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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kurz, K. D. Articles by Grinnell, B. W. Search for Related Content PubMed PubMed Citation Articles by Kurz, K. D. Articles by Grinnell, B. W. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Antithrombotic efficacy in the guinea pig of a derivative of human protein C with enhanced activation by thrombin KD Kurz, T Smith, A Wilson, B Gerlitz, MA Richardson and BW Grinnell Division of Cardiovascular Pharmacology, Lilly Research Laboratories, Indianapolis, IN, USA. Conversion by alpha-thrombin of the zymogen human protein C (HPC) to activated protein C (aPC) is an important physiologic feedback control mechanism for the coagulation cascade. Although activation of HPC by thrombomodulin-bound thrombin is relatively rapid, activation by free thrombin occurs at a significantly slower rate. Previously, we generated a "hyper-activatable" derivative of HPC (FLIN-Q3) with an increased activation rate by free alpha-thrombin in vitro. In this study, the antithrombotic efficacy of FLIN-Q3 was compared with both native zymogen and aPC in an arteriovenous shunt model of thrombosis in the guinea pig. Recombinant proteins were infused 15 minutes before and throughout a 15-minute period while blood was circulated from carotid to jugular through tubing that enclosed a thread on which fibrin was deposited. Parallel dose-dependent antithrombotic responses were observed. Under these non-steady-state conditions, the calculated infusion doses associated with a 50% reduction of thrombus mass were 2.7, 24, and 250 mg/kg/h for aPC, FLIN-Q3, and HPC, respectively. Thrombus weight correlated inversely with plasma concentration of aPC, measured amidolytically, from either direct infusion of aPC or that generated from the zymogens in the animal, and similarly correlated inversely with anticoagulant activity measured by whole blood aPTT. Neither zymogen form showed significant aPC activity before shunt circulation, suggesting a requirement for exposure to thrombin. After the infusion was discontinued for 15 minutes, a second period of thrombus formation in the shunt demonstrated the ability of zymogen forms of PC, unlike aPC, to provide "on-demand" anticoagulant responses to repeated thrombotic stimuli. Thus, a "hyper-activatable" PC molecule such as FLIN-Q3 may represent a superior form of anticoagulant therapy than either the native zymogen or aPC. Volume 89, Issue 2, pp. 534-540, 01/15/1997 Copyright © 1997 by The American Society of Hematology CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. I. Weitz and J. Hirsh New Anticoagulant Drugs Chest, January 1, 2001; 119 (2009): 95S - 107S. [Full Text] [PDF]

	Copyright © 1997 by American Society of Hematology         Online ISSN: 1528-0020