This Article Free upon publication Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by FitzGerald, G. A. PubMed PubMed Citation Articles by FitzGerald, G. A.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:s51.)
© 2008 American Heart Association, Inc.

Translational Therapeutics at the Platelet Vascular Interface: A CME-Certified Activity

Summary

Garret A. FitzGerald

From the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia.

Correspondence to G.A. FitzGerald, 153 Johnson Pavilion, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. E-mail garret{at}spirit.gcrc.upenn.edu

This article is part of a multi-part CME-certified activity titled Translational Therapeutics at the Platelet Vascular Interface. In order to achieve all of the activity’s learning objectives, please read all of the components of the activity listed in the Table of Contents and follow the "Instructions for Participation and Obtaining CME Credit" outlined prior to the Introduction.

This meeting illustrates the power of an integrated translational approach to interrogation of the platelet-vascular interface. Increasingly, the technologies and investigations of drug response in cells, model systems, and humans, described by distinct investigators at this meeting, will be integrated by single research groups. We are only beginning to understand that manipulations of a single signaling pathway in a cell may perturb a complex and interdependent system of informational processing. Already, such biological systems paradigms are being exploited in the process of drug discovery. Perhaps it is time for a public-private partnership to accelerate the population of such physiological networks and improve our understanding of how they are disrupted in disease. Presently, such efforts are pursued in relative isolation within companies and academic groupings. However, an expansion of the "precompetitive space" to include the elaboration of networks, leaving the selection of "hubs" and the attendant targeted chemistry protected as intellectual property, would set the stage for the era of systems physiology and pharmacology. Such an informational substrate would build on the achievements of prior public-private genomics and proteomics consortia and contribute ultimately to the personalization or stratification of medicine.

Drug therapy at the platelet-vascular interface illustrates quite nicely why we need to progress beyond our present approach to drug development. We have, for the past 30 years, ranged among platelet proteins and up and down the coagulation cascade in search of therapeutic targets that segregate antithrombotic benefit from bleeding risk. We have sought, in vain, incremental benefit devoid of therapeutic price. There have been many false dawns.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study¹ illustrated the incremental benefit of adding clopidogrel to aspirin in the secondary prevention of myocardial infarction. However, minor hemorrhages, termed "nuisance" bleeds, complicated therapy in approximately a third of the patients on both drugs. Although bleeding gums, nose bleeds, or excessive bleeding after shaving may not be life-threatening in themselves, they may well impact on drug compliance in the setting of secondary prevention, when the patient is not alarmed by the acuity of a clinical indication for adherence to drug therapy. Indeed, the Management of Artherothrombosis with Clopidogrel in High-risk Patients (MATCH) study went one step further down this path; it found an increase in major cerebral bleeds, but no incremental benefit from adding clopidogrel to aspirin in patients with a recent ischemic stroke or transient ischemic attack.² The limitations of this conventional thinking are illustrated further by the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON), described in the article by Michelson.³ Here, a study of roughly 30 000 patients was performed to discover that harmonization of drug response with the alternative P2Y12 antagonist prasugrel afforded a more clearly defined signal of benefit but also of risk when compared with clopidogrel. Dipyridamole was marketed for many years without convincing evidence of its bioavailability, never mind clinical efficacy.⁴ It was then reformulated to address the pharmacokinetic limitations of the original preparation and its efficacy demonstrated in the secondary prevention of stroke in the European Stroke Prevention Study (ESPS)-2. Interestingly, it was the quite distinct adverse event profiles of aspirin and dipyridamole in ESPS-2⁵ that pointed to the vasculature rather than the platelet as a major site of action of the latter drug, as described in the article by Liao.

All of these studies look for large, average effects of benefit and risk. However, it remains to be determined how closely benefit and risk relate to each other at the individual level. What are the factors that modulate an individual’s relationship between the administered dose of a drug, antithrombotic effect, and bleeding risk?

To address such questions, we need to determine the factors that govern drug exposure, relating this to sensitive and specific quantitative indices of drug response at an individual level. Such information is unlikely to be derived through analysis of DNA collected from participants in large trials designed for other purposes, but rather through an understanding of the complexities of drug response from cells and model systems, the development of appropriate mechanism-based and unbiased analysis of drug response, and their projection across the translational divide to detailed phenotyping studies in humans. Only then can we design a priori cogent clinical trials progressively to personalize our use of therapeutics.

Such an approach may have little appeal to companies operating under the exigencies of the present business model of drug development. However, they have a natural appeal in the academic setting, particularly as academia augments its workforce skilled in interdisciplinary approaches to translational medicine and therapeutics. The contributions of academia to drug development (as opposed to discovery) have waned. However, a note of hope for the future of translational therapeutics at the platelet-vascular interface is afforded by the story of low-dose aspirin—perhaps the most cost-effective drug treatment available to humankind.

Although aspirin was synthesized first at Bayer, the work of Vane and colleagues that revealed cyclooxygenase (COX) as its principle target was initiated at the Royal College of Surgeons in London⁶; the predominant product of platelet COX, thromboxane (Tx)A₂, was identified by Samuellsson at Karolinska⁷; platelet inhibition by aspirin was described first by Weiss, O’Brien, and Born at Cornell, Southampton, and King’s College, respectively,^8–10 whereas irreversible acetylation of platelet COX by aspirin was characterized by Roth and Majerus at Washington University.¹¹ The clinical pharmacology of low-dose aspirin—the dose-dependent inhibition of Tx and prostacyclin,^12,13 its action on platelets in the presystemic circulation,^14,15 its interaction with nonsteroidal antiinflammatory drugs,^16,17 and the identification of clinical settings for the first trials that revealed its efficacy^18,19—derived from work performed by Patrignani and Patrono in Rome and Chieti, and by our group, both at Vanderbilt and Penn. Finally, the randomized trials that established its efficacy were designed and executed by Lewis at the University of Kansas, Collins and Peto in Oxford, and Hennekens at Harvard.^20–22

This example, from an era that long predated the training and infrastructural opportunities fostered by Clinical and Translational Science Awards and other such initiatives,²³ should encourage a renewed engagement of academic institutions in the development of therapeutic modalities that benefit the public health.

"I will prepare and some day my chance will come."

— Abraham Lincoln.

Sources of Funding

Dr FitzGerald is the McNeill Professor of Translational Medicine and Therapeutics. His work is supported by grants RR023567, HL81012, HL083799, HL54500, and HL-053558 from the National Institutes of Health.

Disclosures

During the past year Dr FitzGerald has consulted for AstraZeneca, Daiichi, Merck, Nicox, Novartis, and Wyeth and received grant support for investigator-initiated research from Boehringer Ingelheim, Merck, and Bayer.

References

1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: 494–502.[Abstract/Free Full Text]
2. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004; 364: 331–337.[CrossRef][Medline] [Order article via Infotrieve]
3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann F-J, 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.[Abstract/Free Full Text]
4. FitzGerald GA. Dipyridamole. N Engl J Med. 1987; 316: 1247–1257.[Medline] [Order article via Infotrieve]
5. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143: 1–13.[CrossRef][Medline] [Order article via Infotrieve]
6. Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin abolish prostaglandin (PG) release from the spleen. Nat New Biol. 1971; 231: 237–239.[CrossRef][Medline] [Order article via Infotrieve]
7. Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from PG endoperoxides. Proc Natl Acad Sci U S A. 1975; 72: 2994–2998.[Abstract/Free Full Text]
8. Weiss HJ, Aledort LM. Impaired platelet-connective-tissue reaction in man after aspirin ingestion. Lancet. 1967; 2: 495–497.[CrossRef][Medline] [Order article via Infotrieve]
9. O’Brien JR. Effects of salicylates on human platelets. Lancet. 1968; 1: 779–783.[Medline] [Order article via Infotrieve]
10. Begent NA, Born GVR. Comparison of the effects of drugs on the aggregation of hamster platelets in vivo and in vitro. Br J Pharmacol. 1971; 43: 580–592.[Medline] [Order article via Infotrieve]
11. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J Clin Invest. 1975; 56: 624–632.[Medline] [Order article via Infotrieve]
12. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982; 69: 1366–1372.[Medline] [Order article via Infotrieve]
13. FitzGerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJ II, Lawson JA, Brash AR. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983; 71: 676–688.[Medline] [Order article via Infotrieve]
14. Pedersen AK, FitzGerald GA. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med. 1984; 311: 1206–1211.[Abstract]
15. Clarke RJ, Mayo G, Price P, FitzGerald GA. Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N Engl J Med. 1991; 325: 1137–1141.[Abstract]
16. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001; 345: 1809–1817.[Abstract/Free Full Text]
17. Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Merciaro G, Patrignani P. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol. 2005; 45: 1295–1301.[Abstract/Free Full Text]
18. Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med. 1986; 315: 983–989.[Abstract]
19. Fitzgerald DJ, Catella F, Roy L, FitzGerald GA. Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction. Circulation. 1988; 77: 142–150.[Medline] [Order article via Infotrieve]
20. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983; 309: 396–403.[Abstract]
21. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988; 2: 349–360.[Medline] [Order article via Infotrieve]
22. Manson JE, Tosteson H, Ridker PM, Satterfield S, Hebert P, O’Connor GT, Buring JE, Hennekens CH. The primary prevention of myocardial infarction. N Engl J Med. 1992; 326: 1406–1416.[Medline] [Order article via Infotrieve]
23. Science Careers. Science. 2007; 317: 968–969.

This Article Free upon publication Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by FitzGerald, G. A. PubMed PubMed Citation Articles by FitzGerald, G. A.