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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-08-2546.
Submitted August 20, 2002
Accepted November 11, 2002
Distinct dose-dependent effects of plasmin and TPA on coagulation and hemorrhage
Daphne Stewart, Mansze Kong, Valery Novokhatny, Gary Jesmok, and Victor Marder*
Department of Vascular Medicine, Orthopaedic Hospital of the University of California, Los Angeles, Los Angeles, CA, USA
Department of Pharmacology, Bayer Corp., Research Triangle Park, NC, USA
* Corresponding author; email: vmarder{at}laoh.ucla.edu.
Rationale: All thrombolytic agents in current clinical usage are plasminogen activators. While effective, plasminogen activators uniformly increase the risk of bleeding complications, especially intracranial hemorrhage, and no laboratory test is applicable to avoid such bleeding. Objectives: We report a randomized, blinded, dose-ranging comparison of tissue-type plasminogen activator (TPA) with a direct-acting thrombolytic agent, plasmin, in an animal model of fibrinolytic hemorrhage. This study focuses on the role of plasma coagulation factors in hemostatic competence. Findings: Plasmin at 4-fold, 6-fold and 8-fold the thrombolytic dosage (1 mg/kg) induced a dose-dependent effect on coagulation, depleting antiplasmin activity completely, then degrading fibrinogen and factor VIII. However, even with complete consumption of antiplasmin and decreases in fibrinogen and factor VIII to 20% of initial activity, excessive bleeding did not occur. Bleeding occurred only at 8-fold the thrombolytic dosage, upon complete depletion of fibrinogen and factor VIII, manifest as prolonged primary bleeding, but with minimal effect on stable hemostatic sites. Although TPA had minimal effect on coagulation, hemostasis was disrupted in a dose-dependent manner, even at 25% of the thrombolytic dosage (1 mg/kg), manifest as rebleeding from hemostatically-stable ear puncture sites. Conclusions: Plasmin degrades plasma fibrinogen and factor VIII in a dose-dependent manner, but does not disrupt hemostasis until clotting factors are completely depleted, at an 8-fold higher dose than is needed for thrombolysis. Plasmin has a 6-fold margin of safety, in contrast with TPA, which cause hemorrhage at thrombolytic dosages.
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