Stability of alteplase for ultrasound-facilitated catheter-directed thrombolysis

Abstract

Introduction Ultrasound-facilitated catheter-directed thrombolysis is used with low-dose alteplase to treat pulmonary embolism. This reduces the bleeding risk that accompanies systemic administration of higher alteplase doses. While studies suggest that alteplase given over 2 to 6 hours is safe and effective, few data exist to support alteplase stability under these conditions. Therefore, we undertook this in vitro study to determine the duration of alteplase stability. Methods Alteplase was prepared in solutions of 8 mg in 100 mL, 6 mg in 150 mL, and 8 mg in 200 mL. Solutions were administered through the EkoSonicTM Endovascular System with and without ultrasound, to simulate administration over 2, 4, and 6 hours. Alteplase was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). Assays were performed at time 0 and at 30-minute intervals during simulated infusion. An enzyme-linked immunosorbent assay (ELISA) assay was used to measure alteplase concentrations that were at time 0 and at 15-minute intervals during simulated infusion. Results Using RP-HPLC, in the absence of ultrasound, the alteplase concentration remained within 1% of the original concentration through 120, 240, and 360 minutes of infusion. Using RP-HPLC for measurement, alteplase, in the presence of ultrasound, degraded steadily over time to approximately 90%, 80%, and 70% of its original amounts in 120, 240, and 360 minutes, respectively. Alteplase that remained was available for enzymatic activity. Conclusions Alteplase solutions of 0.04 and 0.08 mg/mL degraded steadily over time during simulated ultrasound-facilitated catheter-directed administration. Alteplase that did not degrade remained available for enzymatic activity.

Fixed-Dose Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Associated with COVID-19

“…All patients received standard treatment with unfractionated heparin (UFH). An initial bolus (80 units/kg) was given upon clinical suspicion/PE diagnosis and, thereafter, anti-factor-Xa-adjusted UFH infusion over at least 24 h. Fibrinogen and anti-factor-Xa levels were monitored every 4–6 h during USAT with a consequent reduction of the alteplase dose if fibrinogen dropped more than 50% from baseline or below 1 g/L or if the anti-faxtor-Xa was outside the institutional reference range of 0.3–0.7 IU/mL [ 17 ]. For this analysis, we calculated the time in therapeutic range for UFH by adapting the Rosendaal’s method of interpolated values [ 18 ].…”

Fixed-Dose Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Associated with COVID-19

“…All patients received standard treatment with unfractionated heparin (UFH). An initial bolus (80 units/kg) was given upon clinical suspicion/PE diagnosis and, thereafter, antifactor-Xa-adjusted UFH infusion over at least 24 h. Fibrinogen and anti-factor-Xa levels were monitored every 4-6 h during USAT with a consequent reduction of the alteplase dose if fibrinogen dropped more than 50% from baseline or below 1 g/L or if the anti-faxtor-Xa was outside the institutional reference range of 0.3-0.7 IU/mL [17]. For this analysis, we calculated the time in therapeutic range for UFH by adapting the Rosendaal's method of interpolated values [18].…”