A1 subunit-mediated regulation of thrombin-activated factor VIII A2 subunit dissociation

The Journal of Biological Chemistry
E T ParkerP Lollar

Abstract

Factor VIII (fVIII) is the plasma protein that is missing or deficient in hemophilia A. In contrast, elevated levels of fVIII are associated with an increased risk of arterial and venous thrombosis. fVIII is activated by thrombin to form a non-covalently linked A1/A2/A3-C1-C2 heterotrimer. At physiological concentrations, fVIIIa decays as a result of A2 subunit dissociation, which may help regulate the balance between hemostasis and thrombosis. A2 subunit dissociation is faster in human fVIIIa than in porcine fVIIIa, which may represent an evolutionary adaptation associated with the development of the upright posture and venous stasis in the lower extremities. To investigate the basis for the different decay kinetics of human and porcine fVIIIa, hybrid fVIII molecules representing all possible combinations of human and porcine A domains were isolated. The kinetics of fVIIIa decay were measured and fit to a model describing a reversible bimolecular reaction in which the dissociation rate constant, k, and dissociation constant, Kd, were the fitted parameters. Substitution of the porcine A1 domain into human fVIIIa produced a dissociation rate constant indistinguishable from porcine fVIIIa. Subsequently, substitution of the second...Continue Reading

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Citations

Nov 18, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·H Trent SpencerChristopher B Doering
Apr 5, 2008·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Herm Jan M BrinkmanKoen Mertens
Nov 16, 2012·PloS One·Philip M ZakasChristopher B Doering
Mar 21, 2007·Journal of Thrombosis and Haemostasis : JTH·H WakabayashiP J Fay
Jan 26, 2013·Blood·Rebecca C MarkovitzPete Lollar
Nov 1, 2016·Nature Biotechnology·Philip M ZakasChristopher B Doering
Feb 27, 2008·The Journal of Biological Chemistry·Hironao Wakabayashi, Philip J Fay
Aug 28, 2019·Journal of Thrombosis and Haemostasis : JTH·Ian W SmithPaul Clint Spiegel
Jan 30, 2021·Blood·Amelia R WilhelmLindsey A George

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