Platelet factor 4 modulation of the thrombomodulin–protein C system

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Abstract
To review published studies of the influence of platelet factor 4 (PF4) and other cationic proteins on the generation of activated protein C (APC) by the thrombomodulin-protein C system. Using the PubMed citation index, literature published from 1973 to 2003 regarding cationic proteins, PF4, and the thrombomodulin-protein C system was reviewed. All other cationic proteins studied to date either impair or do not affect APC generation via the thrombomodulin-protein C system; however, the platelet alpha-granule protein PF4 causes a 25-fold increase in the ability of thrombomodulin polypeptides to generate APC and a ten-fold increase in the ability of cultured endothelial cell-associated thrombomodulin to generate APC. The mechanism underlying this phenomenon depends on binding of the cationic PF4 to the anionic, vitamin K- dependent gamma-carboxyglutamic acid domain of protein C. The extent of PF4's stimulation of APC generation is further increased by its interaction with the anionic glycosaminoglycan moiety that is variably expressed through posttranslational, O-linked glycosylation of thrombomodulin. In an in vivo thrombin-infusion model of thrombomodulin activation in cynomolgus monkeys, previous intravenous infusion of pharmacologic amounts of PF4 resulted in circulating APC levels and APC-dependent prolongation of activated partial thromboplastin times that were two- to three-fold greater than those observed in saline-infused control animals. These findings raise the possibility that PF4 plays a hitherto unsuspected physiologic role in enhancing APC generation in vivo. They also provide a rationale for considering the infusion of PF4 or PF4-related peptides or peptidomimetics as a way of beneficially stimulating "endogenous" APC generation from circulating protein C in pathologic human disease states such as sepsis.