Comparative lytic efficacy of rt-PA and ultrasound in porcine versus human clots

Huang, Shenwen; Shekhar, Himanshu; Holland, Christy K.

doi:10.1371/journal.pone.0177786

Cited by 13 publications

(21 citation statements)

References 73 publications

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“…Furthermore, plasma was found to contain endogenous t-PA, which was likely responsible for the observed lysis (Jern et al 1997). However, the amount of plasminogen was reported to be substantially lower in porcine clots and porcine plasma compared to human clots and human plasma, which resulted in lower porcine clot mass loss measurements (Flight et al 2006; Huang et al 2017, Lewis 1996). The clot mass loss of mildly retracted and highly retracted porcine clots after treatment with rt-PA was significantly higher than that obtained in the plasma alone arm (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…2 and 3) were consistent with these earlier findings. Porcine clots have been reported to be less susceptible to rt-PA lysis due to their lower activation of porcine plasminogen by rt-PA, along with the denser fibrin network and thinner fibrin fibers in porcine clots than those in human clots (Flight et al 2006; Landskroner et al 2005; Huang et al 2017). In addition, clots with denser fibrin network and thinner fibers were found to be stiffer than those with more porous network and thicker fibrin fibers (Li et al 2016; Wufsus et al 2015).…”

Section: Discussionmentioning

confidence: 99%

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Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro

Mercado-Shekhar

Kleven

Rivera

et al. 2018

Ultrasound in Medicine & Biology

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The lytic recombinant tissue plasminogen activator (rt-PA) is the only drug approved by the Food and Drug Administration for treating ischemic stroke. Less than 40% of patients with large vessel occlusions who are treated with rt-PA have improved blood flow. However, up to 6% of all patients receiving rt-PA develop intracerebral hemorrhage. Predicting the efficacy of rt-PA treatment a priori could help guide therapeutic decision-making, such that rt-PA is administered only to those individuals who would benefit from this treatment. Clot composition and structure affect the lytic efficacy of rt-PA and have an impact on elasticity. However, the relationship between clot elasticity and rt-PA lytic susceptibility has not been adequately investigated. The goal of this study was to quantify the relationship between clot elasticity and rt-PA susceptibility in vitro. Human and porcine highly retracted and mildly retracted clots were fabricated in glass pipettes. The rt-PA lytic susceptibility was evaluated in vitro using the percent clot mass loss. The Young’s moduli of the clots were estimated using ultrasound-based single-track-location shear wave elasticity imaging. The percent mass loss in mildly retracted porcine and human clots (28.9 ± 6.1% and 45.2 ± 7.1%, respectively) were significantly higher (p < 0.05) than those in highly retracted porcine and human clots (10.9 ± 2.1% and 25.5 ± 10.0%, respectively). Furthermore, the Young’s moduli of highly retracted porcine and human clots (5.33 ± 0.92 kPa and 3.21 ± 1.97 kPa, respectively) were significantly higher (p < 0.05) than those of mildly retracted porcine and human clots (2.66 ± 0.55 kPa and 0.79 ± 0.21 kPa, respectively). The results revealed an inverse relationship between the percent clot mass loss and Young’s modulus. These findings motivate continued investigation of ultrasound-based methods to assess clot stiffness in order to predict rt-PA thrombolytic efficacy.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro

Mercado-Shekhar

Kleven

Rivera

et al. 2018

Ultrasound in Medicine & Biology

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“…The results of this study suggest that sonothrombolysis can enable a reduction in the quantity of drug required. The drug alone did not produce significant lysis, which is attributable to the relatively short time frame of the experiment (60 min), the low concentration of tPA (0.75 mg/mL) compared with clinical doses and the use of porcine blood and plasma (Huang et al 2017). Even under these conditions, substantial lysis acceleration occurred with US and non-targeted microbubbles.…”

Section: Discussionmentioning

confidence: 94%

“…To further increase clinical relevance, the composition of the plasma solution in the flow loop may also be improved. A recent study by Huang et al (2017) reported that using human plasminogen in the liquid surrounding a porcine clot produces sonothrombolysis behaviours that more closely resemble human clots in human plasma.…”

Section: Limitationsmentioning

confidence: 99%

Sonothrombolysis with Magnetically Targeted Microbubbles

Victor

Barnsley

Carugo

et al. 2019

Ultrasound in Medicine & Biology

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Microbubble-enhanced sonothrombolysis is a promising approach to increasing the tolerability and efficacy of current pharmacological treatments for ischemic stroke. Maintaining therapeutic concentrations of microbubbles and drugs at the clot site, however, poses a challenge. The objective of this study was to investigate the effect of magnetic microbubble targeting upon clot lysis rates in vitro. Retracted whole porcine blood clots were placed in a flow phantom of a partially occluded middle cerebral artery. The clots were treated with a combination of tissue plasminogen activator (0.75 mg/mL), magnetic microbubbles (»10 7 microbubbles/mL) and ultrasound (0.5 MHz, 630-kPa peak rarefactional pressure, 0.2-Hz pulse repetition frequency, 2% duty cycle). Magnetic targeting was achieved using a single permanent magnet (0.08À0.38 T and 12-140 T/m in the region of the clot). The change in clot diameter was measured optically over the course of the experiment. Magnetic targeting produced a threefold average increase in lysis rates, and linear correlation was observed between lysis rate and total energy of acoustic emissions.

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“…However, gas pockets stabilized by a monolayer within the liposome, or within the bilayer shell are hypothesized to be responsible for the echogenicity of these vesicles 31 . We have also demonstrated 120-kHz US-enhanced thrombolysis in the presence of rt-PA and Definity (Lantheus Medical Imaging, North Billerica, MA), an FDA approved contrast agent 32,33 . Stable cavitation and acoustic radiation force were identified as the mechanisms for the lytic enhancement 22,32 .…”

Section: Introductionmentioning

confidence: 99%

In vitro characterization of sonothrombolysis and echocontrast agents to treat ischemic stroke

Shekhar

Kleven

Peng

et al. 2019

Sci Rep

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The development of adjuvant techniques to improve thrombolytic efficacy is important for advancing ischemic stroke therapy. We characterized octafluoropropane and recombinant tissue plasminogen activator (rt-PA)-loaded echogenic liposomes (OFP t-ELIP) using differential interference and fluorescence microscopy, attenuation spectroscopy, and electrozone sensing. The loading of rt-PA in OFP t-ELIP was assessed using spectrophotometry. Further, it was tested whether the agent shields rt-PA against degradation by plasminogen activator inhibitor-1 (PAI-1). An in vitro system was used to assess whether ultrasound (US) combined with either Definity or OFP t-ELIP enhances rt-PA thrombolysis. Human whole blood clots were mounted in a flow system and visualized using an inverted microscope. The perfusate consisted of either (1) plasma alone, (2) rt-PA, (3) OFP t-ELIP, (4) rt-PA and US, (5) OFP t-ELIP and US, (6) Definity and US, or (7) rt-PA, Definity, and US (n = 16 clots per group). An intermittent US insonation scheme was employed (220 kHz frequency, and 0.44 MPa peak-to-peak pressures) for 30 min. Microscopic imaging revealed that OFP t-ELIP included a variety of structures such as liposomes (with and without gas) and lipid-shelled microbubbles. OFP t-ELIP preserved up to 76% of rt-PA activity in the presence of PAI-1, whereas only 24% activity was preserved for unencapsulated rt-PA. The use of US with rt-PA and Definity enhanced lytic efficacy ( p < 0.05) relative to rt-PA alone. US combined with OFP t-ELIP enhanced lysis over OFP t-ELIP alone ( p < 0.01). These results demonstrate that ultrasound combined with Definity or OFP t-ELIP can enhance the lytic activity relative to rt-PA or OFP t-ELIP alone, respectively.

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Comparative lytic efficacy of rt-PA and ultrasound in porcine versus human clots

Cited by 13 publications

References 73 publications

Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro

Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro

Sonothrombolysis with Magnetically Targeted Microbubbles

In vitro characterization of sonothrombolysis and echocontrast agents to treat ischemic stroke

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