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Thrombin, Inflammation, and Cardiovascular Disease: Thrombin-activated fibrinolysis inhibitor

Thrombin is also responsible for the activation of a newly discovered major thrombosis regulator, thrombin-activated fibrinolysis inhibitor, also discussed in more detail by Dr. Nesheim elsewhere in this supplement. Thrombin-activated fibrinolysis inhibitor appears to play a major role in down-regulating fibrinolysis, which may have important implications in heart disease, as has been proposed.
Interestingly, along with being the key final enzyme in fibrin formation, and the most powerful known platelet activator, thrombin is also a major anticoagulant in its role as the thrombomodulin-associated activator of protein C (see the accompanying article by Dr. Esmon in this supplement). APC is a powerful anticoagulant that has recently been established as a critical new therapeutic weapon in the setting of sepsis.2 It is unlikely that in this role thrombin has a major effect on atherosclerosis and clinical heart disease, however, since low protein C levels are not CVD risk factors. comments
This theory is supported by the fact that genotypes associated with low protein C levels (or with cofactors that are refractive to APC activity, eg, Factor V Leiden) have not been linked to CVD risk. We hypothesize that this lack of association may be due to two factors: the heavy dependence of arterial thrombosis on atherosclerotic plaque rupture and/or erosion, and the high flow rates of blood around areas of stenosis, making it likely that available thrombomodulin may reside downstream of the forming thrombus. However, the anticoagulant role of thrombin may be important in arterial disease once an occlusive thrombus has formed with its attendant stasis, just as it is important in venous thrombosis, which is also predominantly stasis dependent. This hypothesis remains to be tested in a clinical setting.