Tissue plasminogen activator (tPA) inhibits plasmin degradation of fibrin. A mechanism that slows tPA-mediated fibrinolysis but does not require alpha 2-antiplasmin or leakage of intrinsic plasminogen.

Wu, Jung He; Diamond, Scott L.

doi:10.1172/jci117949

Cited by 28 publications

(23 citation statements)

References 30 publications

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“…The recommendable dosage of rt-PA in LIF is still being debated. In vitro studies have shown that rt-PA, but not urokinase, caused a dose-dependent inhibition of the fibrinolytic activity of plasmin with slower lysis rates at increasing rt-PA dosages [33]. In the present study, the recanalization rate did not differ between low-dose and high-dose rt-PA treatment; the mortality, however, was lower in cases of high-dose treatment despite the highest rate of lethal PH (n = 4/7).…”

Section: Discussionmentioning

confidence: 99%

Endovascular Therapy of Acute Vertebrobasilar Occlusion: Early Treatment Onset as the Most Important Factor

Eckert¹,

Kucinski²,

et al. 2002

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In view of the poor prognosis for patients with acute intracranial vertebrobasilar occlusion (VBO), factors were sought that predict survival and good neurologic outcome after acute endovascular treatment by means of local intra-arterial fibrinolysis (LIF) and percutaneous transluminal angioplasty (PTA). LIF was performed in 83 patients with angiographically established acute VBO. A significant residual stenosis after LIF was treated by additional PTA in 8 patients. The types of occlusion were classified as either embolic occlusion (EO) or atherothrombotic occlusion (AO). Outcome was evaluated after 3 months by the Barthel Index (BI) as favorable (BI >90), unfavorable (BI <90) or death and compared for each of 3 diagnostic or treatment variables: recanalization success, occlusion type and time to treatment. Four fibrinolytic treatment modes [urokinase, low-dose and high-dose recombinant tissue-type plasminogen activator (rt-PA), rt-PA + Lys-plasminogen] were also analyzed. The outcome was favorable in 19 patients (23%), unfavorable in 14 (17%) and 50 died (60%). Recanalization was successful in 54 patients (66%). The neurologic outcome was better in recanalized than in nonrecanalized patients (favorable outcome: 30 vs. 10%, mortality: 54 vs. 72%; p = 0.118). The neurologic outcome was better in EO than in AO (favorable outcome: 31 vs. 17%, mortality: 47 vs. 70%, p = 0.112). Under combined treatment by LIF and PTA in 8 patients with AO, 4 survived, 3 with a favorable outcome (38%). Early treatment onset (≤6 h) led to a significantly better neurologic outcome than delayed treatment onset (>6 h; favorable outcome: 36 vs. 7%, mortality: 52 vs. 70%, p = 0.005). Although no statistically significant differences were found between the types of fibrinolytic agents, treatment with rt-PA and Lys-plasminogen tended toward better results. Early treatment onset proved to be the most important factor for successful endovascular therapy in acute VBO, whereas recanalization and presence of an embolic occlusion also tended toward better results. Additional PTA may be a promising therapy in cases of significant residual stenosis after LIF.

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Section: Discussionmentioning

confidence: 99%

Endovascular Therapy of Acute Vertebrobasilar Occlusion: Early Treatment Onset as the Most Important Factor

Eckert¹,

Kucinski²,

et al. 2002

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“…4 The reason for the lack of effect of these thrombolytics at higher doses is not clear; however, at least for tPA, the hypothesis is that the drop-off in activity may be related to the "plasminogen-steal" effect, or depletion of available plasminogen, a phenomenon that appears to be associated with blood flow rates at the clot site and the concentration of plasminogen, the precursor to plasmin, on or near the surface of the clot. [23][24][25] Another possibility is that higher doses of tPA may inhibit the fibrinolytic action of plasmin. 24 However, because microplasmin appears to have a low affinity for fibrin 26 and acts directly to lyse a clot, 16 it is unlikely that the classic plasminogen-steal effect applies to its lack of effect at high doses.…”

Section: Discussionmentioning

confidence: 99%

Microplasmin: A Novel Thrombolytic That Improves Behavioral Outcome After Embolic Strokes in Rabbits

Lapchak

Araujo

Pakola

et al. 2002

Stroke

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Background and Purpose-It has been proposed that the novel thrombolytic microplasmin may be useful in the treatment of ischemic stroke. In the present study the effects and safety profile of microplasmin were evaluated in 2 rabbit embolic stroke models that have been used successfully to develop tissue plasminogen activator (tPA) as the only Food and Drug Administration-approved treatment for stroke. The rabbit small clot embolic stroke model (RSCEM) and rabbit large clot embolic stroke model (RLCEM) were used to determine the potential neuroprotective properties and safety profile of microplasmin, respectively, after an embolic stroke. Methods-Rabbits were embolized by injecting small blood clots (RSCEM) or large blood clots (RLCEM) into the cerebral circulation. For the RSCEM, 126 rabbits were included, with behavioral analysis conducted 24 hours later, allowing for determination of the effective stroke dose (ES 50 ) or clot amount (milligrams) that produces severe neurological deficits in 50% of rabbits. For RLCEM safety study analysis, 47 rabbits were included, with postmortem analyses consisting of assessment of hemorrhage and infarct rate and size. In test animals microplasmin was infused intravenously 60 minutes after embolization, whereas control rabbits were given infusions of the saline/Plasma-Lyte vehicle with all assessments performed in a blinded fashion. Results-In the RSCEM, a drug is considered neuroprotective if it significantly increases the ES 50 compared with the vehicle-treated control group. The ES 50 of the vehicle-treated control group 24 hours after embolization was 1.36Ϯ0.42 mg (nϭ38). Microplasmin, infused starting 60 minutes after embolization, increased the ES 50 to 2.32Ϯ0.57 (nϭ21), 1.89Ϯ0.48 (nϭ21), 2.81Ϯ0.55 (nϭ22), and 1.89Ϯ0.28 mg (nϭ24) for the 1-, 2-, 4-, and 8-mg/kg doses, respectively. There was a statistically significant behavioral improvement in the 4-mg/kg dose arm (Pϭ0.040). The microplasmin dose of microplasmin that was statistically significant (4 mg/kg) was subsequently determined to be safe in the RLCEM because it did not increase the incidence of hemorrhages (56%) compared with vehicle-treated rabbits (63%), nor did it significantly alter hemorrhage volume, infarct rate, or infarct volume. Conclusions-The present study shows that microplasmin improves behavioral rating scores in the RSCEM when administered 60 minutes after embolization, at a dose that does not increase hemorrhages in the RLCEM. This is in contrast to tPA, which significantly enhances the hemorrhage rate in the RLCEM.

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“…Typical simulations were completed in less than 5 s on an SGI Indy workstation (175 MHz R4400 processor). By correlating ®brin loss predicted by a well-mixed model of ®brinolysis to dynamic measurements of lysis of dilute FITC-®brin under well-mixed conditions (Wu and Diamond, 1995b), the forward adsorption rates k i f for tPA, plasminogen, and plasmin, and the rates of plasmin-mediated lysis, k catW and k catN , were determined. Speci®cally, k f plm , k catW , and k catN , were determined by correlating ®brin loss to measurements of FITC-®brin¯uorescence dequenching in plasmin-mediated lysis for varying plasmin concentration (Wu and Diamond, 1995b).…”

Section: Heterogeneous Fibrinolysis Modelmentioning

confidence: 99%

An experimental and theoretical study on the dissolution of mural fibrin clots by tissue‐type plasminogen activator

Wootton

Popel

Alevriadou

2002

Biotech & Bioengineering

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During thrombolytic therapy and after recanalization is achieved, reduction in the volume of mural thrombi is desirable. Mural thrombi are known to contribute to rethrombosis and reocclusion. The lysis rate of mural thrombi has been demonstrated to increase with fluid flow in different experimental models, but the mechanisms responsible are unknown. An experimental and a theoretical study were developed to determine the contribution of outer convective transport to the lysis of mural fibrin clots. Normal human plasma containing recombinant tissue-type plasminogen activator (tPA; 0.5 microg/mL) was (re)perfused over mural fibrin clots with fluorescently labeled fibrin at low arterial, arterial, or higher wall shear stresses (4, 18, or 41 dyn/cm(2), respectively) and lysis was monitored in real time. Flow accelerated lysis, but significantly only at the highest shear stress: The average lysis front velocity was 3 x 10(-5) cm/s at 41 dyn/cm(2) vs. almost half of that at the lower shear stresses. Confocal microscopy showed fibrin fibers dissolving only in a narrow region close to the surface when permeation velocity was predicted to be low. A heterogeneous transport-reaction finite element model was used to describe mural fibrinolysis. After scaling the effects of outer and inner convection, inner diffusion, and chemical reactions, a simplified inner diffusion/reaction model was used. Correlation to fibrin lysis data in purified systems dictated higher rates of plasmin(ogen) and tPA adsorption onto fibrin and a decreased catalytic rate of plasmin-mediated fibrin degradation, compared with published parameters. At each shear stress, the model predicted a temporal pattern of lysis of mural fibrin (similar to that observed experimentally), and protease accumulation in a narrow fibrin region and significant lysis inhibition by plasma alpha(2)-antiplasmin (according to the literature). Increasing outer convection accelerated mural fibrinolysis, but the model did not predict the big increase in lysis rate at the highest shear stress. At higher than arterial flows, additional mechanisms not accounted for in the current model, such as fibrin collapse at the fibrin front, may regulate the lysis of mural clots and determine the outcome of thrombolytic therapy.

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Tissue plasminogen activator (tPA) inhibits plasmin degradation of fibrin. A mechanism that slows tPA-mediated fibrinolysis but does not require alpha 2-antiplasmin or leakage of intrinsic plasminogen.

Cited by 28 publications

References 30 publications

Endovascular Therapy of Acute Vertebrobasilar Occlusion: Early Treatment Onset as the Most Important Factor

Endovascular Therapy of Acute Vertebrobasilar Occlusion: Early Treatment Onset as the Most Important Factor

Microplasmin: A Novel Thrombolytic That Improves Behavioral Outcome After Embolic Strokes in Rabbits

An experimental and theoretical study on the dissolution of mural fibrin clots by tissue‐type plasminogen activator

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