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

Arnljots, Björn; Dahlbäck, Björn

doi:10.1172/jci117883

Cited by 27 publications

(22 citation statements)

References 48 publications

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“…12 Protein S in human or Rhesus monkey plasma serves well as a co-factor to human APC, and protein S in bovine, rabbit, or porcine plasmas serves optimally as a co-factor to bovine APC in anticoagulant activity assays. [13][14][15][16][17] Purified rat protein S, however, is a notably inefficient co-factor for human APC, 18 in contrast to purified rabbit protein S. 19 Human protein S is present in plasma at a concentration of 25 µg/mL (or 330 nM) 20 and functions as a non-enzymatic co-factor for APC in the proteolytic inactivation of activated factor V (FVa) and activated factor VIII (FVIIIa). 21 The molecular mechanisms involved in the co-factor function of protein S are incompletely understood.…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

Species-specific anticoagulant and mitogenic activities of murine protein S

Fernández¹,

Heeb²,

Xu³

et al. 2009

Haematologica

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“…The specific anticoagulant activity of APC makes it an attractive candidate as a therapeutic compound and it has already proven its effect in association with severe septic shock [4,17]. In models of arterial thrombosis in the rat, we have previously demonstrated bovine APC to be efficient as an antithrombotic agent when coadministered with bovine protein S [18][19][20]32]. The present in vitro clotting experiments in rat plasma performed with either APTT or PT reagents, showed distinct dose dependent anticoagulant effect, especially with the mutant QGNSEDY-hAPC:B148 with four-fold prolongation at the highest concentration in the APTT system in contrast to WT-hAPC that only slightly prolonged the clotting time.…”

Section: Ex Vivo Coagulation Analysesmentioning

confidence: 99%

“…There are several reports on record investigating the effect of APC in different animal models [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. We have previously described powerful antithrombotic effects of bovine APC (bAPC) in combination with bovine PS (bPS) in both rabbit and rat models of deep arterial injury [18][19][20]32].…”

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confidence: 99%

Antithrombotic and anticoagulant effects of wild type and Gla-domain mutated human activated protein C in rats

Malm

Arnljots

Persson

et al. 2007

Thrombosis Research

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“…In addition, a substantial amount of evidence has been provided showing the importance of protein S for in vivo regulation of the anticoagulant protein C system, the system responsible for the proteolytic regulation of FV and FVIII. 38,39 Moreover, protein S and protein C deficiencies are well-recognized risk factors for venous thrombosis, demonstrating the importance of careful regulation of FV and/or FVIII activities in vivo. 40 Membrane-bound bovine FVa has also been shown in in vitro experiments to be inactivated by plasmin.…”

Section: Regulation Of Procoagulant Fxa-cofactor Activity Of Fvmentioning

confidence: 99%

Factor V and Thrombotic Disease

Nicolaes

Dahlbäck

2002

ATVB

177

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Abstract-The generation of thrombin by the prothrombinase complex constitutes an essential step in hemostasis, with thrombin being crucial for the amplification of blood coagulation, fibrin formation, and platelet activation. In the prothrombinase complex, the activated form of coagulation factor V (FVa) is an essential cofactor to the enzyme-activated factor X (FXa), FXa being virtually ineffective in the absence of its cofactor. Besides its procoagulant potential, intact factor V (FV) has an anticoagulant cofactor capacity functioning in synergy with protein S and activated protein C (APC) in APC-catalyzed inactivation of the activated form of factor VIII. The expression of anticoagulant cofactor function of FV is dependent on APC-mediated proteolysis of intact FV. Thus, FV has the potential to function in procoagulant and anticoagulant pathways, with its functional properties being modulated by proteolysis exerted by procoagulant and anticoagulant enzymes. The procoagulant enzymes factor Xa and thrombin are both able to activate circulating FV to FVa. The activity of FVa is, in turn, regulated by APC together with its cofactor protein S. In fact, the regulation of thrombin formation proceeds primarily through the upregulation and downregulation of FVa cofactor activity, and failure to control FVa activity may result in either bleeding or thrombotic complications. A prime example is APC resistance, which is the most common genetic risk factor for thrombosis. It is caused by a single point mutation in the FV gene ( Key Words: factor V Ⅲ activated protein C resistance Ⅲ factor V Leiden Ⅲ thrombosis Ⅲ protein C H istorically, clinical studies focusing on coagulation factor V (FV) almost exclusively described bleeding tendencies as the result of a deficiency of this procoagulant protein. In fact, the discovery of FV by the Norwegian Paul Owren 1 in 1947 was based on the identification of a patient having a severe bleeding tendency due to the deficiency of a previously unknown coagulation factor (parahemophilia, Owren's disease). FV deficiency is inherited as an autosomalrecessive disorder with an estimated frequency of 1 in 1 million. [2][3][4] Heterozygous cases are usually asymptomatic, whereas homozygous individuals show variable bleeding symptoms. A great increase in research interest in FV has been seen in recent years, but this has not been in the context of bleeding problems but rather in association with thrombosis studies. The reason for the explosive increase of clinical and biochemical interest in FV originates from the discovery of activated protein C (APC) resistance, a laboratory phenotype originally identified in a single patient with venous thrombosis. 5 APC resistance, which is characterized by a reduced anticoagulant response to APC, was subsequently found to be the most common risk factor for thrombosis. The strict correlation of the APC resistance to a single point mutation in the gene for FV (factor V Leiden [FV Leiden ] or FV R506Q), occurring in Ϸ3% to 15% of the general Caucasian population...

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

Cited by 27 publications

References 48 publications

Species-specific anticoagulant and mitogenic activities of murine protein S

Species-specific anticoagulant and mitogenic activities of murine protein S

Antithrombotic and anticoagulant effects of wild type and Gla-domain mutated human activated protein C in rats

Factor V and Thrombotic Disease

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