alpha(2)-Macroglobulin Is a Significant In Vivo Inhibitor of Activated Protein C and Low APC: alpha M-2 Levels Are Associated with Venous Thromboembolism

Autores de IIS La Fe

• Laura Martos Marin

  Autor

• Luis Andres Ramon Nuñez

  Autor

• Ana Julia Oto Martínez

  Autor

• Álvaro Fernández Pardo

  Autor

• Santiago Bonanad Boix

  Autor

• Ana Rosa Cid Haro

  Autor

• Francisco España Furio

  Autor

• Silvia Navarro Rosales

  Autor

• 

  Pilar Medina Badenes

  Autor

Participantes ajenos a IIS La Fe

• Gruber, A
• Griffin, JH

Grupos

• Hemostasia, Trombosis, Arteriosclerosis y Biología vascular

  

  Investigador Principal

  Pilar Medina Badenes

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 (1) -antitrypsin ( (1) AT), and these complexes have been quantified by specific enzyme-linked immunosorbent assays (ELISAs). Also, complexes of APC with (2) -macroglobulin ( (2) M) have been observed by immunoblotting. Here, we report an ELISA for APC: (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: (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 (2) M, PCI and (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, (2) M was a significant APC inhibitor. The VTE case-control study showed that VTE patients had significantly lower APC: (2) M and APC levels than the controls ( p <0.001). Individuals in the lowest quartile of APC: (2) M or the lowest quartile of APC had approximately four times more VTE risk than those in the highest quartile of APC: (2) M or of APC. The risk increased for individuals with low levels of both parameters. Conclusion The APC: (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: (2) M level is associated with increased VTE risk.

Keywords

• activated protein C; 2-macroglobulin; ELISA; baboon; complexes