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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-08-2546.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3002-3007
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Distinct dose-dependent effects of plasmin and TPA on
coagulation and hemorrhage
Daphne Stewart,
Mansze Kong,
Valery Novokhatny,
Gary Jesmok, and
Victor J. Marder
From the Vascular Medicine Program, Los Angeles
Orthopaedic Hospital, The David Geffen School of Medicine at UCLA,
University of California Los Angeles, CA; and Department of
Pharmacology, Bayer Corporation, Research Triangle Park, NC.
All thrombolytic agents in current clinical usage are plasminogen
activators. Although effective, plasminogen activators uniformly increase the risk of bleeding complications, especially intracranial hemorrhage, and no laboratory test is applicable to avoid such bleeding. We report results of 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. Plasmin at 4-fold,
6-fold, and 8-fold the thrombolytic dose (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 dose, on
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
dose (1 mg/kg), manifest as rebleeding from hemostatically stable ear
puncture sites. Plasmin degrades plasma fibrinogen and factor VIII in a
dose-dependent manner, but it 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 causes hemorrhage at thrombolytic dosages.
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