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Measurement of Factor V Activity in Human Plasma Using a Microplate Coagulation Assay
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Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

Hai Po H Liang1, Edward J Kerschen1, Sreemanti Basu1

  • 1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI;

Blood
|September 6, 2015
PubMed

Insights

Activated protein C (aPC) has dual roles in coagulation and cell signaling. This study reveals protein S and factor V as crucial cofactors for aPC's anti-inflammatory signaling, vital in sepsis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Immunology
  • Hematology

Background:

  • Activated protein C (aPC) is a key molecule in the protein C pathway with diverse effects on coagulation, fibrinolysis, and inflammation.
  • Coagulation-independent cell signaling by aPC is considered the primary driver of its therapeutic efficacy in various injury and infection models.
  • Understanding the specific mechanisms of aPC's functions is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the disease stage-specific effects of aPC's anticoagulant and cell signaling functions in a mouse model of Staphylococcus aureus sepsis.
  • To elucidate the role of factor V (fV) and protein S as cofactors in aPC-mediated inhibition of inflammatory signaling.
  • To determine the structural and functional relationship between aPC's anticoagulant and anti-inflammatory cofactor activities.

Main Methods:

  • Utilized a mouse model of Staphylococcus aureus sepsis.
  • Employed aPC resistance of factor V (fV) via the R506Q Leiden mutation to differentiate anticoagulant and signaling effects.
  • Investigated the necessity of procofactor V and protein S for aPC-mediated inhibition of inflammatory tissue-factor signaling.

Main Results:

  • Factor V (fV) R506Q mutation protected against aPC's anticoagulant effects but abolished the anti-inflammatory and mortality-reducing benefits of signaling-selective 5A-aPC.
  • Procofactor V and protein S were identified as essential cofactors for aPC-mediated inhibition of inflammatory tissue-factor signaling.
  • The anti-inflammatory cofactor function of fV utilized the same structural features as its anticoagulant cofactor function, independent of proteolysis of factors Va and VIIIa.

Conclusions:

  • Protein S and the aPC-cleaved form of fV act as cofactors for aPC's anti-inflammatory cell signaling.
  • This reveals a novel biological function of the protein C pathway in regulating inflammation during endotoxemia and infection.
  • These findings highlight the distinct yet interconnected roles of aPC's anticoagulant and signaling pathways.

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