title: Less pronounced enhancement of thrombin-dependent inactivation of plasminogen activator inhibitor type 1 by low molecular weight heparin compared with unfractionated heparin.
abstract: Plasminogen activator inhibitor type 1 (PAI-1), the primary inhibitor of plasminogen activators, also forms high molecular weight complexes with either thrombin or factor Xa (FXa) in the presence of heparin, resulting in the loss of mutual activities of enzyme and inhibitor. We have proposed that the inactivation of PAI-1 by these activated coagulation factors is one of the mechanisms responsible for coagulation-associated enhancement of fibrinolysis. In the present study, we compared the effects of low molecular weight (LMW)- and unfractionated-heparin on the interaction between PAI-1 and either thrombin or FXa. Both types of heparin enhanced the inhibition of thrombin activity by PAI-1 with a bell-shaped pattern, though the magnitude of the enhancement was significantly weaker with LMW-heparin. In FXa inhibition by PAI-1, only unfractionated-heparin enhanced the inhibition. In the presence of vitronectin (Vn), the inhibition of thrombin and FXa by PAI-1 was further promoted by both types of heparin but to a significantly lesser extent with LMW-heparin. We then analyzed the possible enhancing effect of heparin on tissue plasminogen activator (tPA)-induced fibrinolysis. As a consequence of thrombin-dependent inactivation of PAI-1, tPA-induced fibrin clot lysis time in the presence of PAI-1 was shortened by unfractionated-heparin as well as by LMW-heparin with lesser extent, which was further enhanced by Vn. Less pronounced enhancement of complex formation between thrombin and PAI-1 by LMW-heparin appeared to be directly related to the weaker potential of LMW-heparin in enhancing fibrinolysis and accelerating hemorrhagic tendency via neutralization of PAI-1 activity.
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1, Handa-yama, Hamamatsu, 431-3192, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nakamura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umemura
authors.forename: Hisakuni
authors.initials: H
authors.lastname: Hashimmoto
authors.forename: Tetsumei
authors.initials: T
authors.lastname: Urano
mesh_terms: D001777:Blood Coagulation; D002118:Calcium / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D005342:Fibrinolysis; D006493:Heparin / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism
chemical_list: D006495:Heparin, Low-Molecular-Weight; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D019096:Vitronectin; D006493:Heparin; D013917:Thrombin; D015951:Factor Xa; D010959:Tissue Plasminogen Activator; D002118:Calcium