title: Arrhenius temperature dependence of in vitro tissue plasminogen activator thrombolysis.
abstract: Stroke is a devastating disease and a leading cause of death and disability. Currently, the only FDA approved therapy for acute ischemic stroke is the intravenous administration of the thrombolytic medication, recombinant tissue plasminogen activator (tPA). However, this treatment has many contraindications and can have dangerous side effects such as intra-cerebral hemorrhage. These treatment limitations have led to much interest in potential adjunctive therapies, such as therapeutic hypothermia (T <or 35 degrees C) and ultrasound enhanced thrombolysis. Such interest may lead to combining these therapies with tPA to treat stroke, however little is known about the effects of temperature on the thrombolytic efficacy of tPA. In this work, we measure the temperature dependence of the fractional clot mass loss Deltam(T) resulting from tPA exposure in an in vitro human clot model. We find that the temperature dependence is well described by an Arrhenius temperature dependence with an effective activation energy E(eff) of 42.0 +/- 0.9 kJ mole(-1). E(eff) approximates the activation energy of the plasminogen-to-plasmin reaction of 48.9 kJ mole(-1). A model to explain this temperature dependence is proposed. These results will be useful in predicting the effects of temperature in future lytic therapies.
authors.affiliation: Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769, USA. shawge@ucmail.uc.edu
authors.forename: George J
authors.initials: GJ
authors.lastname: Shaw
authors.forename: Ashima
authors.initials: A
authors.lastname: Dhamija
authors.forename: Nazli
authors.initials: N
authors.lastname: Bavani
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Wagner
authors.forename: Christy K
authors.initials: CK
authors.lastname: Holland
mesh_terms: D001703:Biophysics / Q000379:methods; D001777:Blood Coagulation; D002627:Chemistry, Physical / Q000379:methods; D004058:Diffusion; D005342:Fibrinolysis; D006801:Humans; D007035:Hypothermia / Q000473:pathology; D066298:In Vitro Techniques; D008956:Models, Chemical; D015233:Models, Statistical; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013379:Substrate Specificity; D013696:Temperature; D015912:Thrombolytic Therapy / Q000379:methods; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000737:chemistry*
chemical_list: D010959:Tissue Plasminogen Activator