Antithrombotic and prothrombotic molecules Content Points: B. Prothrombotic and antithrombotic pathways in the coronary vasculature Antithrombotic and prothrombotic molecules Content Points: In normal hemostasis and with a healthy endothelium, there is a balance between antithrombotic and prothrombotic molecules.1 Antithrombotic molecules released by the endothelium include: Nitric oxide (NO) and prostacyclin (PGI2), which prevent platelet adhesion and aggregation Enzymes such as the ADPase CD39, which metabolizes the platelet activator adenosine diphosphate Thrombomodulin (TM) and heparin sulfate (HS), which inactivate thrombin Tissue-type plasminogen activator (TPA), which converts plasminogen to plasmin, a protease that degrades fibrin Prothrombotic molecules include: von Willebrand factor (vWF) and P-selectin, which mediate platelet adhesion to the endothelium Tissue factor (TF), which initiates the coagulation cascade (discussed in a later slide) Plasminogen activator inhibitor-1 (PAI-1) Endothelial injury disrupts this balance. Atherosclerosis is characterized by a hypercoagulable state at all stages of the disease. Thus, antithrombotic strategies are central to management and prevention of ACS. 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med. 2002;8:1227-1234.

Plaque rupture Content Points: As shown, proteases expressed by inflammatory mediators degrade the fibrous cap, rendering it susceptible to mechanical rupture.1 Thrombus that has developed on a disrupted plaque causes most ACS.2 Rupture of the fibrous cap accounts for approximately 75% of cases.3,4 1 Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nat Med. 2002;8:1249-1256. 2 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365-372. 3 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657-671. 4 Davies MJ. Stability and instability: Two faces of coronary atherosclerosis. The Paul Dudley White Lecture, 1995. Circulation. 1996;94:2013-2020.

Conversion of fibrinogen to fibrin3 Thrombotic pathways Content Points: The platelet activation and coagulation pathways are both involved in thrombus formation.1 The slide summarizes the main features of these pathways and their points of intersection. Platelet activation pathway: Platelets bind to vWF and collagen at the plaque site.2 Adherent platelets release thromboxane A2 and ADP, which bind to their own platelet receptors and amplify the activation process. Activated platelets undergo a conformational change that exposes GP IIb/IIIa, a binding site with high affinity for fibrinogen. Cross-linking of platelets with fibrinogen then occurs, forming a growing platelet-rich clot. Coagulation pathway: Clotting factors circulate in their inactive forms. The coagulation pathway comprises a regulated series of linked reactions involving the sequential activation of these factors.2,3 The initial trigger is exposure of tissue factor (factor VII) in the plaque core. Thrombin (factor IIa) participates at numerous points in thrombus formation (not shown on slide): Conversion of fibrinogen to fibrin3 Activation of factor VIII, thereby sustaining the cascade4 Activation of factor XIII, the protein that converts soluble fibrin into an insoluble, cross-linked matrix3 Activation of factor V, an essential cofactor for conversion of prothrombin to thrombin4 Platelet activation5 Tissue factor is overexpressed by macrophages in the core of atherosclerotic plaques and constitutes the major stimulus to thrombus formation following plaque rupture. The subendothelial membrane, exposed during plaque erosion, is a source of thrombogenic compounds such as collagen and vWF. 1 Selwyn 76AP. Prothrombotic and antithrombotic pathways in acute coronary syndromes. Am J Cardiol. 2003. In press. 2 Schafer AI, Ali NM, Levine GN. Hemostasis, thrombosis, fibrinolysis, and cardiovascular disease. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease. 6th ed. Philadelphia, Penn: WB Saunders Company; 2001;2099-2132. 3 Mosesson MW. Fibrinogen and fibrin polymerization: Appraisal of the binding events that accompany fibrin generation and fibrin clot assembly. Blood Coagul Fibrinolysis. 1997;8:257-267. 4 Pieters J, Lindhout T, Hemker HC. In situ-generated thrombin is the only enzyme that effectively activates factor VIII and factor V in thromboplastin-activated plasma. Blood. 1989;74:1021-1024. 5 Alberio L, Safa O, Clemetson KJ, Esmon CT, Dale GL. Surface expression and functional characterization of alpha-granule factor V in human platelets: Effects of ionophore A23187, thrombin, collagen, and convulxin. Blood. 2000;95:1694-1702.

The slide provides more details regarding platelet adhesion.1 Platelet activation Content Points: The slide provides more details regarding platelet adhesion.1 Agonists such as thromboxane A2 (TxA2), thrombin, epinephrine, and fibrinogen as well as high shear stress are capable of activating platelets. Under conditions of high shear, characteristic of the coronary vasculature at sites such as stenoses, interaction of vWF with the platelet surface GP Ib/IX-V-receptor complex primarily mediates platelet adherence to collagen. Other collagen-specific receptors on the platelet surface, such as a2b1 and GP VI, may also be involved.2 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med. 2002;8:1227-1234. 2 Selwyn AP. Prothrombotic and antithrombotic pathways in acute coronary syndromes. Am J Cardiol. 2003. In press.