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A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials

John D. Folts, PhD, FACC^a, Andrew I. Schafer, MD^*, Joseph Loscalzo, MD, PhD, FACC, James T. Willerson, MD, FACC and James E. Muller, MD, FACC

^a Coronary Thrombosis Research Laboratory, University of Wisconsin Medical School, Madison, Wisconsin, USA
^* Baylor College of Medicine, Medical Service, Houston Veterans Affairs Medical Center, Houston, Texas, USA
Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA
Department of Internal Medicine, The University of Texas Medical School, Houston, Texas, USA
Division of Cardiology, University of Kentucky Medical Center, Lexington, Kentucky, USA

View larger version (36K): [in a new window]   Figure 1 Schematic diagram showing the different input stimuli on the left that can activate platelets in vivo. These stimuli act by signal transduction through receptors to ultimately increase the free cytosolic Ca2+ level in platelets. In the center are the calcium mobilization reactions that interact with the receptors and regulate cytosolic free Ca2+ ([Ca2+]i). Adenosine triphosphate (ATP) is converted to cyclic adenosine monophosphate (cAMP) by the enzyme adenylate cyclase (AC). cAMP is broken down to AMP by the enzyme phosphodiesterase. When cAMP is elevated, for example by prostacyclin (PGI2) binding to a specific receptor and stimulating adenylate cyclase (AC), some Ca2+ is stored in the dense tubules. This reduces cytosolic free Ca2+ and decreases the level of platelet activation. Another regulator of free cytosolic Ca2+ is cyclic GMP. Guanosine triphosphate (GTP) is converted to cGMP by guanylate cyclase (GC). cGMP is broken down by a phosphodiesterase to produce GMP. When cGMP is elevated by stimulation of GC by NO, free cytosolic Ca2+ is reduced by two mechanisms. Ca2+ is inhibited from entering the platelet from the plasma, and also Ca2+ is inhibited from leaving the dense tubules. This also reduces the available level of cytosolic Ca2+. Thus modulating free cytosolic Ca2+ can increase or decrease platelet activity. The final step in platelet-mediated thrombosis is the exposure/activation of the platelet glycoprotein IIb-IIIa fibrinogen receptor, which binds to fibrinogen to create a platelet aggregate.