Recombinant Tissue Plasminogen Activator-conjugated Nanoparticles Effectively Targets Thrombolysis in a Rat Model of Middle Cerebral Artery Occlusion

The efficacy and safety of recombinant tissue plasminogen activator （rtPA） need to be improved due to its low bioavailability and requirement of large dose administration. The purpose of this study was to develop a fibrin-targeted nanoparticle （NP） drug delivery system for thrombosis combination therapy. We conjugated rtPA to poly（ethylene glycol）- poly（ε-caprolactone） （PEG-PCL） nanoparticles （rtPA-NP） and investigated its physicochemical characteristics such as particle size, zeta potential, enzyme activity of conjugated rtPA and its storage stability at 4℃. The thrombolytic activity of rtPA-NP was evaluated in vitro and in vivo as well as the half-life of rtPA-NP, the properties to fibrin targeting and its influences on systemic hemostasis in vivo. The results showed that rtPA-NP equivalent to 10% of a typical dose of rtPA could dissolve fibrin clots and were demonstrated to have a neuroprotective effect after focal cerebral ischemia as evidenced by decreased infarct volume and improved neurological deficit （P〈0.001）. RtPA-NP did not influence the in vivo hemostasis or coagulation system. The half-life of conjugated rtPA was shown to be approximately 18 times longer than that of free rtPA. These experiments suggested that rtPA-conjugated PEG-PCL nanoparticles might be a promising fibrin-targeted delivery system for a combination treatment of thrombosis.

Therapeutic effect of recombinant tissue plasminogen activator on acute cerebral infarction at different times

BACKGROUND:The study aimed to compare the therapeutic effect of recombinant tissue plasminogen activator(rt-PA) on the onset of acute cerebral infarction(ACI) at different time points of the first 6 hours.METHODS:A retrospective analysis was conducted in 74 patients who received rt-PA thrombolysis treatment within 4.5 hours after ACI and another 15 patients who received rt-PA thrombolysis treatment between 4.5-6 hours after ACI.RESULTS:National Institute of Health Stroke Scale(NIHSS) scores were statistically decreased in both groups(P>0.05) at 24 hours and 7 days after ACI.There was no significant difference in modified ranking scores and mortality at 90 days after the treatment between the two groups(P>0.05).CONCLUSIONS:The therapeutic effect and mortality of rt-PA treatment in patients with ACI between 4.5-6 hours after the onset of the disease were similar to those in patients who received rtPA within 4.5 hours after the onset of this disease.Therefore,intravenous thrombolytic therapy for ACI within 4.5-6 hours after ACI was effective and safe.

Factors influencing clinical outcomes of acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator

Background Thrombolysis with recombinant tissue plasminogen activator （rt-PA） has gained international recognition, clinical outcomes following this thrombolytic therapy varied from patient to patient. Factors affecting clinical outcomes have not been well understood yet, so this retrospective case-control study aimed to investigate factors that may influence clinical outcomes of acute ischemic stroke treated with intravenous rt-PA. Methods One hundred and one patients with acute ischemic stroke who received intravenous rt-PA thrombolysis within 4.5 hours from disease onset were included. Patients were divided into good or poor outcome group according to modified Rankin Scale （mRS） score, good outcome group： mRS score of 0-1; poor outcome group： mRS of 2-6. Stroke characteristics were compared between the two groups. Factors for stroke outcomes were analyzed via univariate analysis and Logistic regression. Results Of the 101 patients studied, patients in good outcome group （n=55） were significantly younger than patients in poor outcome group （n=46, （62.82±14.25） vs. （68.81±9.85） years, P=0.029）. Good outcome group had fewer patients with diabetic history （9.09% vs. 28.26%, P=0.012）, fewer patients with leukoaraiosis （7.27% vs. 28.26%, P=-0.005） and presented with lower blood glucose level （（5.72±1.76） vs. （6.72±1.32） mmol/L, P=0.012）, lower systolic blood pressure level （（135.45±19.36） vs. （148.78±19.39） mmHg, P=0.003）, lower baseline NIHSS score （12.02±5.26 vs. 15.78±4.98, P=0.002） and shorter onset-to-treatment time （OTT） （（2.38±1.21） vs. （2.57±1.03） hours, P=0.044） than poor outcome group. Logistic regression analysis showed that absence of diabetic history （odds ratio （OR） 0.968 （95% CI 0.941-0.996））, absence of leukoaraiosis （OR 0.835 （95% C/0.712-0.980））, lower baseline NIHSS score （OR 0.885 （95% Cl 0.793- 0.989））, lower pre-thrombolysis systolic blood pressure （OR 0.962 （95% CI 0.929-0.997））, and lower blood glucose level （OR 0.699 （95% Cl 0.491-0.994）） before thrombolysis were significantly associated with better outcome. Conclusion Patients with no history of diabetes, no leukoaraiosis, low blood glucose level, low systolic blood pressure level and low baseline NIHSS score before thrombolvsis have a better outcome.

Submacular hemorrhage:treatment update and remaining challenges

Submacular haemorrhage(SMH)is a sight threatening complication that can occur in exudative age related macular degeneration(AMD),but has been described to occur more frequently in eyes with polypoidal choroidal vasculopathy(PCV).Left untreated,SMH carries a grave visual prognosis.Thus,expedient diagnosis and effective management of this complication is of paramount importance.The treatment strategies for SMH include(I)displacement of blood from the fovea,usually by injection of an expansile gas;(II)pharmacologic clot lysis such as with recombinant tissue plasminogen activator(rtPA);and(III)treatment of the underlying choroidal neovascularization(CNV)or PCV,such as with anti-vascular endothelial growth factor(anti-VEGF)agents.These three strategies have been employed in isolation or in combination,some concurrently and others in stages.rtPA has demonstrable effect on the liquefaction of submacular clots but there are remaining uncertainties with regards to the dose,safety and the timing of initial and repeat treatments.Potential side effects of rtPA include retinal pigment epithelial toxicity,increased risk of breakthrough vitreous haemorrhage and systemic toxicity.In cases presenting early,pneumatic displacement alone with anti-VEGF may be sufficient.Anti-VEGF monotherapy is a viable treatment option particularly in patients with thinner SMH and those who are unable to posture post pneumatic displacement.

Platelet-to-neutrophil ratio predicts hemorrhagic transformation and unfavorable outcomes in acute ischemic stroke with intravenous thrombolysis

BACKGROUND Acute ischemic stroke(AIS)retains a notable stance in global disease burden,with thrombolysis via recombinant tissue plasminogen activator(rtPA)serving as a viable management approach,albeit with variable outcomes and the potential for complications like hemorrhagic transformation(HT).The platelet-to-neutrophil ratio(P/NR)has been considered for its potential prognostic value in AIS,yet its capacity to predict outcomes following rtPA administration demands further exploration.AIM To elucidate the prognostic utility of P/NR in predicting HT and clinical outcomes following intravenous rtPA administration in AIS patients.METHODS Data from 418 AIS patients treated with intravenous rtPA at Thammasat University Hospital from January 2018 to June 2021 were retrospectively analyzed.The relationship between P/NR and clinical outcomes[early neurological deterioration(E-ND),HT,delayed ND(D-ND),and 3-mo outcomes]was scrutinized.RESULTS Notable variables,such as age,diabetes,and stroke history,exhibited statistical disparities when comparing patients with and without E-ND,HT,D-ND,and 3-mo outcomes.P/NR prognostication revealed an optimal cutoff of 43.4 with a 60.3%sensitivity and a 52.5%specificity for 90-d outcomes.P/NR prognostic accuracy was statistically significant for 90-d outcomes[area under the curve(AUC)=0.562],D-ND(AUC=0.584),and HT(AUC=0.607).CONCLUSION P/NR demonstrated an association with adverse 3-mo clinical outcomes,HT,and D-ND in AIS patients post-rtPA administration,indicating its potential as a predictive tool for complications and prognoses.This infers that a diminished P/NR may serve as a novel prognostic indicator,assisting clinicians in identifying AIS patients at elevated risk for unfavorable outcomes following rtPA therapy.

Factors Associated with Thrombolysis Outcome in Ischemic Stroke Patients with Atrial Fibrillation

The outcome of early intravenous thrombolysis for ischemic stroke in patients with atrial fibrillation（AF）is worse than that without thrombosis. How to increase the efficacy of intravenous thrombolysis for AF-related ischemic stroke remains largely unknown. In this study, we investigated factors that influence the effect of intravenous thrombolysis in these patients. Our results showed that thrombolysis was independently associated with a favorable outcome（P ／ 0.001） and did not influence the mortality of AF-related ischemic stroke, although it increased the risk of hemorrhage within 24 h after treatment. Risk factors for a poor outcome at admission were：heart failure（P = 0.045）; high systolic pressure（P = 0.039）; high blood glucose（P = 0.030）; and a high National Institutes of Health Stroke Scale（NIHSS） score（P ／ 0.001）. Moreover, high systolic pressure at admission（P = 0.007）, high blood glucose（P = 0.027）, and a high NIHSS score（P ／ 0.001） were independent risk factors for mortality at 3 months. Besides thrombolysis, a high NIHSS score（P = 0.006） and warfarin taken within 48 h before stroke onset（P = 0.032） were also independent risk factors for symptomatic hemorrhage within 24 h after treatment. Ischemic stroke patients with AF benefited from intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 h after stroke.