Abstract
The generation of thrombin and its various activities have to be tightly controlled
in the circulation as well as at extracellular sites to prevent pathological situations.
Both vessel wall-associated thrombomodulin and circulating serine protease inhibitors
meet the requirements for regulation of thrombin function. The final products of thrombin
inhibition are ternary complexes together with the adhesion protein vitronectin. Due
to a conformational switch in the vitronectin molecule, ternary complexes are endowed
with heparin-binding properties and become specifically bound to cell surface sites
on endothelial and other cells. This interaction appears to be responsible for the
clearance and translocation of ternary complexes in the vasculature and at other sites.
In addition, ternary complexes may provoke other cellular activities by binding to
nonintegrin cell surface receptors. Along the vasculature, extracellular-associated
vitronectin serves as a binding and stabilizing cofactor for plasminogen activator
inhibitor 1, which thereby becomes a slow-reacting thrombin inhibitor. It is believed
that clot-associated vitronectin-PAI-1 complex not only stabilizes initial thrombus
formation, but is also responsible for thrombin neutralization and the necessary switch
towards fibrinolysis. Vitronectin thereby becomes an integral cofactor for regulation
and control of thrombin multifunctional activities.
Keywords:
Thrombin - serine protease inhibitors - vitronectin - endothelial cells - plasminogen
activator inhibitor (PAI-1)
