Distinct dose-dependent effects of plasmin and TPA on coagulation and hemorrhage

Abstract

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 directacting 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. (Blood.

Microplasmin and Tissue Plasminogen Activator: Comparison of Therapeutic Effects in Rat Stroke Model at Multiparametric MR Imaging

“…Indeed, all rats in the three treated groups had comparable antistroke effects. However, administration of 10 mg/kg tPA caused significant bleeding, as evidenced with histomorphologic findings, which were in agreement with findings of previous studies (5)(6)(7)(8)23,36). Interestingly, there was a dose-dependent neural and/or vascular protective effect with microplasmin because a significantly lower hemorrhagic rate was found, particularly with a higher dose (10 mg/kg) of microplasmin.…”

“…In our study, the ⌬R2* curve from the tPA group had the largest tail, which implied considerable leakage and contrast material retention in the brain tissue after the first pass (35), which in turn led to a significantly higher ⌬R2* than that in the microplasmin and control groups at 24 hours. Our results suggest that tPA treatment aggravated the blood-brain barrier damage that may herald a higher risk of hemorrhage.The exact dose of thrombolytic drugs seems critical not only in regard to the antistroke effects but also in regard to the hemorrhagic side effect, and the optimal dose of each drug also varies among species of animals (15,23,25,36). For our study, we used 10 mg/kg tPA, which is approximately equivalent to its standard clinical dose of 1 mg/kg for patients.…”

“…The exact dose of thrombolytic drugs seems critical not only in regard to the antistroke effects but also in regard to the hemorrhagic side effect, and the optimal dose of each drug also varies among species of animals (15,23,25,36). For our study, we used 10 mg/kg tPA, which is approximately equivalent to its standard clinical dose of 1 mg/kg for patients.…”

Guideline on the management of bleeding in patients on antithrombotic agents

“…The fibrinolytics also reduce plasma concentrations of antiplasmin leading to plasminaemia and depletion of fibrinogen and other clotting factors, notably factor V (Tracy et al, 1997;Stangl et al, 1998). The magnitude of fibrinogen and factor V reduction does not correlate with the frequency of intracerebral haemorrhage (ICH) during treatment with fibrinolytic drugs (Tracy et al, 1997;Stewart et al, 2003).…”

Intravascular fibrinolysis in treating the thromboembolic changes in lower limbs

“…The safety of using the plasmin is a result of its fast neutralisation with the alpha 2-antiplasmin that prevents filtering of the plasmin to the circulatory system after the end of local thrombolysis. Further studies should evaluate the safety of using the plasmin in comparison to rtPA [29][30][31][32].…”