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A qualitative and quantitative analysis of the activation and inactivation
of protein C in vivo in a primate model
H Hoogendoorn, ME Nesheim and AR Giles
Department of Pathology, Queen's University, Kingston, Ontario, Canada.
A model of Protein C (PC) activation in vivo was used to investigate the
complexing of activated PC (APC) with its plasma inhibitors, PC inhibitor
(PCI) and alpha 1-antitrypsin (alpha 1AT). Chimpanzees were infused with a
bolus of activated factor X (F.Xa) together with vesicles of
phosphatidylcholine and phosphatidylserine (PCPS). Pre- and post-infusion
plasma samples were analyzed using enzyme linked immunosorbent based assays
(ELISA) for PC and APC complexes, and immunoblotting of PC from
nondenaturing polyacrylamide gel electrophoresis. Within 2 minutes of
infusion, a 60% decrease in nonactivated PC zymogen (PCz) levels was
observed. This coincided with a precipitous drop in plasma activities of
cofactors VIIIa and Va. In contrast, total PC antigen (PCt) levels
decreased by only 1%, indicating APC generation. Complexes of APC with both
PCI and alpha 1AT were observed on immunoblots, and further identified and
quantified using a sandwich ELISA employing antibodies to both PC and these
inhibitors. The distribution of APC between these two inhibitors varied
with the dose of F.Xa/PCPS infused. At a dose of F.Xa/PCPS of 24.05 pmol
and 37.70 nmol/kg, respectively, an initial spike of APC generation,
associated with decreases in the levels of factors VIIIa and Va, was noted
but dissipated over the next 30 minutes. During this period, APC/inhibitor
complexes appeared with the levels of APC-PCI and APC-alpha 1AT reaching
8.5 nmol/L and 2.2 nmol/L by 30 minutes, respectively. In contrast, at a
higher dose of F.Xa/PCPS of 36.60 pmol and 56.30 nmol/Kg respectively,
complexes of APC-alpha 1AT appeared rapidly and reached a level of 6 nmol/L
by 30 minutes postinfusion, whereas APC-PCI complexes were only present at
a concentration of 3.4 nmol/L by this time. Additional experiments with
lower doses of F.Xa/PCPS suggest that PCI is the preferred inhibitor of
APC, but as the availability of this inhibitor becomes limiting, alpha 1AT
plays an increasingly crucial role as a secondary inhibitor of endogenously
generated APC. Moreover, evidence is presented suggesting the existence of
additional inhibitor(s) of APC that may have a role similar to alpha 1AT.
Volume 75,
Issue 11,
pp. 2164-2171,
06/01/1990
Copyright © 1990 by The American Society of Hematology
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