Download PDF
Thromb Haemost 2011; 106(03): 491-499
DOI: 10.1160/TH11-04-0216
Platelets and Blood Cells
Schattauer GmbH

Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications

Galia Spectre
1   Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden
3   Department of Hematology, Coagulation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
,
Lisa Arnetz
2   Department of Molecular Medicine and Surgery, Endocrinology & Diabetology Unit, Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden
,
Claes-Göran Östenson
2   Department of Molecular Medicine and Surgery, Endocrinology & Diabetology Unit, Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden
,
Kerstin Brismar
2   Department of Molecular Medicine and Surgery, Endocrinology & Diabetology Unit, Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden
,
Nailin Li
1   Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden
,
Paul Hjemdahl
1   Department of Medicine Solna, Clinical Pharmacology Unit, Karolinska Institutet, Karolinska University Hospital (Solna), Stockholm, Sweden
› Author Affiliations Financial support: The study was supported by grants from the Swedish Research Council/Medicine (5930), the Swedish Heart Lung Foundation, the Erling-Persson Foundation, Karolinska Institutet, and the Stockholm County Council.
Further Information

Publication History

Received: 06 April 2011

Accepted after major revision: 17 June 2011

Publication Date:
24 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

The efficacy of low-dose aspirin in type 2 diabetes mellitus (T2DM) has been questioned. We tested if twice daily dosing of aspirin would be more effective in T2DM, possibly due to increased platelet turnover. A randomised cross-over study compared 75 mg aspirin OD, 75 mg BID and 320 mg OD (≥2 week treatment periods) in 25 patients with T2DM and micro- or macrovascular complications. Platelet responses were examined by impedance aggregometry (WBA) and the IMPACT-R aspirin test in whole blood, light transmittance aggregometry in plateletrich plasma (LTA), and urinary 11-dehydro-thromboxane B2 (TxM). Aspirin 75 mg BID decreased arachidonic acid (AA)-induced WBA compared to 75 mg OD (9.7 ± 4.5 vs. 12.6 ± 3.5 ohm; p=0.003) or to 320 mg OD (11.5 ± 4.2 Ohms; p=0.049). WBA responses to collagen were similarly attenuated by BID or high dosing (by 12–14%; p=0.02 for both). The IMPACT-R showed a better response to 75 mg BID compared to 75 mg OD (p=0.049), but not to 320 mg OD. AA-induced aggregation by LTA was <6.5% on all occasions, with no differences between aspirin dosages. TxM was reduced after 320 mg OD (p=0.002), but not 75 mg BID (p=0.07). Reticulated platelets were highly correlated with mean platelet volume (MPV; r2=0.74, p<0.0001). Both markers for platelet turnover were correlated with AA-induced WBA, but neither identified patients who benefited from BID dosing dependably. In conclusion, twice daily dosing improved laboratory responses to aspirin in high risk T2DM patients. Studies of whether BID dosing of aspirin can improve clinical outcomes in such patients are of interest.

Keywords

Acetylsalicylic acid - aspirin - diabetes mellitus - dosing - platelet function
 

  • References

  • 1 Anti-thrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
    CrossrefPubMedSearch in Google Scholar
  • 2 Baigent C, Blackwell L, Collins R. et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849-1860.
    CrossrefPubMedSearch in Google Scholar
  • 3 Pignone M, Alberts MJ, Colwell JA. et al. Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes. A Position Statement of the American Diabetes Association, a Scientific Statement of the American Heart Association, and an Expert Consensus Document of the American College of Cardiology Foundation. Circulation 2010; 121: 2694-2701.
    CrossrefPubMedSearch in Google Scholar
  • 4 Awtry AH, Loscalzo J. Aspirin. Circulation 2000; 101: 1206-1218.
    CrossrefPubMedSearch in Google Scholar
  • 5 Roth G, Hirsh J, Baigent C. et al. Antiplatelet drugs. American College of Chest Physicians (8th Ed. Physicians Evidence Based Practice Guidelines) Chest 2008: S199-S233.
    PubMed
  • 6 Reilly IAG, FitzGerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 1987; 69: 180-186.
    PubMedSearch in Google Scholar
  • 7 Perneby C, Wallén NH, Rooney C. et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658.
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 DiMinno G, Silver MJ, Cerbone AM, Murphy S. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood 1986; 68: 886-891.
    PubMedSearch in Google Scholar
  • 9 Guthikonda S, Lev EI, Patel R. et al. Reticulated platelets and unhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007; 5: 490-496.
    CrossrefPubMedSearch in Google Scholar
  • 10 Cesari F, Marcucci R, Caporale R. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99: 930-935.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Bath PMW, Butterworth RJ. Platelet size: measurement, physiology and vascular disease. Blood Coag Fibrinol 1996; 7: 157-161.
    CrossrefPubMedSearch in Google Scholar
  • 12 Shenkman B, Einav Y, Salomon O. et al. Testing agonist-induced platelet aggregation by the Impact-R [Cone and plate(let) analyzer (CPA)]. Platelets 2008; 19: 440-446.
    CrossrefPubMedSearch in Google Scholar
  • 13 Spectre G, Brill A, Gural A. et al. A new point-of-care method for monitoring antiplatelet therapy: application of the cone and plate(let) analyzer. Platelets 2005; 16: 293-299.
    CrossrefPubMedSearch in Google Scholar
  • 14 Wallén NH, Held C, Rehnqvist N, Hjemdahl P. Impact of treatment with acetylsalicylic acid on the proaggregatory effects of adrenaline in vitro in patients with stable angina pectoris: influence of the anticoagulant. Clin Sci (Lond.) 1993; 85: 577-583.
    CrossrefPubMedSearch in Google Scholar
  • 15 Perneby C, Granström E, Beck O. et al. Optimization of an enzyme immunoassay for 11-dehydro-thromboxane B2 in urine: comparison with GC-MS. Thromb Res 1999; 96: 427-436.
    CrossrefPubMedSearch in Google Scholar
  • 16 Ertugrul DT, Tutal E, Yildiz M. et al. Aspirin resistance is associated with glycemic control, the dose of aspirin, and obesity in type 2 diabetes mellitus. J Clin Endocrinol Metab 2010; 95: 2897-2901.
    CrossrefPubMedSearch in Google Scholar
  • 17 Santilli F, Rocca B, De Cristofaro R. et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin „resistance“. J Am Coll Cardiol 2009; 53: 667-677.
    CrossrefPubMedSearch in Google Scholar
  • 18 DiChiara J, Bliden KP, Tantry US. et al. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients; an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes 2007; 56: 3014-3019.
    CrossrefPubMedSearch in Google Scholar
  • 19 Li N, Hu H, Lindqvist M. et al. Platelet-leukocyte crosstalk in whole blood. Arterioscl Thromb Vasc Biol 2000; 20: 2702-2708.
    CrossrefPubMedSearch in Google Scholar
  • 20 Hu H, Li N, Yngen M, Östensson C-G. et al. Enhanced leukocyte-platelet crosstalk in type 1 diabetes mellitus: relationship to microangiopathy. J Thromb Haemost 2004; 2: 58-64.
    CrossrefPubMedSearch in Google Scholar
  • 21 Sala A, Folco G, Murphy RC. Transcellular biosynthesis of eicosanoids. Pharmacol Rep 2010; 62: 503-510.
    CrossrefPubMedSearch in Google Scholar
  • 22 Maclouf JA, Murphy RC. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4. J Biol Chem 1988; 263: 174-181.
    PubMedSearch in Google Scholar
  • 23 Rocca B, Secchiero P, Ciabattoni G. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
    CrossrefPubMedSearch in Google Scholar
  • 24 Santos MT, Valles J, Lago A. et al. Residual platelet thromboxane A2 and prothrombotic effects of erythrocytes are important determinants of aspirin resistance in patients with vascular disease. J Thromb Haemost 2008; 6: 615-621.
    CrossrefPubMedSearch in Google Scholar
  • 25 Eikelboom JW, Hankey GJ, Thom J. et al. Incomplete inhibition of thromboxane biosynthesis by aspirin – determinants and effect on cardiovascular risk. Circulation 2008; 118: 1705-1712.
    CrossrefPubMedSearch in Google Scholar
  • 26 Hjemdahl P. Aspirin resistance testing not ready for “prime time“. Heart 2009; 95: 1220-1222.
    CrossrefPubMedSearch in Google Scholar
  • 27 Henry P, Vermillet A, Boval B. et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2011; 105: 336-344.
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance“ and the risk of cardiovascular morbidity: systematic review and meta-analysis. Br Med J 2008; 336: 195-198.
    CrossrefPubMedSearch in Google Scholar
  • 29 Frelinger AL, 3rd Li Y, Linden MD. et al. Association of cyclooxygenase-1 -dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation 2009; 120: 2586-2596.
    CrossrefPubMedSearch in Google Scholar
  • 30 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
    CrossrefPubMedSearch in Google Scholar
  • 31 Würtz M, Grove EL, Wulff LN. et al. Patients with previous definite stent thrombosis have a reduced antiplatelet effect of aspirin and a larger fraction of immature platelets. J Am Coll Cardiol: Cardiovasc Intervent 2010; 3: 828-835.
    PubMedSearch in Google Scholar
  • 32 Lordkipanidzé M. Why an aspirin a day no longer keeps the doctor away. Thromb Haemost 2011; 105: 209-210.
    Thieme ConnectPubMedSearch in Google Scholar