Last update:
11-Jul-2004

Arch Hellen Med, 2000, 17(Supplement):19-25

LECTURE

Regulation of coagulation by the antithrombotic protein C pathway

J.H. GRIFFIN
Department of Molecular & Experimental Medicine,
The Scripps Research Institute, La Jolla, California 92037 USA

The majority of hereditary thrombophilia defects involves the antithrombotic protein C pathway which includes protein C and protein S as anticoagulant factors, thrombomodulin and endothelial protein C receptor as cofactors for activation of protein C, and factors Va and VIIIa as substrates for activated protein C. Activated protein C (APC) is a normal circulating anticoagulant that is generated from the protein C zymogen by proteolysis. Ischemia induces generation of APC in the brain and heart. APC resistance represents a poor anticoagulant response to APC. Variant factor V containing Gln506 in place of Arg506 (factor V-Leiden) causes APC resistance by impairing the anticoagulant efficiency of the protein C pathway. A variety of lipids and lipoproteins can contribute to either procoagulant or anticoagulant reactions. Interestingly, high density lipoprotein (HDL), "the good cholesterol", is an anticoagulant cofactor for the protein C pathway and studies support the hypothesis that specific minor apolipoproteins and/or lipids of HDL are anticoagulants. Statins, normally used to treat hyperlipidemia, are also remarkably antithrombotics. Anticoagulant lipids include phosphatidyl ethanolamine and cardiolipin. Procoagulant lipids/lipoproteins include triglyceride-rich particles in plasma and oxidized low density lipoprotein (LDL). Procoagulant and anticoagulant lipids/lipoproteins in plasma contribute a Yin-Yang balance that helps influence the up-regulation and down-regulation of thrombin generation. Both diagnostic and therapeutic advances for understanding and treating thrombosis continue to emerge from research on the protein C pathway.

Key words: Factor V, High density lipoprotein, Protein C, Protein S, Thrombosis.