title: A kinetic model of the circulatory regulation of tissue plasminogen activator during orthotopic liver transplantation.
abstract: To better understand the regulation of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) during liver transplantation, we used a computer model of the human circulatory system to simultaneously evaluate the effect of t-PA secretion, t-PA inhibition by PAI-1, hepatic clearance of t-PA, blood loss, transfusion and hemodynamics on t-PA and PAI-1 levels during liver transplantation in three patients that differed in severity of liver disease, blood loss and anhepatic changes in t-PA. Higher preoperative t-PA levels were primarily related to underlying liver disease and reduced hepatic clearance. During the anhepatic stage, when hepatic t-PA clearance was eliminated: (1) the expected rise in t-PA was modulated by the extent of bleeding, which acted as an alternate t-PA clearance mechanism; and (2) the ratio of t-PA:PAI-1 was increased due both to lower t-PA clearance and reduced PAI-1 secretion. Recirculation of the new liver was associated with renewed clearance of t-PA, an acute phase increase in PAI-1 and a drop in the t-PA:PAI-1 ratio. Understanding fibrinolytic regulation required simultaneous analysis of t-PA secretion, inhibition and clearance. Anhepatic t-PA levels could be predicted based on preoperative liver function and surgical blood loss, which acted as an alternate t-PA clearance mechanism.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle 98195, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Crookston
authors.forename: C L
authors.initials: CL
authors.lastname: Marsh
authors.forename: W L
authors.initials: WL
authors.lastname: Chandler
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D003198:Computer Simulation; D005069:Evaluation Studies as Topic; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D006439:Hemodynamics; D006470:Hemorrhage / Q000097:blood / Q000209:etiology / Q000601:surgery; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000098:blood supply; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000502:physiology
chemical_list: D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator