Protein C Pathway in Paediatric and Neonatal Sepsis

Abstract

Protein C plays a major role in the physiological regulation of coagulation pathways through inactivation of factor Va, factor VIIIa, and plasminogen activator inhibitor. Protein C is involved in the control of inflammation during sepsis, by inhibiting release of pro-inflammatory cytokines, thereby controlling neutrophil, and monocyte effects on injured tissue. Recombinant human activated protein C (rhAPC) reduced mortality in adult sepsis in earlier studies but had no significant benefit in more recent trials. Protein C levels are reduced during paediatric and neonatal sepsis, which may play a major role in the development of disseminated intravascular thrombosis, purpura fulminans, and multiorgan dysfunction. The role of protein C in paediatric sepsis requires further clinical and immunological evaluation to define the patient subgroups who may benefit from this therapy. Newer versions of rhAPC are under development with less risk of haemorrhage potentially broadening the scope of this intervention.

Keywords: activated protein C; coagulation; neonatal sepsis; paediatric sepsis; rhAPC.

Figure 1

Protein C activation: Protein C binds with thrombin (T)-thrombomodulin (TM) complex on endothelial surface with it is receptor endothelial protein C receptor (EPCR), resulting in activation of protein C (APC). APC proteolytically inactivates FVa and FVIIIa, therefore APC is an important inhibitor of the clotting cascade. APC also inhibits plasminogen activator inhibitor-1 (PAI-1) enhancing profibrinolytic activity.

Figure 2

Pathophysiology of Protein C in Sepsis: during sepsis, bacteria release endotoxins (LPS, LPI, LBP), these endotoxins bind to different receptors on neutrophils and monocytes and stimulate inflammatory cytokine release. These cytokines promote thrombin generation by upregulation of tissue factor (TF) expression on monocytes and endothelium. Inflammatory cytokines also inhibit protein C synthesis in the liver and reduce thrombomodulin (TM) and endothelial protein C receptor (EPCR) expression, and thereby inhibit APC formation. Recombinant human activated protein C (rhAPC) enhances neutrophils and monocytes apoptosis and therefore inhibits cytokines release and reducing tissue damage.