scholarly journals A kinetic model of the circulatory regulation of tissue plasminogen activator during exercise, epinephrine infusion, and endurance training

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3293-3302 ◽  
Author(s):  
WL Chandler ◽  
WC Levy ◽  
RC Veith ◽  
JR Stratton
Keyword(s):  
Blood Flow ◽  
Endurance Training ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Hepatic Blood Flow ◽  
Plasma Epinephrine ◽  
Epinephrine Infusion ◽  
Tissue Plasminogen ◽  
Pai 1 ◽  
Epinephrine Concentration

Abstract A computer simulation of the circulatory system was used to kinetically model secretion, inhibition, and clearance of tissue plasminogen activator (t-PA) during three different processes that increase active t-PA levels: epinephrine infusion, exercise, and endurance training. Infusion of epinephrine stimulated an increase in t-PA secretion that was proportional to the plasma epinephrine concentration. In addition, epinephrine infusion increased hepatic blood flow and t-PA clearance, thus slowing the increase of plasma t-PA levels. During exercise, t-PA levels increased due both to increased t-PA secretion and to decreased clearance secondary to reduced hepatic blood flow. The increase in t-PA secretion during exercise was directly proportional to the epinephrine concentration in blood with the same ratio of t-PA secretion to epinephrine as found during epinephrine infusion, suggesting that increased plasma epinephrine during exercise was the primary stimulus for t-PA secretion. Lastly, the simulation predicted that 6 months of endurance training produced a decrease in resting plasminogen activator inhibitor type 1 (PAI-1) secretion, resulting in less t-PA inhibition and an overall increase in active t-PA after training. Accurate analysis of the regulation of active t-PA levels in blood required simultaneous modeling of t-PA and PAI-1 secretion, hepatic clearance, and inhibition of t-PA by PAI-1.

scholarly journals A kinetic model of the circulatory regulation of tissue plasminogen activator during exercise, epinephrine infusion, and endurance training

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3293-3302
Author(s):  
WL Chandler ◽  
WC Levy ◽  
RC Veith ◽  
JR Stratton
Keyword(s):  
Blood Flow ◽  
Endurance Training ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Hepatic Blood Flow ◽  
Plasma Epinephrine ◽  
Epinephrine Infusion ◽  
Tissue Plasminogen ◽  
Pai 1 ◽  
Epinephrine Concentration

A computer simulation of the circulatory system was used to kinetically model secretion, inhibition, and clearance of tissue plasminogen activator (t-PA) during three different processes that increase active t-PA levels: epinephrine infusion, exercise, and endurance training. Infusion of epinephrine stimulated an increase in t-PA secretion that was proportional to the plasma epinephrine concentration. In addition, epinephrine infusion increased hepatic blood flow and t-PA clearance, thus slowing the increase of plasma t-PA levels. During exercise, t-PA levels increased due both to increased t-PA secretion and to decreased clearance secondary to reduced hepatic blood flow. The increase in t-PA secretion during exercise was directly proportional to the epinephrine concentration in blood with the same ratio of t-PA secretion to epinephrine as found during epinephrine infusion, suggesting that increased plasma epinephrine during exercise was the primary stimulus for t-PA secretion. Lastly, the simulation predicted that 6 months of endurance training produced a decrease in resting plasminogen activator inhibitor type 1 (PAI-1) secretion, resulting in less t-PA inhibition and an overall increase in active t-PA after training. Accurate analysis of the regulation of active t-PA levels in blood required simultaneous modeling of t-PA and PAI-1 secretion, hepatic clearance, and inhibition of t-PA by PAI-1.

scholarly journals Chronic Nicotine Treatment Enhances Focal Ischemic Brain Injury and Depletes Free Pool of Brain Microvascular Tissue Plasminogen Activator in Rats

1997 ◽  
Vol 17 (2) ◽  
pp. 136-146 ◽  
Author(s):  
Liang Wang ◽  
Mamoru Kittaka ◽  
Ning Sun ◽  
Steven S. Schreiber ◽  
Berislav V. Zlokovic
Keyword(s):  
Blood Flow ◽  
Brain Injury ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Mrna Transcript ◽  
Nicotine Treatment ◽  
Chronic Nicotine ◽  
Chronic Nicotine Treatment ◽  
Tissue Plasminogen ◽  
Pai 1

Effects of nicotine treatment (4.5 mg/kg of nicotine-free base/day administered s.c. by osmotic minipumps for 14 days) on focal ischemic stroke and expression of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in cerebral microvessels were studied in rats in vivo using a reversible (1 h) middle cerebral artery occlusion model. Plasma levels of nicotine and its major metabolite cotinine after 14 days of treatment were 88 and 364 ng/ml, respectively. Nicotine treatment resulted in 35–40% ( p <0.001) decrease in the blood flow in the periphery of the ischemic core during reperfusion, an increase in the neurologic score of 2.6-fold ( p <0.01), and 36% ( p <0.05) and 121% ( p <0.01) increases in the injury and edema volume in the pallium, respectively. A free pool of brain microvascular t-PA antigen was completely depleted by nicotine, while the expression of the PAI-1 antigen and/or PAI-1-t-PA complexes remained unchanged. The relative abundance of cerebromicrovascular t-PA mRNA transcript versus β-actin mRNA transcript did not change with nicotine. It is concluded that chronic nicotine treatment impairs the restoration of blood flow, worsens the neurologic outcome, and enhances brain injury following an ischemic insult. These nicotine effects are associated with depletion of brain microvascular t-PA antigen.

Immunoreactivity of Tissue Plasminogen Activator and of Its Inhibitor Complexes

1989 ◽  
Vol 61 (03) ◽  
pp. 409-414 ◽  
Author(s):  
M Rånby ◽  
G Nguyen ◽  
P Y Scarabin ◽  
M Samama
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Degradation Products ◽  
Gel Filtration ◽  
Free Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Plasma Samples ◽  
Significant Difference ◽  
Tissue Plasminogen ◽  
Pai 1

SummaryAn enzyme linked immunosorbent assay (ELISA) based on goat polyclonal antibodies against human tissue plasminogen activator (tPA) was evaluated. The relative immunoreactivity of tPA in free form and tPA in complex with inhibitors was estimated by ELISA and found to be 100, 74, 94, 92 and 8l% for free tPA and tPA in complex with PAI-1, PAI-2, α2-antiplasmin and C1-inhibitor, respectively. Addition of tPA to PAI-1 rich plasma resulted in rapid and total loss of tPA activity without detectable loss of ELISA response, indicating an immunoreactivity of tPA in tPA/PAI-1 complex of about l00%. Three different treatments of citrated plasma samples (acidification/reneutralization, addition of 5 mM EDTA or of 0.5 M lysine) prior to determination by ELISA all resulted in increased tPA levels. The fact that the increase was equally large in all three cases along with good analytical recovery of tPA added to plasffi, supported the notion that all tPA antigen present in plasma samples is measured by the ELISA. Analysis by ELISA of fractions obtained by gel filtration of plasma from a patient undergoing tPA treatment identified tPA/inhibitor complexes and free tPA but no low molecular weight degradation products of tPA. Determinations of tPA antigen were made at seven French clinical laboratories on coded and randomized plasma samples with known tPA antigen content. For undiluted samples there was no significant difference between the tPA levels found and those known to be present. The between-assay coefficient of variation was 7 to 10%. In conclusion, the ELISA appeared suited for determination of total tPA antigen in human plasma samples.

Herpes Simplex Virus Decreases Endothelial Cell Plasminogen Activator Inhibitor

1993 ◽  
Vol 69 (03) ◽  
pp. 253-258 ◽  
Author(s):  
Robert A Bok ◽  
Harry S Jacob ◽  
Jozsef Balla ◽  
Margaret Juckett ◽  
Theresa Stelle ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Plasminogen ◽  
Simplex Virus ◽  
Activator Inhibitor ◽  
Pai 1

SummaryHerpes simplex virus (HSV) infection is histopathologically associated with vascular injury, fibrinoid necrosis and inflammatory cell infiltrates. We have previously shown in vitro that HSV infection of human umbilical vein endothelial cells (HUVEC) promotes a procoagulant phenotype manifest by the induction of tissue factor, the loss of thrombomodulin, and an increase in platelet adhesion. In these studies we examined the effects of HSV infection on HUVEC plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA). HSV infection caused the loss of PAI-1 in the extracellular matrix (ECM) and that released into the supernatant of HUVEC. Both activity and antigen levels of the Serpin inhibitor are diminished as a result of HSV infection. The loss of inhibitor is not secondary to diminished vitronectin (Vn), the primary binding protein of PAI-1 in the ECM, but appears to be secondary to decreased synthesis at the RNA level. Tissue plasminogen activator (t-PA). synthesis is also decreased in endothelial HSV infection. PAI-1 loss may further promote a procoagulant phenotype in HSV infection in vivo.

Tissue Plasminogen Activator Release in Chronic Venous Hypertension due to Heart Failure

1992 ◽  
Vol 68 (03) ◽  
pp. 321-324 ◽  
Author(s):  
Irena Keber ◽  
Dušan Keber ◽  
Mojca Stegnar ◽  
Nina Vene
Keyword(s):  
Heart Failure ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Venous Pressure ◽  
Venous Hypertension ◽  
Plasminogen Activator Inhibitor 1 ◽  
Control Subjects ◽  
Tissue Plasminogen ◽  
Pai 1

SummaryIn order to study the effects of chronic venous hypertension due to heart failure on blood fibrinolytic activity, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor 1 (PAI-1) antigen, t-PA activity and PAI activity were measured before and after venous occlusion of the arm for 20 min in 15 patients with right-sided heart failure, 15 patients with left-sided heart failure, and 30 control healthy subjects. Central venous pressure, measured by observing the jugular veins, was above 15 cm of the blood column in all patients with right-sided heart failure, and normal (below 8 cm) in all patients with left-sided heart failure and control subjects. There was no difference in the basal concentrations of t-PA (11.0, 10.2 and 10.8 ng/ml; all values medians) and PAI-1 antigens and their activities between right and left-sided heart failure and the control subjects. After the occlusion, t-PA antigen increased significantly less in right-sided heart failure (28.6 ng/ml) than in left-sided heart failure and the control subjects (54.5 and 45.9 ng/ml, respectively). It was concluded that the poor increase in fibrinolytic activity that had already been reported in patients with heart failure, was due to low t-PA release during occlusion and not to a high basal PAI level. It was limited to the patients with right-sided heart failure and was probably the consequence of chronic systemic venous hypertension.

scholarly journals The mechanism of the reaction between human plasminogen-activator inhibitor 1 and tissue plasminogen activator

1990 ◽  
Vol 265 (1) ◽  
pp. 109-113 ◽  
Author(s):  
T L Lindahl ◽  
P I Ohlsson ◽  
B Wiman
Keyword(s):  
Amino Acid ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Peptide Bond ◽  
Plasminogen Activator Inhibitor 1 ◽  
Sds Page ◽  
Tissue Plasminogen ◽  
Activator Inhibitor ◽  
Pai 1

The structural events taking place during the reaction between PAI-1 (plasminogen-activator inhibitor 1) and the plasminogen activators sc-tPA (single-chain tissue plasminogen activator) and tc-tPA (two-chain tissue plasminogen activator) were studied. Complexes were formed by mixing sc-tPA or tc-tPA with PAI-1 in slight excess (on an activity basis). The complexes were purified from excess PAI-1 by affinity chromatography on fibrin-Sepharose. Examination of the purified complexes by SDS/polyacrylamide-gel electrophoresis (SDS/PAGE) and N-terminal amino acid sequence analysis demonstrated that a stoichiometric 1:1 complex is formed between PAI-1 and both forms of tPA. Data obtained from both complexes revealed the amino acid sequences of the parent molecules and, in addition, a new sequence: Met-Ala-Pro-Glu-Glu-. This sequence is found in the C-terminal portion of the intact PAI-1 molecule and thus locates the reactive centre of PAI-1 to Arg346-Met347. The proteolytic activity of sc-tPA is demonstrated by its capacity to cleave the ‘bait’ peptide bond in PAI-1. The complexes were inactive and dissociated slowly at physiological pH and ionic strength, but rapidly in aq. NH3 (0.1 mol/l). Amidolytic tPA activity was generated on dissociation of the complexes, corresponding to 0.4 mol of tPA/mol of complex. SDS/PAGE of the dissociated complexes indicated a small decrease in the molecular mass of PAI-1, in agreement with proteolytic cleavage of the ‘bait’ peptide bond during complex-formation.

Gene polymorphism of tissue plasminogen activator and risk of recurrent venous thromboembolism in young patients

2018 ◽  
Author(s):  
А.В. Чечулова ◽  
С.И. Капустин ◽  
В.Е. Солдатенков ◽  
В.Д. Каргин ◽  
Л.П. Папаян ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Young Patients ◽  
Disease Recurrence ◽  
Type I ◽  
Single Episode ◽  
Tissue Plasminogen ◽  
Recurrent Vte ◽  
Pai 1

Введение. Наиболее частые клинические проявления венозного тромбоэмболизма (ВТЭ) — тромбоз глубоких вен (ТГВ) и тромбоэмболия легочной артерии (ТЭЛА) — нередко осложняются рецидивом заболевания, который приводит к увеличению риска тяжелого посттромбофлебитического синдрома и/или жизнеугрожающей ТЭЛА. Роль наследственных факторов в развитии рецидива ВТЭ у лиц молодого возраста изучена недостаточно. Цель исследования: поиск генетических факторов риска рецидивирующего течения ВТЭ у пациентов молодого возраста. Материалы и методы. Обследовано 250 пациентов (117 мужчин и 133 женщины, средний возраст — 37,4 года) с ранним дебютом ВТЭ (в возрасте до 45 лет включительно). У 105 (42%) из них наблюдали рецидивирующее течение тромбоза. Всем пациентам было проведено молекулярно-генетическое исследование ДНК-полиморфизма 9 генов, вовлеченных в регуляцию активности плазменного звена гемостаза: α- и β-субъединицы фактора (F) I (Thr312Ala и –455G/A, соответственно), FII (20210 G/A), FV (1691 G/A), FXII (46 C/T), А-субъединицы FXIII (Val34Leu), ингибитора активатора плазминогена 1 типа (PAI-1, —675 4G/5G), тканевого активатора плазминогена (tPA, 311 п. н. Ins/Del) и эндотелиального рецептора протеина С (EPCR, Ser219Gly). Оценку статистической значимости различий в распределении генотипов между группами пациентов с рецидивирующим течением ВТЭ и с единственным эпизодом тромбоза в анамнезе проводили с помощью точного метода Фишера. Результаты. Рецидив ВТЭ в отдаленном периоде был выявлен у 105 (42%) пациентов. Группу сравнения составили 103 (41,2%) пациента с единственным эпизодом ВТЭ в анамнезе. У 42 (16,8%) человек наличие либо отсутствие рецидива установить не удалось. Генотип «tPA Del/Del» встречался в 2 раза реже в группе пациентов с рецидивирующим течением ВТЭ (14,3% против 28,2% у лиц с единственным эпизодом ВТЭ; ОR = 0,4; 95% CI: 0,2–0,9; p = 0,017), что указывает на его возможный протективный эффект от риска рецидива заболевания. Для остальных генов значимых различий в распределении генотипов между сравниваемыми группами не было обнаружено. Изучение «ген-генных взаимодействий» вариантов tPA и PAI-1 выявило существенные различия между группами пациентов: сочетание «tPA Del/Del + + PAI-1 4G5G» в 3,5 раза реже встречалось в группе с рецидивом венозного тромбоза (3,8% против 13,6%; OR = 0,3; 95% CI: 0,08–0,8; p = 0,011), тогда как сочетание генотипов «PAI-1 5G5G + tPA Ins/Del», напротив, было характерно, для этой группы (13,3% против 5,8% у лиц с единственным эпизодом ВТЭ; OR = 2,5; 95% CI: 0,9–6,7; p = 0,054). Заключение. Группа пациентов молодого возраста с рецидивирующим течением ВТЭ характеризуется значительным снижением частоты встречаемости генотипа tPA Del/Del, а также сочетания «tPA Del/Del + PAI-1 4G5G». Для уточнения характера влияния полиморфизма данных генов на риск развития повторных эпизодов ВТЭ необходимы дополнительные исследования. Introduction. The most frequent clinical manifestations of venous thromboembolism (VTE) — deep vein thrombosis (DVT) and pulmonary embolism (PE) are often complicated by recurrent episodes that lead to an increased risk of severe post-thrombophlebitic syndrome and/or life-threatening PE. The role of hereditary factors in the development of recurrent VTE in young people is still unclear. Aim: identifi cation of genetic risk factors for recurrent VTE in young patients. Materials and methods. We examined 250 patients (117 men and 133 women, mean age — 37.4 years) with early VTE debut (aged up to 45 years inclusive). In 105 (42%) of them, a recurring course of thrombosis was observed. In all patients a molecular genetic study of DNA polymorphism of 9 genes involved in the regulation of hemostasis plasma activity was carried out: α-and β-subunits of factor (F) I (Thr312Ala and –455 G/A, respectively), FII (20210 G/A), FV (1691 G/A), FXII (46 C/T), FXIII A subunit (Val34Leu), plasminogen activator inhibitor type I (PAI-1, —675 4G/5G), tissue plasminogen activator (tPA, 311 bp Ins/Del), and the endothelial protein C receptor (EPCR, Ser219Gly). Assessment of statistical signifi cance of diff erences in genotype distribution between the groups of patients with recurrent VTE and a single episode of thrombosis history was performed using Fisher’s exact method. Results. In the long-term period VTE recurrence was revealed in 105 (42%) patients. The comparison group consisted of 103 (41.2%) patients with a single VTE episode in the anamnesis. In 42 (16.8%) patients the presence or absence of disease recurrence was not revealed. Genotype «tPA Del Del» met 2 times less frequently in patients with recurrent VTE (14.3% vs 28.2% in individuals with a single episode of VTE; OR = 0.4; 95% CI: 0,2–0,9; p = 0.017) that indicates its possible protective effect on the risk of disease recurrence. For the remaining genes no signifi cant diff erences in genotypes distribution between the compared groups were found. Study of «gene-gene interactions» of tPA and PAI-1 variants revealed signifi cant differences between groups of patients: the combination «tPA Del/Del + PAI-1 4G5G» was 3.5 times less frequent in the group with recurrent venous thrombosis (3.8% against 13.6%; OR = 0.3; 95% CI: 0.08–0.8; p = 0.011) while the combination of the genotypes «PAI-1 5G5G + tPA Ins/Del», in contrast, was typical for this group (13.3% vs. 5.8% in individuals with a single episode of VTE; OR = 2.5; 95% CI: 0.9–6.7; p = 0.054). Conclusion. Group of young patients with recurrent VTE is characterized by a signifi cant reduction in the incidence of genotype tPA Del/Del as well as the combination of «tPA Del / Del + PAI-1 4G5G». To clarify the eff ect of polymorphism of these genes on the risk of developing of VTE recurrent episodes additional studies are needed.

Recombinant Tissue Plasminogen Activator Treatment in Two Infants With Fulminant Meningococcemia

PEDIATRICS ◽  
1995 ◽  
Vol 96 (1) ◽  
pp. 144-148
Author(s):  
Werner Zenz ◽  
Wolfgang Muntean ◽  
Siegfried Gallistl ◽  
Gerfried Zobel ◽  
Hans M. Grubbauer
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Prognostic Significance ◽  
Case Fatality ◽  
Plasminogen Activator Inhibitor ◽  
Recombinant Tissue Plasminogen Activator ◽  
Acute Onset ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tissue Plasminogen ◽  
Pai 1

Fulminant meningococcemia defines a life-threatening disease with acute onset, severe septic shock, and progressive hemorrhagic necrosis of the skin. Despite advances in intensive care, the case fatality rate of this disease is still between 30% and 50%.1-5 Disseminated intravascular coagulation (DIC) with deposition of fibrin and histologically demonstrable widespread microvascular thromboses contributes significantly to the pathogenesis.6-9 Impairment of fibrinolysis caused by elevation of plasminogen activator inhibitor 1 (PAI-1), the physiologic inhibitor of tissue plasminogen activator, is part of these clotting abnormalities and has prognostic significance; the extent of elevation of PAI-1 is correlated to the development of shock, renal impairment, and mortality.10,11

Tissue Plasminogen Activator Plasma Levels as a Potential Diagnostic Aid in Acute Pulmonary Embolism

2003 ◽  
Vol 127 (3) ◽  
pp. 310-315
Author(s):  
Julio Flores ◽  
Angel García-Avello ◽  
Victor M. Flores ◽  
JoséL. Navarro ◽  
Felipe Canseco ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Lower Limb ◽  
Pulmonary Angiography ◽  
Enzyme Linked Immunosorbent Assay ◽  
Clinical Probability ◽  
Tissue Plasminogen ◽  
Lung Scan ◽  
Pai 1 ◽  
D Dimer

Abstract Context.—Pulmonary embolism (PE) is a potentially fatal and frequent complication of deep venous thrombosis, and the most reliable techniques for the diagnosis of PE are not universally available and have other limitations. Objective.—To determine the efficacy of 4 different fibrinolysis system parameters, namely, tissue plasminogen activator (tPA), tissue plasminogen activator inhibitor type 1 (PAI-1), plasmin-antiplasmin complexes (PAP), and D-dimer, in the diagnosis of acute PE. Setting.—A 350-bed university hospital serving an area with 280 000 inhabitants. Patients.—Sixty-six consecutive outpatients with clinically suspected PE. The diagnosis of PE was based on ventilation-perfusion (V/Q) lung scan in combination with clinical assessment, lower limb study, and (when required) pulmonary angiography. Main Outcome Measures.—At the moment of clinical suspicion, a sample of venous blood was obtained to measure levels of tPA, PAI-1, PAP, and D-dimer using an enzyme-linked immunosorbent assay method. Results.—Twenty-seven patients (41%) were classified as PE positive (high clinical probability and V/Q lung scan [n = 12], nondiagnostic V/Q lung scan and high clinical probability [n = 1], inconclusive V/Q lung scan and positive lower limb examination for deep venous thrombosis [n = 11], and positive pulmonary angiography [n = 3]), and 39 patients (59%) were classified PE negative. The sensitivity/negative predictive value for tPA, using a cutoff of 8.5 ng/mL, and PAI-1, using a cutoff of 15 ng/mL, were 100%/100% and 100%/100%, respectively. A tPA level lower than 8.5 ng/mL occurred in 13 (19.7%; all PE negative) of 66 patients with suspected PE, and PAI-1 levels were lower than 15 ng/mL in 9 (13.6%; all PE negative) of 66 patients with suspected PE. The D-dimer, using a cutoff of 500 ng/mL, showed a sensitivity and negative predictive value of 92.6% and 87.5%, respectively. Conclusions.—Our data indicate that tPA and PAI-1 levels are potentially useful in ruling out PE, although tPA seems to be the better parameter. The sensitivity levels and negative predictive values for the rapid enzyme-linked immunosorbent assay for D-dimer used in this investigation were low compared with previous studies using the same test.

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