EDITORIAL COMMENT
What Makes Platelets AngryDiabetes, Fibrinogen, Obesity, and Impaired Response to Antiplatelet Therapy?*
Deepak L. Bhatt, MD, FACC*
Veterans' Affairs Boston Healthcare System and Brigham and Women's Hospital, Boston, Massachusetts
* Reprint requests and correspondence: Dr. Deepak L. Bhatt, VA Boston Healthcare System and Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115 (Email: DLBHATTMD{at}ALUM.MIT.EDU).
Key Words: diabetes • platelets
Variability of platelet response to drug therapy has been studied intensely in recent years, though the underlying causes and appropriate actions remain unclear (1,2). It appears that both patient-specific and medication-specific factors contribute to the variability of platelet activity and response. Clopidogrel and its conversion to an active metabolite appear to follow a Gaussian distribution—the classic bell-shaped curve—in which most patients respond just fine, but at either extreme there may be patients who are hypo- or hyper-responders (3). In theory, such outliers may be prone to ischemic or bleeding complications and, therefore, identification of these patients has been thought to carry potential clinical utility (4). Superimposed on variability due to drug metabolism is the variation in platelet activity that may occur in clinical situations such as acute coronary syndromes or other states that may cause heightened platelet activity. Low levels of platelet inhibition after antiplatelet therapy have been repeatedly associated with an elevated risk of ischemic events, both with glycoprotein IIb/IIIa inhibitors as well as with clopidogrel (5,6). Whether persistent platelet activation represents failure of the drug or simply the underlying risk substrate remains uncertain.
In this issue of the Journal, Ang et al. (7) provide great insight into determinants of variability in platelet response to clopidogrel. Using a point-of-care measure of platelet inhibition to clopidogrel, they confirm the usual distribution of clopidogrel response variability in 157 patients with cardiovascular disease. Using multivariable analysis, they find that diabetes mellitus, elevated fibrinogen levels, and obesity are all associated with diminished platelet inhibition. Interestingly, there is a significant interaction between diabetic status and fibrinogen, such that elevated fibrinogen is predictive of lower platelet inhibition only in patients with diabetes, but not in those without diabetes. Therefore, it appeared that the impaired response of the diabetic platelet was, in part, mediated by (or at least associated with) elevated fibrinogen levels. Conversely, fibrinogen elevation in a nondiabetic milieu did not affect the platelet response. Higher body mass index remained associated with impaired platelet inhibition irrespective of fibrinogen levels.
A large body of evidence supports the contention that diabetic patients have "angrier" platelets. While the etiology of their increased platelet activation is multifactorial, the consequences are higher rates of ischemic complications in those with diabetes mellitus. More potent antiplatelet therapy appears to have a greater clinical benefit in diabetic patients versus nondiabetic patients. This has been noted with both intravenous glycoprotein IIb/IIIa inhibitors and adenosine diphosphate receptor blockade (8–10). High platelet reactivity in diabetic patients has been linked with a greater risk of adverse outcomes (11). Potentially, increased doses of clopidogrel, more potent agents such as prasugrel, or novel agents in development may be of incremental benefit (10,12,13).
Future studies will need to confirm whether fibrinogen is indeed a marker of impaired response to antiplatelet therapy in diabetic patients. If so, measurement of fibrinogen levels in diabetic patients could help guide the intensity of the antiplatelet regimen utilized. Also, if the interaction between elevated fibrinogen, diabetes, and impaired platelet response is confirmed in other studies, this might explain why some papers have reported an association between fibrinogen and cardiovascular risk, while others have not (14).
The relationship between obesity and impaired response to antiplatelet therapy is also complex. On one level, it could simply be an issue of underdosing of drugs. On another level, it could be the inflammatory state of obesity leading to platelet activation (15). Adipose cells produce leptin, whose receptor has been identified on platelets. Endocannabinoids also play a role in regulation of obesity and have been demonstrated to activate platelets. Thus, through these and other pathways, obesity could lead to increased platelet activation and consequent impaired response to antiplatelet treatment. Preliminary evidence already supports an association between elevated body mass index and diminished response to antiplatelet therapy (16).
Additionally, there is abundant evidence that low body mass index predisposes to bleeding complications associated with antiplatelet drugs (10,17). Again, this may relate either to relative overdosing of antithrombotic medications or to lower levels of baseline platelet activation in a lean patient (18). The study by Ang et al. (7) adds further evidence that perhaps oral antiplatelet drugs should be dosed based on weight. In the future, clinical trials will need to determine if weight-based dosing of oral antiplatelet therapy might help balance efficacy and safety. The TRILOGY ACS (TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes) trial (19) is currently examining 2 different maintenance doses of prasugrel in patients depending on their weight and age.
While the relationships described by Ang et al. (7) are likely multifactorial and only now starting to be untangled, there is a tantalizing potential to minimize ischemic and bleeding complications by dosage modification guided by platelet response. This appealing theory is being tested in ongoing studies such as in the GRAVITAS (Gauging Responsiveness with A VerifyNow assay–Impact on Thrombosis And Safety) trial (20), which is measuring point-of-care antiplatelet response to clopidogrel and randomizing patients to different intensity of platelet inhibition with clopidogrel. If such clinical investigation supports therapeutic modification based on platelet response, then routine point-of-care platelet function testing may be warranted. Based on the observations of Ang et al. (7), adjustment of dosage by diabetic status and body mass index may be particularly useful in individualizing therapy. Furthermore, it would be a major contribution if future research corroborates that fibrinogen truly is the link that makes diabetic platelets angry.
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Footnotes
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Dr. Bhatt has received research grants (significant, directly to the institution) from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company; has received honoraria (donated to nonprofit organizations for >2 years) from AstraZeneca, Bristol-Myers Squibb, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix, PDL, Sanofi-Aventis, Schering-Plough, The Medicines Company, and TNS Healthcare; was on the Speakers' Bureau (>2 years ago) of Bristol-Myers Squibb, Sanofi-Aventis, and The Medicines Company; was on the consultant/advisory board (donated to nonprofit organizations for >2 years) of Astellas, AstraZeneca, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi-Aventis, Schering-Plough, Scios, Takeda, The Medicines Company, TNS Healthcare, and Vertex; and has provided expert testimony regarding clopidogrel (>2 years ago; the compensation was donated to a nonprofit organization).
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Bhatt DL. Aspirin resistance: more than just a laboratory curiosity J Am Coll Cardiol 2004;43:1127-1129.[Free Full Text]2. Wang TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel resistance: an emerging clinical entity Eur Heart J 2006;27:647-654.[Abstract/Free Full Text] 3. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals J Am Coll Cardiol 2005;45:246-251.[Abstract/Free Full Text] 4. Braunwald E, Angiolillo D, Bates E, et al. Assessing the current role of platelet function testing Clin Cardiol 2008;31:I10-I16.[Medline] 5. Steinhubl SR, Talley JD, Braden GA, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study Circulation 2001;103:2572-2578.[Abstract/Free Full Text] 6. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation Eur Heart J 2008;29:992-1000.[Abstract/Free Full Text] 7. Ang L, Palakodeti V, Khalid A, et al. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel J Am Coll Cardiol 2008;52:1052-1059.[Abstract/Free Full Text] 8. Bhatt DL, Marso SP, Lincoff AM, Wolski KE, Ellis SG, Topol EJ. Abciximab reduces mortality in diabetics following percutaneous coronary intervention J Am Coll Cardiol 2000;35:922-928.[Abstract/Free Full Text] 9. Bhatt DL, Marso S, Hirsch A, Ringleb P, Hacke W, Topol E. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus Am J Cardiol 2002;90:625-628.[CrossRef][Web of Science][Medline] 10. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2007;357:2001-2015.[Abstract/Free Full Text] 11. Angiolillo DJ, Bernardo E, Sabate M, et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease J Am Coll Cardiol 2007;50:1541-1547.[Abstract/Free Full Text] 12. Angiolillo DJ, Shoemaker SB, Desai B, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study Circulation 2007;115:708-716.[Abstract/Free Full Text] 13. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation Circ Res 2007;100:1261-1275.[Abstract/Free Full Text] 14. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies JAMA 1998;279:1477-1482.[Abstract/Free Full Text] 15. Mills R, Bhatt DL. The Yin and Yang of arterial inflammation J Am Coll Cardiol 2004;44:50-52.[Free Full Text] 16. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted? J Invasive Cardiol 2004;16:169-174.[Medline] 17. Bhatt DL. Intensifying platelet inhibition—navigating between Scylla and Charybdis N Engl J Med 2007;357:2078-2081.[Free Full Text] 18. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non–ST-segment elevation acute coronary syndromes JAMA 2005;294:3108-3116.[Abstract/Free Full Text] 19. A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects (TRILOGY ACS) http://www.clinicaltrials.gov/ct2/show/NCT00699998?term=NCT00699998&rank=1 2005Accessed August 6, 2008. 20. GRAVITAS: Gauging Responsiveness With a VerifyNow Assay–Impact On Thrombosis And Safety http://www.clinicaltrials.gov/ct2/show/NCT00645918?term=NCT00645918&rank=1 2005.
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