Abstract

Essentially all of the major coagulation and fibrinolytic system components (including proteases, co-factors, receptors, inhibitors, and substrates) have been experimentally eliminated or functionally altered in gene-targeted mice. Detailed studies of these mutant animals have greatly improved the understanding of the role of these proteins in complex physiological and pathological processes in vivo. Hemostatic derangements were the most predictable consequence of genetically imposed alterations in key coagulation and fibrinolytic factors, but more detailed studies have illuminated another less obvious aspect of the hemostatic system—namely, that coagulation and fibrinolytic factors appear to figure prominently into a wide spectrum of biological processes in vivo that have little or nothing to do with traditional hemostasis. Studies of mice with hemostatic deficits compatible with survival to adulthood (eg, fibrinogen-, plasminogen activator–, and plasminogen-deficient mice) have revealed an important role of these factors in phenomenally diverse biological settings (eg, immune surveillance, neurodegeneration and repair, tumor metastasis, and inflammatory diseases). Regulatory crosstalk between the hemostatic and inflammatory systems has become an increasingly frequent biological theme. The precise mechanisms by which thrombin, fibrinogen, and other hemostatic factors contribute to the inflammatory response remain to be fully defined, but leukocyte receptor interactions with fibrin(ogen) and other hemostatic factors are likely to be one important means of locally regulating leukocyte function. A comprehensive understanding of the role of hemostatic factors in inflammatory processes may suggest new strategies for the treatment of a wide array of inflammatory diseases.

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