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

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.

Antigens of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1: Correlates in Nonsmoking Japanese and Caucasian Men and Women

1993 ◽  
Vol 70 (03) ◽  
pp. 475-480 ◽  
Author(s):  
Hiroyasu Iso ◽  
Aaron R Folsom ◽  
Kazuko A Koike ◽  
Shinichi Sato ◽  
Kenneth K Wu ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Body Mass ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Race Difference ◽  
Tissue Plasminogen ◽  
Caucasian Men ◽  
Pai 1

SummaryWe reported in a 1987 preliminary study that tissue plasminogen activator antigen was significantly higher in American Caucasian men than in Japanese men. To further examine possible differences in fibrinolytic activity between the two races, an expanded study was conducted in a total of 300 nonsmoking men and women aged 47-69 years in two population-based samples: rural Japanese living in Akita and Caucasians living in Minneapolis-St. Paul, MN. Antigens of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) were measured. Mean t-PA antigen was 2.3 ng/ml higher in Caucasian men than in Japanese men (P <0.001), but no race difference was seen for women (P = 0.59). Mean PAI-1 was higher in Caucasians than in Japanese for both sexes, and the race difference in mean was 1.8 ng/ml for men (P = 0.07) and 4.4 ng/ml for women (P <0.001). Both t-PA and PAI-1 were associated positively with body mass index and blood triglycerides for all sex-race groups, and positively with alcohol intake for Japanese and Caucasian men. Compared to Japanese, Caucasians of both sexes had higher levels of body mass index and blood triglycerides, and lower average intake of alcohol among men. Even when adjusted for body mass index, triglycerides, alcohol and other cardiovascular risk factors, the race difference in mean t-PA antigen persisted for men (P <0.001), as did the difference in mean PAI-1 for men (P = 0.03) and women (P = 0.001). If PAI-1 is a risk factor for coronary heart disease, a higher level in Caucasians than Japanese would correspond to the higher mortality rate from coronary heart disease in the United States than in Japan.

scholarly journals Coagulopathy is Initiated with Endothelial Dysfunction and Disrupted Fibrinolysis in Patients with COVID-19

2021 ◽  
Author(s):  
FATMA BURCU BELEN APAK ◽  
Gulbahar Yuce ◽  
Deniz Ilhan Topcu ◽  
Ayse Gultekingil ◽  
Yunus Emre Felek ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Control Group ◽  
Endothelial Protein C Receptor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tissue Plasminogen ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Background: A substantial group of patients suffer coagulopathy of Covid-19 (CAC) and are presented with thrombosis. The pathogenesis involved in CAC is not fully understood.Objectives: We evaluated the hemostatic and inflammatory parameters of 51 hospitalized Covid-19 adult patients and 21 controls. The parameters analyzed were danger signal molecule (High molecular weight group box protein-1/HMGBP-1), platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, fibrinogen, endothelial protein C receptor (EPCR), soluble E-selectin, soluble P-selectin, thrombomodulin, tissue plasminogen activator (TPA), plasminogen activator inhibitor-1 (PAI-1), soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), β-thromboglobulin, antithrombin and protein C. The main objective of our study was to investigate which part of the hemostatic system was mostly affected at the admission of Covid-19 patients and whether these parameters could differentiate intensive care unit (ICU) and non-ICU patients. Patients and Methods:In this prospective case-control study, 51 patients ≥18 years who are hospitalized with the diagnosis of Covid-19 and 21 healthy control subjects were included. We divided the patients into two groups according to their medical progress, either into ICU and non-ICU group. Regarding the outcome, patients were again categorized as survivor and non-survivor groups. Blood samples were collected from patients at admission at the time of hospitalization before administration of any treatment for Covid-19. The analyzes of the study were made with the IBM SPSS V22 program. p < 0.05 was considered statistically significant.Results:A total of 51 adult patients (F/M: 24/27) (13 ICU and 38 non-ICU) were included in the study cohort. The mean age of the patients was 68.1 ± 14.4 years. The control group consisted of 21 age and sex-matched healthy individuals. All of the patients were hospitalized, in a group of 13 patients, Covid-19 progressed to severe form and were hospitalized at ICU. We found out that the levels of fibrinogen, prothrombin time (PT), endothelial protein-C receptor (EPCR), D-dimer, soluble E-selectin, soluble P-selectin, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (TPA) were increased; whereas, the levels of soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), antithrombin and protein-C were decreased in Covid-19 patients compared to the control group at hospital admission. Tissue plasminogen activator was the only marker that had a significantly different median level between ICU and non-ICU groups (p<0.001).Conclusions:In accordance with the previous literature, we showed that Covid-19 associated coagulopathy is distinct from sepsis-induced DIC with prominent early endothelial involvement and fibrinolytic shut-down. Reconstruction of endothelial function at early stages of infection may protect patients to progress to ICU hospitalization. We believe that after considering the patient’s bleeding risk, early administration of LMWH therapy at Covid-19 even in at outpatient setting may be useful both for restoring endothelial function and anticoagulation. The intensity of anticoagulation in non-ICU and ICU Covid-19 patients should be clarified with further studies.

scholarly journals Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina

2005 ◽  
Vol 152 (2) ◽  
pp. 285-291 ◽  
Author(s):  
A M Smith ◽  
K M English ◽  
C J Malkin ◽  
R D Jones ◽  
T H Jones ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Stable Angina ◽  
Chronic Stable Angina ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Bioavailable Testosterone ◽  
Tissue Plasminogen ◽  
Activator Inhibitor ◽  
Pai 1

Objective: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis. Methods: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks. Results: Bioavailable testosterone levels were: 2.58 ± 0.58 nmol/l at baseline, compared with 3.35 ± 0.31 nmol/l at week 14 (P < 0.001) after treatment compared with 2.6 ± 0.18 nmol/l and 2.44 ± 0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03 ± 0.18 g/l at baseline and 3.02 ± 0.18 g/l at week 14, P = 0.24), tPA activity (26.77 ± 4.9 Iu/ml and 25.67 ± 4.4 Iu/ml, P = 0.88) or PAI-1 activity (0.49 ± 0.85 Iu/ml and 0.36 ± 0.06 Iu/ml, P = 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44 ± 0.02 g/l and 1.45 ± 0.02 g/l, P = 0.22). Conclusion: Physiological testosterone replacement does not adversely affect blood coagulation status.

Tissue Plasminogen Activator (t-PA) and Plasminogen Activator Inhibitor-1 (PAI-1) in Essential Thrombocythemia and Polycythemia Vera and Thrombotic Complications.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4879-4879
Author(s):  
Rossella R. Cacciola ◽  
Ernesto Di Francesco ◽  
Rosario Giustolisi ◽  
Emma Cacciola
Keyword(s):  
Polycythemia Vera ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Essential Thrombocythemia ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tissue Plasminogen ◽  
Thrombotic Complications ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Thrombotic complications are frequent in patients with essential thrombocythemia (ET) and polycythemia vera (PV). While a thrombin- and tissue plasminogen activator (t-PA)-regulated release of t-PA and plasminogen activator inhibitor-1 (PAI-1), respectively, has been shown and an association between elevated t-PA and PAI-1 and thrombogenesis has been studied for several vascular diseases, few studies have concentrated on the correlation between t-PA and PAI-1 levels and thrombogenesis in these myeloproliferative disorders. Therefore, we investigated prothrombin fragment 1+2 (F1+2), as marker of thrombin generation, and t-PA and PAI-1 in patients with ET and PV and thrombosis. We included 44 patients, 22 ET (5 men and 17 women, mean age 55 years) and 22 PV (17 men and 5 women, mean age 60 years) who fulfilled PVSG. The mean duration of disease was 4.5 years. Most received cytoreduction, such as hydroxyurea (13 ET and 14 PV), interferon-alpha (2 ET), anagrelide hydrochloride (5 ET) or phlebotomy (8 PV). None of studied patients had thrombotic risk factors. Of 44 patients, 25 (12 ET and 13 PV) developed thrombosis, whereas 19 (10 ET and 9 PV) did not. Measurements were assayed by ELISA. All patients had increased F1+2 (2.8±2.8 nmol/L vs 0.7±0.2 nmol/L) (p=0.001). t-PA and PAI-1 were higher in those patients with previous thrombosis than in asymptomatic patients (130±62 ng/ml vs 89±69 ng/ml and 45±20 ng/ml vs 57±27 ng/ml, respectively) (p=0.043 and p=0.085, respectively). A positive correlation there was between F1+2 and t-PA and t-PA and PAI-1 (p<0.0001 and p<0.0001, respectively). These findings suggest that a disfibrinolysis may be in ET and PV and that t-PA and PAI-1 may be predictive additional factors of the thrombotic tendency of these patients.

Effect of Peptides on the Inactivation of Tissue Plasminogen Activator by Plasminogen Activator Inhibitor-1 and on the Binding of Tissue Plasminogen Activator to Endothelial Cells

1990 ◽  
Vol 64 (02) ◽  
pp. 270-275 ◽  
Author(s):  
A J Wittwer ◽  
M A Sanzo
Keyword(s):  
Endothelial Cells ◽  
Thrombolytic Therapy ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Amino Acid Sequences ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tissue Plasminogen ◽  
Two Factors ◽  
Pai 1

SummaryThe effectiveness of tissue plasminogen activator (tPA) in thrombolytic therapy is dependent upon the rate at which therapeutically administered tPA reaches the clot site and the proportion of that tPA which is enzymatically active. Interactions between tPA and its main plasma inhibitor (PAI-1) and between tPA and the endothelial cells lining blood vessels are two factors which may limit efficacy. In an attempt to identify the regions of the tPA molecule involved in these interactions, we have examined a series of synthetic peptides with amino acid sequences corresponding to different regions of the tPA molecule for their ability to protect tPA from inactivation by PAI-1 and for their ability to reduce the binding of tPA to endothelial cells. Three peptides were identified which were especially effective at maintaining tPA activity in the presence of PAI-1 and three others were found which had a lesser effect. These same peptides were also found to inhibit the binding of tPA to endothelial cells. This suggests that the same regions of the tPA molecule are involved in both processes. None of the peptides inhibited the binding of tPA to fibrin. These peptides may serve as models for the development of agents for enhancing the activity of both endogenous tPA and of tPA administered in thrombolytic therapy.

scholarly journals Inhibition of tissue plasminogen activator activity by aspirin in vivo and its relationship to levels of tissue plasminogen activator inhibitor antigen, plasminogen activator and their complexes

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1635-1643 ◽  
Author(s):  
RI Levin ◽  
PC Harpel ◽  
JG Harpel ◽  
PA Recht
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Venous Occlusion ◽  
Plasminogen Activator Inhibitor 1 ◽  
Subsequent Formation ◽  
Tissue Plasminogen ◽  
Plasmin Inhibitor ◽  
Activator Inhibitor ◽  
Pai 1

Abstract The observation that aspirin inhibits the increment in tissue plasminogen activator (t-PA) activity induced by venous occlusion of the forearm became controversial with the publication of several nonconfirmatory studies. The current study was performed to confirm the original observation and determine the mechanism by which aspirin suppresses the incremental t-PA activity induced by venous occlusion. Aspirin (650 mg/d X 2) caused no change in resting levels of t-PA antigen (t-PA:Ag) or activity, plasminogen activator inhibitor 1 antigen (PAI-1:Ag), or activity or t-PA-PAI-1 complexes. In contrast, aspirin reduced the increments induced by venous occlusion as follows: t-PA:Ag by 45% (P = .001); t-PA activity (euglobulin lysis time, ELT) by 43% (P = .006); and t-PA activity (alpha 2-plasmin inhibitor-plasmin complexes, PIPC) by 41% (P = .003). The inhibition of incremental t-PA activity measured as ELT or PIPC was linearly correlated with the inhibition of incremental t-PA:Ag (respectively, r = .75, P less than .02; r = .67, P less than .05). Aspirin had no effect on the increment in PAI-1:Ag induced by venous occlusion, but similar to the effect on t- PA:Ag, aspirin induced a 51% inhibition of the increment in t-PA-PAI-1 complex formation. Aspirin did not alter the ability of alpha 2-plasmin inhibitor to bind plasmin, nor the ability of plasma to support the fibrin-catalyzed generation of plasmin by t-PA, nor the subsequent formation of PIPC. Aspirin inhibits the t-PA activity induced by venous occlusion primarily by inhibiting the release of t-PA antigen.

scholarly journals High levels of plasminogen activator inhibitor-1, tissue plasminogen activator and fibrinogen in patients with severe COVID-19

2021 ◽  
Author(s):  
David Cabrera-Garcia ◽  
Andrea Miltiades ◽  
Samantha M Parsons ◽  
Katerina Elisman ◽  
Mohammad Taghi Mansouri ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activation ◽  
Plasmin Activity ◽  
Plasminogen Activator Inhibitor 1 ◽  
Partial Explanation ◽  
Tissue Plasminogen ◽  
Activator Inhibitor ◽  
Pai 1

We measured plasma levels of fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and plasminogen activation inhibitor 1 (PAI-1) in blood from 37 patients with severe coronavirus disease-19 (COVID-19) and 23 controls. PAI-1, t-PA and fibrinogen levels were significantly higher in the COVID-19 group. Increased levels of PAI-1 likely result in lower plasmin activity and hence decreased fibrinolysis. These observations provide a partial explanation for the fibrin-mediated increase in blood viscosity and hypercoagulability that has previously been observed in COVID-19. Our data suggest that t-PA administration may be problematic, but that other interventions designed to enhance fibrinolysis might prove useful in the treatment of the coagulopathy that is often associated with severe COVID-19.

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