α 2 -Macroglobulin Is a Significant in Vivo Inhibitor of Activated Protein C and Low APC:α 2 M Levels Are Associated with Venous Thromboembolism

Laura Martos, Luis Andrés Ramón, Julia Oto, Álvaro Fernández-Pardo, Santiago Bonanad, Ana Rosa Cid, Andras Gruber, John H. Griffin, Francisco España, Silvia Navarro, Pilar Medina

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background Activated protein C (APC) is a major regulator of thrombin formation. Two major plasma inhibitors form complexes with APC, protein C inhibitor (PCI) and α 1 -antitrypsin (α 1 AT), and these complexes have been quantified by specific enzyme-linked immunosorbent assays (ELISAs). Also, complexes of APC with α 2 -macroglobulin (α 2 M) have been observed by immunoblotting. Here, we report an ELISA for APC:α 2 M complexes in plasma. Methods Plasma samples were pre-treated with dithiothreitol and then with iodoacetamide. The detection range of the newly developed APC:α 2 M assay was 0.031 to 8.0 ng/mL of complexed APC. Following infusions of APC in humans and baboons, complexes of APC with α 2 M, PCI and α 1 AT were quantified. These complexes as well as circulating APC were also measured in 121 patients with a history of venous thromboembolism (VTE) and 119 matched controls. Results In all the in vivo experiments, α 2 M was a significant APC inhibitor. The VTE case-control study showed that VTE patients had significantly lower APC:α 2 M and APC levels than the controls (p < 0.001). Individuals in the lowest quartile of APC:α 2 M or the lowest quartile of APC had approximately four times more VTE risk than those in the highest quartile of APC:α 2 M or of APC. The risk increased for individuals with low levels of both parameters. Conclusion The APC:α 2 M assay reported here may be useful to help monitor the in vivo fate of APC in plasma. In addition, our results show that a low APC:α 2 M level is associated with increased VTE risk.

Original languageEnglish (US)
Pages (from-to)630-638
Number of pages9
JournalThrombosis and Haemostasis
Volume118
Issue number4
DOIs
StatePublished - Apr 1 2018

Keywords

  • ELISA
  • activated protein C
  • baboon
  • complexes
  • α2-macroglobulin

ASJC Scopus subject areas

  • Hematology

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