Platelet-targeted thrombolysis for treatment of acute ischemic stroke

Palazzolo, Jason S.; Ale, Anukreity; Ho, Heidi; Jagdale, Shweta; Broughton, Brad R.S.; Medcalf, Robert L.; Wright, David K.; Alt, Karen; Hagemeyer, Christoph E.; Niego, Be׳eri

doi:10.1182/bloodadvances.2021006691

Cited by 7 publications

(3 citation statements)

References 51 publications

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“…To the best of our knowledge, only one preclinical study performed in 2004 in a rabbit model of embolic stroke supported the bene ts of TNK with respect to rtPA [26]. Other preclinical studies with TNK have used a non-clinical dose (5 mg/kg) [27,28], or tested the effect of TNK in a platelet-rich thrombotic model [29] resistant to brin-directed thrombolysis, where TNK was ineffective [30]. The present study complemented these earlier ndings by testing the potential bene ts of TNK over rtPA.…”

Section: Discussionmentioning

confidence: 99%

Multicenter preclinical analysis of tenecteplase versus alteplase

Correa-Paz,

Pérez-Mato,

Bellemain-Sagnard

et al. 2023

Preprint

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Recombinant tissue plasminogen activator (rtPA/Alteplase) remains the gold standard thrombolytic drug for acute ischemic stroke. However, new rtPA-derived molecules such as Tenecteplase (TNK) with longer plasmatic half-life, practical delivery advantages as a fast, single bolus and increased fibrin binding have been developed. In spite of the recommendations on the bi-directionality of the basic/clinical research relationship, TNK is being tested in clinical trials without a preclinical basis on its toxicity and efficacy. In this study, toxicities of rtPA and TNK were evaluated on endothelial, astrocytes and neuronal culture; and efficacy was independently tested by two research centres in a thromboembolic model of ischemic stroke in mice. Both therapies were tested after early (20 and 30 min) and late administration (4 and 4.5 h) of ischemia onset. rtPA and TNK did not affect the viability of the endothelial cells or astrocytes. In neuronal cultures, rtPA, but not TNK, increased cell death at 24 h by itself. A single bolus dose of TNK showed an infarct volume reduction similar to that obtained after the perfusion of rtPA. TNK has a therapeutic window similar to rtPA and loses its beneficial effect when administered late. Early administration of TNK decreases the risk of haemorrhagic transformations compared to rtPA, but not when it is administered as a late treatment. These two independent preclinical studies support the use of TNK as a promising reperfusion alternative to rtPA treatment, mainly due to lower neurotoxicity and risk of haemorrhagic transformation when administered early after stroke onset.

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Section: Discussionmentioning

confidence: 99%

Multicenter preclinical analysis of tenecteplase versus alteplase

Correa-Paz,

Pérez-Mato,

Bellemain-Sagnard

et al. 2023

Preprint

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“…Targeting of activated platelets is therefore an attractive therapeutic strategy. Single-chain antibodies to the platelet integrin α IIb β 3 fused to scuPA have shown promise in a mouse ischemic stroke model ( 116 ).…”

Section: Localization Of Fibrinolytic Activitymentioning

confidence: 99%

Location, location, location: Fibrin, cells, and fibrinolytic factors in thrombi

Narwal

Whyte

Mutch

2023

Front. Cardiovasc. Med.

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Thrombi are heterogenous in nature with composition and structure being dictated by the site of formation, initiating stimuli, shear stress, and cellular influences. Arterial thrombi are historically associated with high platelet content and more tightly packed fibrin, reflecting the shear stress in these vessels. In contrast, venous thrombi are generally erythrocyte and fibrin-rich with reduced platelet contribution. However, these conventional views on the composition of thrombi in divergent vascular beds have shifted in recent years, largely due to recent advances in thromboectomy and high-resolution imaging. Interestingly, the distribution of fibrinolytic proteins within thrombi is directly influenced by the cellular composition and vascular bed. This in turn influences the susceptibility of thrombi to proteolytic degradation. Our current knowledge of thrombus composition and its impact on resistance to thrombolytic therapy and success of thrombectomy is advancing, but nonetheless in its infancy. We require a deeper understanding of thrombus architecture and the downstream influence on fibrinolytic susceptibility. Ultimately, this will aid in a stratified and targeted approach to tailored antithrombotic strategies in patients with various thromboembolic diseases.

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“…Stroke is a disease with a high incidence, disability rate and mortality rate worldwide [1]. With aging, the prevalence of stroke in patients is projected to exhibit a progressive increase, necessitating the development of superior therapeutic interventions to enhance stroke treatment outcomes [2].…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of arterial injection of tirofiban in treating ischemic stroke beyond the window period

Rong,

Chen,

et al. 2023

Trop. J. Pharm Res

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Purpose: To investigate the efficacy of intraarterial administration of tirofiban for stroke treatment beyond the conventional window period and evaluate its impact on prognosis.Methods: A retrospective study was conducted on ninety (90) acute ischemic stroke patients admitted to The First Affiliated Hospital of Hainan Medical University, Haikou, China from July 2021 to October 2022. The patients were divided into Tirofiban group (50) and non-Tirofiban group (40) based on whether the patients received arterial clopidogrel. National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel index (BI) scores were used to evaluate adverse drug reactions and its impact on prognosis for patients with symptoms onset within 6 - 24 h.Results: No significant differences were observed between the groups in terms of age, gender, medical history, personal history, blood indicators and neurologic function scores (p > 0.05). The median NIHSS score on admission and after 24 h of treatment was 4 in both groups and 3 in both groups after 72 h of treatment. However, after 7 days of treatment, the median NIHSS score was lower in Tirofiban group (2.0) than in non-Tirofiban group (2.5; p > 0.05). Tirofiban group demonstrated higher rates of effective treatment and good prognosis compared to non-Tirofiban group. Importantly, there was no significant difference in the occurrence of adverse reactions between the two groups (p > 0.05).Conclusion: Tirofiban, given via the arteries, improves neurological functions following hyper-acute stroke even beyond the window period and without adverse reactions. It is a safe and effective antiplatelet drug for late-life treatment. For future studies, it will be necessary to broaden the treatment scope and gather more robust and reliable data in order to enhance data quality.

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Platelet-targeted thrombolysis for treatment of acute ischemic stroke

Cited by 7 publications

References 51 publications

Multicenter preclinical analysis of tenecteplase versus alteplase

Multicenter preclinical analysis of tenecteplase versus alteplase

Location, location, location: Fibrin, cells, and fibrinolytic factors in thrombi

Safety and efficacy of arterial injection of tirofiban in treating ischemic stroke beyond the window period

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