Cross-Species Pharmacologic Evaluation of Plasmin as a Direct-Acting Thrombolytic Agent: Ex Vivo Evaluation for Large Animal Model Development

Landskroner, Kyle; Olson, N. C.; Jesmok, Gary

doi:10.1097/01.rvi.0000148828.40438.d3

Cited by 15 publications

(8 citation statements)

References 25 publications

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“…Landskroner et al . attributed this decreased thrombolysis in porcine clots to a denser fibrin network as observed on scanning electron microscopy [44]. Our study also showed that porcine clots have a denser fibrin network (Fig 5) with smaller diameter fibrin diameters than human clots (Fig 6).…”

Section: Discussionsupporting

confidence: 78%

“…(2005), 5 mg human plasmin produced 50±4% mass loss from porcine clots, compared to 80±2% mass loss from human clots after a 60-min treatment period [44]. Landskroner et al .…”

Section: Discussionmentioning

confidence: 99%

“…Porcine clots are characterized by a denser fibrin network compared to human clots, and demonstrate higher lytic resistance when treated with human plasmin [44]. Activation of plasminogen to form plasmin relies on the presence of both rt-PA and fibrin [45].…”

Section: Introductionmentioning

confidence: 99%

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

2017

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IntroductionPorcine thrombi are employed routinely in preclinical models of ischemic stroke. In this study, we examined the differential lytic susceptibility of porcine and human whole blood clots with and without the use of microbubbles and ultrasound (US) as an adjuvant.Materials and methodsAn in vitro system equipped with time-lapse microscopy was used to evaluate recombinant tissue-plasminogen activator (rt-PA) lysis of porcine and human clots in the same species or cross species plasma. Human and porcine whole blood clots were treated with rt-PA and an echo contrast agent, Definity®, and exposed to intermittent 120 kHz US.Results and conclusionsThe rt-PA lytic efficacy observed for porcine clots in porcine plasma was 22 times lower than for human clots in human plasma reported previously. Further, porcine clots did not exhibit increased lysis with adjuvant Definity® and US exposure. However, the rt-PA lytic susceptibility of the porcine clots in human plasma was similar to that of human clots in human plasma. Human clots perfused with porcine plasma did not respond to rt-PA, but adjuvant use of Definity® and US enhanced lysis. These results reveal considerable differences in lytic susceptibility of porcine clots and human clots to rt-PA. The use of porcine clot models to test new human thrombolytic therapies may necessitate modulation of coagulation and thrombolytic factors to reflect human hemostasis accurately.

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Section: Discussionsupporting

confidence: 78%

“…(2005), 5 mg human plasmin produced 50±4% mass loss from porcine clots, compared to 80±2% mass loss from human clots after a 60-min treatment period [44]. Landskroner et al .…”

Section: Discussionmentioning

confidence: 99%

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

2017

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“…The thrombi were filtered through 200 μm mesh pores to produce MT < 200 μm (Leeman et al 2012). The bovine blood was chosen for this study as it has been determined previously that bovine clots treated with plasmin most closely resemble the lysis observed with human clots (Landskroner et al 2005). …”

Section: Methodsmentioning

confidence: 99%

Sonoreperfusion Therapy Kinetics in Whole Blood Using Ultrasound, Microbubbles and Tissue Plasminogen Activator

Roos

Kamp

et al. 2016

Ultrasound in Medicine & Biology

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Coronary intervention for myocardial infarction often results in microvascular embolization of thrombus. Sonoreperfusion therapy (SRP) using ultrasound and microbubbles restored perfusion in our in vitro flow model of microvascular obstruction. In this study, we assessed SRP efficacy using whole blood as the perfusate with and without tissue plasminogen activator (tPA). In a phantom vessel bearing a 40-μm pore mesh to simulate the microvasculature, microthrombi were injected to cause microvascular obstruction and were treated using SRP. Without tPA, the lytic rate increased from 2.6±1.5 mmHg/min with 1000 cycles to 7.3±3.2 mmHg/min with 5000 cycles ultrasound pulses (p<0.01). The lytic index was similar between tPA-only [(2.0±0.5)×10−3 mmHg−1min−1] and 5000 cycles without tPA [(2.3±0.5)×10−3 mmHg−1min−1] (p=0.5) but increased [(3.6±0.8)×10−3 mmHg−1min−1] with tPA in conjunction with 5000 cycles ultrasound (p<0.01). In conclusion, SRP restored microvascular perfusion in whole blood and SRP lytic rate in experiments without tPA increased with ultrasound pulse length and efficacy increased with the addition of tPA.

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“…In a pig model of arteriovenous graft thrombosis, recombinant plasmin exceeded t-PA in efficacy, as shown by less residual clot (69 ± 26 mg vs. 140 ± 22 mg) and more released clot (241 ± 23 mg vs. 52 ± 23 mg) [38]. Plasmin dissolves fibrin of all species thus far tested (humans, rabbits, pigs, sheep, cattle, and dogs) at approximately 2 mg mg )1 clot [53]. In a rabbit model of selective, thrombin-induced middle cerebral artery occlusion, plasmin (1-3 mg) administered into the downstream internal carotid artery induced rapid (within 10 min) recanalization [54].…”

Section: Preclinical Foundationmentioning

confidence: 99%

Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential

Marder¹,

Novokhatny²

2010

Journal of Thrombosis and Haemostasis

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Summary. Direct fibrinolytics are proteolytic enzymes that degrade fibrin without requiring an intermediate step of plasminogen activation. This review summarizes the current information available for five such agents, namely, plasmin (the prototypical form), three derivatives of plasmin (mini‐plasmin, micro‐plasmin, and delta‐plasmin), and alfimeprase, a recombinant variant of a snake venom α‐fibrinogenase, fibrolase. Biochemical attributes of molecular size, fibrin binding and inhibitor neutralization are compared. Preclinical investigations that assess the potential for thrombolytic efficacy in vitro and in animal models of vascular occlusion and for hemostatic safety in animal models of bleeding are detailed. Clinical potential has been assessed in patients with peripheral arterial and graft occlusion, acute ischemic stroke, and access catheter and hemodialysis shunt occlusions. The direct fibrinolytic agents have impressive biochemical and preclinical foundations for ultimate clinical application. However, clinical trial results for micro‐plasmin and alfimeprase have not measured up to their anticipated benefit. Plasmin has thus far shown encouraging hemostatic safety, but efficacy data await completion of clinical trials. Whether direct fibrinolytics will provide clinical superiority in major thrombotic disorders over currently utilized indirect fibrinolytics such as tissue plasminogen activator remains to be determined.

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Cross-Species Pharmacologic Evaluation of Plasmin as a Direct-Acting Thrombolytic Agent: Ex Vivo Evaluation for Large Animal Model Development

Cited by 15 publications

References 25 publications

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

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

Sonoreperfusion Therapy Kinetics in Whole Blood Using Ultrasound, Microbubbles and Tissue Plasminogen Activator

Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential

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