Thrombin hypothesis of thrombus generation and vascular lesion formation.

Thrombin plays a central role in vascular lesion formation. It is the principal mediator of thrombogenesis, which is interrupted when direct antithrombins (including hirudin and its synthetic peptide analogs), thrombin receptor antagonist peptides, or thrombin generation inhibitors (including active-site inhibited factor VIIa, recombinant tick anticoagulant peptide, and omega-3 fatty acids) are used to block thrombin. Thrombin is also a potent growth factor, initiating smooth muscle cell proliferation at injury sites. In baboons, this reaction is 80% reduced by hirudin (p < 0.01). Thrombin also plays a role in modulating the effects of other growth factors such as platelet-derived growth factor (PDGF). Thus, Phe-Pro-Arg-CH2Cl prevents expression in baboons of PDGF-A mRNA induced by vascular injury due to balloon angioplasty; untreated mechanical injury results in a 3-fold increase in PDGF-A mRNA expression. Thrombin also regulates inflammatory processes, inducing expression both of leukocyte adhesion molecules and of their counterreceptors by endothelium.