title: Activated protein C increases fibrin clot lysis by neutralization of plasminogen activator inhibitor--no evidence for a cofactor role of protein S.
abstract: The effect of purified human activated protein C (APC) on fibrinolysis was studied using a clot lysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125I-fibrinogen and thrombin. All proteins were of human origin. In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-1) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropyl-fluorophosphate. Addition of the cofactors of APC-protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.
authors.affiliation: Gaubius Institute TNO, Leiden, The Netherlands.
authors.forename: N J
authors.initials: NJ
authors.lastname: de Fouw
authors.forename: Y F
authors.initials: YF
authors.lastname: de Jong
authors.forename: F
authors.initials: F
authors.lastname: Haverkate
authors.forename: R M
authors.initials: RM
authors.lastname: Bertina
mesh_terms: D005176:Factor XIII; D005342:Fibrinolysis / Q000187:drug effects*; D006023:Glycoproteins / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D010743:Phospholipids / Q000302:isolation & purification; D010958:Plasminogen / Q000302:isolation & purification; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors*; D015849:Plasminogen Inactivators; D011486:Protein C / Q000494:pharmacology*; D017293:Protein S; D013917:Thrombin / Q000302:isolation & purification; D010959:Tissue Plasminogen Activator / Q000302:isolation & purification
chemical_list: D006023:Glycoproteins; D010743:Phospholipids; D015849:Plasminogen Inactivators; D011486:Protein C; D017293:Protein S; D010958:Plasminogen; D005176:Factor XIII; D010960:Plasminogen Activators; D013917:Thrombin; D010959:Tissue Plasminogen Activator