Effective thrombolysis without marked plasminemia after bolus intravenous administration of vampire bat salivary plasminogen activator in rabbits.
BACKGROUND
The use of recombinant tissue-type plasminogen activator (t-PA) in thrombolytic therapy is frequently associated with significant fibrinogenolysis. In contrast, recombinant vampire bat salivary plasminogen activator (Bat-PA) displays strict fibrin specificity, an attribute that could be desirable in a fibrinolytic agent.


RESULTS
The efficacy and fibrin selectivity of Bat-PA was evaluated and compared with that of t-PA using a rabbit model of femoral arterial thrombosis. Administration of 8.1, 14, and 42 nmol Bat-PA/kg by bolus intravenous injection restored flow in 50%, 75%, and 80% of the rabbits, respectively. The incidence of reperfusion after bolus intravenous injection of 14 and 42 nmol t-PA/kg was 15% and 78%, respectively. The maximal femoral artery reperfusion flows were equivalent after treatment with 42 nmol Bat-PA/kg or 42 nmol t-PA/kg, but the time to reach maximal flow for Bat-PA was approximately one half that of t-PA. Furthermore, the rapid restoration of flow by 42 nmol Bat-PA/kg, in contrast to equimolar t-PA, was accomplished without fibrinogenolysis and with only small decreases in the plasminogen and alpha 2-antiplasmin levels. Equipotent doses of Bat-PA and t-PA both resulted in approximate 2.5-fold increases in the template bleeding times of aspirin-pretreated rabbits. The clearance of Bat-PA from rabbits exhibited biexponential elimination kinetics; approximately 80% was cleared by the relatively slow beta phase (half-life of 17.1 minutes). Overall, Bat-PA was cleared approximately fourfold slower than t-PA.


CONCLUSIONS
Bolus intravenous administration of Bat-PA would facilitate prompt initiation of thrombolytic therapy, and the avoidance of plasminemia could result in fewer and less severe bleeding complications.
Gardell
S J
SJ
Department of Biological Chemistry, Merck Research Laboratories, West Point, Pa, Sharp & Dohme 19486.
Ramjit
D R
DR
Stabilito
I I
II
Fujita
T
T
Lynch
J J
JJ
Cuca
G C
GC
Jain
D
D
Wang
S P
SP
Tung
J S
JS
Mark
G E
GE
D000818:Animals; D001760:Bleeding Time; D004353:Drug Evaluation, Preclinical; D005263:Femoral Artery; D008297:Male; D010958:Plasminogen / Q000378:metabolism*; D010960:Plasminogen Activators / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D015912:Thrombolytic Therapy / Q000009:adverse effects; D013927:Thrombosis / Q000097:blood* / Q000628:therapy*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects
C069588:salivary plasminogen activator alpha 1, Desmodus rotundus; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator