title: Inhibition of factor IX(a) is protective in a rat model of thromboembolic stroke.
abstract: OBJECTIVE
  Although used clinically to prevent stroke, there are few examples of anticoagulant investigations in the treatment of acute thromboembolic stroke in animal models. The treatment of thromboembolic stroke in experimental models has been investigated almost exclusively around the use of tissue plasminogen activator (tPA). In this study, using a rat thromboembolic stroke model, we investigated the use of an inhibitory anti-factor IX(a) monoclonal antibody (SB 249417) for the treatment of thromboembolic stroke and compared its efficacy to that of tPA.
  
  
  METHODS
  Stroke was initiated by delivering 6 clots into the internal carotid artery. After 2, 4, or 6 hours, rats received either intravenous vehicle, 10.0 mg/kg tPA, or 1.0, 2.0, or 3.0 mg/kg SB 249417. At 24 hours after stroke, infarct volumes and neurological deficits were assessed.
  
  
  RESULTS
  Treatment with tPA 2, 4, or 6 hours after stroke reduced infarct volumes by 35% (P=NS), 45%, and 39%, respectively. tPA treatment did not improve neurological deficits at any time point. Treatment with SB 249417 (3.0 mg/kg) 2, 4, or 6 hours after stroke reduced infarct volumes by 44%, 50%, and 13% (P=NS), respectively. Neurological deficits were reduced by 49%, 42%, and 13% (P=NS), respectively. Neither mortality nor hemorrhage was affected by either treatment.
  
  
  CONCLUSIONS
  The data indicate that the inhibition of factor IX(a) within 4 hours of thromboembolic stroke produced a more favorable outcome than tPA. When treatment was initiated 6 hours after stroke, the benefits of factor IX(a) inhibition were lost, whereas tPA continued to suppress lesion development, albeit without a corresponding improvement in functional deficits. This study suggests that cerebral ischemia and the resultant perfusion deficit are exacerbated by the activation of blood coagulation and that anticoagulants like SB 249417 may find utility in the treatment of ischemic stroke.
authors.affiliation: Department of Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pa 19406, USA. John_R_Toomey@gsk.com
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
authors.forename: Richard E
authors.initials: RE
authors.lastname: Valocik
authors.forename: Paul F
authors.initials: PF
authors.lastname: Koster
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Gabriel
authors.forename: Matt
authors.initials: M
authors.lastname: McVey
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Hart
authors.forename: Eliot H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Parsons
authors.forename: Frank C
authors.initials: FC
authors.lastname: Barone
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D015949:Factor IXa / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D009460:Neurologic Examination; D010960:Plasminogen Activators / Q000627:therapeutic use; D016548:Prosencephalon / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D051381:Rats; D020521:Stroke / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D015996:Survival Rate; D013923:Thromboembolism / Q000150:complications / Q000473:pathology / Q000628:therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; C447080:SB 249417; D010960:Plasminogen Activators; D015949:Factor IXa; D010959:Tissue Plasminogen Activator