title: Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects.
abstract: OBJECTIVE
  Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects.
  
  
  METHODS
  Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting.
  
  
  RESULTS
  In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance.
  
  
  CONCLUSIONS
  In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.
authors.affiliation: Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Floyd
authors.forename: Timothy
authors.initials: T
authors.lastname: Goodman
authors.forename: Silke
authors.initials: S
authors.lastname: Becker
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.forename: Agnesa
authors.initials: A
authors.lastname: Mustafa
authors.forename: Emma
authors.initials: E
authors.lastname: Schofield
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ward
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: Albert
authors.initials: A
authors.lastname: Ferro
mesh_terms: D000328:Adult; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D039661:Integrin beta3 / Q000096:biosynthesis*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine
chemical_list: D039661:Integrin beta3; D016718:Arachidonic Acid; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D001241:Aspirin
keywords: aspirin resistance; glycoprotein IIIa; platelets; proteomics
references.citation: Lancet. 1988 Aug 13;2(8607):349-60
references.pmid: 2899772
references.citation: Platelets. 2006 Dec;17(8):586-90
references.pmid: 17127487
references.citation: Eur Heart J. 2007 Jul;28(14):1702-8
references.pmid: 17569678
references.citation: Proteomics. 2010 Jan;10(1):38-47
references.pmid: 19882661
references.citation: Circulation. 1999 Feb 9;99(5):620-5
references.pmid: 9950658
references.citation: Am J Hypertens. 2006 Sep;19(9):970-7; discussion 978
references.pmid: 16942942
references.citation: Proc Natl Acad Sci U S A. 1975 Aug;72(8):3073-6
references.pmid: 810797
references.citation: Semin Thromb Hemost. 2008 Nov;34(8):709-33
references.pmid: 19214910
references.citation: Int J Clin Pract. 2007 May;61(5):826-34
references.pmid: 17391325
references.citation: Anal Chem. 2003 Apr 15;75(8):1895-904
references.pmid: 12713048
references.citation: Am J Med. 2014 Jan;127(1):95.e1-9
references.pmid: 24384107
references.citation: J Thromb Haemost. 2006 Feb;4(2):312-9
references.pmid: 16420557
references.citation: Circulation. 2007 Jun 26;115(25):3156-64
references.pmid: 17562955
references.citation: Am J Cardiol. 2001 Aug 1;88(3):230-5
references.pmid: 11472699
references.citation: BMJ. 1994 Jan 22;308(6923):235-46
references.pmid: 8054013
references.citation: J Proteome Res. 2007 Jul;6(7):2481-7
references.pmid: 17555340
references.citation: Proteomics. 2007 Oct;7(20):3651-60
references.pmid: 17880003
references.citation: J Proteome Res. 2010 May 7;9(5):2725-33
references.pmid: 20218731
references.citation: J Clin Invest. 1975 Sep;56(3):624-32
references.pmid: 1159076
references.citation: Circulation. 2003 Jun 3;107(21):2670-6
references.pmid: 12742982
references.citation: Am Heart J. 2007 Feb;153(2):175-81
references.pmid: 17239674
references.citation: Circulation. 2009 Dec 22;120(25):2586-96
references.pmid: 19996015
references.citation: Lancet. 2006 Feb 18;367(9510):606-17
references.pmid: 16488805
references.citation: J Am Coll Cardiol. 2003 Sep 17;42(6):1115-9
references.pmid: 13678940
references.citation: Semin Thromb Hemost. 1995;21 Suppl 2:113-21
references.pmid: 7660152
references.citation: Nature. 1962 Jun 9;194:927-9
references.pmid: 13871375
references.citation: Methods. 2011 Aug;54(4):361-9
references.pmid: 21397697
references.citation: Thromb Haemost. 2002 Nov;88(5):711-5
references.pmid: 12428082
references.citation: Mol Cell Proteomics. 2004 Dec;3(12):1154-69
references.pmid: 15385600
references.citation: BMJ. 2002 Jan 12;324(7329):71-86
references.pmid: 11786451
references.citation: Nat Rev Drug Discov. 2003 Jan;2(1):15-28
references.pmid: 12509756
references.citation: BMJ. 1994 Jan 15;308(6922):159-68
references.pmid: 8312766
references.citation: Am J Cardiol. 2006 Nov 20;98(10A):4N-10N
references.pmid: 17097417
references.citation: J Thromb Haemost. 2006 Apr;4(4):813-9
references.pmid: 16634751
references.citation: Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):1980-7
references.pmid: 15388526
references.citation: Thromb Res. 2007;119(2):209-16
references.pmid: 16473396
references.citation: Am J Med. 2005 Jul;118(7):723-7
references.pmid: 15989905