Identification of divalent metal ion-dependent inhibition of activated protein C by α2-macroglobulin and α2-antiplasmin in blood and comparisons to inhibition of Factor Xa, thrombin, and plasmin

M. J. Heeb, A. Gruber, J. H. Griffin

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62 Scopus citations

Abstract

The half-life of activated protein C (APC) was 31 min in citrated blood and 18 min in whole blood. Immunoblotting analysis of citrated blood identified APC-protein C inhibitor (APC-PCI) and APC-α1-antitrypsin complexes. Whole blood contained two additional APC-inhibitor complexes, one stimulated by Ca2+ and another by Mg2+. The former was identified as APC-α2-macroglobulin (APC-α2M) while the latter was not identified. APC-α2-antiplasmin complexes (APC-α2AP) were identified, comigrating with APC-PCI complexes. Purified α2M and α2AP inhibited APC in the presence of Ca2+ (k2 = 99 and 100 M-1 s-1, respectively. Inhibition of APC and Factor Xa by α2M and inhibition of APC by α2AP was stimulated by Ca2+, Mn2+, and Mg2+. Inhibition of thrombin by α2M and of plasmin by α2AP was not altered by EDTA or Ca2+, suggesting divalent metal ions affect APC and Factor Xa rather than the inhibitors. k2 values for the APC inhibitors and their plasma concentrations suggest that PCI and α1-antitrypsin are the more important APC inhibitors and that α2M and α2AP are metal ion-dependent auxiliary inhibitors. Inhibitors can account for the in vivo half-life of APC.

Original languageEnglish (US)
Pages (from-to)17606-17612
Number of pages7
JournalJournal of Biological Chemistry
Volume266
Issue number26
StatePublished - Nov 7 1991

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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