Summary
Background: The pathogenesis of bleeding associated with thrombolytic therapy remains largely
unknown, although spontaneous bleeding appears to correlate with bleeding time prolongation.
Here, the comparative effects on cuticle bleeding times (CBT) and ear puncture bleeding
times (EBT) of recombinant staphylokinase (Sak) and alteplase (recombinant tissue-type
plasminogen activator, rt-PA) at equivalent doses, alone and in combination with aspirin
and heparin, were studied in rabbits.
Methods and Results: Groups of 4 to 9 rabbits were allocated to one of the 8 following intravenous infusions:
saline; aspirin 15 mg/kg and heparin - 100 IU/kg bolus and 10 IU/kg infusion over
one hour; 1.5 mg/kg rt-PA; 1.5 mg/kg rt-PA plus aspirin and heparin; 4.5 mg/kg rt-PA;
0.5 mg/kg Sak; 0.5 mg/kg Sak plus aspirin and heparin and 1.5 mg/kg Sak. Bleeding
times were determined 30 and 15 min before and 5,15,30 and 60 min after the administration
over one min of saline, rt-PA or Sak, by simultaneously severing a nail cuticle (CBT)
and by puncturing the ear (EBT). Bleeding times were unaffected by saline and by both
doses of Sak in monotherapy. Heparin-aspirin and low dose rt-PA significantly lengthened
EBT but not CBT. Both CBT and EBT were significantly prolonged (to a mean of >4 times
pretreatment at 5 min) after high-dose rt-PA and after the combined administration
of heparin and aspirin with either Sak or rt-PA. rt-PA provoked significantly longer
bleeding than Sak in the CBT (p = 0.001; mean estimated difference = 23 min), but
not in the EBT. rt-PA but not Sak degraded plasma fibrinogen dose-dependently. CBT
correlated inversely with fibrinogen (r = −0.66, p = 0.001) but EBT did not.
Conclusions: At equivalent doses Sak displays a significantly higher fibrin specificity and prolongs
bleeding time less than rt-PA, particularly in the nail cuticle bleeding time model
in which larger vessels are injured that require fibrinogen for hemostasis.
