IMR Press / FBL / Volume 6 / Issue 3 / DOI: 10.2741/castelli

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Article
Gene targeting in hemostasis: protein C
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1 W.M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
Front. Biosci. (Landmark Ed) 2001, 6(3), 807–819; https://doi.org/10.2741/castelli
Published: 1 July 2001
Abstract

Protein C (PC) is the zymogen form of a serine protease, activated protein C (APC), a naturally occurring anticoagulant. In control of the coagulation of blood, APC functions by attenuating thrombin formation. It serves this role through inactivation, by limited proteolysis, of two important cofactors for overall clot formation, one of which, Factor Va (FVa), stimulates prothrombin activation, and another, Factor VIIIa (FVIIIa), enhances activation of coagulation Factor X (FX). In maintaining the fluidity of blood, APC also indirectly functions in fibrinolysis, in one manner by directly inactivating an inhibitor of plasminogen activation, plasminogen activation inhibitor-1 (PAI-1), and in another manner via its role in attenuating thrombin production, with the resulting effect of limiting production of another thrombin-dependent fibrinolytic inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI). PC, and other components of the PC anticoagulant pathway, e.g., protein S (PS), thrombomodulin (Tm), and endothelial cell protein C receptor (EPCR), also can serve as anti-inflammatory mediators, through a number of different thrombin-dependent and thrombin-independent mechanisms. A large number of symptomatic and asymptomatic mutations occur in PC in humans, which express a variety of phenotypes. Generation and characterization of a murine model of a total PC gene inactivation has demonstrated that while an untreated total PC deficiency results in neonatal death through DIC-related abnormalities, a valuable resource is now available to study phenotypes of less severe deficiencies of this protein. Such studies will lead to advances in an understanding of the relative role of this protein system in the various pathways in which it has an influence.

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