A faster-acting and more potent form of tissue plasminogen activator (original) (raw)
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Tissue Plasminogen Activator: A Literature Review
The production of thrombolytic agents started in 1930s and thrombolytic therapy for stroke began in 1958, on a case by case basis, and, in 1963, a small trial performed. Evidence Acquisition: Intravenous tissue plasminogen activator (t-PA) was recognized and approved as the thrombolytic agent for acute ischemic stroke that can improve patients' outcome and resolve their neurological deficits. The main reason for the difficulty of stroke treatment is the narrow time window, which leads to a small proportion of eligible patients to be treated with t-PA. The cost-effectiveness and feasibility of intravenous t-PA for treatment of acute stroke in 3 -4.5 hour time window, after symptom onset, have been confirmed in previous studies. Results: Data about thrombolytic therapy, at the national level, are scarce in Asia and developing countries, compared to developed world. Thrombolytic therapy using t-PA is used in few low-income countries, including Iran. According to estimations of Iranian stroke patients, eligible for thrombolysis therapy, only 30% of Iranian stroke patients received t-PA. Conclusions: The high cost of t-PA and lack of appropriate infrastructure are the main barriers for thrombolytic therapy, in developing countries like Iran. On the other hand, most stroke units and centers, which have the infrastructure to deliver thrombolysis, are predominantly available only in large urban areas.
Human tissue-type plasminogen activator
Thrombosis and Haemostasis, 2014
SummaryTissue-type plasminogen activator (t-PA ) plays an important role in the removal of intravascular fibrin deposits and has several physiological roles and pathological activities in the brain. Its production by many other cell types suggests that t-PA has additional functions outside the vascular and central nervous system. Activity of t-PA is regulated at the level of its gene transcription, its mRNA stability and translation, its storage and regulated release, its interaction with cofactors that enhance its activity, its inhibition by inhibitors such as plasminogen activator inhibitor type 1 or neuroserpin, and its removal by clearance receptors. Gene transcription of t-PA is modulated by a large number of hormones, growth factors, cytokines or drugs and t-PA gene responses may be tissue-specific. The aim of this review is to summarise current knowledge on t-PA function and regulation of its pericellular activity, with an emphasis on regulation of its gene expression.
Dosing of Tissue Plasminogen Activator Often Differs from 0.9 mg/kg, but Does Not Affect the Outcome
Journal of Stroke and Cerebrovascular Diseases, 2013
Background: The safety and efficacy of low-and high-dose intravenous tissue plasminogen activator (t-PA) for the treatment of acute ischemic stroke are poorly understood. In this multicenter study, we examined the relationships between different doses of t-PA and outcome. Methods: Between 2006 and 2010, patients were enrolled if they were treated with t-PA on the basis of estimated body weight and on the subsequent availability of actual body weight. Based on the actual weight, patients were divided into lower (,0.85 mg/kg), standard (0.85-0.95 mg/kg), and higher (.0.95 mg/kg) t-PA dose groups. Differences in the outcomes of these groups were compared in terms of functional recovery (modified Rankin Scale [mRS] 0-1) at 3 months and the incidence of parenchymal hemorrhages on follow-up computed tomographic scans. Results: This cohort study included 272 patients: 171 (63%) patients received the standard t-PA dose, 62 (23%) a lower dose, and 39 (14%) a higher dose. At 3 months, 51% of the standard dose patients achieved a mRS score of 0 to 1, compared with 50% in the lower dose and 44% in the higher dose groups. Parenchymal hemorrhage occurred in 4.7%, 6.5%, and 7.7% of patients in standard, lower, and higher dose groups, respectively. Compared with standard dose groups, no significant differences in functional recovery and parenchymal hemorrhage were observed in the lower and higher dose groups. Conclusions: In clinical practice, the actual dose of t-PA often differs from the recommended dose of 0.9 mg/kg, but this has no significant impact on the outcome after t-PA treatment. Key Words: Acute ischemic stroke-efficacy of treatment-safety of treatment-thrombolysis-tissue plasminogen activator dose.
Scientific Reports, 2017
Because of high mortality caused by cardiovascular diseases, various fibrinolytic agents with diverse pharmacokinetic and pharmacodynamic properties have been developed. A novel mutated chimeric tissue plasminogen activator (mt-PA) was developed by the removal of first three domains of t-PA, insertion of GHRP sequence and mutation towards resistance to plasminogen activator inhibitor-1 (PAI-1). Mt-PA protein was expressed in Expi293F cells. The expression level of mt-PA was found to be 5000 IU/ mL. Following purification, the pharmacokinetic properties of mt-PA were evaluated in three doses in rats. Data related to mt-PA were best fitted to two compartment model. With the increase in dose, the Area Under the plasma concentration-time Curve (AUC 0→∞) increased. The elimination half-life (t 1/2) of mt-PA was in the range of 19.1-26.1 min in three doses while that of Alteplase was 8.3 min. The plasma clearance (CLp) of mt-PA ranged from 3.8 to 5.9 mL/min in three doses, which was several times lower than that of Alteplase (142.6 mL/min). The mean residence time (MRT) of mt-PA ranged from 23.3-31.8 min in three doses, which was 4-5 times greater than that of Alteplase (6 min). Mt-PA showed extended half-life and mean residence time and is a good candidate for further clinical studies. Cardiovascular diseases, caused by disorders of heart and blood vessels, account for 17.3 million deaths per year that is expected to grow to more than 23.6 million by 2030 1,2. In 2011, the estimated annual costs of cardiovascular diseases and stroke amounted to a total of more than $320.1 billion 1. Thrombolytic drugs particularly plasminogen activators (PAs) play an essential role in this respect and PAs can clear circulatory occlusions due to fibrin clot or thrombus. PAs convert plasminogen to the active serine protease plasmin which, in turn, dissolves fibrin, the insoluble matrix of clots 3. Tissue-type plasminogen activator (t-PA) is one of the fibrin-specific serine proteases that plays a crucial part in the fibrinolytic system 4,5. T-PA is composed of a single chain polypeptide of 527 amino acids and includes 17 disulfide bridges 6. The mature form of t-PA comprises five distinct domains: a finger domain (F) involved in the high-affinity binding of t-PA to fibrin and hepatic clearance of t-PA 7 , an epidermal growth factor-like domain (EGF) which contributes to the hepatic clearance of t-PA 8 , a kringle 1 domain (K1) which is important in the uptake of t-PA by mannose receptors on liver cells 9 , a K2 domain involved in the high-affinity binding to fibrin and activation of plasminogen, and a serine protease domain (S) where the catalytic activity of t-PA takes place 10. The main inhibitor of t-PA is PAI-1, a member of the serpin family (serine-protease inhibitor), which plays its role as a pseudo-substrate for target serine proteases 11. PAI-1 is synthesized by endothelial cells and hepatocytes, and partially by the α-granules of platelets 12. Similarly, plasmin is inhibited mainly by α 2-antiplasmin, yet plasmin-bounded fibrin is never inhibited 6. Because of the short plasma half-life (4-6 min) of Alteplase 13 , a large dose is required to obtain therapeutic blood levels, which in turn may lead to higher bleeding and re-occlusion risks due to a decreased plasma
Clinical Deterioration After Intravenous Recombinant Tissue Plasminogen Activator Treatment
Stroke, 2006
Background and Purpose— Patients may experience clinical deterioration (CD) after treatment with intravenous recombinant tissue plasminogen activator (rt-PA). We evaluated the ability of flow findings on transcranial Doppler to predict CD and outcomes on modified Rankin Scale. Methods— Patients with acute stroke received intravenous rt-PA within 3 hours of symptom onset at four academic centers. CD was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score by 4 points or more within 24 hours. Poor long-term outcome was defined by modified Rankin Scale ≥2 at 3 months. Transcranial Doppler findings were interpreted using the Thrombolysis in Brain Ischemia flow grading system as persistent arterial occlusion, reocclusion, or complete recanalization. Multiple regression analysis was used to identify transcranial Doppler flow as a predictor for CD after controlling for age, sex, baseline NIHSS, hypertension, and glucose. Results— A total of 374 patients re...
A sensitive assay for tissue plasminogen activator
Thrombosis Research, 1982
Tissue plasminogen activator (t-PA) in plasma was separated from inhibitors by adsorption on lysine-Sepharose. It was then determined indirectly by measuring the plasmin generated from plasminogen with poly-lysine as stimulator, in a chromogenic, parabolic rate assay. The reaction proceeded with tissue plasminogen activator and plasmin(ogen) adsorbed on the gel, and followed the kinetics described for similar parabolic rate assays in soluble systems. The assay was standardized against melanoma plasminogen activator (m-PA) and had the sensitivity range of 0.001-0.020 IU (4-80 pg). Antim-PA IgG quenched the activity generated in plasma on venous occlusion and part of the activity in pre-occlusion plasma. The method was sensitive to purified urokinase,
Determinants of clearance of tissue-type plasminogen activator (t-PA) from the circulation
Fibrinolysis, 1987
SC'MMAR Y. Elucidation of determinants of the clearance of tissue-type plasminogen activator (t-PA) from the circulation is necessary in order to identify subjects in whom dose regimens will require modification in order to maxim&e safety and efficiency. Preliminary observations in hepatectomised animals suggest that the liver is a primary site of metabolism of t-PA. To determine whether alterations in hepatic blood flow simulating those encountered clinically in patients with congestive heart failure affect the rate of clearance of t-PA from plasma, t-PA was administered intravenously to nine dogs before and after hepatic blood flow had been reduced by induction of systemic hypotension. Hepatic blood flow was evaluated sequentially by analysis of the plasma clearance of carbon-14 labelled taurocholic acid, a novel tracer selected because of its high hepatic extraction fraction. The extraction fraction of t-PA by the liver was measured directly by assay of the concentration of t-PA in simultaneously obtained arterial and hepatic venous blood samples. Both the concentration of t-PA antigen and t-PA functional activity were determined. t-PA was cleared from plasma in a bi-exponential manner with an early brisk (a) and a relatively less steep brisk (/3) phase. At baseline, the half-life (t 12) of t-PA during the cc-phase was 3.5kO.2 (f SEM) min. It did not change appreciably, averaging 4.4 + 0.6 mitt, despite marked reduction of hepaticlblood flow accompanying profound hypotension with a 45",, reduction of mean arterial pressure. Similarly, the half-life of t-PA during the /?-phase of clearance at baseline (12.6* 1.1 min) was not significantly altered by reduction of hepatic blood flow ( 12.5 + 0.9 min). The hepatic extraction fraction of t-PA declined progressively with time after administration of bolus of t-PA from 41 Ifr27",, (n==3) 1 min after injection to 34+ 16'!,, (n=4), 145 13",, (n=6) and 1Of 11"" (n=6) 12, 20 and 30 min after injection in normotensive animals. Overall, the extraction fraction of t-PA by the liver increased 66.2_+ 19.2";, above the baseline level when hypotension was present compared to the case with normotension. This increase in extraction fraction associated with a diminution of hepatic blood flow probably accounts for the relatively consistent rate of clearance of t-PA from the circulation despite reduction of hepatic blood flow. The results obtained indicate that the rate of clearance of t-PA from the circulation does not diminish markedly despite profound hemodynamic perturbations and reduction of hepatic blood flow to levels simulating those likely to be encountered in patients with severe cardiovascular disease. Accordingly, they suggest that major modifications in dosage will not be required to compensate for derangements in hepatic perfusion. The bi-exponential nature of clearance of t-PA from the circulation and the diminished hepatic extraction fraction as a function of time underscore the likelihood that accumulation of t-PA may be encountered with prolonged administration.
Thrombosis Research, 1997
Intramuralthrombosisis a consistentfinding in the arteries of patients who die following coronary angioplasty.This thrombosis is thought to have a role in restenosis, which is a common complicationof coronary angioplasty.It has been hypothesised that antithrombotics such as hirudin or tissue -type plasminogen activator (tPA), may be therapeutically usefil following angioplasty.This report describesthe bioavailabilityof both agents following subcutaneous(SC)injection in cholesterol-fedrabbits. Intravenously delivered tPA has a half-life of 3-5 minutes. The half-life of intravenouslyadministered hirudin is less than one hour in many species.In order to prolongthe durationof action recombinant hirudin was conjugated to polyethylene glycol (PEG). Polyethylene glycol conjugated recombinant hirudin (PEG-rH) (0.7mg/kg) antigen and activity were measurableafter just 1 hr, reaching a maximum (663 and 884 rig/mlrespectively)at 12hours. Significantlevels were present in rabbit plasma 24 hours after injection. Subcutaneouslydeliveredrecombinant(r-tPA) (lmg/kg) was present in significant amounts lhr after injection, reaching a muimu (92 IU/ml) at 2 hours. Levels of tPA at 9 hours v.fereapproximately 80x normal circulatinglevels. High and constantlevels of functionalactivity of both PEG-rH and r-tPA in rabbitplasmaare achievedby subcutaneousdelivery. @1997E.kevier Science L.4d