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Role of gamma-carboxyglutamic acid residues in the binding of factor IXa to
platelets and in factor-X activation
R Rawala-Sheikh, SS Ahmad, DM Monroe, HR Roberts and PN Walsh
Department of Medicine, Temple University School of Medicine, Philadelphia,
PA 19140.
To study the requirements for factor-IXa binding to platelets and factor-X
activation, we examined the consequences of chemical modification (factor
IXMOD) or enzymatic removal (factor IXDES) of gamma-carboxyglutamic acid
(Gla) residues. In the presence of factor VIIIa and factor X, there were
344 (+/- 52) binding sites/platelet for factor IXaMOD (apparent
dissociation constant [kdapp] = 4.5 +/- 0.9 nmol/L) and 275 (+/- 35)
sites/platelet for factor IXaDES (kdapp = 5.0 +/- 0.8 nmol/L) compared with
580 (+/-65) sites/platelet for normal factor IXa (factor IXaN) (kdapp =
0.61 +/- 0.1 nmol/L) and 300 (+/-62) sites/platelet for factor IX (kdapp =
2.9 +/- 0.29 nmol/L). The concentrations of factor IXaN, factor IXaMOD and
factor IXaDES required for half-maximal rates of factor-Xa formation were
0.67 nmol/L, 3.5 nmol/L, and 6.7 nmol/L. Whereas maximal velocities (Vmax)
of factor Xa formation by factor IXaMOD (approximately 0.8 nmol/L.min-1)
and factor IXaN (approximately 10.5 nmol/L.min-1), turnover numbers (kcat
expressed as moles of factor Xa formed per minute per mole of factor IXa
bound), and values of catalytic efficiency (kcat/Km) were normal,
indicating that the decreased rates of factor X activation observed with
factor IXaMOD and factor IXaDES are solely a consequence of the abnormal
binding of these proteins to thrombin-activated platelets in the presence
of factor VIIIa and factor X. Thus, factor IXa binding to platelets is
mediated in part, but not exclusively, by high-affinity Ca2+ binding sites
in the Gla domain of factor IX.
Volume 79,
Issue 2,
pp. 398-405,
01/15/1992
Copyright © 1992 by The American Society of Hematology
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