Abstract SCI-43

Myocardial infarction due to rupture of atherosclerotic plaques is a leading contributor to morbidity and mortality in the United States, Europe, and other industrialized nations. Although pathoanatomic studies of human atherosclerotic lesions suggest that large plaques can cause ischemic symptoms, a key contributing factor to the morbidity and mortality associated with atherosclerosis is excessive platelet thrombus formation on exposed collagen surfaces following acute plaque rupture. Following their initial tethering to subendothelial collagen and matrix proteins, activation of transiently adhered platelets by autocrine mediators is critical for propagation of the platelet thrombus. Reinforcement of the transient adhesive contacts by activating G protein-dependent shape change, granule release, and integrins permits growth of a stable thrombus that is resistant to the high shear stress of arterial blood flow. Drugs that target the secondary autocrine mediators of platelet thrombus formation such as aspirin and thienopyridines have proven to be beneficial; however, many patients taking these drugs still sustain thrombotic events and might benefit from new therapeutics that interfere with matrix-dependent platelet activation. Matrix metalloproteases (MMPs) have recently emerged as important mediators of platelet function and vascular biology. Initially described as matrix remodeling enzymes involved in tissue repair and cancer invasion, a renewed focus has centered on MMPs and the related metalloprotease disintegrins because of their prominence in vascular wall inflammation and thrombotic thrombocytopenic purpura. Endogenous platelet metalloproteases have been shown to damage platelet function by cleaving cell surface receptors and broad-spectrum metalloprotease inhibitors improve post-transfusion recovery of platelet concentrates. Platelets express several metalloproteases including MMP-1, MMP-2, MMP-3, and MMP-14 on their surface but their roles in platelet aggregation are not well understood. It was recently shown that the G protein-coupled receptor, PAR1, is directly cleaved and activated on the surface of cancer cells by fibroblast-derived MMP-1. PAR1 is the major thrombin receptor of human platelets and is an important mediator of platelet aggregation following tissue factor (TF)-dependent generation of thrombin. However, under pathophysiologic conditions of acute plaque rupture, exposed collagen is the most efficient stimulus of the critical early events of platelet recruitment and propagation under arterial flow, which could trigger metalloprotease activation on the platelet surface. We found that exposure of platelets to collagen caused activation of MMP-1, which in turn directly cleaved PAR1 on the surface of platelets. Unexpectedly, MMP-1 cleaved the N-terminal extracellular domain of PAR1 at a distinct site from the thrombin cleavage site. This cleavage event generated a longer tethered peptide ligand, which was an agonist of platelet activation and PAR1 signaling. Blocking the MMP1-PAR1 pathway inhibited collagen-dependent thrombogenesis, arterial thrombosis and clot retraction, suggesting that therapeutics that target this metalloprotease-receptor system could be a new strategy in the treatment of patients with acute coronary syndromes.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.