The scientific basis for combined platelet and thrombin-directed pharmacotherapy in acute coronary syndromes.
There exists incontrovertible scientific evidence that vascular endothelial cell dysfunction and atheromatous plaque disruption are causative pathobiologic events governing the clinical expression of disease in humans with coronary arteriosclerosis. A comprehensive understanding of vascular biology, platelet behavior, and coagulation protein bioamplification sequences forms the scientific basis for pharmacotherapy in acute coronary syndromes (ACS), and identifies the platelet as an attractive target. The three Food and Drug Administration-approved glycoprotein (GP) IIb/IIIa antagonists effectively prevent platelet aggregation. In vitro experiments also showed a dose-dependent decrease in prothrombinase activity and thrombin generation revealing that the GP IIb/IIIa antagonists possess anticoagulant properties as well. Combination pharmacotherapy in ACS is supported by the contribution of platelets and coagulation proteins to coronary artery thrombosis. While unfractionated heparin (UFH) is commonly used conjunctively with GP IIb/IIIa antagonists, several inherent limitations exist, including unpredictable pharmacodynamics, no established therapeutic standards, and the fact that the use of UFH has been associated with platelet activation. Low-molecular-weight heparin preparations offer several potential advantages over UFH: a greater degree of Xa inhibition; more predictable pharmacokinetic profile; the absence of significant platelet activation; and the confirmation of clinical superiority in several large-scale clinical trials. Randomized trials will be required to establish the full clinical impact of combined pharmacotherapy in ACS.
Becker
R C
RC
Cardiovascular Thrombosis Research Center, Division of Cardiovascular Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. becker@ummhc.org
D000208:Acute Disease; D000925:Anticoagulants / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects; D002986:Clinical Trials as Topic / Q000379:methods; D003327:Coronary Disease / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D012107:Research Design; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013917:Thrombin