¬¬¬Role of Activated Protein C (APC) in Sepsis

Abstract

S epsis is defined as systematic inflammatory response syndrome (SIRS) caused by infection. Levels of severity vary widely depending on the presence of shock and organ failure. Sepsis is a leading cause of morbidity and mortality in intensive care units. Due to its significant impact on global health, every effort has been made to improve the survival of patients with sepsis. One such initiative is the Surviving Sepsis Campaign (SSC) with the objective of reducing mortality from sepsis by 25%. Prompt recognition of the septic patient is critical, and early localization along the sepsis spectrum of illness (sepsis, severe sepsis, septic shock) helps to define the early goals of management. A key distinction should be made between sepsis and severe sepsis/septic shock (SS/SS), the latter of which are the focus of the Surviving Sepsis Campaign guidelines. It is recommended that patients with SS/SS undergo a protocol-driven approach to treatment using quantitative resuscitation. APC is an endogenous protein with the ability to modulate both inflammation and coagulation. Protein C is made in the liver and circulates as a plasma zymogen (an inactive precursor of a protease). Protein C is "activated" to become APC on the endothelial surface by the thrombin-thrombomodulin complex. Several studies have reported that the level of APC is low in septic patients and these levels predict the outcome. Activated protein C (aPC) has pleiotropic biological effects and plays a pivotal role in modulating the severe inflammatory response which occurs in sepsis. Its biological effects include, but are not limited to, reduction of thrombin production by inactivating factors Va and VIII, and inhibition of IL-1, IL-6 and TNF-α production by monocytes. A novel therapy, infusion of activated protein C(recombinant activated protein C) , an agent with multiple mechanisms of action (antithrombotic, profibrinolytic, and anti-inflammatory), in patients with sepsis significantly reduced morbidity and mortality in a large phase 3 clinical trials. In reviewing the current clinical trials, there is ongoing debate about the effectiveness of severe sepsis therapies, in several large, multicenter randomized controlled trials (RCTs). Concerns remain about the therapy’s effectiveness, both overall and for particular patient subgroups.APC may be best reserved for individuals with severe sepsis at a high risk of death (APACHE >25).