title: Antithrombotic activity of protein S infused without activated protein C in a baboon thrombosis model.
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.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. heeb@scripps.edu
authors.forename: M J
authors.initials: MJ
authors.lastname: Heeb
authors.forename: U
authors.initials: U
authors.lastname: Marzec
authors.forename: A
authors.initials: A
authors.lastname: Gruber
authors.forename: S R
authors.initials: SR
authors.lastname: Hanson
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006487:Hemostasis; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D010215:Papio; D011486:Protein C / Q000378:metabolism*; D020151:Protein C Deficiency / Q000378:metabolism; D017293:Protein S / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D015032:Zinc / Q000737:chemistry
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D009363:Neoplasm Proteins; D011486:Protein C; D017293:Protein S; D005337:Fibrin; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant; D015032:Zinc