The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining the permeability of blood vessel walls in humans and other animals.

Research into the clinical use of a recombinant form of human Activated Protein C (rhAPC) known as Drotrecogin alfa-activated, branded Xigris by Eli Lilly and Company, has been surrounded by controversy.

[11] In October 2011, Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.

[22] In 1987 a seminal experiment was performed (Taylor et al.) whereby it was demonstrated that activated protein C prevented coagulopathy and death in baboons infused with lethal concentrations of E.

[α][5] Beginning with the PROWESS clinical trial of 2001,[26] it was recognised that many of the symptoms of sepsis may be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased.

[21]: 1215  Protein C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acid N-terminus signal peptide preceding a propeptide.

If either of these two proteins is absent in murine specimens, the mouse dies from excessive blood-clotting while still in an embryonic state.

[32]: 1983 [33]: 43335  On the endothelium, APC performs a major role in regulating blood clotting, inflammation, and cell death (apoptosis).

[5]: 6823 The protein C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body.

When still bound to EPCR, activated protein C performs its cytoprotective effects, acting on the effector substrate PAR-1, protease-activated receptor-1.

To a degree, APC's anticoagulant properties are independent of its cytoprotective ones, in that expression of one pathway is not affected by the existence of the other.

Activated leukocytes release these inflammatory mediators during inflammation, inhibiting the creation of both thrombomodulin and EPCR, and inducing their shedding from the endothelial surface.

[9]: 3162 Treatment of cells with APC demonstrates that its gene expression modulation effectively controls major pathways for inflammatory and apoptotic behaviour.

APC's mechanisms for altering gene expression profiles are not well understood, but it is believed that they at least partly involve an inhibitory effect on transcription factor activity.

APC affects endothelial cells by inhibiting inflammatory mediator release and down-regulating vascular adhesion molecules.

Studies on both rats and humans have demonstrated that APC reduces endotoxin-induced pulmonary injury and inflammation.

[9]: 3164 Scientists recognise activated protein C's antiapoptotic effects, but are unclear as to the exact mechanisms by which apoptosis is inhibited.

[9]: 3165 Several studies have indicated that the proteolytic activity of APC contributes to the observed cytoprotective properties of APC, but variants that are proteolytically inactive also are able to regulate formation of PAR-activators thrombin and factor Xa and express cytoprotective properties in vitro and in vivo.

[37][38] A genetic protein C deficiency, in its mild form associated with simple heterozygosity, causes a significantly increased risk of venous thrombosis in adults.

Fetal mice with no protein C develop normally at first, but experience severe bleeding, coagulopathy, deposition of fibrin and necrosis of the liver.

The most common mutation leading to activated protein C resistance among Caucasians is at the cleavage site in Factor V for APC.

[41]: 3  Individuals heterozygous for the Factor VLeiden mutation carry a risk of venous thrombosis 5–7 times higher than in the general population.

A variant of this response presents as venous limb gangrene when warfarin is used to treat deep vein thrombosis associated with cancer.

In these situations, warfarin may be restarted at a low dosage to ensure that the protein C deficiency does not present before the vitamin K coagulation factors II, IX and X are suppressed.

[42] In November 2001, the Food and Drug Administration approved Drotrecogin alfa-activated (DrotAA) for the clinical treatment of adults suffering from severe sepsis and with a high risk of death.

It is marketed as Xigris by Eli Lilly and Company,[27]: 224 Drotrecogin alfa-activated was the subject of significant controversy while it was approved for clinical use as it was found to increase bleeding and not to reduce mortality.

[44][needs update] In October 2011 rhAPC (Xigris) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.

[9]: 3167, 8  APC also has been considered for use in improving patient outcome in cases of ischemic stroke, a medical emergency in which arterial blockage deprives a region of brain of oxygen, causing tissue death.

[45]: 211  Clinical use of APC has also been proposed for improving the outcome of pancreatic islet transplantation in treating type I diabetes.

[46] Ceprotin is indicated in purpura fulminans and coumarin-induced skin necrosis in people with severe congenital protein C deficiency.