COMMENTARIES

Platelet Hyperactivity: An Unrecognized Vascular Risk Factor in Patients with Metabolic Syndrome

Victor Serebruany, M.D., Ph.D., HeartDrugTM Research LLC,
Johns Hopkins University Baltimore,
Maryland,
USA
Please address correspondence to:
Dr. Victor L. Serebruany
HeartDrugTM Research Laboratories
Osler Medical Center
7600 Osler Drive, Ste.307
Towson, MD, 21204, USA
E-mail: Heartdrug@aol.com

Serebruany

Vascular occlusive events, dependent on the location of the targeted vessel, including myocardial infarction, unstable angina, stroke, and peripheral vascular diseases, are the leading causes of death in developed countries. Coronary atherosclerosis is responsible for nearly 40% of all deaths in the U.S.A. [1], and nearly half of the mortality in the European Union [2]. The World Health Organization estimates that close to 17 million patients die around the globe each year of vascular disease and, by 2020, this number is projected to grow to 25 million annually [3]. In terms of years lost, vascular death will rise from fourth to first, while as a cause of premature death and disability, from fifth to first, thus becoming the leading cause of death in the world by 2020 [4]. As the cornerstone to the clinical complications of atherothrombosis, blood platelets are unquestionably involved in the pathophysiology of the thrombotic events [5,6]. This concept has been proven by the numerous large clinical trials of antiplatelet therapy that demonstrate significant benefit of moderate platelet inhibition with various pharmacological agents including aspirin [7], ticlopidine [8], or clopidogrel [9].

          The metabolic syndrome represents a constellation of risk factors caused by insulin resistance, dyslipidemia, hypertension, and obesity, resulting in elevated risk for vascular occlusion. There are numerous reports suggesting that the existence of the metabolic syndrome worsens cardiovascular [10] and cerebrovascular [11] outcomes. On the other hand, patients with the metabolic syndrome are known to exhibit higher platelet activity [12,13] which may provide a pathophysiological link between platelets and adverse thrombotic occlusive events. Importantly, the association between the metabolic syndrome and activated platelets is not unique; other established risk factors of atherothrombosis not directly affiliated with the metabolic syndrome such as smoking [14], and family history [15] cause platelet activation as well. How much burden each risk factor holds for platelet activation is entirely unknown, including those which constitute the metabolic syndrome state. However, these data potentially may be important in helping predict future thrombotic risks, but mostly in justifying the early initiation of antiplatelet strategies preventing vascular events.

          We recently showed that patients with the metabolic syndrome exhibited higher platelet activity when compared with subjects with multiple contemporary risk factors for vascular disease [16], despite the fact that most platelet biomarkers including similar aggregation responses did not differ substantially between study groups. Analyzer readings, and especially up-regulation of key surface receptors, provide strong evidence that the metabolic challenge holds higher thrombotic risks than conventional risk factors for cardiovascular disease and ischemic stroke.

          Although the precise role of lipid abnormalities in patients with the metabolic syndrome is not yet clarified, the association between platelet activation and the metabolic syndrome is not entirely new. In fact, every risk factor and/or clinical symptom affiliated with the metabolic syndrome such as insulin resistance [17], vascular inflammation [18], dyslipidemia [19], hypertension [20], and obesity [21] may per se cause platelet activation, and, therefore, potentially increase thrombotic risks. As a combination of the above-mentioned features, the metabolic syndrome obviously represents the high risk thrombophilic state due to the activation of primary platelet hemostasis [12,13], hypercoagulation [22], and impaired fibrinolysis [23]. The clinical utility of these findings is far from being conclusive, but the index results justify further prospective studies with mild antiplatelet strategies in patients with metabolic syndrome. Finally, activation of G-coupled protease-activated receptor (PAR) thrombin receptor in patients with the metabolic syndrome observed in the index study, and the ability of statins to downregulate this receptor [24] in a similar cohort strongly suggests that not only platelets, but also excessive thrombin formation participates in the progression of metabolic syndrome. This particular observation may also help to introduce the novel PAR-1 antagonists, which are presently in late clinical development.

          Our data are also important for better understanding that the metabolic syndrome is a preexisting condition for the future transformation into type 2 diabetes mellitus. Similar platelet characteristics indirectly support this hypothesis providing the potential early treatment opportunity to delay if not eliminate such harmful transformation of the metabolic challenge.

          In conclusion, patients with the metabolic syndrome exhibited a higher degree of platelet activation than subjects with conventional risk factors for vascular disease. Therefore, applying moderate antiplatelet strategies for the risk reduction of vascular thrombotic events in such patients in future prospective studies is well justified.

References

  1.    American Heart Association. Heart Disease and Stroke Statistics - 2003 Update. American Heart Association, Dallas, Texas 2002.
  2.    European Cardiovascular Disease Statistics, 2000 Edition, British Heart Foundation. 2000.
  3.    Chockalingam A, Balaguer-Vintro I. Impending global pandemic of cardiovascular diseases. Prous Science: Barcelona, Spain, 1999.
  4.    Hennekens CH. Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation 1998;97:1095-102.
  5.    Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary disease and the acute coronary syndromes. N Engl J Med 1992;326(4):242-50.
  6.    Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986;315(16):983-89.
  7.    ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2(8609):349-60.
  8.    Hass WK, Easton JD, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989;321(8):501-7.
  9.    CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996;348(9038):1329-39.
  10.    Shaw LJ, Berman DS, Hendel RC, et al Cardiovascular disease risk stratification with stress single-photon emission computed tomography technetium-99m tetrofosmin imaging in patients with the metabolic syndrome and diabetes mellitus. Am J Cardiol 2006;97:1538-44.
  11.    Ovbiagele B, Saver JL, Lynn MJ, Chimowitz M; WASID Study Group. Impact of metabolic syndrome on prognosis of symptomatic intracranial atherostenosis. Neurology 2006;66:1344-49.
  12.    Anfossi G, Russo I, Massucco P, et al. Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity. Eur J Clin Invest 2004;34:482-89.
  13.    Arteaga RB, Chirinos JA, Soriano AO, et al. Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am J Cardiol 2006;98:70-74.
  14.    Morita H, Ikeda H, Haramaki N, Eguchi H, Imaizumi T. Only two-week smoking cessation improves platelet aggregability and intraplatelet redox imbalance of long-term smokers. J Am Coll Cardiol 2005;45:589-94.
  15.    Lilienberg G, Venge P. Platelet adhesion in patients prone to arterial and venous thrombosis: the impact of gender, smoking and heredity. Scand J Clin Lab Invest 1998;58:279-86.
  16.    Serebruany V, Malinin A, Ong S, Atar D. Patients with metabolic syndrome exhibit higher platelet activity than those with conventional risk factors for vascular disease. J Thromb Thrombolys 2007; May [Epub ahead of print].
  17.    Anfossi G, Russo I, Massucco P, Mattiello L, Trovati M. Platelet resistance to the antiaggregating effect of N-acetyl-L-cysteine in obese, insulin-resistant subjects. Thromb Res 2003;110:39-46.
  18.    Esposito K, Marfella R, Ciotola M, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004; 292:1440-46.
  19.    Arruzazabala ML, Molina V, Mas R, et al. Antiplatelet effects of policosanol (20 and 40 mg/day) in healthy volunteers and dyslipidaemic patients. Clin Exp Pharmacol Physiol 2002;29:891-97.
  20.    Serebruany VL, Pokov AN, Malinin AI, et al. Valsartan inhibits platelet activity at different doses in mild to moderate hypertensives: Valsartan Inhibits Platelets (VIP) trial. Am Heart J 2006;151:92-99.
  21.    Jesri A, Okonofua EC, Egan BM. Platelet and white blood cell counts are elevated in patients with the metabolic syndrome. J Clin Hypertens 2005;7:705-11.
  22.    Nieuwdorp M, Stroes ES, Meijers JC, Buller H. Hypercoagulability in the metabolic syndrome. Curr Opin Pharmacol 2005;5:155-59.
  23.    Trost S, Pratley R, Sobel B. Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes. Curr Diab Rep 2006;6:47-54.
  24.    Serebruany VL, Miller M, Pokov AN, et al. Statins inhibit platelet PAR-1 thrombin receptor in patients with metabolic syndrome: The PAR-1 Inhibition by Statins (PARIS) Study. Am J Cardiol 2006;97:1332-36.

 

 

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