubMedCrossRefGoogle Scholar
  23. 23.
    Mickelson JK, Lakkis NM, Villarreal-Levy G et al (1996) Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease? J Am Coll Cardiol 28:345–353PubMedCrossRefGoogle Scholar
  24. 24.
    Serrano CV Jr, Ramires JA, Venturinelli M et al (1997) Coronary angioplasty results in leukocyte and platelet activation with adhesion molecule expression. Evidence of inflammatory responses in coronary angioplasty. J Am Coll Cardiol 29:1276–1283PubMedCrossRefGoogle Scholar
  25. 25.
    Tenaglia AN, Buda AJ, Wilkins RG et al (1997) Levels of expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris. Am J Cardiol 79:742–747PubMedCrossRefGoogle Scholar
  26. 26.
    Rinder CS, Bonan JL, Rinder HM et al (1992) Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood 79:1201–1205PubMedGoogle Scholar
  27. 27.
    May AE, Neumann FJ, Gawaz M et al (1997) Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation. Eur Heart J 18:1913–1920PubMedGoogle Scholar
  28. 28.
    Kazatchkine MD, Carreno MP (1988) Activation of the complement system at the interface between blood and artificial surfaces. Biomaterials 9:30–35PubMedCrossRefGoogle Scholar
  29. 29.
    Peerschke EI, Ghebrehiwet B (1998) Platelet receptors for the complement component C1q: implications for hemostasis and thrombosis. Immunobiology 199:239–249PubMedGoogle Scholar
  30. 30.
    Yamashita A, Furukoji E, Marutsuka K et al (2004) Increased vascular wall thrombogenicity combined with reduced blood flow promotes occlusive thrombus formation in rabbit femoral artery. Arterioscler Thromb Vasc Biol 24:2420–2424PubMedCrossRefGoogle Scholar
  31. 31.
    Al-Nozha MM, Abdel-Gader AG, Arafah MR et al (2005) Tissue factor pathway inhibitor, natural coagulation inhibitors and hemostatic activation markers in patients with acute coronary syndromes. Saudi Med J 26:937–942PubMedGoogle Scholar
  32. 32.
    Brogan GX (2003) Update on acute coronary syndromes and implications for therapy. Expert Opin Investig Drugs 12:1971–1983PubMedCrossRefGoogle Scholar
  33. 33.
    Moake JL, Turner NA, Stathopoulos NA et al (1988) Shear-induced platelet aggregation can be mediated by vWF released from platelets, as well as by exogenous large or unusually large vWF multimers, requires adenosine diphosphate, and is resistant to aspirin. Blood 71:1366–1374PubMedGoogle Scholar
  34. 34.
    O’Brien JR (1990) Shear-induced platelet aggregation. Lancet 335:711–713PubMedCrossRefGoogle Scholar
  35. 35.
    Wagner CT, Kroll MH, Chow TW et al (1996) Epinephrine and shear stress synergistically induce platelet aggregation via a mechanism that partially bypasses VWF-GP IB interactions. Biorheology 33:209–229PubMedCrossRefGoogle Scholar
  36. 36.
    McCarty RJ, Glasser SP (1973) Thrombogenicity of guide wires. Am J Cardiol 32:943–946PubMedCrossRefGoogle Scholar
  37. 37.
    Cramer R, Moore R, Amplatz K (1973) Reduction of the surgical complication rate by the use of a hypothrombogenic catheter coating. Radiology 109:585–588PubMedGoogle Scholar
  38. 38.
    Esquivel CO, Bjorck CG, Bergentz SE et al (1984) Reduced thrombogenic characteristics of expanded polytetrafluoroethylene and polyurethane arterial grafts after heparin bonding. Surgery 95:102–107PubMedGoogle Scholar
  39. 39.
    Roberts GM, Roberts EE, Davies RL et al (1977) Thrombogenicity of arterial catheters and guidewires. Br J Radiol 50:415–418PubMedCrossRefGoogle Scholar
  40. 40.
    Sawyer PN, Pate JW, Weldon CS (1953) Relations of abnormal and injury electric potential differences to intravascular thrombosis. Am J Physiol 175:108–112PubMedGoogle Scholar
  41. 41.
    Kallmes DF, McGraw JK, Evans AJ et al (1997) Thrombogenicity of hydrophilic and nonhydrophilic microcatheters and guiding catheters. AJNR Am J Neuroradiol 18:1243–1251PubMedGoogle Scholar
  42. 42.
    Krishnan A, Cha P, Liu YH et al (2006) Interfacial energetics of blood plasma and serum adsorption to a hydrophobic self-assembled monolayer surface. Biomaterials 27:3187–3194PubMedCrossRefGoogle Scholar
  43. 43.
    Bertrand ME, Esplugas E, Piessens J et al (2000) Influence of a nonionic, iso-osmolar contrast medium (iodixanol) versus an ionic, low-osmolar contrast medium (ioxaglate) on major adverse cardiac events in patients undergoing percutaneous transluminal coronary angioplasty: a multicenter, randomized, double-blind study. Visipaque in percutaneous transluminal coronary angioplasty [VIP] trial investigators. Circulation 101:131–136PubMedGoogle Scholar
  44. 44.
    Schrader R, Esch I, Ensslen R et al (1999) A randomized trial comparing the impact of a nonionic (Iomeprol) versus an ionic (Ioxaglate) low osmolar contrast medium on abrupt vessel closure and ischemic complications after coronary angioplasty. J Am Coll Cardiol 33:395–402PubMedCrossRefGoogle Scholar
  45. 45.
    Becker RC (2007) Atherothrombosis at a distance: contributing role of existing large-burden vascular disease, circulating biosignals and modulating extravascular tissues. Thromb Res 119:761–768PubMedCrossRefGoogle Scholar
  46. 46.
    Busing KA, Schulte-Sasse C, Fluchter S et al (2005) Cerebral infarction: incidence and risk factors after diagnostic and interventional cardiac catheterization-prospective evaluation at diffusion-weighted MR imaging. Radiology 235:177–183PubMedCrossRefGoogle Scholar
  47. 47.
    Schlitt A, Rupprecht HJ, Reindl I et al (2008) In vitro comparison of fondaparinux, unfractionated heparin, and enoxaparin in preventing cardiac catheter-associated thrombus. Coron Artery Dis 19:279–284PubMedCrossRefGoogle Scholar
  48. 48.
    Maegdefessel L, Buerke M, Schubert S et al (2008) Comparison of bivalirudin, enoxaparin, and unfractionated heparin in preventing cardiac catheter thrombosis Results of an in vitro study. Thromb Haemost 100:693–698PubMedGoogle Scholar
  49. 49.
    Schlitt A, Hamilton K, Maegdefessel L et al (2006) Comparison of fondaparinux, low molecular-weight heparin and unfractionated heparin in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Heart Valve Dis 15:809–814PubMedGoogle Scholar
  50. 50.
    Sachs UJ, Nieswandt B (2007) In vivo thrombus formation in murine models. Circ Res 100:979–991PubMedCrossRefGoogle Scholar
  51. 51.
    Thierry B, Merhi Y, Bilodeau L et al (2002) Nitinol versus stainless steel stents: acute thrombogenicity study in an ex vivo porcine model. Biomaterials 23:2997–3005PubMedCrossRefGoogle Scholar
  52. 52.
    Ahn T, Shin E, Merhi Y et al (2001) Influence of stent expansion states on platelet deposition in an extracorporeal porcine arteriovenous shunt model using a multichannel perfusion chamber. J Korean Med Sci 16:31–38PubMedGoogle Scholar
  53. 53.
    Zafar MU, Vorchheimer DA, Gaztanaga J et al (2007) Antithrombotic effects of factor Xa inhibition with DU-176b: phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost 98:883–888PubMedGoogle Scholar
  54. 54.
    Merhi Y, King M, Guidoin R (1997) Acute thrombogenicity of intact and injured natural blood conduits versus synthetic conduits: neutrophil, platelet, and fibrin(ogen) adsorption under various shear-rate conditions. J Biomed Mater Res 34:477–485PubMedCrossRefGoogle Scholar
  55. 55.
    Wessler S (1952) Studies in intravascular coagulation I. Coagulation changes in isolated venous segments. J Clin Invest 31:1011–1014PubMedCrossRefGoogle Scholar
  56. 56.
    Ferns GA, Avades TY (2000) The mechanisms of coronary restenosis: insights from experimental models. Int J Exp Pathol 81:63–88PubMedCrossRefGoogle Scholar
  57. 57.
    Mehta SR, Steg PG, Granger CB et al (2005) Randomized, blinded trial comparing fondaparinux with unfractionated heparin in patients undergoing contemporary percutaneous coronary intervention: arixtra study in percutaneous coronary intervention: a randomized evaluation (ASPIRE) pilot trial. Circulation 111:1390–1397PubMedCrossRefGoogle Scholar
  58. 58.
    Steinhubl SR, Berger PB, Mann JT 3rd et al (2002) Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288:2411–2420PubMedCrossRefGoogle Scholar
  59. 59.
    Denardo SJ, Davis KE, Tcheng JE (2005) Elective percutaneous coronary intervention using broad-spectrum antiplatelet therapy (eptifibatide, clopidogrel, and aspirin) alone, without scheduled unfractionated heparin or other antithrombin therapy. Am Heart J 149:138–144PubMedCrossRefGoogle Scholar
  60. 60.
    Valencia R, Price MJ, Sawhney N et al (2007) Efficacy and safety of triple antiplatelet therapy with and without concomitant anticoagulation during elective percutaneous coronary intervention (the REMOVE trial). Am J Cardiol 100:1099–1102PubMedCrossRefGoogle Scholar
  61. 61.
    Stabile E, Nammas W, Salemme L et al (2008) The CIAO (Coronary interventions antiplatelet-based only) study: a randomized study comparing standard anticoagulation regimen to absence of anticoagulation for elective percutaneous coronary intervention. J Am Coll Cardiol 52:1293–1298PubMedCrossRefGoogle Scholar
  62. 62.
    Weitz JI, Hirsh J, Samama MM (2008) New antithrombotic drugs: American College of chest physicians evidence-based clinical practice guidelines (8th Edition). Chest 133:234S–256SPubMedCrossRefGoogle Scholar
  63. 63.
    Brandt JT, Payne CD, Wiviott SD et al (2007) A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153(66):e9–e16PubMedGoogle Scholar
  64. 64.
    Casarella WJ, Wilner GD (1977) Guide wire thrombogenicity measured by fibrinopeptide. A radioimmunoassay. AJR Am J Roentgenol 128:363–366PubMedGoogle Scholar
  65. 65.
    Garachemani A, Meier B (1998) Heparin for coronary angioplasty: high dose, low dose, or no dose? Heart 80:3–4PubMedGoogle Scholar
  66. 66.
    Brener SJ, Moliterno DJ, Lincoff AM et al (2004) Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention. Circulation 110:994–998PubMedCrossRefGoogle Scholar
  67. 67.
    Mahaffey KW, Becker RC (2006) The scientific community’s quest to identify optimal targets for anticoagulant pharmacotherapy. Circulation 114:2313–2316PubMedCrossRefGoogle Scholar
  68. 68.
    Ferguson JJ, Califf RM, Antman EM et al (2004) Enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 292:45–54PubMedCrossRefGoogle Scholar
  69. 69.
    Montalescot G, White HD, Gallo R et al (2006) Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 355:1006–1017PubMedCrossRefGoogle Scholar
  70. 70.
    Zalc S, Lemos PA, Esteves A et al (2006) Early ambulation and variability in anticoagulation during elective coronary stenting with a single intravenous bolus of low-dose, low-molecular weight heparin enoxaparin. J Invasive Cardiol 18:45–48PubMedGoogle Scholar
  71. 71.
    Chen Q, Hou K, Zhang ZX et al (2006) Acute occlusion of the left subclavian artery with artery dissection. Chin Med J (Engl) 119:255–258Google Scholar
  72. 72.
    Buller CE, Pate GE, Armstrong PW et al (2006) Catheter thrombosis during primary percutaneous coronary intervention for acute ST elevation myocardial infarction despite subcutaneous low-molecular-weight heparin, acetylsalicylic acid, clopidogrel and abciximab pretreatment. Can J Cardiol 22:511–515PubMedGoogle Scholar
  73. 73.
    Natarajan MK, Velianou JL, Turpie AG et al (2006) A randomized pilot study of dalteparin versus unfractionated heparin during percutaneous coronary interventions. Am Heart J 151:175PubMedCrossRefGoogle Scholar
  74. 74.
    Al Dieri R, Peyvandi F, Santagostino E et al (2002) The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding. Thromb Haemost 88:576–582PubMedGoogle Scholar
  75. 75.
    Allen GA, Monroe DM 3rd, Roberts HR et al (2000) The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation. Blood Coagul Fibrinolysis 11(Suppl 1):S3–S7PubMedGoogle Scholar
  76. 76.
    Stief TW (2008) Kallikrein activates prothrombin. Clin Appl Thromb Hemost 14:97–98PubMedCrossRefGoogle Scholar
  77. 77.
    Cohen M, Bhatt DL, Alexander JH et al (2007) Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 115:2642–2651PubMedCrossRefGoogle Scholar
  78. 78.
    Gibson CM, Morrow DA, Murphy SA et al (2006) A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: the PROTECT-TIMI-30 trial. J Am Coll Cardiol 47:2364–2373PubMedCrossRefGoogle Scholar
  79. 79.
    Stone GW, Witzenbichler B, Guagliumi G et al (2008) Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 358:2218–2230PubMedCrossRefGoogle Scholar
  80. 80.
    Giugliano RP, Wiviott SD, Stone PH et al (2007) Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol 49:2398–2407PubMedCrossRefGoogle Scholar
  81. 81.
    Lincoff AM, Bittl JA, Harrington RA et al (2003) Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 289:853–863PubMedCrossRefGoogle Scholar
  82. 82.
    Stone GW, McLaurin BT, Cox DA et al (2006) Bivalirudin for patients with acute coronary syndromes. N Engl J Med 355:2203–2216PubMedCrossRefGoogle Scholar
  83. 83.
    Kastrati A, Neumann FJ, Mehilli J et al (2008) Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 359:688–696PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Mark Y. Chan
    • 1
    • 2
  • Jeffrey I. Weitz
    • 3
  • Yahye Merhi
    • 4
  • Robert A. Harrington
    • 5
  • Richard C. Becker
    • 6
  1. 1.National University Heart CentreSingaporeSingapore
  2. 2.SingaporeSingapore
  3. 3.Henderson Research Center and McMaster UniversityHamiltonCanada
  4. 4.Thrombosis and Hemostasis Laboratory, Montreal Heart InstituteUniversity of MontrealMontrealCanada
  5. 5.Division of Cardiovascular Medicine, Duke Cardiovascular Thrombosis Center and Duke Clinical Research InstituteDuke University School of MedicineDurhamUSA
  6. 6.Divisions of Cardiovascular Medicine & Hematology, Duke Cardiovascular Thrombosis Center and Duke Clinical Research InstituteDuke University School of MedicineDurhamUSA

Personalised recommendations