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
References
May 1, 1992·The Journal of Clinical Investigation·A M Aly, L W Hoyer
Jan 24, 1989·Biochemistry·P Lollar, C G Parker
Sep 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·D C Hill-EubanksP Lollar
Dec 30, 1986·Biochemistry·D L EatonC Gorman
Jan 28, 1986·Biochemistry·D EatonG A Vehar
Apr 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·D D Pittman, R J Kaufman
Dec 31, 1985·Biochemistry·P LollarD N Fass
Nov 22, 1984·Nature·G A VeharD J Capon
Nov 18, 1981·Biochimica Et Biophysica Acta·A LajmanovichG Marguerie
Oct 15, 1981·The Biochemical Journal·L O Andersson, J E Brown
Jun 16, 1995·The Journal of Biological Chemistry·J F HealeyP Lollar
Aug 15, 1995·European Journal of Biochemistry·P LindH Sandberg
Apr 14, 1995·The Journal of Biological Chemistry·L M Regan, P J Fay
Sep 1, 1993·British Journal of Haematology·K MertensJ A van Mourik
Jan 1, 1993·Methods in Enzymology·R M HortonL R Pease
Nov 1, 1995·Protein Science : a Publication of the Protein Society·C N PaceT Gray
Jun 7, 1996·The Journal of Biological Chemistry·C T Esmon, P Lollar
Aug 1, 1996·British Journal of Haematology·Z RudzkiJ V Lloyd
Nov 14, 1997·Current Opinion in Biotechnology·N G Seidah, M Chrétien
Nov 11, 1999·British Journal of Haematology·D M KeelingJ V Lloyd
May 8, 2001·Annual Review of Biophysics and Biomolecular Structure·E Evans
May 23, 2001·Arteriosclerosis, Thrombosis, and Vascular Biology·P W KamphuisenR M Bertina
Jul 26, 2002·The Journal of Biological Chemistry·Christopher B DoeringPete Lollar
Dec 9, 2003·The Journal of Biological Chemistry·Christopher B DoeringPete Lollar
Citations
Aug 7, 2007·Biochemistry·Ernest T Parker, Pete Lollar
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
Sep 13, 2007·Blood·Shannon L MeeksPete Lollar
Nov 16, 2012·PloS One·Philip M ZakasChristopher B Doering
Mar 21, 2007·Journal of Thrombosis and Haemostasis : JTH·H WakabayashiP J Fay
Jun 22, 2014·Biochemical and Biophysical Research Communications·Divi Venkateswarlu
Jan 26, 2013·Blood·Rebecca C MarkovitzPete Lollar
Aug 3, 2012·Blood·Shannon L MeeksPete Lollar
Jan 11, 2011·Blood·Ryan J SummersPete 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
Jul 7, 2016·Blood·Glaivy BatsuliShannon L Meeks
Jan 30, 2021·Blood·Amelia R WilhelmLindsey A George