- Email: [email protected]
The new platelet inhibitors in coronary intervention
INTERVENTIONALamm,vE~ David P. Faxon, MD
22~~:.
NE
W SLETTER
VOLUME 4, NUMBER P
Jr., m
Timothy A. Sanbom, h4D New York, NY
MARCH 1996
GUESTEDllOR James E. Tcheng, MD Durham, NC
The New Platelet Inhibitors in Coronary Intervention James E. Tcheng, MD Dr. Tcheng i.satDukeUniversity Medical Center in Durham North Carolina. Introduction lthough appreciation of the central role of platelets in the pathophysiology of the acute coronary syndromes is a relatively recent phenomenon, a plethora of evidence now implicates platelets as critical in the pathogenesis of the acute coronary syndromes.‘**The most common etiology of unstable angina is the development of near-occlusive thrombus at the site of injury to the vessel wall; myocardial infarction is typically a result of complete occlusion from coronary thrombosis; and the bulk of the (nonmechanical) complications of coronary intervention result from the consequences of platelet aggregation left unchecked. In fact, anything
A
from mild fissuring to gross rupture of the soft, lipid-laden atherosclerotic plaque provides an ideal environment for the formation of thrombus3 Identification of potential pharmacologic approaches to modulating the activity of the platelet began with an understanding of the vascular biology of the platelet. Three processes-adhesion, activation, and aggregation-provide a useful construct to describe the activities of the plateletP Adhesion, a largely passive process, occurs with exposure of subendothelial constituents (particularly collagen and von Willebrand factor) following vascular trauma. Adhesion results in deposition of a monolayer of platelets at the site of injury. Activation follows adhesion. Activation can be induced by a myriad of stimuli, including the very act of platelet adhesion, agonists such as thrombin, serotonin, thromboxane AZ, and adenosine diphosphate, alterations in
local blood flow rheology, and even thrombolytic agents. Activation both induces the release of further vasoactive substances from dense granules in the platelet and produces a conformational change in the integrin glycoprotein IMIIa. This cottformational change results in conversion of GP IIb/lIIa into a receptive state that can bind to fibrinogen and other adhesive proteins. The last step in the schema is aggregation. Aggregation occurs when fibrinogen crosslinks adjacent platelets leading to formation of a stable platelet plug. The purpose of this article is to review the current state of the art of antiplatelet therapeutics directed at this “final common pathway” of platelet activity, the integrin GP IIb/lIIa.
continuedon page 10
Interview with Eric I. Topol, AD. Dr. Eric J. Top01 is Chairman and Professor in the Department of Cardiology at The Cleveland Clinic Foundation
Q:Eric, you have been involved with the study of the GP IIb/IIIa inhibitors from the very beginning. What have been the highlights of this journey? A: The highlights of the GP Ilb/IIIa journey have been numerous. Rarely in medicine do we have an opportunity to bring in an entirely new class of agents. KANEB 4(!2)1994,9-PO
We have been able to link a potent, new biological pathway with adverse clinical outcomes. As you well know, the most dreaded aspect of coronary intervention is abrupt vessel closure. It is fascinating that we have learned, via the probe of the IIb/IIIa inhibitors, that platelets are the key mediator of abrupt closure when there is not a propagated, complex dissection. In fact, during the past several years continuedon page 17 Q ELSEVlERXIENCE INC.
10&4BBB/%/$0.00
+ 15.00
22~~:.
NE
W SLETTER
VOLUME 4, NUMBER P
Jr., m
Timothy A. Sanbom, h4D New York, NY
MARCH 1996
GUESTEDllOR James E. Tcheng, MD Durham, NC
The New Platelet Inhibitors in Coronary Intervention James E. Tcheng, MD Dr. Tcheng i.satDukeUniversity Medical Center in Durham North Carolina. Introduction lthough appreciation of the central role of platelets in the pathophysiology of the acute coronary syndromes is a relatively recent phenomenon, a plethora of evidence now implicates platelets as critical in the pathogenesis of the acute coronary syndromes.‘**The most common etiology of unstable angina is the development of near-occlusive thrombus at the site of injury to the vessel wall; myocardial infarction is typically a result of complete occlusion from coronary thrombosis; and the bulk of the (nonmechanical) complications of coronary intervention result from the consequences of platelet aggregation left unchecked. In fact, anything
A
from mild fissuring to gross rupture of the soft, lipid-laden atherosclerotic plaque provides an ideal environment for the formation of thrombus3 Identification of potential pharmacologic approaches to modulating the activity of the platelet began with an understanding of the vascular biology of the platelet. Three processes-adhesion, activation, and aggregation-provide a useful construct to describe the activities of the plateletP Adhesion, a largely passive process, occurs with exposure of subendothelial constituents (particularly collagen and von Willebrand factor) following vascular trauma. Adhesion results in deposition of a monolayer of platelets at the site of injury. Activation follows adhesion. Activation can be induced by a myriad of stimuli, including the very act of platelet adhesion, agonists such as thrombin, serotonin, thromboxane AZ, and adenosine diphosphate, alterations in
local blood flow rheology, and even thrombolytic agents. Activation both induces the release of further vasoactive substances from dense granules in the platelet and produces a conformational change in the integrin glycoprotein IMIIa. This cottformational change results in conversion of GP IIb/lIIa into a receptive state that can bind to fibrinogen and other adhesive proteins. The last step in the schema is aggregation. Aggregation occurs when fibrinogen crosslinks adjacent platelets leading to formation of a stable platelet plug. The purpose of this article is to review the current state of the art of antiplatelet therapeutics directed at this “final common pathway” of platelet activity, the integrin GP IIb/lIIa.
continuedon page 10
Interview with Eric I. Topol, AD. Dr. Eric J. Top01 is Chairman and Professor in the Department of Cardiology at The Cleveland Clinic Foundation
Q:Eric, you have been involved with the study of the GP IIb/IIIa inhibitors from the very beginning. What have been the highlights of this journey? A: The highlights of the GP Ilb/IIIa journey have been numerous. Rarely in medicine do we have an opportunity to bring in an entirely new class of agents. KANEB 4(!2)1994,9-PO
We have been able to link a potent, new biological pathway with adverse clinical outcomes. As you well know, the most dreaded aspect of coronary intervention is abrupt vessel closure. It is fascinating that we have learned, via the probe of the IIb/IIIa inhibitors, that platelets are the key mediator of abrupt closure when there is not a propagated, complex dissection. In fact, during the past several years continuedon page 17 Q ELSEVlERXIENCE INC.
10&4BBB/%/$0.00
+ 15.00