Current state and novel approaches of antiplatelet therapy

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 35, Issue 6, 2015, Pages 1327-1338

  Metharom, Pat ^a   Berndt, Michael C ^a   Baker, Ross I ^b   Andrews, Robert K ^c  

^a CURTIN UNIVERSITY   (Australia)

^b MURDOCH UNIVERSITY   (Australia)

^c MONASH UNIVERSITY   (Australia)

Author keywords

anticoagulants; blood coagulation; blood platelets; drug therapy; platelet adhesion inhibitor

Indexed keywords

ABCIXIMAB; ACETYLSALICYLIC ACID; ANFIBATIDE; ANTITHROMBOCYTIC AGENT; APTAMER; ARC 15105; ATOPAXAR; BERAPROST; CANGRELOR; CAPLACIZUMAB; CILOSTAZOL; CLOPIDOGREL; DABIGATRAN; DIPYRIDAMOLE; EPTIFIBATIDE; HIRULOG; IFETROBAN; ILOPROST; PRASUGREL; PROSTACYCLIN; REVACEPT; TERUTROBAN; TICAGRELOR; TIROFIBAN; TREPROSTINIL; UNCLASSIFIED DRUG; VORAPAXAR;

ACUTE CORONARY SYNDROME; ANTICOAGULANT THERAPY; ARTICLE; BLEEDING; BLOOD CLOTTING; BLOOD VESSEL WALL; HEART INFARCTION; HUMAN; NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; NONHUMAN; PLATELET REACTIVITY; PRESCRIPTION; PRIORITY JOURNAL; PULMONARY HYPERTENSION; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; THROMBOCYTE ACTIVATION; THROMBOCYTE ADHESION; THROMBOSIS; THROMBOTIC THROMBOCYTOPENIC PURPURA; TRANSIENT ISCHEMIC ATTACK; CHEMICALLY INDUCED; DRUG EFFECTS; DRUG RESISTANCE; PATHOPHYSIOLOGY; RISK FACTOR; THROMBOCYTE AGGREGATION;

DRUG RESISTANCE; HEMORRHAGE; HUMANS; PLATELET ACTIVATION; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; RISK FACTORS; THROMBOSIS;

EID: 84933046240     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.114.303413     Document Type: Article

References (148)

1. Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov. 2003;2:15-28. doi: 10.1038/nrd985.
2. Ungerer M, Münch G. Novel antiplatelet drugs in clinical development. Thromb Haemost. 2013;110:868-875. doi: 10.1160/TH13-02-0084.
3. Bhatt DL, Hulot JS, Moliterno DJ, Harrington RA. Antiplatelet and anticoagulation therapy for acute coronary syndromes. Circ Res. 2014;114:1929-1943. doi: 10.1161/CIRCRESAHA.114.302737.
4. Lussana F, Squizzato A, Permunian ET, Cattaneo M. A systematic review on the effect of aspirin in the prevention of post-operative arterial thrombosis in patients undergoing total hip and total knee arthroplasty. Thromb Res. 2014;134:599-603. doi: 10.1016/j.thromres.2014.06.027.
5. Nairooz R, Sardar P, Amin H, Swaminathan RV, Kim LK, Chatterjee S, Feldman DN. Meta-analysis of randomized clinical trials comparing bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention and in patients with ST-segment elevation myocardial infarction. Am J Cardiol. 2014;114:250-259. doi: 10.1016/j.amjcard.2014.04.033.
6. Carreras ET, Mega JL. Dual antiplatelet therapy for heart disease. Circulation. 2014;129:e506-e508. doi: 10.1161/CIRCULATIONAHA.113.004305.
7. Berndt MC, Metharom P, Andrews RK. Primary haemostasis: newer insights. Haemophilia. 2014;20(suppl 4):15-22. doi: 10.1111/hae.12427.
8. Andrews RK, Berndt MC. Chapter 10-The gpib-ix-v complex. In: Michelson AD, ed. Platelets. 3rd ed. San Diego: Academic Press; 2013:195-213.
9. Moog S, Mangin P, Lenain N, Strassel C, Ravanat C, Schuhler S, Freund M, Santer M, Kahn M, Nieswandt B, Gachet C, Cazenave JP, Lanza F. Platelet glycoprotein V binds to collagen and participates in platelet adhesion and aggregation. Blood. 2001;98:1038-1046.
10. Andrews RK, Arthur JF, Gardiner EE. Targeting GPVI as a novel antithrombotic strategy. J Blood Med. 2014;5:59-68. doi: 10.2147/JBM. S39220.
11. Gardiner EE, Andrews RK. Platelet receptor expression and shedding: glycoprotein Ib-IX-V and glycoprotein VI. Transfus Med Rev. 2014;28:56-60. doi: 10.1016/j.tmrv.2014.03.001.
12. Gawaz M, Vogel S, Pfannenberg C, Pichler B, Langer H, Bigalke B. Implications of glycoprotein VI for theranostics. Thromb Haemost. 2014;112:26-31. doi: 10.1160/TH13-09-0756.
13. Zahid M, Mangin P, Loyau S, Hechler B, Billiald P, Gachet C, Jandrot-Perrus M. The future of glycoprotein VI as an antithrombotic target. J Thromb Haemost. 2012;10:2418-2427. doi: 10.1111/jth.12009.
14. Stegner D, Haining EJ, Nieswandt B. Targeting glycoprotein VI and the immunoreceptor tyrosine-based activation motif signaling pathway. Arterioscler Thromb Vasc Biol. 2014;34:1615-1620. doi: 10.1161/ATVBAHA.114.303408.
15. Kroll MH, Hellums JD, McIntire LV, Schafer AI, Moake JL. Platelets and shear stress. Blood. 1996;88:1525-1541.
16. Han BW, Herrin BR, Cooper MD, Wilson IA. Antigen recognition by variable lymphocyte receptors. Science. 2008;321:1834-1837. doi: 10.1126/science.1162484.
17. Arthur JF, Qiao J, Shen Y, Davis AK, Dunne E, Berndt MC, Gardiner EE, Andrews RK. ITAM receptor-mediated generation of reactive oxygen species in human platelets occurs via Syk-dependent and Sykindependent pathways. J Thromb Haemost. 2012;10:1133-1141. doi: 10.1111/j.1538-7836.2012.04734.x.
18. Arthur JF, Shen Y, Gardiner EE, Coleman L, Murphy D, Kenny D, Andrews RK, Berndt MC. TNF receptor-associated factor 4 (TRAF4) is a novel binding partner of glycoprotein Ib and glycoprotein VI in human platelets. J Thromb Haemost. 2011;9:163-172. doi: 10.1111/j.1538-7836.2010.04091.x.
19. Vara D, Campanella M, Pula G. The novel NOX inhibitor 2-acetylphenothiazine impairs collagen-dependent thrombus formation in a GPVI-dependent manner. Br J Pharmacol. 2013;168:212-224. doi: 10.1111/j.1476-5381.2012.02130.x.
20. Walsh TG, Berndt MC, Carrim N, Cowman J, Kenny D, Metharom P. The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation. Redox Biol. 2014;2:178-186. doi: 10.1016/j. redox.2013.12.023.
21. Mu FT, Andrews RK, Arthur JF, Munday AD, Cranmer SL, Jackson SP, Stomski FC, Lopez AF, Berndt MC. A functional 14-3-3zeta-independent association of PI3-kinase with glycoprotein Ib alpha, the major ligandbinding subunit of the platelet glycoprotein Ib-IX-V complex. Blood. 2008;111:4580-4587. doi: 10.1182/blood-2007-09-111096.
22. Mu FT, Cranmer SL, Andrews RK, Berndt MC. Functional association of phosphoinositide-3-kinase with platelet glycoprotein Ibalpha, the major ligand-binding subunit of the glycoprotein Ib-IX-V complex. J Thromb Haemost. 2010;8:324-330. doi: 10.1111/j.1538-7836.2009.03672.x.
23. Schmaier AA, Zou Z, Kazlauskas A, Emert-Sedlak L, Fong KP, Neeves KB, Maloney SF, Diamond SL, Kunapuli SP, Ware J, Brass LF, Smithgall TE, Saksela K, Kahn ML. Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role. Proc Natl Acad Sci U S A. 2009;106:21167-21172. doi: 10.1073/pnas.0906436106.
24. Ozaki Y, Suzuki-Inoue K, Inoue O. Platelet receptors activated via mulitmerization: glycoprotein VI, GPIb-IX-V, and CLEC-2. J Thromb Haemost. 2013;11(suppl 1):330-339. doi: 10.1111/jth.12235.
25. De Candia E, Hall SW, Rutella S, Landolfi R, Andrews RK, De Cristofaro R. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets. J Biol Chem. 2001;276:4692-4698. doi: 10.1074/jbc.M008160200.
26. Wallace EL, Smyth SS. Targeting platelet thrombin receptor signaling to prevent thrombosis. Pharmaceuticals (Basel). 2013;6:915-928. doi: 10.3390/ph6080915.
27. Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost. 2008;99:466-472. doi: 10.1160/TH07-11-0673.
28. Estevez B, Shen B, Du X. Targeting integrin and integrin signaling in treating thrombosis. Arterioscler Thromb Vasc Biol. 2015;35:24-29. doi: 10.1161/ATVBAHA.114.303411.
29. Nuyttens BP, Thijs T, Deckmyn H, Broos K. Platelet adhesion to collagen. Thromb Res. 2011;127(suppl 2):S26-S29. doi: 10.1016/S0049-3848(10)70151-1.
30. Deckmyn H, De Meyer S, Broos K, Vanhoorelbeke K. Inhibitors of the interactions between collagen and its receptors on platelets. In: Gresele P, Born GVR, Patrono C, Page CP, eds. Antiplatelet agents, Handbook of Experimental Pharmacology. Springer: Berlin Heidelberg; 2012:311-337.
31. Alshahrani MM, Yang E, Yip J, Ghanem SS, Abdallah SL, deAngelis AM, O'Malley CJ, Moheimani F, Najjar SM, Jackson DE. CEACAM2 negatively regulates hemi (ITAM-bearing) GPVI and CLEC-2 pathways and thrombus growth in vitro and in vivo. Blood. 2014;124:2431-2441. doi: 10.1182/blood-2014-04-569707.
32. Smolenski A. Novel roles of cAMP/cGMP-dependent signaling in platelets. J Thromb Haemost. 2012;10:167-176. doi: 10.1111/j.1538-7836.2011.04576.x.
33. Zhang G, Xiang B, Dong A, Skoda RC, Daugherty A, Smyth SS, Du X, Li Z. Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation. Blood. 2011;118:3670-3679. doi: 10.1182/blood-2011-03-341107.
34. Li Z, Xi X, Gu M, Feil R, Ye RD, Eigenthaler M, Hofmann F, Du X. A stimulatory role for cGMP-dependent protein kinase in platelet activation. Cell. 2003;112:77-86.
35. Andrews RK, Du X, Berndt MC. The 14-3-3zeta-GPIb-IX-V complex as an antiplatelet target. Drug News Perspect. 2007;20:285-292. doi: 10.1358/dnp.2007.20.5.1120215.
36. Flaumenhaft R, Furie B, Zwicker JI. Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease. Arterioscler Thromb Vasc Biol. 2015;35:16-23. doi: 10.1161/ATVBAHA.114.303410.
37. Durante W, Schafer AI, Hrbolich JK, Claure RA, Mendelsohn ME, Kroll MH. Endothelium-derived relaxing factor inhibits shear stress-induced platelet aggregation. Platelets. 1993;4:135-140. doi: 10.3109/09537109309013209.
38. Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Itagaki I. The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest. 1991;87:1234-1240. doi: 10.1172/JCI115124.
39. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A; Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative metaanalysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860. doi: 10.1016/S0140-6736(09)60503-1.
40. Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e89S-119S. doi: 10.1378/chest.11-2293.
41. Sandercock PA, Counsell C, Tseng MC, Cecconi E. Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:CD000029. doi: 10.1002/14651858.CD000029.pub3.
42. Ciccone A, Motto C, Abraha I, Cozzolino F, Santilli I. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:CD005208. doi: 10.1002/14651858.CD005208.pub3.
43. Mehta SR, Tanguay JF, Eikelboom JW, et al; CURRENT-OASIS 7 Trial Investigators. Double-dose versus standard-dose clopidogrel and highdose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (current-oasis 7): a randomised factorial trial. Lancet. 2010;376:1233-1243. doi: 10.1016/S0140-6736(10)61088-4.
44. Roe MT, Armstrong PW, Fox KA, et al; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367:1297-1309. doi: 10.1056/NEJMoa1205512.
45. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015. doi: 10.1056/NEJMoa0706482.
46. Pilgrim T, Windecker S. Antiplatelet therapy for secondary prevention of coronary artery disease. Heart. 2014;100(22):1750-1756. doi: 10.1136/heartjnl-2013-305399.
47. Becker RC, Bassand JP, Budaj A, et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2011;32:2933-2944. doi: 10.1093/eurheartj/ehr422.
48. Stone GW, Bertrand ME, Moses JW, et al; ACUITY Investigators. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY timing trial. JAMA. 2007;297:591-602. doi: 10.1001/jama.297.6.591.
49. Habib A, Finn AV. Endothelialization of drug eluting stents and its impact on dual anti-platelet therapy duration. Pharmacol Res. 2015;93:22-27. doi: 10.1016/j.phrs.2014.12.003.
50. Tantry US, Bonello L, Aradi D, et al; Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol. 2013;62:2261-2273. doi: 10.1016/j. jacc.2013.07.101.
51. Li J, Jian Z, Song M, Guo W, Chen G, Lu W, Qian D, Ouyang J, Yu J, Hu H, Jin J, Wu X, Huang L. Tailored antiplatelet therapy and clinical adverse outcomes. Heart. 2014;100:41-46. doi: 10.1136/heartjnl-2013-304461.
52. Lewis JP, Ryan K, O'Connell JR, et al. Genetic variation in PEAR1 is associated with platelet aggregation and cardiovascular outcomes. Circ Cardiovasc Genet. 2013;6:184-192. doi: 10.1161/CIRCGENETICS.111.964627.
53. Aradi D, Tornyos A, Pintér T, Vorobcsuk A, Kónyi A, Faluközy J, Veress G, Magyari B, Horváth IG, Komócsi A. Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol. 2014;63:1061-1070. doi: 10.1016/j.jacc.2013.12.023.
54. Price MJ, Berger PB, Teirstein PS, et al; GRAVITAS Investigators. Standard-vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305:1097-1105. doi: 10.1001/jama.2011.290.
55. Collet JP, Cuisset T, Rangé G, et al; ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100-2109. doi: 10.1056/NEJMoa1209979.
56. Gurbel PA, Erlinge D, Ohman EM, et al; TRILOGY ACS Platelet Function Substudy Investigators. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA. 2012;308:1785-1794. doi: 10.1001/jama.2012.17312.
57. Montalescot G, Rangé G, Silvain J, et al; ARCTIC Investigators. High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: A landmark analysis of the ARCTIC study. Circulation. 2014;129:2136-2143. doi: 10.1161/CIRCULATIONAHA.113.007524.
58. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304:1821-1830. doi: 10.1001/jama.2010.1543.
59. Fuster V, Sweeny JM. Clopidogrel and the reduced-function CYP2C19 genetic variant: a limited piece of the overall therapeutic puzzle. JAMA. 2010;304:1839-1840. doi: 10.1001/jama.2010.1566.
60. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376:1312-1319. doi: 10.1016/S0140-6736(10)61273-1.
61. Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KA, Eikelboom JW. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010;363:1704-1714. doi: 10.1056/NEJMoa1008410.
62. Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC; PLATO Investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376:1320-1328. doi: 10.1016/S0140-6736(10)61274-3.
63. Bergmeijer TO, Janssen PW, Schipper JC, et al. CYP2C19 genotypeguided antiplatelet therapy in ST-segment elevation myocardial infarction patients-rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J. 2014;168:16-22.e1. doi: 10.1016/j.ahj.2014.03.006.
64. López JA, Andrews RK, Afshar-Kharghan V, Berndt MC. Bernard-Soulier syndrome. Blood. 1998;91:4397-4418.
65. Andrews RK, Berndt MC. Bernard-Soulier syndrome: an update. Semin Thromb Hemost. 2013;39:656-662. doi: 10.1055/s-0033-1353390.
66. Arthur JF, Dunkley S, Andrews RK. Platelet glycoprotein VI-related clinical defects. Br J Haematol. 2007;139:363-372. doi: 10.1111/j.1365-2141.2007.06799.x.
67. Bergmeier W, Piffath CL, Goerge T, Cifuni SM, Ruggeri ZM, Ware J, Wagner DD. The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci U S A. 2006;103:16900-16905. doi: 10.1073/pnas.0608207103.
68. Massberg S, Gawaz M, Grüner S, Schulte V, Konrad I, Zohlnhöfer D, Heinzmann U, Nieswandt B. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med. 2003;197:41-49.
69. Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation. 2007;115:2323-2330. doi: 10.1161/CIRCULATIONAHA.107.691279.
70. Wijeyewickrema LC, Berndt MC, Andrews RK. Snake venom probes of platelet adhesion receptors and their ligands. Toxicon. 2005;45:1051-1061. doi: 10.1016/j.toxicon.2005.02.025.
71. Lee's Pharmaceutical Limited. Anfibatide phase 1 clinical trial in healthy volunteers. http://clinicaltrials.gov/ct2/show/NCT01588132. 2011.
72. Lee's Pharmaceutical Limited. Anfibatide phase ib-iia clinical trial. http://www.clinicaltrials.gov/ct2/show/NCT01585259. 2012.
73. Hou Y, Li BX, Dai X, Yang Z, Qian F, Zhang G, Xu Z, Liu J, Liang C, Zhao Y, Shen J, Zhou H, Wang Y, Marshall AH, Ni H. The first in vitro and in vivo assessment of anfibatide, a novel glycoprotein ib antagonist, in mice and in a phase i human clinical trial. Blood. 2013;122:577.
74. Ungerer M, Rosport K, Bültmann A, Piechatzek R, Uhland K, Schlieper P, Gawaz M, Münch G. Novel antiplatelet drug revacept (dimeric glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation. 2011;123:1891-1899. doi: 10.1161/CIRCULATIONAHA.110.980623.
75. AdvanceCor GmbH. Revacept in symptomatic carotid stenosis (revacept/cs/02). http://clinicaltrials.gov/ct2/show/NCT01645306. 2014.
76. Gardiner EE, Arthur JF, Kahn ML, Berndt MC, Andrews RK. Regulation of platelet membrane levels of glycoprotein VI by a plateletderived metalloproteinase. Blood. 2004;104:3611-3617. doi: 10.1182/blood-2004-04-1549.
77. Gardiner EE, Karunakaran D, Shen Y, Arthur JF, Andrews RK, Berndt MC. Controlled shedding of platelet glycoprotein (GP)VI and GPIb-IX-V by ADAM family metalloproteinases. J Thromb Haemost. 2007;5:1530-1537. doi: 10.1111/j.1538-7836.2007.02590.x.
78. Al-Tamimi M, Tan CW, Qiao J, et al. Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. Blood. 2012;119:4311-4320. doi: 10.1182/blood-2011-10-386607.
79. Al-Tamimi M, Grigoriadis G, Tran H, Paul E, Servadei P, Berndt MC, Gardiner EE, Andrews RK. Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa. Blood. 2011;117:3912-3920. doi: 10.1182/blood-2010-08-301523.
80. Gardiner EE, Andrews RK. Plasma sGPVI: changing levels in human disease. Thromb Res. 2014;133:306-307. doi: 10.1016/j. thromres.2013.12.028.
81. Shen B, Zhao X, O'Brien KA, Stojanovic-Terpo A, Delaney MK, Kim K, Cho J, Lam SC, Du X. A directional switch of integrin signalling and a new anti-thrombotic strategy. Nature. 2013;503:131-135. doi: 10.1038/nature12613.
82. Schaff M, Tang C, Maurer E, et al. Integrin ?6?1 is the main receptor for vascular laminins and plays a role in platelet adhesion, activation, and arterial thrombosis. Circulation. 2013;128:541-552. doi: 10.1161/CIRCULATIONAHA.112.000799.
83. McEwan PA, Andrews RK, Emsley J. Glycoprotein Ibalpha inhibitor complex structure reveals a combined steric and allosteric mechanism of von Willebrand factor antagonism. Blood. 2009;114:4883-4885. doi: 10.1182/blood-2009-05-224170.
84. Benard SA, Smith TM, Cunningham K, Jacob J, DeSilva T, Lin L, Shaw GD, Kriz R, Kelleher KS. Identification of peptide antagonists to glycoprotein Ibalpha that selectively inhibit von Willebrand factor dependent platelet aggregation. Biochemistry. 2008;47:4674-4682. doi: 10.1021/bi702428q.
85. Hohmann JD, Wang X, Krajewski S, Selan C, Haller CA, Straub A, Chaikof EL, Nandurkar HH, Hagemeyer CE, Peter K. Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding? Blood. 2013;121:3067-3075. doi: 10.1182/blood-2012-08-449694.
86. Pellegatta M, De Arcangelis A, D'Urso A, et al. 61 and 71 integrins are required in Schwann cells to sort axons. J Neurosci. 2013;33:17995-18007. doi: 10.1523/JNEUROSCI.3179-13.2013.
87. Staquicini FI, Dias-Neto E, Li J, Snyder EY, Sidman RL, Pasqualini R, Arap W. Discovery of a functional protein complex of netrin-4, laminin gamma1 chain, and integrin alpha6beta1 in mouse neural stem cells. Proc Natl Acad Sci U S A. 2009;106:2903-2908. doi: 10.1073/pnas.0813286106.
88. Larrieu-Lahargue F, Welm AL, Thomas KR, Li DY. Netrin-4 activates endothelial integrin {alpha}6{beta}1. Circ Res. 2011;109:770-774. doi: 10.1161/CIRCRESAHA.111.247239.
89. Witzig TE, Gupta M. Signal transduction inhibitor therapy for lymphoma. Hematology Am Soc Hematol Educ Program. 2010;2010:265-270. doi: 10.1182/asheducation-2010.1.265.
90. Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIbdependent thrombus formation in vivo. Blood. 2006;108:2596-2603. doi: 10.1182/blood-2006-01-011817.
91. Kamel S, Horton L, Ysebaert L, Levade M, Burbury K, Tan S, Cole-Sinclair M, Reynolds J, Filshie R, Schischka S, Khot A, Sandhu S, Keating MJ, Nandurkar H, Tam CS. Ibrutinib inhibits collagen-mediated but not adp-mediated platelet aggregation [published online ahead of print August 20, 2014]. Leukemia. 10.1038/leu.2014.247.
92. Qiao J, Schoenwaelder SM, Mason KD, Tran H, Davis AK, Kaplan ZS, Jackson SP, Kile BT, Andrews RK, Roberts AW, Gardiner EE. Low adhesion receptor levels on circulating platelets in patients with lymphoproliferative diseases before receiving Navitoclax (ABT-263). Blood. 2013;121:1479-1481. doi: 10.1182/blood-2012-12-467415.
93. Gray SP, Di Marco E, Okabe J, et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation. 2013;127:1888-1902. doi: 10.1161/CIRCULATIONAHA.112.132159.
94. Violi F, Pignatelli P. Platelet NOX, a novel target for anti-thrombotic treatment. Thromb Haemost. 2014;111:817-823. doi: 10.1160/TH13-10-0818.
95. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4:181-189. doi: 10.1038/nri1312.
96. Loyau S, Dumont B, Ollivier V, Boulaftali Y, Feldman L, Ajzenberg N, Jandrot-Perrus M. Platelet glycoprotein VI dimerization, an active process inducing receptor competence, is an indicator of platelet reactivity. Arterioscler Thromb Vasc Biol. 2012;32:778-785. doi: 10.1161/ATVBAHA.111.241067.
97. Gurbel PA, Kuliopulos A, Tantry US. G-protein-coupled receptors signaling pathways in new antiplatelet drug development. Arterioscler Thromb Vasc Biol. 2015;35:500-512. doi: 10.1161/ATVBAHA.114.303412.
98. US Food and Drug Administration. Drugs@fda. http://www.accessdata. fda.gov/Scripts/cder/drugsatfda/index.cfm. Accessed April 4, 2014.
99. US National Library of Medicine. Dailymed. http://dailymed.nlm.nih. gov/dailymed/about.cfm. Accessed April 4, 2014.
100. Law V, Knox C, Djoumbou Y, et al. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 2014;42(database issue):D1091-D1097. doi: 10.1093/nar/gkt1068.
101. Cavalca V, Rocca B, Squellerio I, Dragani A, Veglia F, Pagliaccia F, Porro B, Barbieri SS, Tremoli E, Patrono C. In vivo prostacyclin biosynthesis and effects of different aspirin regimens in patients with essential thrombocythaemia. Thromb Haemost. 2014;112:118-127. doi: 10.1160/TH13-10-0844.
102. Malloy RJ, Kanaan AO, Silva MA, Donovan JL. Evaluation of antiplatelet agents for secondary prevention of stroke using mixed treatment comparison meta-analysis. Clin Ther. 2013;35:1490-1500.e7. doi: 10.1016/j.clinthera.2013.09.004.
103. Gouya G, Arrich J, Wolzt M, Huber K, Verheugt FW, Gurbel PA, Pirker-Kees A, Siller-Matula JM. Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis. Stroke. 2014;45:492-503. doi: 10.1161/STROKEAHA.113.002590.
104. Alvarez-Sabín J, Quintana M, Santamarina E, Maisterra O. Triflusal and aspirin in the secondary prevention of atherothrombotic ischemic stroke: a very long-term follow-up. Cerebrovasc Dis. 2014;37:181-187. doi: 10.1159/000357662.
105. Anninos H, Andrikopoulos G, Pastromas S, Sakellariou D, Theodorakis G, Vardas P. Triflusal: an old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic J Cardiol. 2009;50:199-207.
106. The European Stroke Organisation Executive C, the ESOWC. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovascular Diseases. 2008;25:457-507.
107. Piccolo R, Galasso G, De Luca G, Parodi G, Antoniucci D, Esposito G, Trimarco B, Piscione F. Relationship between changes in platelet reactivity and ischemic events following percutaneous coronary intervention: a meta-regression analysis of 30 randomized trials. Atherosclerosis. 2014;234:176-184. doi: 10.1016/j.atherosclerosis.2014.02.024.
108. Wang X, Gong X, Zhu T, Zhang Q, Zhang Y, Wang X, Yang Z, Li C. Clopidogrel improves aspirin response after off-pump coronary artery bypass surgery. J Biomed Res. 2014;28:108-113. doi: 10.7555/JBR.28.20120139.
109. Schulz S, Richardt G, Laugwitz KL, Mehran R, Gershlick AH, Morath T, Mayer K, Neudecker J, Tolg R, Ibrahim T, Hauschke D, Braun D, Schunkert H, Kastrati A, Mehilli J. Comparison of prasugrel and bivalirudin vs clopidogrel and heparin in patients with st-segment elevation myocardial infarction: design and rationale of the bavarian reperfusion alternatives evaluation (brave) 4 trial. Clinical cardiology. 2014;37(5):270-276. doi: 10.1002/clc.22268.
110. Nanau RM, Delzor F, Neuman MG. Efficacy and safety of prasugrel in acute coronary syndrome patients. Clin Biochem. 2014;47:516-528. doi: 10.1016/j.clinbiochem.2014.03.005.
111. Hibbert B, Maze R, Pourdjabbar A, Simard T, Ramirez FD, Moudgil R, Blondeau M, Labinaz M, Dick A, Glover C, Froeschl M, Marquis JF, So DY, Le May MR. A comparative pharmacodynamic study of ticagrelor versus clopidogrel and ticagrelor in patients undergoing primary percutaneous coronary intervention: the CAPITAL RELOAD study. PLoS One. 2014;9:e92078. doi: 10.1371/journal.pone.0092078.
112. Henriksson M, Nikolic E, Ohna A, Wallentin L, Janzon M. Ticagrelor treatment in patients with acute coronary syndrome is cost-effective in Sweden and Denmark. Scand Cardiovasc J. 2014;48:138-147. doi: 10.3109/14017431.2014.902494.
113. Bonaca MP, Bhatt DL, Braunwald E, Cohen M, Steg PG, Storey RF, Held P, Jensen EC, Sabatine MS. Design and rationale for the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial. Am Heart J. 2014;167:437-444.e5. doi: 10.1016/j.ahj.2013.12.020.
114. Parikh D, Juergens CP. Abciximab as an adjunctive therapy for patients undergoing percutaneous coronary interventions. Expert Opin Biol Ther. 2011;11:235-246. doi: 10.1517/14712598.2011.551113.
115. Xu Q, Yin J, Si LY. Efficacy and safety of early versus late glycoprotein IIb/IIIa inhibitors for PCI. Int J Cardiol. 2013;162:210-219. doi: 10.1016/j.ijcard.2012.06.001.
116. Bledzka K, Smyth SS, Plow EF. Integrin ?IIb?3: from discovery to efficacious therapeutic target. Circ Res. 2013;112:1189-1200. doi: 10.1161/CIRCRESAHA.112.300570.
117. Lang SH, Manning N, Armstrong N, Misso K, Allen A, Di Nisio M, Kleijnen J. Treatment with tirofiban for acute coronary syndrome (ACS): a systematic review and network analysis. Curr Med Res Opin. 2012;28:351-370. doi: 10.1185/03007995.2012.657299.
118. Waxman AB, Zamanian RT. Pulmonary arterial hypertension: new insights into the optimal role of current and emerging prostacyclin therapies. Am J Cardiol. 2013;111(5 suppl):1A-16A; quiz 17A. doi: 10.1016/j.amjcard.2012.12.002.
119. McLaughlin VV, Palevsky HI. Parenteral and inhaled prostanoid therapy in the treatment of pulmonary arterial hypertension. Clin Chest Med. 2013;34:825-840. doi: 10.1016/j.ccm.2013.09.003.
120. Torres F, Rubin LJ. Treprostinil for the treatment of pulmonary arterial hypertension. Expert Rev Cardiovasc Ther. 2013;11:13-25. doi: 10.1586/erc.12.160.
121. Channick RN, Voswinckel R, Rubin LJ. Inhaled treprostinil: a therapeutic review. Drug Des Devel Ther. 2012;6:19-28. doi: 10.2147/DDDT.S19281.
122. Ndrepepa G, Neumann FJ, Deliargyris EN, Mehran R, Mehilli J, Ferenc M, Schulz S, Schömig A, Kastrati A, Stone GW. Bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention after clopidogrel pretreatment: pooled analysis from the ACUITY and ISAR-REACT 4 trials. Circ Cardiovasc Interv. 2012;5:705-712. doi: 10.1161/CIRCINTERVENTIONS.112.972869.
123. Shah A, Feldman DN. Outcome of the HORIZONS-AMI trial: bivalirudin enhances long-term survival in patients with ST-elevation myocardial infarction undergoing angioplasty. Vasc Health Risk Manag. 2012;8:115-123. doi: 10.2147/VHRM.S23491.
124. Bloom BJ, Filion KB, Atallah R, Eisenberg MJ. Meta-analysis of randomized controlled trials on the risk of bleeding with dabigatran. Am J Cardiol. 2014;113:1066-1074. doi: 10.1016/j.amjcard.2013.11.049.
125. Providência R, Albenque JP, Combes S, Bouzeman A, Casteigt B, Combes N, Narayanan K, Marijon E, Boveda S. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart. 2014;100:324-335. doi: 10.1136/heartjnl-2013-304386.
126. Gresele P, Momi S, Falcinelli E. Anti-platelet therapy: phosphodiesterase inhibitors. Br J Clin Pharmacol. 2011;72:634-646. doi: 10.1111/j.1365-2125.2011.04034.x.
127. De Schryver EL, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane Database Syst Rev. 2007; Issue 3. Art. No.: CD001820. doi: 10.1002/14651858.CD001820.pub3.
128. Lee BK, Lee SW, Park SW, Lee SW, Park DW, Kim YH, Lee CW, Hong MK, Kim JJ, Jang S, Chi HS, Park SJ. Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coronary artery stent implantation. Am J Cardiol. 2007;100:610-614. doi: 10.1016/j.amjcard.2007.03.070.
129. Stevens JW, Simpson E, Harnan S, Squires H, Meng Y, Thomas S, Michaels J, Stansby G. Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication. Br J Surg. 2012;99:1630-1638. doi: 10.1002/bjs.8895.
130. Kunieda T, Nakanishi N, Matsubara H, Ohe T, Okano Y, Kondo H, Nishimura M, Shirato K, Tanabe N, Homma S, Yoshida S, Inokuma S, Kodama M, Koike T, Hishida H. Effects of long-acting beraprost sodium (TRK-100STP) in Japanese patients with pulmonary arterial hypertension. Int Heart J. 2009;50:513-529.
131. Na KY, Kim DK, Kim SG, Lee YK, Lim CS. Effect of beraprost sodium on arterial stiffness in patients with type 2 diabetic nephropathy. Trials. 2013;14:275. doi: 10.1186/1745-6215-14-275.
132. Firbas C, Siller-Matula JM, Jilma B. Targeting von Willebrand factor and platelet glycoprotein Ib receptor. Expert Rev Cardiovasc Ther. 2010;8:1689-1701. doi: 10.1586/erc.10.154.
133. Jilma-Stohlawetz P, Gorczyca ME, Jilma B, Siller-Matula J, Gilbert JC, Knöbl P. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost. 2011;105:545-552. doi: 10.1160/TH10-08-0520.
134. Jilma B, Paulinska P, Jilma-Stohlawetz P, Gilbert JC, Hutabarat R, Knöbl P. A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb Haemost. 2010;104:563-570. doi: 10.1160/TH10-01-0027.
135. Ulrichts H, Silence K, Schoolmeester A, de Jaegere P, Rossenu S, Roodt J, Priem S, Lauwereys M, Casteels P, Van Bockstaele F, Verschueren K, Stanssens P, Baumeister J, Holz JB. Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs. Blood. 2011;118:757-765. doi: 10.1182/blood-2010-11-317859.
136. Bartunek J, Barbato E, Heyndrickx G, Vanderheyden M, Wijns W, Holz JB. Novel antiplatelet agents: ALX-0081, a Nanobody directed towards von Willebrand factor. J Cardiovasc Transl Res. 2013;6:355-363. doi: 10.1007/s12265-012-9435-y.
137. Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Fox KM, Hennerici MG, Mattle HP, Rothwell PM, de Cordoüe A, Fratacci MD; PERFORM Study Investigators. Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, doubleblind, parallel-group trial. Lancet. 2011;377:2013-2022. doi: 10.1016/S0140-6736(11)60600-4.
138. Mearns BM. Antiplatelet therapy: terutroban does not out-PERFORM aspirin in secondary prevention. Nat Rev Cardiol. 2011;8:423. doi: 10.1038/nrcardio.2011.93.
139. Daví G, Santilli F, Vazzana N. Thromboxane receptors antagonists and/or synthase inhibitors. In: Gresele P, Born GVR, Patrono C, Page CP, eds. Antiplatelet agents, Handbook of Experimental Pharmacology. Springer: Berlin Heidelberg; 2012:261-286.
140. US National Institutes of Health. Safety and pharmacokinetics of ifetroban in hepatorenal syndrome patients. http://clinicaltrials.gov/show/NCT01436500. Accessed April 4, 2014.
141. de Souza Brito F, Tricoci P. Novel anti-platelet agents: focus on thrombin receptor antagonists. J Cardiovasc Transl Res. 2013;6:415-424. doi: 10.1007/s12265-013-9454-3.
142. Rosser G, Tricoci P, Morrow D, Christopoulos C, Niespialowska-Steuden MN, Kozarski R, Wilcox R, Gorog DA. Par-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease. J Thromb Thrombolysis. 2014;38(4):423-429. doi: 10.1007/s11239-014-1075-4.
143. Garde D. Merck clears an fda panel with its clot-fighting vorapaxar. http://www.fiercebiotech.com/story/merck-clears-fda-panel-its-clotfighting-vorapaxar/2014-01-16.
144. O'Donoghue ML, Bhatt DL, Flather MD, Goto S, Angiolillo DJ, Goodman SG, Zeymer U, Aylward PE, Montalescot G, Ziecina R, Kobayashi H, Ren F, Wiviott SD. Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program. J Thromb Thrombolysis. 2012;34:36-43. doi: 10.1007/s11239-012-0750-6.
145. Wiviott SD, Flather MD, O'Donoghue ML, Goto S, Fitzgerald DJ, Cura F, Aylward P, Guetta V, Dudek D, Contant CF, Angiolillo DJ, Bhatt DL; LANCELOT-CAD Investigators. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of Thrombin-Coronary Artery Disease Trial. Circulation. 2011;123:1854-1863. doi: 10.1161/CIRCULATIONAHA.110.001404.
146. Waite LH, Phan YL, Spinler SA. Cangrelor: a novel intravenous antiplatelet agent with a questionable future. Pharmacotherapy. 2014;34:1061-1076. doi: 10.1002/phar.1471.
147. Serebruany VL, Pokov AN, Fortmann SD, DiNicolantonio JJ. Disbalance between mortality and non-fatal vascular events in the CHAMPIONPHOENIX trial: the cangrelor efficacy challenge. Thromb Haemost. 2014;111:3-7. doi: 10.1160/TH13-08-0631.
148. Serebruany VL, Aradi D, Kim MH, Sibbing D. Cangrelor infusion is associated with an increased risk for bleeding: meta-analysis of randomized trials. Int J Cardiol. 2013;169:225-228. doi: 10.1016/j. ijcard.2013.08.133.