Inhibition of the tissue factor-thrombin pathway limits infarct size aftermyocardial ischemia-reperfusion injury by reducing inflammation

Functional inhibition of tissue factor (TF) has been shown to improve coron ary blood flow after myocardial ischemia/reperfusion (I/R) injury TF initia tes the coagulation protease cascade, resulting in the generation of the se rine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vas cular endothelial cells. We used a rabbit coronary Ligation model to invest igate the role of TF in acute myocardial VR injury. At-risk areas of myocar dium showed increased TF expression in the sarcolemma of cardiomyocytes, wh ich was associated with a low level of extravascular fibrin deposition. Fun ctional inhibition of TF activity with an anti-rabbit TF monoclonal antibod y administered either 15 minutes before or 30 minutes after coronary ligati on reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectivel y, Similarly, we found that inhibition of thrombin with hirudin reduced inf arct size by 59% (p = 0.014). Ln contrast, defibrinogenating the rabbits wi th ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TI; or thro mbin reduced leukocyte infiltration. We propose that cardiomyocyte TF initi ates extravascular thrombin generation, which enhances inflammation and inj ury during myocardial I/R.