In the decade after World War II, there was a strong positive correlation between the human birth rate and the number of storks observed to be nesting in the city of Copenhagen. It would have been erroneous to conclude from this statistical fact that storks bring babies. Likewise, one should not jump to the conclusion that HCII directly influences the development of in-stent restenosis or carotid atherosclerosis. Nevertheless, one can imagine scenarios in which inhibition of thrombin by HCII in the vessel wall might delay the development of these pathological lesions. Stent placement almost certainly triggers thrombin generation by disrupting the endothelium and/or the fibrous cap of an atheromatous plaque, allowing plasma factor VIIa to come in contact with tissue factor in the intima. 7, 8 The factor VIIa/tissue factor complex then converts factor X to factor Xa, which in combination with factor Va converts prothrombin to thrombin. Thrombin proteolytically converts fibrinogen to fibrin monomers, which polymerize to form a clot, and cleaves G-protein–coupled protease activated receptors (specifically, PAR1 and PAR4) on the platelet membrane to stimulate platelet aggregation and degranulation. 9 The earliest histological response to stent placement includes local deposition of fibrin and platelets, providing good evidence for the presence of thrombin in this setting. 10 Thrombin can also activate PAR1 on nearby endothelial cells. 9 In response, the endothelial cells express adhesion molecules on their surface and release a variety of chemokines and other mediators that recruit platelets and leukocytes. Thus, thrombin could play a role in the infiltration of neutrophils, lymphocytes, and macrophages that occurs within the first few days after stent placement. Over the next 2 to 4 weeks, the fibrin and platelets disappear, and restenosis occurs as a result of proliferation of smooth muscle cells and deposition of extracellular matrix in the neointima. 10 Thrombin may induce smooth muscle cell proliferation both directly, by activation of PAR1 on these cells, and indirectly, by causing platelets to secrete plateletderived growth factor. Therefore, thrombin could have multiple effects in both the early and late stages of in-stent restenosis.

Several lines of experimental evidence suggest that thrombin participates in formation of the neointima. For example, neointima formation in response to mechanical injury of the carotid artery is less intense in PAR1-null mice than in wild-type mice. 11 This difference seems to reflect defective thrombin signaling in smooth muscle cells or perhaps endothelial cells, as the platelets of PAR1-null mice remain responsive to thrombin (in contrast to human platelets, mouse platelets express PAR3 and PAR4, but not PAR1). In addition, a synthetic peptide analog that selectively antagonizes PAR1 reduces neointima formation in rats. 12 Various thrombin-specific inhibitors (eg, hirudin and derivatives thereof) also diminish neointima formation in experimental animals, 13 but other anticoagulants such as heparin are