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In vivo and in vitro complexes of activated protein C with two inhibitors
in baboons
F Espana, A Gruber, MJ Heeb, SR Hanson, LA Harker and JH Griffin
Committee on Vascular Biology, Scripps Clinic and Research Foundation, La
Jolla, CA.
In vivo complex formation of activated protein C with protein C inhibitor
(APC-PCI) and with alpha 1-antitrypsin (APC-alpha 1AT) following infusion
of 0.25 or 1.0 mg APC/kg in 1 hour into baboons was studied using
immunoblotting and sandwich enzyme-linked immunosorbent assay (ELISA)s.
Before APC infusion, detectable plasma levels (about 30 ng/mL) of APC-alpha
1AT complex were found in the baboon plasma. At the lower APC dose, APC-PCI
and APC-alpha 1AT complex levels were 1.4 +/- 0.3 (mean +/- SD) and 0.8 +/-
0.1 microgram/mL after 1 hour of infusion. At the higher APC dose, the
APC-PCI level was similar to the APC-alpha 1AT level during the first 30
minutes, but after 1 hour of infusion the APC-alpha 1AT level was higher
than the APC-PCI level, reaching 4.1 +/- 1.2 and 2.9 +/- 1.2 microgram/mL,
respectively. After 24 hours, complex levels had returned to basal
conditions. During infusion of protein C (1.0 mg/kg in 1 hour), both
complexes were detected in low concentrations. Following bolus injection of
APC, half- lives (t1/2) for APC and APC-PCI and APC-alpha 1AT complexes of
10, 40, and 140 minutes, respectively, were observed. After 1-hour
incubation with 2.5 micrograms/mL APC, baboon plasma contained 1.0 +/- 0.2
and 0.8 +/- 0.1 microgram/mL of APC-PCI and APC-alpha 1AT, respectively.
Addition of 10 micrograms/mL APC to baboon plasma yielded 2.5 and 2.4
micrograms/mL APC-PCI and APC-alpha 1AT after 1 hour, respectively.
Immunoblotting analysis also showed in vivo formation of complexes of APC
with an auxilliary inhibitor but not in vitro in citrated plasma. These
data show that both PCI and alpha 1AT are physiologic inhibitors of APC and
suggest that when PCI is depleted by a high dose of APC, alpha 1AT becomes
the major inhibitor of APC.
Volume 77,
Issue 8,
pp. 1754-1760,
04/15/1991
Copyright © 1991 by The American Society of Hematology
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