Activated protein C (APC) is a naturally occurring protein in the human body that plays a role in maintaining the delicate balance of various physiological processes. It is a serine protease, a type of enzyme that breaks down proteins. APC participates in regulating blood clotting, modulating inflammatory responses, and protecting cells from damage. Understanding APC’s functions offers insights into how the body manages complex systems like hemostasis and immune responses.
What is Activated Protein C?
Activated protein C originates from its inactive precursor, Protein C. Protein C is a vitamin K-dependent glycoprotein produced primarily in the liver. The activation of Protein C into APC is a regulated process that occurs on the surface of endothelial cells.
The conversion of Protein C into APC is primarily facilitated by thrombin, a key enzyme in blood coagulation. This activation is enhanced by thrombomodulin, a protein on the surface of endothelial cells. The endothelial protein C receptor (EPCR) further promotes this activation by binding Protein C and presenting it to the thrombin-thrombomodulin complex.
How Activated Protein C Works
Activated protein C acts as an anticoagulant by regulating blood clotting. It achieves this by inactivating two important coagulation cofactors, Factor Va and Factor VIIIa. These factors are essential in the generation of thrombin, an enzyme that converts fibrinogen into fibrin, forming a blood clot. By degrading Factor Va and Factor VIIIa, APC slows thrombin production and inhibits excessive clot formation. This process is further enhanced by Protein S, a cofactor that helps APC bind to the surfaces where these coagulation factors are assembled.
Beyond its role in anticoagulation, APC also exhibits anti-inflammatory effects. It can directly modulate immune responses by interacting with endothelial cells and leukocytes. APC influences cellular signaling networks and gene expression, for instance, by activating protease-activated receptors 1 and 3 (PAR1 and PAR3). This interaction can lead to a reduction in the expression of inflammatory cytokines, such as TNF-α, IL-6, and IL-8, and a decrease in the expression of adhesion molecules on endothelial cells, limiting the infiltration of immune cells into tissues.
APC also possesses cytoprotective properties, meaning it helps protect cells from damage and promotes cell survival. This protective action involves counteracting cellular stress and preventing programmed cell death, known as apoptosis. For example, APC can stabilize the endothelial barrier, preventing vascular leakage, which is particularly relevant in inflammatory conditions. These cytoprotective effects are mediated through signaling pathways, often involving its binding to EPCR and activation of PAR1 and other receptors.
Activated Protein C in Health and Disease
Activated protein C plays a role in maintaining hemostasis, the body’s process of stopping bleeding while also preventing excessive clotting. Its functions ensure that blood remains fluid within vessels and that clots form only when and where they are needed.
Imbalances in APC levels or activity can contribute to various health conditions. For instance, a deficiency in Protein C, the precursor to APC, can lead to an increased risk of thrombosis, which is the formation of blood clots inside blood vessels. Individuals with moderately severe protein C deficiency may experience recurrent venous thrombotic events, such as deep vein thrombosis (DVT) and pulmonary embolism (PE). Homozygous protein C deficiency, a more severe form, can manifest in newborns with life-threatening conditions like purpura fulminans, characterized by widespread blood clots and skin lesions.
Dysregulation of APC is also observed in severe inflammatory states, such as sepsis, a life-threatening condition caused by the body’s overwhelming response to infection. In sepsis, there can be a reduction in Protein C levels and activity, which contributes to a cycle of uncontrolled coagulation and inflammation, potentially leading to organ failure. The understanding of APC’s role in these complex interactions led to its exploration as a therapeutic agent.
Recombinant human activated protein C was investigated for the treatment of severe sepsis, with the aim of blunting inflammatory and coagulant responses. While initial studies showed some promise in reducing mortality in high-risk patients with severe sepsis, the therapy was eventually withdrawn due to concerns regarding bleeding risk and inconsistent efficacy across patient subgroups. Despite this, research continues into the pathways regulated by APC, with efforts to develop engineered variants that retain its anti-inflammatory and cytoprotective benefits while minimizing anticoagulant activity and associated bleeding risks.