Inhibition of the Tissue Factor-Thrombin Pathway Limits Infarct Size after Myocardial Ischemia-Reperfusion Injury by Reducing Inflammation

Abstract

Functional inhibition of tissue factor (TF) has beenshown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P ‫؍‬ 0.004) and 44% (P ‫؍‬ 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P ‫؍‬ 0.014). In contrast, defibrinogenating the rabbits with 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 TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R. (Am J Pathol 2000, 157:1849 -1862)

Myocardial expression analysis of osteopontin and its splice variants in patients affected by end-stage idiopathic or ischemic dilated cardiomyopathy

“…The above mentioned proteomic findings well support the detection of higher levels of OPN-a in the presence of higher thrombin levels in our DCM failing hearts. Therefore, thrombin may be considered only an hallmark of myocardial pro-inflammatory response, in accord with previous study [44]. Even if we don't have data on protein detection of OPN-b and -c isoforms, we have first proof of modulation of myocardial OPN mRNA alternative splicing in failing myocardium, which is one of the main post-transcriptional modifications.…”

The blood coagulation system as a molecular machine

“…Two examples of elegant animal studies illustrate the principle. In a model of experimental myocardial ischemia in rabbits, myocardial inflammation and damage was shown to be due to enhanced expression of tissue factor by cardiomyocytes and increased local thrombin formation, (78,79) while the contribution of fibrin was irrelevant to heart damage. In an experimental model of glomerulonephritis in mice, thrombin was also the critical mediator of inflammatory damage to the kidney, (80,81) its activity being mediated through activation of one of the protease-activated receptors that appear to be critical in mediating the serine protease effects on cells, Ref.…”

Novel Aspects of Fibrin(ogen) Fragments during Inflammation

“…TF, the initiator of the coagulation cascade, is strongly induced during inflammation in endothelial cells (ECs) and leukocytes (11), which in turn activates thrombin. Blocking TF using neutralizing antibodies abrogates the inflammatory and coagulopathic response in two experimental in vivo models of sepsis (12) and ischemia/ reperfusion (13). When TF is blocked, thrombin generation is also compromised.…”