The protein C anticoagulant pathway serves as a major system for controlling thrombosis,
limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis
in response to inflammatory cytokines and ischemia. The essential components of the
pathway involve thrombin, thrombomodulin, the endothelial cell protein C receptor
(EPCR), protein C, and protein S. Thrombomodulin binds thrombin, directly inhibiting
its clotting and cell activation potential while at the same time augmenting protein
C (and thrombin activatable fibrinolysis inhibitor [TAFI]) activation. Furthermore,
thrombin bound to thrombomodulin is inactivated by plasma protease inhibitors > 20
times faster than free thrombin, resulting in increased clearance of thrombin from
the circulation. The inhibited thrombin rapidly dissociates from thrombomodulin, regenerating
the anticoagulant surface. Thrombomodulin also has direct anti-inflammatory activity,
minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial
cell adhesion. EPCR augments protein C activation approximately 20-fold in vivo by
binding protein C and presenting it to the thrombin-thrombomodulin activation complex.
Activated protein C (APC) retains its ability to bind EPCR, and this complex appears
to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory
cytokine formation (tumor necrosis factor, interleukin-6). Once APC dissociates from
EPCR, it binds to protein S on appropriate cell surfaces where it inactivates factors
Va and VIIIa, thereby inhibiting further thrombin generation. Clinical studies reveal
that deficiencies of protein C lead to microvascular thrombosis (purpura fulminans).
During severe sepsis, a combination of protein C consumption, protein S inactivation,
and reduction in activity of the activation complex by oxidation, cytokine-mediated
down-regulation, and proteolytic release of the activation components sets in motion
conditions that would favor an acquired defect in the protein C pathway, which in
turn favors microvascular thrombosis, increased leukocyte adhesion, and increased
cytokine formation. APC has been shown clinically to protect patients with severe
sepsis. Protein C and thrombomodulin are in early stage clinical trials for this disease,
and each has distinct potential advantages and disadvantages relative to APC.