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

Mary J. Heeb; Ulla Marzec; Andras Gruber; Stephen R. Hanson

doi:10.1160/TH11-10-0699

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(04): 690-698
DOI: 10.1160/TH11-10-0699

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Mary J. Heeb

¹Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

,

Ulla Marzec

²Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA

,

Andras Gruber

²Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA

,

Stephen R. Hanson

²Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, USA

› Author Affiliations

Abstract

Summary

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 arterialtype 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.

These studies were presented in part in abstract form at an oral presentation at the XXIth Congress of the International Society on Thrombosis and Haemo -stasis, Geneva, Switzerland, August 2007.

Keywords

Anticoagulants - platelets - protein S - thrombosis model

Full Text

References

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