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Related Experiment Videos

Activated protein C.

J H Griffin1, J A Fernández, A J Gale

  • 1Division of Translational Vascular Medicine, Department of Molecular and Experimental Medicine (MEM-180), The Scripps Research Institute, La Jolla, CA, USA. jgriffin@scripps.edu

Journal of Thrombosis and Haemostasis : JTH
|August 1, 2007
PubMed
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Activated protein C (APC) has dual roles in preventing blood clots and protecting cells. Engineered APC variants offer targeted therapies with reduced bleeding risks and improved survival rates.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Protein C is a vitamin K-dependent plasma protein.
  • Deficiencies in Protein C are linked to thrombosis and purpura fulminans.
  • Activated protein C (APC) traditionally inactivates factors Va and VIIIa, down-regulating thrombin generation.

Purpose of the Study:

  • To explore the direct cytoprotective effects of APC beyond its anticoagulant properties.
  • To investigate the potential of engineered APC variants for therapeutic applications.
  • To differentiate the molecular mechanisms underlying APC's antithrombotic and cytoprotective actions.

Main Methods:

  • Review of basic and preclinical research on APC's cytoprotective effects.
  • Analysis of studies involving endothelial cell protein C receptor (EPCR) and protease activated receptor-1.

Related Experiment Videos

  • Examination of engineered recombinant APC variants with selective activities.

    • Main Results:

    • APC exhibits direct cytoprotective effects including gene expression modulation, anti-inflammatory and anti-apoptotic activities, and endothelial barrier stabilization.
    • APC reduces mortality in preclinical models of endotoxemia and sepsis, and in human sepsis patients (PROWESS trial).
    • Engineered APC variants demonstrate distinct anticoagulant and cytoprotective activities, allowing for tailored therapeutic profiles.

    Conclusions:

    • APC possesses significant cytoprotective functions mediated through EPCR and PAR-1.
    • APC variants can be developed to selectively enhance cytoprotective or anticoagulant effects.
    • APC variants with reduced anticoagulant activity but retained cytoprotective actions may offer safer therapeutic options with reduced bleeding risk.