Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates

Stephen R. Hanson, John H. Griffin, Laurence A. Harker, Andrew B. Kelly, Charles T. Esmon, Andras Gruber

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

The effects on thrombosis and hemostasis of thrombin-induced activation of endogenous protein C (PC) were evaluated in baboons. Thrombosis was induced by placing into arteriovenous shunts a segment of Dacron vascular graft, which generated arterial platelet-rich thrombus, followed by an expansion region of low-shear blood flow, which in turn accumulated fibrin-rich venous-type thrombus. Thrombosis was quantified by 111In-platelet imaging and 125I-fibrinogen accumulation. Intravenous infusion of α-thrombin, 1-2 U / kg-min for 1 h, increased baseline activated PC levels (∼ 5 ng/ml) to 250-500 ng/ml (P <0.01). The lower thrombin dose, which did not deplete circulating platelets, fibrinogen, or PC, reduced arterial graft platelet deposition by 48% (P <0.05), and platelet and fibrin incorporation into venous-type thrombus by > 85% (P <0.01). Thrombin infusion prolonged the activated partial thromboplastin clotting time, elevated fibrinopeptide A (FPA), thrombin antithrombin III complex (T:AT III), and fibrin D-dimer plasma levels (P <0.01), but did not affect bleeding times. Thrombin's antithrombotic effects were blocked by infusing a monoclonal antibody (HPC-4) which prevented PC activation in vivo, caused shunt occlusion, increased the consumption of platelets and fibrinogen, elevated plasma FPA and T:AT III levels, and reduced factor VIII (but not factor V) procoagulant activity (P <0.05). We conclude that activated PC is a physiologic inhibitor of thrombosis, and that activation of endogenous PC may represent a novel and effective antithrombotic strategy.

Original languageEnglish (US)
Pages (from-to)2003-2012
Number of pages10
JournalJournal of Clinical Investigation
Volume92
Issue number4
StatePublished - 1993
Externally publishedYes

Fingerprint

Protein C
Thrombin
Primates
Thrombosis
Fibrinopeptide A
Blood Platelets
Fibrinogen
Bleeding Time
Polyethylene Terephthalates
Partial Thromboplastin Time
Papio
Factor VIII
Hemostasis
Fibrin
Intravenous Infusions
Blood Vessels
Monoclonal Antibodies
Transplants

Keywords

  • Anti-thrombotic therapy
  • Protein c
  • Thrombin
  • Thrombosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hanson, S. R., Griffin, J. H., Harker, L. A., Kelly, A. B., Esmon, C. T., & Gruber, A. (1993). Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. Journal of Clinical Investigation, 92(4), 2003-2012.

Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. / Hanson, Stephen R.; Griffin, John H.; Harker, Laurence A.; Kelly, Andrew B.; Esmon, Charles T.; Gruber, Andras.

In: Journal of Clinical Investigation, Vol. 92, No. 4, 1993, p. 2003-2012.

Research output: Contribution to journalArticle

Hanson, SR, Griffin, JH, Harker, LA, Kelly, AB, Esmon, CT & Gruber, A 1993, 'Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates', Journal of Clinical Investigation, vol. 92, no. 4, pp. 2003-2012.
Hanson, Stephen R. ; Griffin, John H. ; Harker, Laurence A. ; Kelly, Andrew B. ; Esmon, Charles T. ; Gruber, Andras. / Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. In: Journal of Clinical Investigation. 1993 ; Vol. 92, No. 4. pp. 2003-2012.
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