ArticleThe Journal of biological chemistry2008
Detailed mechanisms of the inactivation of factor VIIIa by activated protein C in the presence of its cofactors, protein S and factor V.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 59 citations in OpenAlex.
- Factor IXa and factor X influence factor VIIIa stability and inactivation mechanisms in vitro and in vivo.Blood · 2025Article
- Transamniotic Delivery of Coagulation Factor VIII mRNA: A Step Toward a Potential Novel Strategy for the Perinatal Management of Hemophilia A.FASEB bioAdvances · 2025Article
- Review
- Exploring the Diversity and Function of Serine Proteases in Toxicofera Reptile Venoms: A Comprehensive Overview.Toxins · 2024Review
- The combination of Asp519Val/Glu665Val and Lys1813Ala mutations in FVIII markedly increases coagulation potential.Blood advances · 2024Article
- Factor V variants in bleeding and thrombosis.Research and practice in thrombosis and haemostasis · 2024Article
- Impaired factor V-related anticoagulant mechanisms and deep vein thrombosis associated with A2086D and W1920R mutations.Blood advances · 2023Article
- Factor VIII mutated with Lys1813Ala within the factor IXa-binding region enhances intrinsic coagulation potential.Blood advances · 2023Article
- Article
- Redox control of vascular biology.BioFactors (Oxford, England) · 2020Review
- Regulation of immune cell signaling by activated protein C.Journal of leukocyte biology · 2018Review
- Comparative response of platelet fV and plasma fV to activated protein C and relevance to a model of acute traumatic coagulopathy.PloS one · 2014Article
- Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway.Journal of thrombosis and haemostasis : JTH · 2013Review
- Protein C anticoagulant and cytoprotective pathways.International journal of hematology · 2012Review
- Function of the activated protein C (APC) autolysis loop in activated FVIII inactivation.British journal of haematology · 2011Article
- Factor V is an anticoagulant cofactor for activated protein C during inactivation of factor Va.Pathophysiology of haemostasis and thrombosis · 2010Article
- Prothrombin amino terminal region helps protect coagulation factor Va from proteolytic inactivation by activated protein C.Thrombosis and haemostasis · 2009Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Factor VIIIa is inactivated by a combination of two mechanisms. Activation of factor VIII by thrombin results in a heterotrimeric factor VIIIa that spontaneously inactivates due to dissociation of the A2 subunit. Additionally, factor VIIIa is cleaved by the anticoagulant serine protease, activated protein C, at two cleavage sites, Arg(336) in the A1 subunit and Arg(562) in the A2 subunit. We previously characterized an engineered variant of factor VIII which contains a disulfide bond between the A2 and the A3 subunits that prevents the spontaneous dissociation of the A2 subunit following thrombin activation. Thus, in the absence of activated protein C, this variant has stable activity following activation by thrombin. To isolate the effects of the individual activated protein C cleavage sites on factor VIIIa, we engineered mutations of the activated protein C cleavage sites into the disulfide bond-cross-linked factor VIII variant. Arg(336) cleavage is 6-fold faster than Arg(562) cleavage, and the Arg(336) cleavage does not fully inactivate factor VIIIa when A2 subunit dissociation is blocked. Protein S enhances both cleavage rates but enhances Arg(562) cleavage more than Arg(336) cleavage. Factor V also enhances both cleavage rates when protein S is present. Factor V enhances Arg(562) cleavage more than Arg(336) cleavage as well. As a result, in the presence of both activated protein C cofactors, Arg(336) cleavage is only twice as fast as Arg(562) cleavage. Therefore, both cleavages contribute significantly to factor VIIIa inactivation.
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