Objective-In acute myocardial infarction (AMI), proinflammatory plasma C-reactive protein values are strongly associated with postinfarction morbidity and mortality. So far, the cause of these inflammatory changes is not well understood. Therefore, we sought to investigate the relationship between the activation of coagulation and subsequent systemic inflammatory changes in AMI. Methods and Results-Factor Xa (FXa) bound to tissue factor pathway inhibitor and prothrombin fragments F1ϩ2 (F1ϩ2) were used as a measure for activated coagulation. To assess systemic inflammatory changes, plasma interleukin (IL)-6 and IL-8 concentrations were analyzed by immunoassay. Blood samples were taken from 21 patients with AMI and 20 patients with stable angina pectoris. In AMI, tissue factor pathway inhibitor FXa but not F1ϩ2 plasma levels were associated with circulating IL-8 (Pϭ0.01). In vitro experiments revealed that FXa stimulated IL-8 and monocyte chemoattractant protein-1 release and RNA expression in endothelial cells and mononuclear leukocytes by activation of protease-activated receptor-1. Key Words: coagulation Ⅲ myocardial infarction Ⅲ inflammation Ⅲ cytokines T he main initiator of the extrinsic coagulation cascade is tissue factor (TF), the receptor and cofactor for plasma coagulation factor VII/VIIa. Under physiological conditions TF is mainly expressed at extravascular sites. However, TF is induced by several inflammatory mediators such as interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. 1,2 In acute myocardial infarction (AMI), disruption of atherosclerotic plaques exposes TF-positive cells within the plaque-to-plasma clotting factors and initiates local thrombosis with subsequent occlusion of the coronary vessel. 3 In addition, increased TF expression occurs on circulating monocytes and microparticles in acute coronary syndromes and may thereby contribute to activation of coagulation. 4 -6 A soluble form of TF within the circulating blood may also support coronary thrombosis. 7 Stimulation of the TF-thrombin pathway does not only occur at the site of the plaque but also within the ischemic myocardium where activated coagulation factors may enhance inflammatory responses and deteriorate infarct size. 8 The endogenous Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI)-1 inhibits initiation of TF-induced blood coagulation. TFPI binds and inactivates factor Xa (FXa). The TFPI-FXa complex then binds and inactivates FVIIa. Increased levels of the TFPI-FXa complex may reflect both increased FXa generation and increased TFPI concentrations. 9 In addition to the full length TFPI, most of the plasma TFPI circulates in truncated forms that are bound to plasma lipoproteins. These truncated forms lack their C-terminal domains and exhibit reduced affinity for vascular wall proteolysis. Conclusion-OurBinding of the serine protease FVII to TF results in generation of the coagulation protease FXa and subsequently thrombin, both known to induce cell signaling. FXa shows dose-dependent inductio...

During systemic inflammation, neutrophil activation is accompanied by endothelial cell damage and hypercoagulability. Activated neutrophils release serine proteases that participate in tissue injury. We sought to investigate the effects of neutrophil proteases on proinflammatory and procoagulant changes in endothelial cells. The effects of elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3) on expression of tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI) were examined in human umbilical vein endothelial cells. Flow cytometry demonstrated that these proteases proteolytically degraded endothelial cell-bound TFPI. TFPI mRNA expression was reduced by HNE and CG. PR3, but not HNE or CG, increased surface expression of TF and TF mRNA. Yet, increased TF expression did not enhance TF activity suggesting induction of encrypted TF. Using antibodies and siRNA to inhibit and silence PAR-1 and PAR-2, we observed that PR3 upregulation of TF is at least in part mediated by PAR-1. Although CG and HNE cleaved PAR-1, antibody reactivity to the PAR-1 hirudin-like sequence demonstrated inactivating cleavage, accounting for the selective ability of PR3 to induce PAR-1-mediated procoagulant effects. This was supported by induction of p42/44 MAPK by PR3. In conclusion, PR3 degradation of TFPI increases the procoagulant activity of endothelial cells. Release of PR3 after neutrophil activation may represent an important step in neutrophil-mediated vascular injury.