Dose-related efficacy and bleeding complications of double-chain tissue plasminogen activator in acute myocardial infarction

Turi, Zoltan G.; Goldberg, Sheldon; LittleJohn, Judith K.; Vanderark, C R; Shadoff, Neal; Karlsberg, Ronald P.; Williams, John A.; Butman, Samuel; Stadius, Michael L.; Wise, Kent; Buchbinder, Maurice; Genton, Edward; Laskey, Warren K.; DeMaria, Anthony N.; White, C J; Sheehan, Florence H.; Wynne, Joshua; Batson-Fowler, Gail; Edwards, Suzanne

doi:10.1016/0002-9149(93)90564-s

Cited by 14 publications

(15 citation statements)

References 19 publications

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“…At present, the only thrombolytic therapy that is approved by the FDA for the treatment of ischemic stroke is recombinant tissue-type plasminogen activator (rt-PA). However, this potent thrombolytic is only administered in 1.5% of cases (Go et al, 2013) due to potential bleeding complications and strict contraindication criteria (Turi et al, 1993). Adjuvant therapies that lower the dose of rt-PA or increase efficacy would represent an important breakthrough.…”

Section: Introductionmentioning

confidence: 99%

Shaken and Stirred: Mechanisms of Ultrasound-Enhanced Thrombolysis

Bader

Gruber

Holland

2015

Ultrasound in Medicine & Biology

110

191

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The use of ultrasound and microbubbles as an effective adjuvant to thrombolytics has been demonstrated in vitro, ex vivo, and in vivo. However, the specific mechanisms of ultrasound-enhanced thrombolysis (UET) have yet to be elucidated. We present visual observations illustrating two mechanisms of UET: acoustic cavitation and radiation force. An in vitro flow model was developed to observe human whole blood clots exposed to human fresh-frozen plasma, rt-PA (0, 0.32, 1.58, or 3.15 μg/mL), and the ultrasound contrast agent Definity® (2 μL/mL). Intermittent, continuous-wave, ultrasound (120 kHz, 0.44 MPa peak-to-peak pressure) was used to insonify the perfusate. Ultraharmonic (UH) emissions indicative of stable cavitation were monitored with a passive cavitation detector. The clot was observed with an inverted microscope, and images were recorded with a charge-coupled device (CCD) camera. The images were post processed to determine the time-dependent clot diameter and root-mean-square velocity of the clot position. Clot lysis occurred preferentially surrounding large, resonant-sized bubbles undergoing stable oscillations. UH emissions from stable cavitation were found to correlate with the lytic rate. Clots were observed to translate synchronously with the initiation and cessation of the ultrasound exposure. The root-mean-square velocity of the clot correlated with the lytic rate. These data provide visual documentation of stable cavitation activity and radiation force during sub-megahertz sonothrombolysis. The observations of this study suggest that the process of clot lysis is complex, and both stable cavitation and radiation force are mechanistically responsible for this beneficial bioeffect in this in vitro model.

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Section: Introductionmentioning

confidence: 99%

Shaken and Stirred: Mechanisms of Ultrasound-Enhanced Thrombolysis

Bader

Gruber

Holland

2015

Ultrasound in Medicine & Biology

110

191

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“…4 demonstrate an apparent saturation in fractional clot loss for rt-PA concentrations Ͼ1 g/mL in both rt-PA and UET-treated groups. Because the bleeding complications of lytic therapy are dose related (Adams et al 1996;Haley et al 2005;Turi et al 1993), it would be reasonable to suggest that using the lowest concentration of rt-PA yields the greatest UET lytic enhancement. The data shown in Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Similar results were observed in an in vitro human clot model by others (Prokop et al 2007), strongly suggesting that stable cavitation is likely responsible for much of the ultrasonic enhancement of rt-PA lytic efficacy. In addition, it is known that the bleeding complications of rt-PA lytic therapies are dose related (Turi et al 1993). This suggests that it may be possible to optimize the lytic and acoustic parameters of UET therapy to minimize rt-PA dosage and ultrasound bioeffects, while maximizing lytic efficacy.…”

Section: Introductionmentioning

confidence: 99%

Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound-Enhanced Thrombolysis

Shaw

Meunier

Lindsell

et al. 2008

Ultrasound in Medicine & Biology

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It has been known for some time that the application of ultrasound can enhance the efficacy of thrombolytic medications such as recombinant tissue plasminogen activator (rt-PA). Potential clinical applications of this ultrasound-enhanced thrombolysis (UET) include the treatment of myocardial infarction, acute ischemic stroke, deep venous thrombosis and other thrombotic disorders. It may be possible to reduce the dose of rt-PA while maintaining lytic efficacy; however there is little data on the rt-PA concentration dependence of UET. In this work, the rt-PA concentration dependence of clot lysis resulting from 120 kHz UET exposure was measured in an in vitro human clot model. Clots were exposed to rt-PA for 30 min, with (UET treated) or without 120 kHz ultrasound (rt-PA treated) at 37 degrees C, and the clot width measured as a function of time. The rt-PA concentration ranged from 0-10 microg/mL. The initial lytic rate for the UET-treated group was greater than that of the rt-PA group at almost all rt-PA concentrations, and exhibited a maximum over concentration values of 1-3 microg/mL.

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“…In the prevention of early (within 2 weeks) recurrence of cerebral embolism, aspirin use caused ICHs including asymptomatic ones in 14.2% of patients and symptomatic ones in 1.8%, while the use of low-molecular-weight heparin caused asymptomatic and symptomatic ICHs in 11.6% and 2.7%, respectively 320 (Ib). The frequency of ICH associated with thrombolytic therapy is 0.5%-1.1% in myocardial infarction and 1.6%-1.9% in pulmonary embolism [321][322][323][324] (IIb); however, the frequency of symptomatic ICH associated with thrombotic therapy for cerebral infarction is as high as 3.3%-13% and the frequency including asymptomatic bleeding is 12%-58% 325-329 (Ib-III). Risk factors for ICH associated with thrombolytic therapy are advanced age (aged 65-75 years or older), hypertension, diabetes mellitus, low body weight, history of cerebrovascular disorder, extensive cerebral ischemia on MRI (diffusion-weighted) and the presence of cerebral amyloid angiopathy 321,[323][324][325]327,330 (Ib-IIb).…”

Section: Evidencementioning

confidence: 99%

“…The mortality rate of acute ICH secondary to anticoagulant therapy and thrombolytic therapy is as high as 43%-54% and 33%-60%, respectively 321,324,326,[341][342] (IIb-III). Antiplatelet therapy also contributes to death and hematoma growth in patients with acute ICH [343][344] (III).…”

Section: Evidencementioning

confidence: 99%