scholarly journals Not all clots are created equal: a review of deficient thrombolysis with tissue plasminogen activator (tPA) in patients with metabolic syndrome

2018 ◽  
Vol 129 (6) ◽  
pp. 612-618 ◽  
Author(s):  
Charles I. Mosimah ◽  
Pamela J. Murray ◽  
James W. Simpkins
Keyword(s):  
Metabolic Syndrome ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Tissue Plasminogen

Regulation of primary hemostasis and vascular endothelial function by glyprolines in metabolic syndrome

2019 ◽  
Author(s):  
М.Е. Григорьева ◽  
Л.А. Ляпина ◽  
Т.Ю. Оберган
Keyword(s):  
Nitric Oxide ◽  
Metabolic Syndrome ◽  
Platelet Aggregation ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Structural Characteristics ◽  
Tissue Plasminogen ◽  
Anticoagulation System

Введение. Метаболический синдром (МС) сопровождается гиперлипемией, гиперкоагуляцией, дисфункцией эндотелия и др. В связи с этим не вызывает сомнений актуальность поиска новых средств комбинированного действия, восстанавливающих как жировой обмен, так и нормальную функцию эндотелия и сосудистотромбоцитарный гемостаз. Цель исследования: изучить в сравнительном аспекте влияние глипролинов ProGlyPro, ProArgPro, ArgProGlyPro и ProGlyProLeu на характеризующие эндотелиальную функцию и состояние сосудистотромбоцитарного гемостаза тканевой активатор плазминогена, уровень конечных метаболитов оксида азота и агрегацию тромбоцитов у крыс с МС. Материалы и методы. Для развития метаболических нарушений крысы получали высококалорийную диету (ВКД). Спустя 6 нед при продолжении ВКД животным интраназально вводили исследуемые пептиды в дозе 50 мкг/кг ежедневно в течение 7 сут. В плазме крови крыс через 20 ч и через 7 сут после последнего введения препаратов определяли показатели системы фибринолиза, АДФагрегацию тромбоцитов, конечные метаболиты оксида азота. Результаты. Развитие МС у крыс приводило к депрессии функции противосвертывающей системы и дисфункции эндотелия. Пролинсодержащие пептиды, применяемые в моделируемых условиях, вызывали активацию антитромбоцитарного звена противосвертывающей системы и эндотелиальной функции. Установлено, что исследуемые глипролины оказывали в кровотоке при их многократном применении выраженные в разной степени однонаправленные изменения в тромбоцитарном гемостазе. Максимальное снижение агрегации тромбоцитов выявлено для ProArgPro. Этот трипептид также в значительной степени активировал сосудистоэндотелиальную функцию путем усиленного выброса в кровоток маркеров тканевого активатора плазминогена и конечных метаболитов оксида азота. Заключение. Наиболее выраженное и устойчивое действие на гемостатическую и эндотелиальную функции в моделируемых условиях у глипролина ProArgPro может быть обусловлено структурными особенностями регуляторных пептидов, а именно, расположением аминокислот аргинина и пролина в непосредственной близости друг от друга. Introduction. Metabolic syndrome (MS) is accompanied by hyperlipemia, hypercoagulability, endothelial dysfunction. The search for new means of combined action, restoring fat metabolism and normal function of the endothelium and platelet hemostasis is relevant. Aim: to study the effect of ProGlyPro, ProArgPro, ArgProGlyPro and ProGlyPro Leu on tissue plasminogen activator, level of final nitric oxide metabolites and platelet aggregation in MS rats. Materials and methods. Rats received a highcalorie diet for the development of MS. After 6 weeks, the peptides were administered intranasally to animals at a dose 50 g/kg daily for 7 days. Parameters of fibrinolysis system, ADPplatelet aggregation, and final metabolites of nitric oxide were determined in rat blood plasma 20 hours and 7 days after the last drugs administration. Results. The development of MS in rats led to depression of anticoagulation system and endothelial dysfunction. Prolinecontaining peptides in simulated conditions caused activation of anticoagulation system and endothelial function. The studied peptides with their repeated use led in the bloodstream to unidirectional changes of varying degrees in platelet haemostasis after their multiple intranasal applications to animals. The maximum reduction in platelet aggregation was detected for ProArgPro. This tripeptide significantly increased the levels of final metabolites of nitric oxide and tissue plasminogen activator. Conclusion. The most pronounced and stable effect on hemostatic and endothelial functions in simulated conditions was identified for ProArgPro. Perhaps this effect is due to the structural characteristics of peptides, namely, the position of arginine in close proximity of proline.

scholarly journals The effect of glyproline peptides on levels of nitric oxide metabolites and tissue plasminogen activator activity in healthy rats and rats with metabolic syndrome

2020 ◽  
pp. 88-94
Author(s):  
Т.Ю. Оберган ◽  
М.Е. Григорьева ◽  
Л.А. Ляпина ◽  
Т.А. Шубина ◽  
Н.Ф. Мясоедов ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Metabolic Syndrome ◽  
Endothelial Function ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Tissue Plasminogen ◽  
Male Wistar Rats ◽  
Nitric Oxide Metabolites ◽  
Nitrate And Nitrite ◽  
Academy Of Sciences

Введение. Короткие регуляторные пролинсодержащие пептиды могут оказывать противосвертывающие эффекты в организме и проявлять защитное действие при тромбозах. Цель исследования - выявление косвенных эффектов пептидов глипролинового ряда Pro-Gly-Pro (PGP) и Arg-Glu-Arg-Pro-Gly-Pro (RERPGP) на функцию эндотелия сосудов и состояние системы фибринолиза в норме и при нарушении липидного обмена. Методика. Пептиды были синтезированы в институте молекулярной генетики РАН. В экспериментах использовано 60 лабораторных белых крыс-самцов линии Wistar. Проведено 2 серии экспериментов - на здоровых крысах и животных с экспериментально воспроизведенным метаболическим синдромом (МС). Пептиды вводили интраназально в течение 7 сут через каждые 24 ч (100 мкг/кг) ежедневно. Анализ крови осуществляли через 20 и 168 ч после завершающего введения пептидов. Определяли уровни метаболитов оксида азота (NO) и активности тканевого активатора плазминогена (ТАП). Результаты. Выявлены различия в действии PGP и RERPGP на исследуемые параметры у здоровых животных. В плазме крови крыс через 20 ч после семикратного введения пептида PGP установлено значительное повышение активности ТАП и метаболитов NO, которое сохранялось на протяжении 168 ч эксперимента, в то время как под влиянием RERPGP отмечалось повышение только уровня нитратов и нитритов через 168 ч после его применения. Пептид PGP также оказывал выраженные эффекты на функцию эндотелия организма и при развитии МС. Активность ТАП значительно и статистически значимо увеличивалась через 20 ч после семикратного введения пептида, эти изменения наблюдались также спустя 168 ч после применения PGP. Эти величины практически соответствовали значениям ТАП у здоровых крыс. Уровень метаболитов NО также значимо повышался при воздействии PGP на фоне МС. Сделано предположение о возможных механизмах действия пептидов на сосудистый эндотелий. Заключение. Пептиды глипролинового ряда оказывали стимулирующее влияние на функцию эндотелия в организме как в норме, так и при патологии, повышая активность тканевого активатора плазминогена и концентрацию метаболитов оксида азота. Short regulatory proline-containing peptides can exert an anticoagulation effect and be protective in thrombosis. The aim of this study was to identify indirect effects of glyproline peptides Pro-Gly-Pro (PGP) и Arg-Glu-Arg-Pro-Gly-Pro (RERPGP) on vascular endothelial function and the fibrinolytic system in normal and impaired lipid metabolism. Methods. Peptides were synthesized at the Institute of Molecular Genetics, Russian Academy of Sciences. Experiments were performed on 60 male Wistar rats divided into healthy animals and animals with experimental metabolic syndrome (MS). Peptides (100 μg/kg) were administered intranasally, once a day for 7 days. Blood tests were performed 20 h and 168 h after the last administration of the peptides. Concentrations of nitric oxide (NO) metabolites (sum plasma concentration of nitrate and nitrite) and the activity of tissue plasminogen activator (TAP) were measured. Results. The effects of PGP and RERPGP on the endothelial function in healthy animals were different. Significant increases in both TAP activity and NO metabolite concentration were found in plasma 20 h after 7 PGP administrations, which persisted throughout 168 h of the experiment. Only an increase in nitrate/nitrite was observed at 168 h after the RERPGP administration. PGP also exerted pronounced effects on the endothelial function, including in MS. TAP activity was significantly increased at 20 h after 7 administrations of the peptide, and this effect remained at 168 h after the PGP administration. These values were practically similar to the TAP values in healthy rats. Concentrations of NO metabolites were also significantly increased after the PGP exposure of MS rats. Possible mechanisms for the peptide activation of vascular endothelium are discussed. Conclusion. Glyproline peptides had a stimulatory effect on the endothelial function both in normal and pathological conditions by increasing the TAP activity and the concentration of NO metabolites.

Tissue plasminogen activator as a novel diagnostic aid in acute pulmonary embolism

VASA ◽  
2014 ◽  
Vol 43 (6) ◽  
pp. 450-458 ◽  
Author(s):  
Julio Flores ◽  
Ángel García-Avello ◽  
Esther Alonso ◽  
Antonio Ruíz ◽  
Olga Navarrete ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Negative Predictive Value ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Predictive Value ◽  
Acute Pulmonary Embolism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diagnostic Utility ◽  
Tissue Plasminogen ◽  
D Dimer

Background: We evaluated the diagnostic efficacy of tissue plasminogen activator (tPA), using an enzyme-linked immunosorbent assay (ELISA) and compared it with an ELISA D-dimer (VIDAS D-dimer) in acute pulmonary embolism (PE). Patients and methods: We studied 127 consecutive outpatients with clinically suspected PE. The diagnosis of PE was based on a clinical probability pretest for PE and a strict protocol of imaging studies. A plasma sample to measure the levels of tPA and D-dimer was obtained at enrollment. Diagnostic accuracy for tPA and D-dimer was determined by the area under the receiver operating characteristic (ROC) curve. Sensitivity, specificity, predictive values, and the diagnostic utility of tPA with a cutoff of 8.5 ng/mL and D-dimer with a cutoff of 500 ng/mL, were calculated for PE diagnosis. Results: PE was confirmed in 41 patients (32 %). Areas under ROC curves were 0.86 for D-dimer and 0.71 for tPA. The sensitivity/negative predictive value for D-dimer using a cutoff of 500 ng/mL, and tPA using a cutoff of 8.5 ng/mL, were 95 % (95 % CI, 88–100 %)/95 % (95 % CI, 88–100 %) and 95 % (95 % CI, 88–100 %)/94 %), respectively. The diagnostic utility to exclude PE was 28.3 % (95 % CI, 21–37 %) for D-dimer and 24.4 % (95 % CI, 17–33 %) for tPA. Conclusions: The tPA with a cutoff of 8.5 ng/mL has a high sensitivity and negative predictive value for exclusion of PE, similar to those observed for the VIDAS D-dimer with a cutoff of 500 ng/mL, although the diagnostic utility was slightly higher for the D-dimer.

Desmopressin Stimulates Parallel Norepinephrine and Tissue Plasminogen Activator Release in Normal Subjects and Patients with Diabetes Mellitus

1988 ◽  
Vol 59 (02) ◽  
pp. 269-272 ◽  
Author(s):  
M B Grant ◽  
C Guay ◽  
R Lottenberg
Keyword(s):  
Diabetes Mellitus ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Time Course ◽  
Vascular Endothelial Cells ◽  
Normal Subjects ◽  
Plasma Norepinephrine ◽  
Endogenous Catecholamine ◽  
Tissue Plasminogen ◽  
Patients With Diabetes

SummaryDesmopressin acetate administration markedly stimulates release of tissue plasminogen activator (t-PA) from vascular endothelial cells. The mechanism for this effect is unknown. Because infusion of epinephrine has been shown to increase t-PA levels, we examined the role of endogenous catecholamine mediation of t-PA release by desmopressin. Intravenous desmopressin acetate (0.3 μg/kg) was infused over 30 min in 9 controls and 11 subjects with diabetes mellitus, a condition associated with abnormalities of the fibrinolytic system. Plasma was collected in the supine, overnight fasted state at 15 min intervals (0-60 min) for measurement of t-PA activity, t-PA antigen and fractionated catecholamines. t-PA activity peaked at 30-45 min and subsequently decreased. The norepinephrine levels paralleled the t-PA activity. t-PA activity increased 10-fold from 0.14 ± .12 to 1.49 ± 0.79 IU/ml (Mean ± SD) and plasma norepinephrine increased 2- fold from 426 ± 90 to 780 ± 292 pg/ml. However, epinephrine and dopamine levels did not change significantly. The response to desmopressin of control and diabetic subjects was not shown to differ and their data were combined. We conclude that desmopressin increases plasma norepinephrine in addition to t-PA and that the parallel time course of change suggests a possible role for norepinephrine in mediating endothelial cell t-PA release.

A Collaborative Study to Establish the 2nd International Standard for Tissue Plasminogen Activator (t-PA)

1987 ◽  
Vol 58 (04) ◽  
pp. 1085-1087 ◽  
Author(s):  
P J Gaffney ◽  
A D Curtis
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Collaborative Study ◽  
Chinese Hamster ◽  
World Health ◽  
Clot Lysis ◽  
Expert Committee ◽  
Single Chain ◽  
International Standard ◽  
Tissue Plasminogen

SummaryAn international collaborative study involving ten laboratories located in eight different countries was undertaken in order to replace the current International Standard (I.S.) for tissue plasminogen activator (t-PA). Two lyophilised candidate preparations of high purity were assessed in comparison with the current I.S. for t-PA using only a clot lysis assay. One preparation (coded 861670) was purified from a cultured melanoma cell supernatant and was about 98% single chain t-PA while the other preparation (coded 861624) was derived from Chinese hamster ovary (CHO) cells following DNA recombinant procedures and was 75% single chain t-PA.Both candidate preparations of t-PA compared in quite a satisfactory manner with the current I.S. from the viewpoint of the biometrics of parallel line bioassays and both preparations were quite stable for long periods at low temperatures and stable from up to 1 month at temperatures of 20° and 38° C. Both fultil the criteria to serve as a satisfactory Znd International Standard for t-PA. The Fibrinolysis Subcommittee of the International Committee for Thrombosis and Haemostasis recommended the melanoma source t-PA (861670) as the next I.S. in order to maintain continuity with the 1st I.S. which was also a melanomatype preparation. The data from the ten laboratories indicated that each ampoule of the new proposed standard contains 850 international units of t-PA activity by the clot lysis assay. It is planned to present the results of this study to the Expert Committee on Biological Standardization of the World Health Organization at its next meeting and to request that the preparation of t-PA, coded 861670, be established as the 2ndlnternational Standard for t-PA.

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