A long-half-life and fibrin-specific form of tissue plasminogen activator in rabbit models of embolic stroke and peripheral bleeding.
OBJECTIVE
We compared the activity of a new long-half-life, fibrin-specific tissue-type plasminogen activator (TPA) variant with that of wild-type TPA in rabbit models of embolic stroke and peripheral bleeding.


METHODS
In the embolic stroke model. TPA-induced clot lysis is followed by continuous monitoring of a radiolabeled clot lodged in the middle cerebral artery. Twenty-four hours after embolization and treatment with either thrombolytic agent or excipient, the brains are removed, fixed, and evaluated for cerebral hemorrhage. In a parallel template bleeding time experiment, the effects of equipotent doses of the two TPA molecules were measured.


RESULTS
Infusion of wild-type TPA or bolus administration of the TPA variant resulted in dose-dependent clot lysis. The TPA variant was found to be an order of magnitude more potent than wild-type TPA on a milligram-per-kilogram basis. Unlike wild-type TPA, the variant caused less systemic activation of plasminogen (P < .05) and fewer hemorrhagic transformations in this model (P < .05). The TPA variant did not extend template bleeding times.


CONCLUSIONS
These findings show that by combining increased fibrin specificity with decreased plasma clearance, it is possible to produce a thrombolytic agent that is more convenient and more potent than wild-tpe TPA. At the same time the significant reduction in hemorrhagic conversions may be attributable to the conservation of systemic plasminogen seen with this molecule.
Thomas
G R
GR
Department of Cardiovascular Research, Genentech Inc, San Francisco 94080.
Thibodeaux
H
H
Errett
C J
CJ
Badillo
J M
JM
Keyt
B A
BA
Refino
C J
CJ
Zivin
J A
JA
Bennett
W F
WF
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism*; D005340:Fibrinogen / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects; D006207:Half-Life; D006470:Hemorrhage / Q000139:chemically induced*; D002542:Intracranial Embolism and Thrombosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D010958:Plasminogen / Q000032:analysis; D011817:Rabbits; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000979:alpha-2-Antiplasmin / Q000032:analysis
D000979:alpha-2-Antiplasmin; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; C083865:T103N; D010959:Tissue Plasminogen Activator