Low doses of activated protein C delay arterial thrombosis in rats

Smirnov, Mikhail D.; Pyzh, M V; Borovikov, D. V.; Atorozhilova, A.N.; Dobrovolsky, A. B.; Golubych, V.L.; Gratsiansky, N.A.

doi:10.1016/0049-3848(90)90082-n

Cited by 20 publications

(12 citation statements)

References 11 publications

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“…Studies using human APC in vivo in antithrombotic rat models are controversial, as Smirnov reported antithrombotic effects of low doses of human APC in the rat, 39 whereas others failed to demonstrate antithrombotic effects of human APC in rat arterial thrombosis models. 40,41 Human and rabbit APC can function with protein S from certain species and not others.…”

Section: Discussionmentioning

confidence: 99%

Species-specific anticoagulant and mitogenic activities of murine protein S

Fernández¹,

Heeb²,

Xu³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundThe protein C pathway down-regulates thrombin generation and promotes cytoprotection during inflammation and stress. In preclinical studies using models of murine injury (e.g., sepsis and ischemic stroke), murine protein S may be required because of restrictive species specificity. Design and MethodsWe prepared and characterized recombinant murine protein S using novel coagulation assays, immunoassays, and cell proliferation assays. ResultsPurified murine protein S had good anticoagulant co-factor activity for murine activated protein C, but not for human activated protein C, in mouse or rat plasma. In human plasma, murine protein S was a poor co-factor for murine activated protein C and had no anticoagulant effect with human activated protein C, suggesting protein S species specificity for factor V in addition to activated protein C. We estimated that mouse plasma contains 22±1 µg/mL protein S and developed assays to measure activated protein C co-factor activity of the protein S in murine plasma. Activated protein C-independent anticoagulant activity of murine protein S was demonstrable and quantifiable in mouse plasma, and this activity was enhanced by exogenous murine protein S. Murine protein S promoted the proliferation of mouse and human smooth muscle cells. The potency of murine protein S was higher for mouse cells than for human cells and similarly, human protein S was more potent for human cells than for mouse cells. ConclusionsThe spectrum of bioactivities of recombinant murine protein S with mouse plasma and smooth muscle cells is similar to that of human protein S. However, in vitro and in vivo studies of the protein C pathway in murine disease models are more appropriately performed using murine protein S. This study extends previous observations regarding the remarkable species specificity of protein S to the mouse.

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Section: Discussionmentioning

confidence: 99%

Species-specific anticoagulant and mitogenic activities of murine protein S

Fernández¹,

Heeb²,

Xu³

et al. 2009

Haematologica

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“…The antithrombotic features of APC have been demonstrated in different animal studies. Thus, human APC blocks the lethal effects of Escherichia coli endotoxin shock in baboons (21), reduces jugular vein thrombus formation in dogs (22), delays anodal current-induced aorta thrombus formation in rats (23), and reduces intermittent platelet thrombus formation in rat microvessels (24). Human APC is also an effective antithrombotic agent in a hypertraumatic arteriovenous graft model in baboons, when infused in close proximity to the trauma area (25,26).…”

Section: Introductionmentioning

confidence: 99%

Protein S as an in vivo cofactor to activated protein C in prevention of microarterial thrombosis in rabbits.

Arnljots¹,

Dahlbäck²

1995

J. Clin. Invest.

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The antithrombotic effects of bovine activated protein C (APC) and protein S were investigated in a rabbit model of microarterial thrombosis. Because of the species specificity of the APC-protein S interaction, bovine APC expresses potent anticoagulant activity in rabbit plasma only when bovine protein S is also present. This provided a way to assess the contribution of bovine protein S to the antithrombotic effect of bovine APC. Rabbits were infused with boluses of activated protein C (0.1, 0.2, 0.4, or 0.8 mg/kg), protein S (0.5 mg/kg), or activated protein C (0.1 or 0.01 mg/kg) plus protein S (0.5 mg/kg). APC alone produced a dose-dependent antithrombotic effect, but only the group receiving the highest dose differed signiflcantly from controls. While a low dose of activated protein C (0.1 mg/kg) alone had no antithrombotic effect, together with protein S (0.5 mg/kg) it produced a potent response. The presented results demonstrate the in vivo significance of protein S as a cofactor to activated protein C. The data show that a potent antithrombotic effect, without hemorrhagic side effects or significant systemic anticoagulation, may be achieved by low doses of activated protein C when combined with protein S. (J.

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“…Smirnov et al 1990 demonstrated that injection of low doses of hAPC (15 or 30 µg/kg) prolonged the time to complete occlusion of rat abdominal aorta that was made thrombogenic by electrical current [27]. Araki et al 1991 showed that intravenous injection of hAPC (0.9 or 3.0 mg/kg) significantly decreased the number of thrombotic occlusions and the total time the vessels were occluded in rat mesenteric artery after compression injury [25].…”

Section: Ex Vivo Coagulation Analysesmentioning

confidence: 99%

“…The discrepancy between our and these previous findings may in part be explained by differences in the type of vascular injury used. In contrast to the previous studies [25,[27][28][29][30], the vascular trauma in our model was designed to mimic conditions that may be encountered in clinical settings, such as avulsion trauma or exposure of deep vascular layers in diseased vessels after atherosclerotic plaque rupture, i.e. a crude vascular trauma that produces occlusive thrombus formation and an injury that is prone to be relatively resistant to therapeutic intervention.…”

Section: Ex Vivo Coagulation Analysesmentioning

confidence: 99%