tPA Involvement in Ovulation──Studies on Mechanism of Ovulation：Role of Tissue Type Plasminogen Activator

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Inhibiting endogenous tissue plasminogen activator enhanced neuronal apoptosis and axonal injury after traumatic brain injury

Tissue plasminogen activator is usually used for the treatment of acute ischemic stroke,but the role of endogenous tissue plasminogen activator in traumatic brain injury has been rarely reported.A rat model of traumatic brain injury was established by weight-drop method.The tissue plasminogen activator inhibitor neuroserpin(5μL,0.25 mg/mL)was injected into the lateral ventricle.Neurological function was assessed by neurological severity score.Neuronal and axonal injuries were assessed by hematoxylin-eosin staining and Bielschowsky silver staining.Protein level of endogenous tissue plasminogen activator was analyzed by western blot assay.Apoptotic marker cleaved caspase-3,neuronal marker neurofilament light chain,astrocyte marker glial fibrillary acidic protein and microglial marker Iba-1 were analyzed by immunohistochemical staining.Apoptotic cell types were detected by immunofluorescence double labeling.Apoptotic cells in the damaged cortex were detected by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling staining.Degenerating neurons in the damaged cortex were detected by Fluoro-Jade B staining.Expression of tissue plasminogen activator was increased at 6 hours,and peaked at 3 days after traumatic brain injury.Neuronal apoptosis and axonal injury were detected after traumatic brain injury.Moreover,neuroserpin enhanced neuronal apoptosis,neuronal injury and axonal injury,and activated microglia and astrocytes.Neuroserpin further deteriorated neurobehavioral function in rats with traumatic brain injury.Our findings confirm that inhibition of endogenous tissue plasminogen activator aggravates neuronal apoptosis and axonal injury after traumatic brain injury,and activates microglia and astrocytes.This study was approved by the Biomedical Ethics Committee of Animal Experiments of Shaanxi Province of China in June 2015.

一例川崎病多发冠状动脉瘤合并血栓患儿行极低剂量tPA溶栓的护理

总结1例川崎病多发冠状动脉瘤合并冠状动脉血栓行极低剂量组织型纤溶酶原激活物(tissue plasminogen activator,tPA)溶栓的护理体会。护理重点为选择tPA输注静脉方案、确定基线凝血状态及是否符合tPA输注标准、被动减少tPA输注剂量,促使局部出血减缓(或停止)、加强心脏及心外并发症观察及处理、制订个体化tPA撤离方案,保证抗凝连续性。经过16 d积极治疗和精心护理,患儿救治成功,顺利出院。

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.

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.

Roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy

AIMTo investigate the role of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in proliferative diabetic retinopathy (PDR) and to discuss the correlations among t-PA, PAI and vascular endothelial growth factor (VEGF) expressions.

The relativity of the activity change of tissue-type plasminogen activator and type 1 plasminogen activator inhibitor in patients with cerebral infarction and defect of nerve function

AIM:To explore the dynamic changes of the activity of tissue type plasminogen activator (t PA) and type 1 plasminogen activator inhibitor (PAI 1)and its clinical significance by observing the activity of t PA and PAI 1 in patients in acute and recovery phases of arteriosclerotic cerebral infarction.METHODS:Testing the activity of plasma t PA and PAI 1 of 91 patients with arteriosclerotic cerebral infarction and 80 healthy old ages by Chromgenic substrate methods and controlling them.RESULTS:The activity of t PA in acute and recovery stage of arteriosclerotic cerebral infarction patients were apparently lower than that of control and the activity of PAI 1 were higher than that of control.Volume of cerebral infarction was negatively related to the activity of t PA and positively related to the activity of PAI 1. CONCLUSION:The plasma fibrinolytic activities of the acute and recovery stage patients with arteriosclerotic cerebral infarction declined.

The pleiotropic effects of tissue plasminogen activator in the brain:implications for stroke recovery

Tissue plasminogen activator （tPA） use in the treatment of isch- emic stroke： tPA is a serine protease that catalyzes the breakdown of blood dots. Because of its thrombolytic properties, tPA is used to treat specific types of stroke, including ischemia, but is contra- indicated for treatment of hemorrhagic stroke or head trauma. Although a life saving and powerful ＇dot buster＇, tPA has a short therapeutic window. When administered outside of this prescribed timeframe, research suggests that tPA can produce neurotoxic ef- fects in the brain, due in part to activation of several signalling pro- cesses associated with cell apoptosis, degradation of the extracel- lular matrix, and increase in the permeability of the neurovascular unit （Yepes et al., 2009）. Concerted research has been dedicated to- ward understanding the mechanisms mediating the impact of tPA on the brain, using both in vivo and in vitro animal models.

Intraclot Recombinant Tissue-type Plasminogen Activator Reduces Perihematomal Edema and Mortality in Patients with Spontaneous Intracerebral Hemorrhage

The study aimed to investigate the impact of intraclot recombinant tissue-type plasminogen activator （rt-PA） on perihematomal edema （PHE） development in patients with intracerebral hemorrhage （ICH） treated with minimally invasive surgery （MIS） and the effects of intraclot rt-PA on the 30-day survival. We reviewed the medical records of ICH patients undergoing MIS between October 2011 and July 2013. A volumetric analysis was done to assess the change in PHE and ICH volumes at pre-MIS （T1）, post-MIS （T2） and day 10-16 （T3） following diagnostic computed tomographic scans （To）. Forty-three patients aged 52.8±11.1 years with （n=30） or without rt-PA （n=13） were enrolled from our institutional ICH database. The median rt-PA dose was 1.5 （1） mg, with a maximum dose of 4.0 mg. The ratio of clot evacuation was significantly increased by intraclot rt-PA as compared with controls （77.9%±20.4% vs. 64%±15%; P=0.046）. From TI to T2, reduction in PHE volume was strongly associ- ated with the percentage of clot evacuation （p=0.34; P=-0.027）. In addition, PHE volume was positively correlated with residual ICH volume at the same day （p ranging from 0.39-0.56, P〈0.01）. There was no correlation between the cumulative dose of rt-PA and early （T2） PHE volume （p=0.24; P=0.12） or de- layed （T3） PHE volume （p=0.19; P=0.16）. The 30-day mortality was zero in this cohort. In the selected cohort of ICH patients treated with MIS, intraclot rt-PA accelerated clot removal and had no effects on PHE formation. MIS aspiration and low dose of rt-PA seemed to be feasible to reduce the 30-day mor- tality in patients with severe ICH. A large, randomized study addressing dose titration and long-term outcome is needed.

Activity of Ginkgo biloba Extract and Quercetin on Thrombomodulin Expression and Tissue-type Plasminogen Activator Secretion by Human Umbilical Vein Endothelial Cells

Objective In order to investigate the pharmacological properties of Ginkgo biloba extract （GBE） on improving blood circulation, the regulating action of GBE and quercetin （a main flavonoid ingredient in GBE） on thrombomodulin （TM） expression and tissue-type plasminogen activator （t-PA） secretion was studied. Methods Using flow cytometer and gel image system respectively, we evaluated the TM expression and the t-PA secretion by human umbilical vein endothelial cells （HUVECs） in vitro. Results The increase of TM expression on HUVECs surface was induced by GBE rather than quercetin in a dose- and time-dependent manner. Both GBE and quercetin increased the t-PA release significantly. Conclusion The effect of GBE on improving blood circulation may be partly attributed to its promoting TM expression and t-PA secretion by endothelial ceils, and quercetin participated in the effect of GBE on t-PA secretion. However, the action of GBE on increasing TM expression needs further study.

Experimental Study of Tissue-type Plasminogen Activator Gene to Prevent Vein Grafts Stenosis

The effects of in vivo local expression of recombined human tissue-type plasminogen activator （t-PA） gene on the thrombosis and neointima formation of vein grafts were explored. Jugular vein-to-artery bypass grafting was performed on 72 New Zealand white rabbits. The rabbits were divided into 3 groups according to the different processing methods： transfected t-PA gene group （n = 24）, vector group （n= 24） and blank control group （n = 24）. Samples of vein grafts were harvested at different time points after surgery. The expression of t-PA gene in vein graft was detected by RT-PCR and the synthesis of t-PA protein by Western-Blot assay. The t-PA activity was measured by chromogenic substrate assay. The Cr51 labeled platelets accumulation in vein grafts was counted. The histopathological changes were compared in intima hyperplasia index among the three groups after operation. The results showed that at the 2^nd , 5^th , 14^th and 28^th day after operation, RT-PCR and Western-blot confirmed the expression of t-PA mRNA and protein at the site of gene transfer. The t-PA activity detected on the 2^nd, 5^th, 14^th and 28^th day in experimental group was 370. 63±59. 44, 344. 13±48. 47, 252.87±51.80 and 161.75±68. 94 U/g respectively, and disappeared on the 60^th day and undetected in the control groups. The number of platelets accumulated in the vein grafts in gene group, vector group and blank control group was （85. 04 ± 21.58） 10s, （225.87±85.13） 10^6 and （211.57±78.02） 10^6 respectively. The number of platelets accumulated in gene group was significantly fewer than that in the control groups. Morphometric analysis revealed that intimal hyperplasia was markedly reduced in the t-PA gene group as compared with that in the control groups. It was suggested that the local expression of t-PA gene in vein graft significantly inhibited the accumulation of platelets, thrombosis and concomitant intimal hyperplasia, by which stenosis of bypass graft could be prevented effectively.

Elevated Plasma Tissue-type Plasminogen Activator (t-PA) and Soluble Throm-bomodulin in Patients Suffering From Severe Acute Respiratory Syndrome (SARS) as a Possible Index for Prognosis and Treatment Strategy

To detect the presence of endothelial injury in patients with severe acute respiratory syndrome （SARS） via enhanced levels of tissue-type plasminogen activator （t-PA） and soluble thrombomodulin （sTM）. Methods Case patients were from Xuanwu Hospital （Capital University of Medical Sciences, Beijing, China）, and all of them met clinical criteria for SARS. Healthy controls were some of the hospital employees. Endothelial injury bio-markers tPA and sTM were detected by commercial ELISA-methods. Results Classic plasma markers of endothelial injury, tPA and sTM significantly elevated in SARS patients in comparison to controls [t-PA： 1.48±0.16 nmol/L versus 0.25±0.03 nmol/L （P〈0.0001）, and sTM： 0.26±0.06 nmol/L versus 0.14±0.02 nmol/L （P〈0.05）]. The only patient who died had extremely high levels of these endothelial injury markers （t-PA： 2.77 nmol/L and sTM： 1.01 nmol/L）. The likelihood ratio analysis indicated the excellent discriminating power for SARS at the optimal cut-point of 0.49 nmol/L for tPA and 0.20 nmol/L for sTM, respectively. Significant numerical correlations were found among these endothelial injury markers in SARS patients. The numerical coefficient of correlation Pearson r between t-PA and sTM was 0.5867 （P〈0.05）. Conclusion Increased plasma concentrations of tPA and sTM in patients with SARS suggest the possibility of endothelial injury. SARS patients might need anticoagulant therapy or fibrinolytic therapy in order to reverse intraalveolar coagulation, microthrombi formation, alveolar and interstitial fibrin deposition. It may not only provide a useful treatment and prognostic index but also allow a further understanding of the pathological condition of the disease.

Tissue-type plasminogen activator is a homeostatic regulator of synaptic function in the central nervous system

Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density（PSD） that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^（2＋）/calmodulin-dependent protein kinase IIα（pCa MKIIα）,followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid（AMPA） receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate（NMDA） receptors and cyclin-dependent kinase 5（Cdk5）-induced phosphorylation of the protein phosphatase 1（PP1） at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.

Tissue plasminogen activator via cross-collateralization for tandem internal carotid and middle cerebral artery occlusion

Tandem internal carotid and middle cerebral artery occlusion after carotid dissection predicts poor outcome after systemic thrombolysis. Current treatments include the use of endovascular carotid stenting, which carries with it a high risk of propagating further embolic events and worsening the dissection. New strategies for avoiding the aforementioned side-effects include recanalization using cross-collaterals for delivery of intra-lesional tissue plasminogen activator(t PA). We present two cases that provide further support for this novel approach. Both patients presented with a National Institute of Health Stroke Scale of 20, received intra-arterial t PA via cross-collateralization, and made full recoveries without the need for stenting.

The Role of Tissue-type Plasminogen Activator in Rat Corpus Luteum

It is here reported for the first time that luteal cells are capable of secreting plasminogen activators(PA),(both tissue-type,tPA,and urokinase-type,uPA),and plasminogen activator inhibitor type-1(PAl-1).Using organ culture model,we have demonstrated that tPA,but not uPA,showed markedchange during luteolytic period in rat corpus luteum.A great amount oftPA was secreted in corpusluteum on D 14 and D 17 while very low level of tPA activity was detected before D 12.Correspondingly,the progesterone production in the corpus luteum increased gradually in a time-dependent manner from D 1 to D 12 but dropped abruptly to a very low level on D 14.Additionof exogenous tPA to the CL culture caused considerable decrease in progesterone secretion whileinclusion of purified monoclone tPA antibodies in the culture augmented progesterone productionof CL.It is therefore suggested that tPA may play an important role in luteolytic process.

Description of Prescribing Practices of Intrapleural Tissue Plasminogen Activator and Intrapleural DNase Administration at a Tertiary Academic Medical Center

Objectives: To describe the prescribing practices, preparation and administration techniques of intrapleural (IP) tissue plasminogen activator (t-PA) and IP DNase in patients at a tertiary academic medical center. Methods: Adult patients receiving IP t-PA and IP DNase between January 1-December 31, 2012 were retrospectively evaluated. Patients were included if they received IP t-PA and/or IP DNase for a pleural infection and were excluded if they received IP t-PA or IP DNase for chest tube clearance. Results: A total of 197 doses of IP t-PA and IP DNase received amongst 30 patients were included. The mean age of the patients included was 62 years old with 50% of the patients being female. Of the 30 patients included, 18 patients (60%) received both IP t-PA and IP DNase and 12 patients (40%) received only IP t-PA. The median dose of IP t-PA received was 4 mg (IQR 2-10) and the median dose of IP DNase received was 5 mg (IQR 5-5). Systemic antibiotics were administered to 77% of patients prior to IP t-PA or IP DNase administration. Improved pleural effusion drainage was reported in 70% of patients. Increased pain in the chest cavity during administration of IP t-PA or IP DNase was reported in 7% of patients. Conclusion: The majority of patients at our institution received concomitant IP t-PA and IP DNase after systemic therapy for treatment of pleural infections had been attempted. Administration of IP t-PA and IP DNase demonstrated improved drainage of pleural infections with minimal harm to patients.

Comment on roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy

Dear Sir,We congratulate Wu et al for their study entitled＂Roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy＂.The authors investigated the effects of tissue plasminogen activator（t-PA）and plasminogen activator inhibitor（PAI）in the pathogenesis of proliferative diabetic retinopathy（PDR）.The authors reported that t-PA and PAI are involved in the pathogenesis of PDR.

Influences on the activities of tissue-type plasminogen activator of mouse brain in asphyxia

Objective To observe the changes of the activity of tissue -type plasminogen activa tor(TPA)after asphyxia.Methods As-phyxia was induced in mouse pups by performing a ‘delayed cesarean section’.The experiment was designed for a co ntrol group and 4asphyctic groups to detect the activity of TPA.Results TPAactivity of brain increased afte r asphyxia(P <0.01).Conclusion TPAincreased after asphyxia might be able to attack the b asement membrane of microvessels,t hen opened the blood -brain barrier a nd induced neuronal damage.

EXPRESSION OF TISSUE－TYPE PLASMINOGENACTIVATOR IN SMOOTH MUSCLE CELLS OF INJUREDILIAC ARTERIES IN RABBITS

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Labeling and stability study On^（99m）Tc－tissue plasminogen activator as thrombus and tumor imaging agent

ＬａｂｅｌｉｎｇａｎｄｓｔａｂｉｌｉｔｙｓｔｕｄｙＯｎ￣（９９ｍ）Ｔｃ－ｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒａｓｔｈｒｏｍｂｕｓａｎｄｔｕｍｏｒｉｍａｇｉｎｇａｇｅｎｔＬｉＷｅｉ－Ｙｉ（李卫一），ＣａｏＧｕｏ－Ｘｉａｎ（曹国宪），Ｙｕ...