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Antithrombotic activity of protein S infused without activated protein C in a baboon thrombosis model

Academic Article
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Overview

authors

  • Heeb, Mary Jo
  • Marzec, U.
  • Gruber, A.
  • Hanson, S. R.

publication date

  • April 2012

journal

  • Thrombosis and Haemostasis  Journal

abstract

  • Protein S (ProS) is an essential plasma protein that enhances the anticoagulant activity of activated protein C (APC). In vitro , purified native human Zn2+-containing ProS also exerts direct anticoagulant activity by inhibiting prothrombinase and extrinsic FXase activities independently of APC. We investigated antithrombotic effects of ProS infused without APC in a baboon shunt model of thrombogenesis that employs a device consisting of arterial and venous shear flow segments. In in vitro experiments, the Zn2+-containing human ProS used for the studies displayed >10-fold higher prothrombinase inhibitory activity and anticoagulant activity in tissue factor-stimulated plasma, and four-fold higher inhibition of the intrinsic pathway than the Zn2+-deficient ProS used. In the thrombosis model, ProS (33 μg/minute for 1 hour) or saline was infused locally; platelet and fibrin deposition in the shunt were measured over 2 hours. During experiments performed at 50 ml/minute blood flow, Zn2+-containing ProS inhibited platelet deposition 73-96% in arterial-type flow segments and 90-99% in venous-type flow segments; Zn2+-deficient ProS inhibited platelet deposition 52% in arterial-type flow segments and 65-73% in venous-type flow segments. At 100 ml/min blood flow rate, Zn2+-containing ProS inhibited platelet deposition by 39% and 73% in the respective segments; Zn2+-deficient ProS inhibited platelet deposition by 5% and 0% in the respective segments. Zn2+-containing ProS suppressed fibrin deposition by 67-90%. Systemic APC-independent ProS activity was significantly increased and thrombin-antithrombin complex levels were significantly decreased after infusion of ProS. Thus, infused human Zn2+-containing ProS is antithrombotic in primates, and may have therapeutic potential even in protein C-deficient human patients.

subject areas

  • Animals
  • Anticoagulants
  • Blood Platelets
  • Cysteine Endopeptidases
  • Disease Models, Animal
  • Fibrin
  • Fibrinolytic Agents
  • Hemostasis
  • Humans
  • Male
  • Neoplasm Proteins
  • Papio
  • Protein C
  • Protein C Deficiency
  • Protein S
  • Thrombosis
  • Time Factors
  • Zinc
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Research

keywords

  • Anticoagulants
  • platelets
  • protein S
  • thrombosis model
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Identity

PubMed Central ID

  • PMC3319843

International Standard Serial Number (ISSN)

  • 0340-6245

Digital Object Identifier (DOI)

  • 10.1160/th11-10-0699

PubMed ID

  • 22370911
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Additional Document Info

start page

  • 690

end page

  • 698

volume

  • 107

issue

  • 4

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