The nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 reduces tissue plasminogen activator-induced intracerebral hemorrhage after thromboembolic stroke.
OBJECTIVE
Platelet activation and deposition in brain microvessels appear to be key events in the pathogenesis of ischemia-induced neuronal degeneration and behavioral deficits. It has been hypothesized that activated platelets in combination with polymorphonuclear leukocytes and fibrin may play a role in vessel reocclusion leading to the "no-reflow" phenomenon after administration of the thrombolytic tissue plasminogen activator (tPA). We studied the effects of the novel glycoprotein IIb/IIIa platelet receptor antagonist SM-20302 when administered in combination with tPA on infarct and hemorrhage rate and volume to determine whether activated platelets are involved in either infarct or hemorrhage generation after a thromboembolic stroke.


METHODS
One hundred thirty-two male New Zealand White rabbits were included in the present study. Rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five or 65 minutes after embolization, SM-20302 (5 mg/kg) was infused intravenously. In drug combination studies, tPA was infused intravenously for 30 minutes starting 60 minutes after embolization, and SM-20302 was administered 5 or 65 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis.


RESULTS
In the vehicle control group, the hemorrhage rate after a thromboembolic stroke was 33%. There was a significant increase (109%) in the hemorrhage rate in the group of rabbits treated with the thrombolytic tPA. SM-20302 by itself did not significantly alter the embolism-induced hemorrhage rate when administered either 5 or 65 minutes after embolism. The SM-20302 groups had a 42% and 33% incidence of hemorrhage in the 5- and 65-minute groups, respectively. In groups treated with a combination of drugs, the SM-20302/tPA group had a 31% and 71% incidence of hemorrhage when SM-20302 was administered 5 and 65 minutes after embolization, respectively. SM-20302 in combination with tPA also significantly increased infarct rate, but not hemorrhage or infarct volume.


CONCLUSIONS
This study suggests that treatment of thromboembolic stroke with the combination of a platelet inhibitor and tPA may have a beneficial outcome on the basis of the following: First, acute administration of SM-20302 did not significantly increase hemorrhage rate. Second, SM-20302 in combination with tPA significantly reduced tPA-induced intracerebral hemorrhage. Third, there appears to be a specific window of opportunity when a platelet inhibitor must be administered to produce a beneficial effect. Overall, on the basis of our results, we hypothesize that the increased rate of intracerebral hemorrhage observed after tPA administration may be partly due to increased reocclusion of cerebral vessels following lysis of the emboli and that reocclusion can be controlled by administration of a platelet inhibitor.
Lapchak
Paul A
PA
Department of Neuroscience, University of California at San Diego, La Jolla 92093-0624, USA. plapchak@ucsd.edu
Araujo
Dalia M
DM
Song
Donghuan
D
Zivin
Justin A
JA
D000818:Animals; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000627:therapeutic use*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D004336:Drug Antagonism; D005343:Fibrinolytic Agents; D020766:Intracranial Embolism / Q000209:etiology; D020767:Intracranial Thrombosis / Q000209:etiology; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011817:Rabbits; D015427:Reperfusion Injury / Q000139:chemically induced / Q000188:drug therapy; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D013997:Time Factors; D010959:Tissue Plasminogen Activator
D001555:Benzene Derivatives; D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C112851:SM 20302; D010959:Tissue Plasminogen Activator