Effects of prothrombin on the individual activated protein C-mediated cleavages of coagulation factor Va

The Journal of Biological Chemistry
Sinh TranB Dahlbäck

Abstract

The factor Va (FVa) inactivation by activated protein C (APC), mediated by cleavages at Arg306 and Arg506 in FVa, is inhibited by both factor Xa (FXa) and prothrombin. Although FXa is known to specifically inhibit the Arg506 cleavage, the effect of prothrombin has not been confined to one cleavage site. We used recombinant FV variants, FV:R506Q/R679Q and FV:R306Q/R679Q, to investigate the effect of prothrombin on the individual cleavage sites. The APC-mediated FVa inhibition was monitored by a prothrombinase-based FVa assay, and apparent first order rate constants were calculated for each of the cleavage sites both in the presence and absence of prothrombin. Prothrombin impaired cleavages at both Arg306 and Arg506 and the inhibition correlated with a delayed appearance of proteolytic products on Western blots. Almost complete inhibition was obtained at around 3 microm prothrombin, whereas half-maximal inhibition was obtained at 0.7 microm prothrombin. After cleavage of prothrombin by thrombin, the inhibitory activity was lost. The inhibitory effect of prothrombin on APC-mediated inhibition of FVa was seen both in the presence and absence of protein S, but in particular for the Arg306 sites, it was more pronounced in the presenc...Continue Reading

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Citations

Oct 16, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jeremy P WoodAlan E Mast
May 21, 2010·The Journal of Biological Chemistry·Gerry A F NicolaesJan Rosing
Dec 17, 2011·The Journal of Trauma·Sandro B RizoliHomer C Tien
May 27, 2010·Pathophysiology of Haemostasis and Thrombosis·Thomas J CramerAndrew J Gale
Aug 28, 2013·The Journal of Clinical Investigation·Lisa M VincentBjörn Dahlbäck
May 23, 2012·BMC Systems Biology·Maria Cristina BravoStephen J Everse
Dec 17, 2009·Journal of Thrombosis and Haemostasis : JTH·E Castoldi, J Rosing
Oct 31, 2009·Journal of Thrombosis and Haemostasis : JTH·S Tran, B Dahlbäck
Jul 8, 2015·Journal of Thrombosis and Haemostasis : JTH·S A Maroney, A E Mast
Apr 20, 2017·The Journal of Biological Chemistry·Salvatore SantamariaJosefin Ahnström
Oct 8, 2009·Expert Review of Hematology·Mary J Heeb
Jan 9, 2009·The Journal of Biological Chemistry·Roger J S PrestonJames S O'Donnell
Jul 24, 2020·Journal of Thrombosis and Haemostasis : JTH·Magdalena Gierula, Josefin Ahnström
May 19, 2019·Journal of Thrombosis and Haemostasis : JTH·Mark SchreuderMettine H A Bos

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