Zinc ions bind to and inhibit activated protein C

Zhu, Tianqing; Ubhayasekera, Wimal; Nickolaus, Noëlle; Sun, Wei; Tingsborg, Susanne; Mowbray, Sherry L.; Schedin‐Weiss, Sophia

doi:10.1160/th09-12-0862

Cited by 7 publications

(4 citation statements)

References 49 publications

(55 reference statements)

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“…In addition to binding to the Gla domain of APC, zinc also binds to its protease domain and induces a conformational change. In the absence of calcium, zinc inhibits the amidolytic activity of APC by ~7-fold, but the impact of this phenomenon on the anticoagulant activity of APC is unclear (92,96). Zinc attenuates the capacity of APC to inactivate FVa in the presence of phospholipid vesicles (96), but not on the EC surface (92); differences that suggest that APC activity varies depending on the membrane surface (97).…”

Section: Modulation Of Activated Protein C Generation and Activitymentioning

confidence: 99%

Zinc: An important cofactor in haemostasis and thrombosis

Vu¹,

Fredenburgh²,

Weitz³

2013

Thromb Haemost

103

113

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SummaryThere is mounting evidence that zinc, the second most abundant transition metal in blood, is an important mediator of haemostasis and thrombosis. Prompted by the observation that zinc deficiency is associated with bleeding and clotting abnormalities, there now is evidence that zinc serves as an effector of coagulation, anticoagulation and fibrinolysis. Zinc binds numerous plasma proteins and modulates their structure and function. Because activated platelets secrete zinc into the local microenvironment, the concentration of zinc increases in the vicinity of a thrombus. Consequently, the role of zinc varies depending on the microenvironment; a feature that endows zinc with the capacity to spatially and temporally regulate haemostasis and thrombosis. This paper reviews the mechanisms by which zinc regulates coagulation, platelet aggregation, anticoagulation and fibrinolysis and outlines how zinc serves as a ubiquitous modulator of haemostasis and thrombosis.

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Section: Modulation Of Activated Protein C Generation and Activitymentioning

confidence: 99%

Zinc: An important cofactor in haemostasis and thrombosis

Vu¹,

Fredenburgh²,

Weitz³

2013

Thromb Haemost

103

113

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“…Thus, this study gives further support for the concept that Zn 2+ is an important modulator of hemostasis. Recent reports have revealed Zn 2+ binding to protein S, activated protein C, and FVIIa. − Moreover, Zn 2+ promotes the binding of histidine-rich glycoprotein to FXIIa which attenuates contact-mediated activation of coagulation . The potential for modulation of Zn 2+ levels by localized platelet activation provides a mechanism by which Zn 2+ -dependent interactions can be regulated.…”

Section: Discussionmentioning

confidence: 99%

By Increasing the Affinity of Heparin for Fibrin, Zn²⁺ Promotes the Formation of a Ternary Heparin–Thrombin–Fibrin Complex That Protects Thrombin from Inhibition by Antithrombin

et al. 2012

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Heparin binds fibrin and, by bridging thrombin onto fibrin, promotes the formation of a ternary heparin-thrombin-fibrin complex that protects thrombin from inhibition by antithrombin. Because thrombin binds γ(A)/γ'-fibrin, a variant with an extended γ-chain, with higher affinity than the bulk γ(A)/γ(A)-fibrin, γ(A)/γ'-fibrin affords bound thrombin more protection from inhibition by antithrombin-heparin. We examined the effect of Zn(2+) on heparin-thrombin-fibrin complex formation because Zn(2+) modulates heparin-protein interactions. Zn(2+) increased the affinity of heparin for γ(A)/γ(A)- and γ(A)/γ'-fibrin by 4.3- and 3.7-fold, respectively, but had no effect on the affinity of thrombin for either form of fibrin. In contrast, in the presence of heparin, Zn(2+) increased the affinity of thrombin for γ(A)/γ(A)-fibrin 4-fold (from a K(d) value of 0.8 to 0.2 μM) and slowed the rate of thrombin dissociation from γ(A)/γ(A)-fibrin clots. These findings suggest that Zn(2+) enhances the formation of ternary heparin-thrombin-fibrin complexes with γ(A)/γ(A)-fibrin but does not influence the already high affinity interaction of thrombin with γ(A)/γ'-fibrin. Consistent with this concept, in the presence of Zn(2+), γ(A)/γ(A)-fibrin protected thrombin from inhibition by antithrombin-heparin to a similar extent as γ(A)/γ'-fibrin. Therefore, by enhancing the binding of heparin to fibrin, physiological concentrations of Zn(2+) render fibrin-bound thrombin more protected from inhibition by antithrombin. Because fibrin-bound thrombin can trigger thrombus expansion, these findings help to explain why recurrent thrombosis can occur despite heparin treatment.

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“…Zn 2+ content does not affect the APC cofactor activity of ProS in vitro (12), but it did affect the antithrombotic effect of ProS in the baboon thrombosis model. Zn 2+ is known to inhibit the amidolytic activity but not anticoagulant activity of APC and to enhance protein C and APC binding to endothelial cell protein C receptor (23,24). Zn 2+ induces conformational change in protein C and APC; Zn 2+ -containing ProS also has a different conformation than Zn 2+ -deficient ProS (12).…”

Section: Discussionmentioning

confidence: 99%

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

Heeb

Marzec

Gruber³

et al. 2012

Thromb Haemost

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SummaryProtein 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.

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Zinc ions bind to and inhibit activated protein C

Cited by 7 publications

References 49 publications

Zinc: An important cofactor in haemostasis and thrombosis

Zinc: An important cofactor in haemostasis and thrombosis

By Increasing the Affinity of Heparin for Fibrin, Zn²⁺ Promotes the Formation of a Ternary Heparin–Thrombin–Fibrin Complex That Protects Thrombin from Inhibition by Antithrombin

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

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Zinc ions bind to and inhibit activated protein C

Cited by 7 publications

References 49 publications

Zinc: An important cofactor in haemostasis and thrombosis

Zinc: An important cofactor in haemostasis and thrombosis

By Increasing the Affinity of Heparin for Fibrin, Zn2+ Promotes the Formation of a Ternary Heparin–Thrombin–Fibrin Complex That Protects Thrombin from Inhibition by Antithrombin

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

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By Increasing the Affinity of Heparin for Fibrin, Zn²⁺ Promotes the Formation of a Ternary Heparin–Thrombin–Fibrin Complex That Protects Thrombin from Inhibition by Antithrombin