Increased shear stress overcomes the antithrombotic platelet inhibitory effect of aspirin in stenosed dog coronary arteries.

BACKGROUND Shear stress is one of the known platelet activating mechanisms that leads to thrombosis. Increased shear stress has also been postulated to reverse the antithrombotic effect of some drugs such as aspirin (ASA). METHODS AND RESULTS Experiments were conducted in five dogs to determine the minimal shear stress levels that produce acute platelet thrombus formation in mechanically stenosed arteries and the increase in shear required to reverse the antithrombotic effect of ASA. After intimal and medial damage, stenosis was produced in the circumflex coronary artery. We used the finite-difference numerical solution of the Navier-Stokes equation to determine the wall shear stresses in the area of stenosis. At 70+/-6% coronary diameter reduction, cyclic flow reductions (CFRs) caused by acute platelet thrombus formation were observed in the stenosed lumen. At this level of stenosis, the shear stress was 144+/-15 Pa. ASA given at a dose of 5 mg/kg IV inhibited in vivo acute platelet-mediated thrombus formation and abolished CFRs in all dogs. However, increasing the stenosis level to 80+/-5% caused the CFRs to return. The shear stress increased with the increased level of stenosis to 226+/-22 Pa. Thus, an average 10% increase in diameter narrowing caused a 56+/-20% increase in shear stress (P<.005) and renewed platelet activation and thrombus formation despite ASA pretreatment. CONCLUSIONS Individuals who take ASA daily to prevent coronary artery thrombus formation may not be well protected when a change in hemodynamics, such as an acute hypertensive episode, or an increase in stenosis severity due a ruptured atherosclerotic plaque causes an increase in shear stress.

[1]  C. Patrono Aspirin as an antiplatelet drug. , 1994, The New England journal of medicine.

[2]  J. Moake,et al.  Shear stress-induced von Willebrand factor binding to platelet glycoprotein Ib initiates calcium influx associated with aggregation. , 1992, Blood.

[3]  V. Fuster,et al.  The pathogenesis of coronary artery disease and the acute coronary syndromes (2). , 1992, The New England journal of medicine.

[4]  J. Folts An in vivo model of experimental arterial stenosis, intimal damage, and periodic thrombosis. , 1991, Circulation.

[5]  M. Noble,et al.  Inhibition of acute platelet thrombosis formation in stenosed canine coronary arteries by specific serotonin 5HT2 receptor antagonist ritanserin. , 1990, Cardiovascular research.

[6]  J. O'brien,et al.  Shear-induced platelet aggregation , 1990, The Lancet.

[7]  R. Jordan,et al.  Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. Correlation with bleeding time, platelet aggregation, and blockade of GPIIb/IIIa receptors. , 1989, Circulation.

[8]  J. Eidt,et al.  Specific Platelet Mediators and Unstable Coronary Artery Lesions: Experimental Evidence and Potential Clinical Implications , 1989, Circulation.

[9]  D. Weber Absolute diameter measurements of coronary arteries based on the first zero crossing of the Fourier spectrum. , 1989, Medical physics.

[10]  J. O'brien,et al.  Shear stress activation of platelet glycoprotein IIb/IIIa plus von Willebrand factor causes aggregation: filter blockage and the long bleeding time in von Willebrand's disease , 1987 .

[11]  W. Campbell,et al.  Cooperative mediation by serotonin S2 and thromboxane A2/prostaglandin H2 receptor activation of cyclic flow variations in dogs with severe coronary artery stenoses. , 1987, Circulation.

[12]  B. Coller,et al.  Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model. , 1986, Blood.

[13]  H. Goldsmith,et al.  Rheological Aspects of Thrombosis and Haemostasis: Basic Principles and Applications , 1986, Thrombosis and Haemostasis.

[14]  C. Benedict,et al.  Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries. , 1986, Circulation.

[15]  W. Campbell,et al.  Effects of the selective thromboxane synthetase inhibitor dazoxiben on variations in cyclic blood flow in stenosed canine coronary arteries. , 1984, Circulation.

[16]  O. V. Miller,et al.  Endogenous prostacyclin contributes to the efficacy of a thromboxane synthetase inhibitor for preventing coronary artery thrombosis. , 1981, The Journal of pharmacology and experimental therapeutics.

[17]  L. Hillis,et al.  Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease. , 1981, The New England journal of medicine.

[18]  J. Joist,et al.  Role of platelet-prostaglandin synthesis in shear-induced platelet alterations. , 1980, Blood.

[19]  M. Davies,et al.  The relation of coronary thrombosis to ischaemic myocardial necrosis , 1979, The Journal of pathology.

[20]  D. E. Gregg,et al.  Regression and reappearance of coronary collaterals. , 1971, The American journal of physiology.

[21]  M. Rosolowsky,et al.  ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endothelium-injured canine coronary arteries. , 1992, Circulation research.

[22]  J. Folts A model of experimental arterial platelet thrombosis, platelet inhibitors, and their possible clinical relevance : an update , 1990 .

[23]  E. Haber,et al.  The heart and cardiovascular system , 1986 .

[24]  D. Bergel Cardiovascular fluid dynamics , 1972 .