Factor VIIa-catalyzed activation of factor X independent of tissue factor:
its possible significance for control of hemophilic bleeding by infused
factor VIIa
LV Rao and SI Rapaport
Department of Medicine, UCSD Medical Center 92103.
Infusing factor VIIa (FVIIa) has been reported to control bleeding in
hemophilic patients with factor VIII (FVIII) inhibitors. This is difficult
to attribute to an enhanced FVIIa/tissue factor (TF) activation of factor
X, since in vitro studies suggest that infusion of FVIIa should neither
increase substantially the rate of formation of FVIIa/TF complexes during
hemostasis (Proc Natl Acad Sci USA 85:6687, 1988) nor bypass the dampening
of TF-dependent coagulation by the extrinsic pathway inhibitor (EPI) (Blood
73:359, 1989). Partial thromboplastin times have also been reported to
shorten after infusion of FVIIa. The experiments reported herein establish
that shortening of partial thromboplastin times after adding FVIIa to
hemophilic plasma in vitro stems from an FVIIa-catalyzed activation of
factor X independent of possible trace contamination of reagents with TF.
Experiments in purified systems confirmed that FVIIa can slowly activate
factor X in a reaction mixture containing Ca2+ and phospholipid but no
source of TF. The rate of activation was sufficient to account for the
shortening of partial thromboplastin times observed. EPI, which turned off
continuing FVIIa/TF activation of factor X, was unable to prevent
continuing FVIIa/phospholipid activation of factor X. Because circulating
plasma contains only a trace, if any, free FVIIa, such a reaction could
never occur physiologically. However, infusing FVIIa creates a
nonphysiologic circumstance in which a continuing slow FVIIa/phospholipid
catalyzed activation of factor X could conceivably proceed in vivo
unimpeded by EPI. Such a mechanism of factor X activation might compensate
for an impaired factor IXa/FVIIIa/phospholipid activation of factor X
during hemostatis, and therefore control bleeding in a hemophilic patient.
Volume 75,
Issue 5,
pp. 1069-1073,
03/01/1990
Copyright © 1990 by The American Society of Hematology
