Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion

Ebben, Harm P.; Nederhoed, J.H.; Slikkerveer, Jeroen; Kamp, Otto; Tangelder, Geert W.J.M.; Musters, René J.P.; Wisselink, Willem; Yeung, Kak K.

doi:10.1016/j.jvs.2014.02.057

Cited by 18 publications

(22 citation statements)

References 16 publications

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“…Activated platelets are targeted and bound to RGDS-modified liposomes, resulting in platelets aggregation 27 , suggesting the feasibility of developing a delivery system of platelet-targeted anti-thrombogenic drug. Studies on thrombolysis by ultrasound combined with microbubble contrast agent and urokinase has been proven in animal models to be a better alternative therapy to drug alone or surgical intervention 28 . Nevertheless, the mechanisms of the thrombolysis therapy and in vivo histological changes are still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

A thrombolytic therapy using diagnostic ultrasound combined with RGDS-targeted microbubbles and urokinase in a rabbit model

Guan

Wang

Xue

et al. 2020

Sci Rep

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This study aimed to explore thrombolysis therapy based on ultrasound combined with urokinase and Arg–Gly–Asp sequence (RGDS)-targeted microbubbles by evaluating the histological changes in a thrombotic rabbit model. Forty-two New Zealand rabbits featuring platelet-rich thrombi in the femoral artery were randomized to (n = 6/group): ultrasound alone (US); urokinase alone (UK); ultrasound plus non-targeted microbubbles (US + M); ultrasound plus RGDS-targeted microbubbles (US + R); RGDS-targeted microbubbles plus urokinase (R + UK); ultrasound, non-targeted microbubbles and urokinase (US + M + UK); and ultrasound, RGDS-targeted microbubbles and urokinase (US + R + UK) groups. Diagnostic ultrasound was used transcutaneously over the thrombus for 30 min. We evaluated the thrombolytic effect based on ultrasound thrombi detection, blood flow, and histological observations. Among all study groups, complete recanalization was achieved in the US + R + UK group. Hematoxylin and eosin staining showed that the thrombi were completely dissolved. Scanning electron microscopy examination demonstrated that the fiber network structure of the thrombi was damaged. Transmission electron microscopy showed that the thrombus was decomposed into high electron-dense particles. Histology for von Willebrand factor and tissue factor were both negative in the US + R + UK group. This study revealed that a thrombolytic therapy consisting of diagnostic ultrasound together with RGDS-targeted and urokinase coupled microbubbles.

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Section: Introductionmentioning

confidence: 99%

A thrombolytic therapy using diagnostic ultrasound combined with RGDS-targeted microbubbles and urokinase in a rabbit model

Guan

Wang

Xue

et al. 2020

Sci Rep

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“…Finally, research data have emerged advocating the combined use of contrast-enhanced ultrasound (CEUS) and thrombolysis in the treatment of peripheral arterial thrombosis. In an experimental study by Ebben and colleagues [Ebben et al 2015], the addition of CEUS accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. The contrast agent consists of microsized gas-filled bubbles that collapse when exposed to ultrasound, causing destabilization of the clot and making the clot surface more susceptible to fibrinolytics [Acconcia et al 2014].…”

Section: Major Trialsmentioning

confidence: 99%

Thrombolysis in peripheral artery disease

Giannakakis

Galyfos

Sachmpazidis

et al. 2017

Therapeutic Advances in Cardiovascular Disease

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Peripheral artery disease (PAD) has been associated with severe morbidity and mortality worldwide, affecting the quality of life for millions of patients. Acute thrombosis has been identified as a major complication of PAD, with proper management including both open as well as endovascular techniques. Thrombolysis has emerged as a reasonable option in the last decades to treat such patients although data produced by randomized trials have been limited. This review aims to present major aspects of thrombolysis in PAD regarding its indications and contraindications, technique tips as well as to review literature data in order to produce useful conclusions for everyday clinical practice.

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“…The improvement of specificity of the thrombolytic agents is a way to overcome the drawbacks of the rt-PA or uPA treatment. Many studies showed that entrapment of the proteins into a delivery system like liposomes could benefit the thrombolysis primarily resulting from the prolongation of circulation duration and the capacity of endowing passive or active targeting ability [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] . Among them, ultrasonic (US) induced delivery of thrombolytic proteins using microbubbles has demonstrated promising properties for site-specific release of payloads from the carrier through cavitational effects and acoustic radiation force on the carrier [21] .…”

Section: Introductionmentioning

confidence: 99%

In vivo evaluation of urokinase-loaded hollow nanogels for sonothrombolysis on suture embolization-induced acute ischemic stroke rat model

Teng

Jin

Nan

et al. 2018

Bioactive Materials

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The urokinase-type plasminogen activator (uPA) loaded hollow nanogels (nUK) were synthesized by a one-step reaction of glycol chitosan and aldehyde capped poly (ethylene oxide). The resultant formulation is sensitive to diagnostic ultrasound (US) of 2 MHz. Herein, we evaluated the in vivo sonothrombolysis performance of the nUK on acute ischemic stroke rat model which was established by suture embolization of middle cerebral artery (MCA). Via intravenous (i.v.) administration, the experimental data prove a controlled release of the therapeutic protein around the clots under ultrasound stimulation, leading to enhanced thrombolysis efficiency of the nUK, evidenced from smaller infarct volume and better clinical scores when compared to the i.v. dose of free uPA no matter with or without US intervention. Meanwhile, the preservation ability of the nanogels not only prolonged the circulation duration of the protein, but also resulted in the better blood-brain barrier protection of the nUK formulation, showing no increased risk on the hemorrhagic transformation than the controls. This work suggests that the nUK is a safe sonothrombolytic formulation for the treatment of acute ischemic stroke.

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Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion

Abstract: In this experimental pilot study, the addition of contrast-enhanced US accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. Further clinical studies are warranted.

Cited by 18 publications

References 16 publications

A thrombolytic therapy using diagnostic ultrasound combined with RGDS-targeted microbubbles and urokinase in a rabbit model

A thrombolytic therapy using diagnostic ultrasound combined with RGDS-targeted microbubbles and urokinase in a rabbit model

Thrombolysis in peripheral artery disease

In vivo evaluation of urokinase-loaded hollow nanogels for sonothrombolysis on suture embolization-induced acute ischemic stroke rat model

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