Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator

Victor Gurewich*, R. Pannell, A. Symmons-Byrd, P. Sarmientos, J. N. Liu, S. F. Badylak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Background: A single site mutant (M5) of prourokinase (proUK) was developed to make proUK less vulnerable to spontaneous activation in plasma. This was a problem that seriously compromised proUK in clinical trials, as it precluded proUK-mediated fibrinolysis at therapeutic concentrations. Methods and results: After completing dose- finding studies, 12 anesthetized dogs with femoral artery thrombosis were given either M5 (2.0 mg kg-1) or tissue plasminogen activator (t-PA) (1.4 mg kg-1) by i.v. infusion over 60 min (20% administered as a bolus). Two pairs of standardized injuries were inflicted at which hemostasis was completed prior to drug administration. Blood loss was quantified by measuring the hemoglobin in blood absorbed from these sites. Thrombolysis was evaluated at 90 min and was comparably effective by both activators. Rethrombosis developed in one t-PA dog. The principal difference found was that blood loss was 10-fold higher with t-PA (mean ∼40 mL) than with M5 (mean ∼4 mL) (P = 0.026) and occurred at more multiple sites (mean 2.7 vs. 1.2). This effect was postulated to be related to differences in the mechanism of plasminogen activation by t-PA and M5 in which the latter is promoted by degraded rather than intact (hemostatic) fibrin. In addition, two-chain M5 was efficiently inactivated by plasma C1 inactivator, an exceptional property which helped contain its non-specific proteolytic effect. Conclusions: Intravascular thrombolysis by M5 was accompanied by significantly less bleeding from hemostatic sites than by t-PA. This was attributed to the proUK paradigm of fibrinolysis being retained at therapeutic concentrations by the mutation.

Original languageEnglish
Pages (from-to)1559-1565
Number of pages7
JournalJournal of Thrombosis and Haemostasis
Issue number7
StatePublished - Jul 2006
Externally publishedYes


  • Fibrinolysis
  • Hemorrhage
  • Plasminogen activators
  • Urokinase


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