Protein C is a naturally occurring plasma protein synthesized primarily in the liver, circulating in the blood as an inactive enzyme known as a zymogen. This vitamin K-dependent molecule acts as a molecular switch, maintaining the delicate balance between blood clotting and fluid blood flow. When the body requires a halt to clotting, Protein C is converted into its active form, Activated Protein C (APC). APC is a serine protease with a dual biological function, providing both potent anticoagulant activity and direct protective effects on cells lining the blood vessels.
The Coagulation Cascade and APC’s Anticoagulant Function
The primary function of Activated Protein C is to prevent the coagulation process from becoming excessive, serving as the body’s natural brake on clot formation. This anticoagulant action begins with its activation, which occurs on the surface of endothelial cells. Activation is a highly regulated process where the potent clotting enzyme thrombin binds to a receptor called thrombomodulin.
The thrombin-thrombomodulin complex transforms thrombin into an enzyme that efficiently converts the circulating inactive Protein C into the active APC. This conversion is significantly accelerated by the presence of the endothelial protein C receptor (EPCR) on the cell surface, ensuring that APC is generated precisely where it is needed. Once formed, APC dissociates from the receptor to exert its primary anticoagulant effect.
APC functions by selectively inactivating two crucial components of the coagulation cascade: Factor Va and Factor VIIIa. These two factors normally act as cofactors, greatly accelerating the steps that lead to the mass production of thrombin and the subsequent formation of the fibrin clot. By degrading the activated forms of these factors, APC significantly dampens the entire clotting mechanism.
The process of inactivating these cofactors is significantly enhanced by another vitamin K-dependent protein, Protein S, which acts as a necessary partner. Protein S binds to APC and the cell membrane surface, helping to position APC to cleave and destroy Factor Va and Factor VIIIa with greater efficiency.
The Protein C system thus provides a major regulatory loop, ensuring that the initial burst of thrombin production required for hemostasis does not spiral out of control into a life-threatening widespread thrombosis. When this system is working correctly, it rapidly restores the blood vessel lining to a non-thrombogenic state after an injury has been sealed. A failure in any part of this specific pathway directly predisposes an individual to excessive blood clotting.
Non-Coagulation Roles in Cell Protection
Beyond its well-defined role in anticoagulation, Activated Protein C possesses distinct, non-hemostatic functions that directly protect cells and tissues, collectively known as cytoprotective activities. These protective effects are mediated through a separate signaling pathway that does not rely on APC’s ability to degrade clotting factors. Instead, these functions are initiated when APC remains bound to the endothelial protein C receptor (EPCR).
While bound to EPCR, APC acts as a signaling molecule, specifically activating protease-activated receptor 1 (PAR-1) on the endothelial cell surface. This activation initiates a cascade of intracellular signaling events that promotes cell survival and maintains the integrity of the vascular lining. This signaling mechanism differs from the way thrombin activates the same receptor, which often leads to pro-inflammatory outcomes.
One significant cytoprotective function of APC is its anti-inflammatory property, which involves reducing the release of pro-inflammatory signaling molecules called cytokines. APC also helps to stabilize the endothelial barrier, preventing the leakage of fluid and cells out of the blood vessel and into the surrounding tissue, which is particularly important in conditions of severe stress.
APC also exhibits anti-apoptotic, or anti-cell death, activity in various cell types, including endothelial cells and neurons. By promoting cell survival signaling, APC helps to preserve the function of organs under stress, such as during ischemic events or systemic inflammation.
Inherited and Acquired Impairments of Protein C
Malfunctions in the Protein C system are highly significant because they directly lead to a predisposition for developing dangerous blood clots, a condition known as thrombophilia. These impairments can be broadly categorized as either inherited genetic defects or acquired conditions arising later in life. Protein C deficiency represents a rare inherited disorder where the body produces insufficient amounts of the functional protein.
Individuals who are heterozygous for Protein C deficiency face a significantly increased risk of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) or pulmonary embolism (PE). A much more severe, albeit extremely rare, condition is homozygous deficiency, where an infant inherits two non-functional genes. This results in neonatal purpura fulminans, a life-threatening disorder characterized by widespread, severe blood clotting shortly after birth.
A much more common acquired impairment is Activated Protein C Resistance (APCR), which is most frequently caused by the Factor V Leiden mutation. This specific genetic change involves a single amino acid substitution in the Factor V clotting protein, rendering it resistant to inactivation by APC. In effect, the body’s natural brake on clotting is unable to effectively turn off the pro-clotting Factor V.
Factor V Leiden is the most common inherited cause of thrombophilia among people of European descent. Carriers of this mutation have a Factor Va that is degraded at a much slower rate than normal, leading to a prolonged pro-coagulant state and an increased risk of VTE. This inherited resistance is often asymptomatic until combined with other risk factors, such as surgery, pregnancy, or oral contraceptive use.
The History of APC as a Sepsis Treatment
The dual anti-thrombotic and anti-inflammatory properties of Activated Protein C led to its investigation as a therapeutic agent for severe sepsis, a life-threatening condition driven by systemic infection and uncontrolled inflammation. This research resulted in the development of drotrecogin alfa (activated), a recombinant form of human APC marketed under the trade name Xigris. The drug was intended to address the widespread microvascular clotting and dysregulated inflammation seen in septic patients.
Xigris received initial approval in the United States in 2001 for adult patients with severe sepsis based primarily on results from the PROWESS trial, which suggested a reduction in mortality among high-risk patients. The premise was that supplementing the body’s natural APC, often depleted or inhibited during severe sepsis, could restore balance to the coagulation and inflammatory systems.
However, the approval was controversial, partly due to concerns over the single pivotal trial and the significant side effect of increased bleeding risk, which is inherent to any potent anticoagulant. Subsequent, larger clinical trials were conducted to confirm the drug’s efficacy and safety. These post-market studies, including the PROWESS-SHOCK trial, failed to replicate the initial survival benefit.
The PROWESS-SHOCK trial showed no reduction in mortality and highlighted the increased incidence of serious bleeding events associated with the drug. Because the therapy failed to demonstrate a favorable risk-benefit profile in the definitive trials, Eli Lilly and Company voluntarily withdrew Xigris from the global market in October 2011. This outcome concluded the drug’s decade-long history as the only approved pharmacological treatment specifically for severe sepsis.