Protective mechanisms of activated protein C in severe inflammatory disorders

Area of Science:

• Biochemistry
• Physiology
• Pharmacology

Background:

• The protein C system is a key anticoagulant mechanism involving activated protein C (APC).
• APC exhibits cytoprotective effects, including anti-inflammatory and anti-apoptotic properties, mediated via co-receptors like EPCR and PAR-1.
• Dysregulation of the protein C system is implicated in acute lung injury and severe sepsis, characterized by inflammation, coagulation, and fibrinolysis issues.

Purpose of the Study:

• To explore the multifaceted roles of the protein C system and APC beyond anticoagulation.
• To review the development of APC variants with enhanced cytoprotective and reduced anticoagulant activities.
• To assess the clinical efficacy of recombinant human APC (rhAPC) in sepsis and acute lung injury.

Main Methods:

• Review of existing literature on the protein C system's structure-function relationships and biological effects.
• Analysis of clinical trial data, including the PROWESS trial for severe sepsis and subsequent studies in other populations.
• Investigation into the mechanisms underlying APC's cytoprotective and anticoagulant actions.

Main Results:

• APC possesses significant anticoagulant and cytoprotective functions, crucial for maintaining vascular integrity.
• rhAPC demonstrated reduced mortality in severe sepsis patients (PROWESS trial).
• Subsequent clinical trials in acute lung injury and less severe sepsis populations did not confirm these benefits, posing challenges for APC therapy.

Conclusions:

• The protein C system is vital for hemostasis and cytoprotection, with APC playing a central role.
• While rhAPC showed promise in severe sepsis, its broader clinical application is not supported by current evidence.
• Further research is needed to elucidate APC's mechanisms and identify optimal therapeutic strategies.