Application Of Tissue Plasminogen Activator Research Articles

COVID-19 Pandemic Brings Challenges to the Management of Stroke-The Differences Between Stroke Cases Admitted to a Tertiary Hospital Before and During COVID-19 Pandemic in China.

An international public health emergency has resulted from the emergence of the new coronavirus-2. Both direct and indirect influences have been felt on the treatment of acute stroke. However, no conclusive link between COVID-19 and the alleged decline in admissions for stroke-related reasons has been established, and the findings of recent studies are contentious. Most of those researches are not made use of authentic data. Therefore, the goal of this study is to examine how the COVID-19 pandemic has affected hospital admissions for stroke patients, to provide a basis for managing stroke patients in hospitals during COVID-19 pandemic. This retrospective study took place at the People's Hospital of Peking University in Beijing, China. For each patient, interventions such as the application of tissue plasminogen activator (tPA) were examined. We recorded each patient's outcomes. The stroke patients' hospital admissions were compared to the average of the prior year. As the time span of interest, we selected the epidemic period (January 2020 to December 2020). When compared to the previous year in the pre-COVID period, mean monthly stroke hospitalizations decreased during the pandemic by 54.42% (P<0.001); average lengths of stay (ALOS) increased; and non-emergency admissions decreased by 78.8% (P<0.001). The monthly volume of stroke patients exceeding the intravenous thrombolysis (IVT) window decreased by 25% and 59.73%, respectively (P <0.001). There was a 5.3% increase in the percentage of IVT or within IVT time window in male stroke patients (p=0.019; p=0.049). During COVID-19, the proportion of non-local patients among male stroke patients decreased by 10% compared with the previous year (p=0.006). The COVID-19 epidemic has had a negative impact on stroke management in China, healthcare systems must work to assess and adapt to the new reality.

Clot‐targeted magnetic hyperthermia permeabilizes blood clots to make them more susceptible to thrombolysis

BackgroundThrombolysis is a frontline treatment for stroke, which involves the application of tissue plasminogen activator (tPA) to trigger endogenous clot‐degradation pathways. However, it is only effective within 4.5 h of symptom onset because of clot contraction preventing tPA permeation into the clot. Magnetic hyperthermia (MH) mediated by tumor‐targeted magnetic nanoparticles is used to treat cancer by using local heat generation to trigger apoptosis of cancer cells. ObjectivesTo develop clot‐targeting magnetic nanoparticles to deliver MH to the surface of human blood clots, and to assess whether this can improve the efficacy of thrombolysis of contracted blood clots. MethodsClot‐targeting magnetic nanoparticles were developed by functionalizing iron oxide nanoparticles with an antibody recognizing activated integrin αIIbβ3 (PAC‐1). The magnetic properties of the PAC‐1‐tagged magnetic nanoparticles were characterized and optimized to deliver clot‐targeted MH. ResultsClot‐targeted MH increases the efficacy of tPA‐mediated thrombolysis in contracted human blood clots, leading to a reduction in clot weight. MH increases the permeability of the clots to tPA, facilitating their breakdown. Scanning electron microscopy reveals that this effect is elicited through enhanced fibrin breakdown and triggering the disruption of red blood cells on the surface of the clot. Importantly, endothelial cells viability in a three‐dimensional blood vessel model is unaffected by exposure to MH. ConclusionsThis study demonstrates that clot‐targeted MH can enhance the thrombolysis of contracted human blood clots and can be safely applied to enhance the timeframe in which thrombolysis is effective.

Using Nature's Collaterals: Contralateral Access for Application of Tissue Plasminogen Activator in the Setting of Acute Ischemic Stroke (P01.018)

Using Nature's Collaterals: Contralateral Access for Application of Tissue Plasminogen Activator in the Setting of Acute Ischemic Stroke (P01.018)

Hindered dissolution of fibrin formed under mechanical stress

BackgroundRecent data indicate that stretching forces cause a dramatic decrease in clot volume accompanied by gross conformational changes of fibrin structure.ObjectiveThe present study attempts to characterize the lytic susceptibility of fibrin exposed to mechanical stress as a model for fibrin structures observed in vivo.Methods and resultsThe relevance of stretched fibrin models was substantiated by scanning electron microscopic (SEM) evaluation of human thrombi removed during surgery, where surface fibrin fibers were observed to be oriented in the direction of shear forces, whereas interior fibers formed a random spatial meshwork. These structural variations were modeled in vitro with fibrin exposed to adjustable mechanical stress. After two- and three-fold longitudinal stretching (2 × S, 3 × S) the median fiber diameter and pore area in SEM images of fibrin decreased two- to three-fold. Application of tissue plasminogen activator (tPA) to the surface of model clots, which contained plasminogen, resulted in plasmin generation which was measured in the fluid phase. After 30-min activation 12.6 ± 0.46 pmol mm−2 plasmin was released from the non-stretched clot (NS), 5.5 ± 1.11 pmol mm−2 from 2 × S and 2.3 ± 0.36 pmol mm−2 from 3 × S clot and this hampered plasmin generation was accompanied by decreased release of fibrin degradation products from stretched fibrins. Confocal microscopic images showed that a green fluorescent protein-fusion variant of tPA accumulated in the superficial layer of NS, but not in stretched fibrin.ConclusionMechanical stress confers proteolytic resistance to fibrin, which is a result of impaired plasminogen activation coupled to lower plasmin sensitivity of the denser fibrin network.

Acute renal artery thrombosis treated with t-PA power-pulse spray rheolytic thrombectomy

To describe a new application of tissue plasminogen activator (t-PA) power-pulse spray rheolytic (pharmacomechanical) thrombectomy in the treatment of acute renal artery thrombosis. Acute renal artery thrombosis is a relatively rare, but serious condition in which it is imperative to restore perfusion as quickly as possible. Percutaneous pharmacomechanical thrombectomy technique was utilized to provide an effective means of restoring renal flow and function. We therefore present two unique cases of spontaneous and iatrogenic renal artery thromboses that were treated successfully with t-PA power-pulse spray rheolytic thrombectomy. t-PA Power-pulse spray rheolytic (pharmacomechanical) thrombectomy has the potential to be a useful means to restore perfusion and function in the setting of acute renal artery thrombosis.

Is topical tissue plasminogen activator application effective on prevention of post-laminectomy epidural fibrosis? An experimental study

Objective: Impaired fibrinolytic activity has been shown to be associated with poor outcome after lumbar disc surgery. The purpose of this study was to determine the efficacy of topical tissue plasminogen activator (t-PA) in preventing epidural fibrosis in rats.Methods: L4–L5 laminectomy was performed under surgical microscope in 40 rats. Animals received either normal saline (control; n=20) or 0.5 mg/kg t-PA (n=20), topically to the operative sites. All animals were killed 1, 2, 4 and 6 weeks after surgery. Fibrosis, inflammation, necrosis and abscess formation were evaluated histopathologically.Results: The results showed that 6 weeks after surgery, inhibition in formation of epidural fibrosis was noted in both control and treatment animals. We found no significant differences in inflammation, tissue necrosis and abscess formation between groups.Conclusion: A meticulous microsurgical technique with careful hemostasis seems to be an effective and adequate method for prevention of epidural fibrosis.

Clinical investigation on application of tissue plasminogen activator in glaucoma filtering surgery

目的 研究组织型纤溶酶原激活剂(t-PA)在青光眼滤过术中的作用.方法采用随机对照的临床验证方法,将76例(86眼)难治性青光眼分为用药组42例(44眼)和对照组34例(42眼).用药组术中及术后均应用t-PA;对照组未用t-PA.术后随访18～48个月(平均36个月).采用寿命表分析法统计.结果用药组与对照组手术成功率及功能性滤过泡的累计百分率差异有显著性(P＜0.05).而眼毒性作用的发生率无显著性差异(P＞0.05).结论t-PA是安全有效的治疗滤过性手术失败的药物.至少可以在术后3年内将眼压维持在正常水平。

Therapeutic application of tissue plasminogen activator for fibrin reaction after cataract surgery

Purpose: To evaluate the efficacy and safety of therapeutic application of recombinant tissue plasminogen activator (rtPA) for fibrin reaction after uneventful cataract surgery. Setting: Department of Ophthalmology, SSK Istanbul Hospital, Istanbul, Turkey. Method: In a prospective study between January and June 2000, 26 eyes of 26 patients with fibrin reaction after uneventful cataract surgery received 3 μg of intracameral rtPA. Patients were evaluated for recurrences of fibrin reaction or complications by slitlamp biomicroscopy 2, 12, and 24 hours, 1 week, and 1 and 6 months after rtPA application. Intraocular pressure (IOP) was measured by Goldmann applanation tonometry. Visual acuity was tested using a standard Snellen chart 1 week after rtPA application. Results: All 26 eyes had complete fibrinolysis. Three eyes (11.5%) had corneal edema that lasted fewer than 24 hours. Visual acuity improved by 0 to 7 lines in 19 patients (73.1%). No patient had an increase in IOP. At 6 months, no patient had hyphema or recurrence of fibrin reaction. Conclusions: Complete lysis of fibrin after cataract surgery with conventional topical medications can take a long time and is not successful in some patients. Intracameral application of 3 μg rtPA was an efficient, safe method for the treatment of fibrin reaction after cataract surgery.

Effects of Adenosine on Thrombosis and Thrombolysis in a Canine Experimental Preparation

Intracoronary infusion of adenosine is reported to inhibit cyclic flow variations after coronary artery injury and stenosis. This study was performed in the anesthetized dog to determine if adenosine prevents arterial thrombosis and/or reocclusion after thrombolysis. Carotid and coronary arteries were instrumented with Doppler^TM flow probes, a critical stenosis, infusion line and an anodal electrode. Two protocols were employed. In the thrombosis protocol, intracarotid infusion of adenosine (20 µg/kg/min for 3 h) did not alter cyclic flow variations or patency during induction of vessel wall injury. In the second protocol, occlusive arterial thrombi were induced by anodal current injury and lysed with local application of tissue plasminogen activator. Whereas adenosine prolonged the time to arterial occlusion, it did not affect cyclic flow variations or time to reocclusion after thrombolysis.

Therapeutic and prophylactic application of TPA (recombinant tissue plasminogen activator) into the anterior chamber of the eye

In therapy-resistant fibrin reactions within the anterior chamber, especially following combined cataract and glaucoma surgery, injection of TPA is indicated. We report our results. From August 1994 to August 1998 we applied TPA 185 times into anterior chambers. A total of 123 injections were for therapeutic reasons (if local therapy with eyedrops showed no fibrinolytic effect), 32 for prophylactic reasons at the end of operations with intensive manipulation of the iris and following postoperative fibrin risk, and 30 applications for nonfunctional filtering blebs following glaucoma surgery. We applied 10 microg/0.1 ml. On the first day after therapeutic application of TPA, the fibrin was completely dissolved in 61 % of the eyes, and in 36.6 % of the eyes partial fibrinolysis occurred (total 97.6 %). Only 2.4 % of the eyes showed no fibrinolysis. Seventy-five percent of the eyes showed no fibrin reaction within the anterior chamber after prophylactic application of TPA. In all eyes (100 %) we would have expected fibrin reactions. Application of TPA for a filtering blebs disorder after glaucoma surgery resulted in restoration of the filtering bleb function in two-thirds of the eyes. After 185 applications of TPA into the anterior chamber we saw ten occurrences anterior chamber bleeding (5.4 %). In six eyes (3.2 %) we saw transcient clouding of the corneal endothelium and/or corneal stroma. These complications were reversible, except for irreversible endothelial decompensation in one eye with Fuchs' corneal dystrophy. TPA is effective for treating fibrin formation within the anterior chamber and maintaining the function of the filtering bleb. To confirm and quantify the efficiency of prophylactic use, a controlled prospective study is recommended.

Antagonists of the mannose receptor and the LDL receptor-related protein dramatically delay the clearance of tissue plasminogen activator.

Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor-related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake. In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster mannoside carrying six mannose groups (M6L5) displayed a subnanomolar affinity for the mannose receptor (Ki = 0.41 +/- 0.09 nmol/L). Preinjection of M6L5 (1.2 mg/kg) reduced the clearance of 125I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M6L5, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent to improve the pharmacokinetics of TPA. Blockade of LRP by 39-kD receptor-associated protein (GST-RAP) also inhibited TPA clearance by 60%. Finally, combined preinjection of M6L5 and GST-RAP almost completely abolished reduced liver uptake of TPA and delayed its clearance by a factor of 10. It can be concluded that (1) the mannose receptor and LRP appear to be the sole major receptors responsible for TPA clearance and (2) therapeutic levels of TPA can be maintained for a prolonged time span by coadministration of the aforementioned receptor antagonists.

Evaluation of topically administered tissue plasminogen activator for intraocular fibrinolysis in dogs

Summary Fibrin dots were induced in eyes of dogs by injection of autogenous citrated plasma into the anterior chamber. Twenty-four hours after dot formation, one 50-μl drop of tissue plasminogen activator at a concentration of 5 mg/ml (group 1, n = 7) was administered topically 9 times at 5-minute intervals, or a collagen shield that was hydrated with tissue plasminogen activator at a concentration of 5 mg/ml (group 2, n = 7) was applied. The contralateral eye served as a nontreated control. Serial photographs were taken of the fibrin dots after topical application of tissue plasminogen activator. Computerized morphometric analysis was then used to evaluate changes in cross-sectional surface area of the fibrin dot. There was no significant mean percentage decrease in dot surface area of treated eyes of group-1 dogs or in treated eyes of group-2 dogs. In addition, there was no significant difference in mean percentage decrease in dot surface area between treated eyes of group-1 and group-2 dogs.