A Novel Approach to Arterial Thrombolysis

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Presentation transcript:

A Novel Approach to Arterial Thrombolysis by Petr Klement, Peng Liao, and Laszlo Bajzar Blood Volume 94(8):2735-2743 October 15, 1999 ©1999 by American Society of Hematology

Schematic representation of the rabbit thrombolysis model. Schematic representation of the rabbit thrombolysis model. A thrombus, formed from rabbit whole blood, is depicted superimposed on a stenosis in a denuded and damaged segment of the aorta. The external constrictor, by itself, restricts blood flow by at least 66%, reducing the flow from 15 mL/min to 3 to 5 mL/min, thereby producing a critical stenosis. Blood flow is not observed after production of the thrombus. The spatial relationship of both the blood pressure and flow probes with respect to the thrombus is indicated. To the right of the schematic representation of the rabbit are tracings from both blood pressure and flow probes, which indicate a representative recording of cyclic flow observed during treatment with tPA and PTI. Petr Klement et al. Blood 1999;94:2735-2743 ©1999 by American Society of Hematology

Schematic representation of the time course of thrombus formation and subsequent treatment. Schematic representation of the time course of thrombus formation and subsequent treatment. The time course indicates initiation of thrombus formation, thrombus maturation during the first 30 minutes, and the following 60 minutes of treatment. The duration of experiment extends for a total of 90 minutes, during which 7 separate blood samples are obtained at the indicated times. Thirty minutes were allowed for tissue factor exposed on the denuded aorta to produce a thrombus from rabbit whole blood containing radiolabeled rabbit fibrinogen. PTI or saline was administered immediately before obtaining the second blood sample at 30 minutes. After the blood sample was obtained at the 30-minute time point, but before the next blood sample at 35 minutes, a bolus of tPA or saline was administered and an infusion of each was initiated. Petr Klement et al. Blood 1999;94:2735-2743 ©1999 by American Society of Hematology

Petr Klement et al. Blood 1999;94:2735-2743 ©1999 by American Society of Hematology

Petr Klement et al. Blood 1999;94:2735-2743 ©1999 by American Society of Hematology

Pharmacokinetics of PTI. One milliliter of PTI (0 Pharmacokinetics of PTI. One milliliter of PTI (0.5 mg/mL containing 1 × 106 cpm/mL 125I-PTI) was injected IV into each of 3 conscious rabbits. Pharmacokinetics of PTI. One milliliter of PTI (0.5 mg/mL containing 1 × 106 cpm/mL 125I-PTI) was injected IV into each of 3 conscious rabbits. At the indicated times, blood was obtained and plasma was produced by centrifugation. The presence of PTI in each plasma sample was assessed by determination of lysis time (○) and the results are plotted as a function of time. The amount of 125I-PTI (•) in each plasma sample was also assessed and is similarly plotted. Indicated values are the mean of 3 experiments, in duplicate, in which the SEM did not exceed 8% for lysis times and 3% for radioactivity. The data indicate that the PTI concentration maximally potentiates fibrinolysis ex vivo for up to 60 minutes after its administration to the rabbit and exhibits a half-life of approximately 25 minutes. Petr Klement et al. Blood 1999;94:2735-2743 ©1999 by American Society of Hematology

Compliance with treatment. Compliance with treatment. Ex vivo clot lysis time was used to assess the presence of both PTI and tPA administered to rabbits. Lysis times were determined in duplicate for 6 rabbits treated with Sal/Sal (□), 5 rabbits treated with Sal/PTI (▪), 4 rabbits treated with tPA/Sal (○), and 4 rabbits treated with tPA/PTI (•). Lysis time is reduced to approximately 40 minutes after the administration of PTI to the rabbit at 30 minutes. Subsequent administration of tPA, at 35 minutes, induces a reduction in lysis time to approximately 10 minutes. Each point reflects either 8, 10, or 12 individual measurements, in which the standard error of the mean is less than 10% of the indicated lysis time. Petr Klement et al. Blood 1999;94:2735-2743 ©1999 by American Society of Hematology