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Thrombin, Inflammation, and Cardiovascular Disease: Conclusions

Thrombin, Inflammation, and Cardiovascular Disease: ConclusionsThis statistical association may be mediated by the key proinflammatory cytokine (also an adipokine) TNF-a, which is a so-called first-wave cytokine influencing IL-6 production, as well as many other cellular functions. TNF-a receptor (TNFR) I signals programmed cell death, while TNFR II may signal survival or proliferation through cytoplasmic TNFR-associated proteins, which can both negatively regulate apoptosis and positively promote survival. Although the role (if any) of circulating TNF-a in humans remains uncertain, TNF-a induces insulin resistance in tissue culture and in animal models.’ Plasma levels are also elevated in the metabolic syndrome, and are associated with insulin resistance in humans. fully

We now know that thrombin generation is critical in atherosclerotic heart disease in at least two ways: as the ultimate clotting and platelet-activating enzyme, and as an important cell-signaling effector molecule. While thrombosis remains a major contributor to the morbidity and mortality of atherosclerotic disease, the other roles of thrombin in vascular biology may prove to be the more critical in the overall scheme. We also now know that coagulation, fibrinolysis, and inflammation are critically interconnected, and markers related to all of these activities are associated cross-sectionally with both subclinical and clinical heart disease, and epidemiologically are predictors of future clinical events. These new insights highlight the need to engage in integrative molecular physiology, with the goal of understanding in detail not just the individual pathways, but the ways they intersect and interact. In particular, we will need to understand how to interrupt “pathologic” activities (eg, thrombosis or foam cell proliferation) without interrupting homologous “physiologic” activities (eg, hemostasis or wound repair), which often involve the same mediators and effectors. It is likely that in the future important therapeutic and preventive advances will have to be made with such integrated knowledge in mind.