Progress in the understanding of the protein C anticoagulant pathway.
A natural anticoagulant pathway denoted the protein C system provides specific and efficient control of blood coagulation. Protein C is the key component of the system and circulates in the blood as a zymogen to an anticoagulant serine protease. Activation of protein C is achieved on the surface of endothelial cells by thrombin bound to the membrane protein thrombomodulin. The endothelial protein C receptor stimulates the activation of protein C on the endothelium. Activated protein C (APC) modulates blood coagulation by cleaving a limited number of peptide bonds in factor VIIIa (FVIIIa) and factor Va (FVa), cofactors in the activation of factor X and prothrombin, respectively. Vitamin K-dependent protein S stimulates the APC-mediated regulation of coagulation. Not only is protein S involved in the degradation of FVIIIa, but so is FV, which in recent years has been found to be a Janus-faced protein with both procoagulant and anticoagulant potentials. A number of genetic defects affecting the anticoagulant function of the protein C system, eg, APC resistance (Arg506Gln or FV Leiden) and deficiencies of protein C and protein S constitute major risk factors of venous thrombosis. The protein C system also has anti-inflammatory and antiapoptotic potentials, the molecular mechanisms of which are beginning to be unraveled. APC has emerged in recent years as a useful therapeutic compound in the treatment of severe septic shock. The beneficial effect of APC is believed be due to both its anticoagulant and its anti-inflammatory properties.
Dahlbäck
Björn
B
Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, The Wallenberg Laboratory, University Hospital, Malmö, Malmö, Sweden. bjorn.dahlback@klkemi.mas.lu.se
D001777:Blood Coagulation / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000378:metabolism*; D006801:Humans; D011486:Protein C / Q000378:metabolism*
D001779:Blood Coagulation Factors; D011486:Protein C