Sex Differences in the Determinants of Fibrinolytic Activity

1998 ◽  
Vol 79 (03) ◽  
pp. 587-590 ◽  
Author(s):  
J. A. Cooper ◽  
D. J. Howarth ◽  
T. W. Meade ◽  
G. J. Miller ◽  
P. K. MacCallum
Keyword(s):  
Plasminogen Activator ◽  
Whole Blood ◽  
Fibrinolytic Activity ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Clot Lysis ◽  
Significant Difference ◽  
Main Determinants ◽  
Activator Inhibitor Type ◽  
Pai 1

SummaryImpaired whole blood fibrinolytic activity (FA), measured by the dilute clot lysis time (DCLT), is associated with first episodes of ischaemic heart disease (IHD) in the Northwick Park Heart Study in men, especially under 55 years, and in women. In a community-based study to investigate possible determinants of the DCLT, and therefore to assess which fibrinolytic components might be predictors of first IHD events, we measured fibrinolytic variables in a sub-sample of 150 healthy adults (73 males, 77 females) randomly selected from a single general practice.Most of the variance in DCLT (68% in men, 63% in women) was explained by tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) activities. In multiple regression analysis there was a significant difference in the strength of the association of t-PA activity with DCLT in men compared to women (test for interaction p = 0.05), the association of t-PA activity with DCLT being significant in males but not in females. Plasma PAI-1 activity was strongly associated with DCLT in both sexes. There was no independent association of DCLT with plasma fibrinogen, t-PA antigen, other fibrinolytic inhibitors, body mass index, serum lipids or C-reactive protein.Plasma PAI-1 activity in females and both t-PA and PAI-1 activities in males are the main determinants of whole blood FA measured by DCLT. It is therefore likely that these modulators of the plasma fibrinolytic system are associated with the onset of first clinical episodes of IHD. Elevated levels of t-PA antigen were positively associated with DCLT after adjustment for age and sex and therefore indicate impaired rather than enhanced FA. Further studies of the association of FA with risk of IHD should include not only “global” measures but also assessment of t-PA and PAI-1 activities, particularly as our results suggest that their associations with IHD may differ in men and women.

Diurnal Variation of the Fibrinolytic System

1988 ◽  
Vol 59 (03) ◽  
pp. 495-499 ◽  
Author(s):  
V Grimaudo ◽  
J Hauert ◽  
F Bachmahh ◽  
E K O Kruithof
Keyword(s):  
Diurnal Variation ◽  
Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Significant Proportion ◽  
Plasminogen Activator Inhibitor ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Euglobulin Clot Lysis Time ◽  
Pai 1

AbstractTo elucidate which component(s) of thei fibrinolytic system is (are) responsible for the diurnal variation of fibrinolytic activity we have studied several parameters of this system in 8 healthy male volunteers during a period of. 24 h. Blood was collected at 8 a. m., 10 a. m., 12 a. m., 4 p.m., 8 p.m. and 8 a. m. next morning. The following tests were performed: euglobulin clot lysis time (ECLT), fibrinolytic activity of euglobulins on fibrin plates in the presence and absence of blocking antibodies to tissue-type plasminogen activator (t-PA) and/or urokinase (u-PA), overall plasminogen activator inhibitor (PAI) activity, antigen levels of t-PA, u-PA and PAI-I and zymography of the euglobulin fraction after SDS-PAGE. From 8-10 a. m. to 4-8 p. m., total fibrinolytic activity increased by 1l3% (p <0.01) or 71%h (p <0.01) when measured by ECIX or by fibrin plate assay, respectively. The immunoquenching experiments showed that this increase was entirely due to t-PA related activity whereas u-PA activity and t-PA/u-PA independent activity remained constant during the day. Average antigen levels of u-PA and t-PA in the afternoon were 6% and 25% lower than those measured in the morning. During this period, overall PAI activity and PAI-1 antigen decreased by 3l% (p <0.01) and 52% (p <0.01) respectively. Electrophoretic-zymographic analysis of_ the euglobulins revealed that throughout the day the majority of t-PA was present in the form of the 110 kDa t-PA/PAI-I complex. The intensity of this cornplex was lowest in the afternoon. Free t-PA was almost undetectable in morning samples, but constituted a significant proportion of total t-PA in the afternoon. The diurnal increase of fibrinolytic activity, therefore, is not due to an augmentation of antigen levels of t-PA and/or u-PA but to a decline of those of PAI-1.

Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

1988 ◽  
Vol 60 (02) ◽  
pp. 328-333 ◽  
Author(s):  
N J de Fouw ◽  
Y F de Jong ◽  
F Haverkate ◽  
R M Bertina
Keyword(s):  
Plasminogen Activator ◽  
Protein C ◽  
Blood Platelets ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Tissue Type ◽  
Clot Lysis ◽  
Activator Inhibitor ◽  
Pai 1

summaryThe effect of purified human activated protein G (APC) on fibrinolysis was studied using a clot iysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125T-fibrinogen and thrombin. All proteins were of human origin.In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-l) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropylfluorophosphate. Addition of the cofactors of APC:protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.

A Specific Immunologic Assay for Functional Plasminogen Activator Inhibitor 1 in Plasma – Standardized Measurements of the Inhibitor and Related Parameters in Patients with Venous Thromboembolic Disease

1992 ◽  
Vol 68 (05) ◽  
pp. 486-494 ◽  
Author(s):  
Malou Philips ◽  
Anne-Grethe Juul ◽  
Johan Selmer ◽  
Bent Lind ◽  
Sixtus Thorsen
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Normal Subjects ◽  
Tissue Type ◽  
Blood Collection ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Significant Difference ◽  
Activator Inhibitor ◽  
Pai 1

SummaryA new assay for functional plasminogen activator inhibitor 1 (PAI-1) in plasma was developed. The assay is based on the quantitative conversion of PAI-1 to urokinase-type plasminogen activator (u-PA)-PAI-l complex the concentration of which is then determined by an ELISA employing monoclonal anti-PAI-1 as catching antibody and monoclonal anti-u-PA as detecting antibody. The assay exhibits high sensitivity, specificity, accuracy, and precision. The level of functional PAI-1, tissue-type plasminogen activator (t-PA) activity and t-PA-PAI-1 complex was measured in normal subjects and in patients with venous thromboembolism in a silent phase. Blood collection procedures and calibration of the respective assays were rigorously standardized. It was found that the patients had a decreased fibrinolytic capacity. This could be ascribed to high plasma levels of PAI-1. The release of t-PA during venous occlusion of an arm for 10 min expressed as the increase in t-PA + t-PA-PAI-1 complex exhibited great variation and no significant difference could be demonstrated between the patients with a thrombotic tendency and the normal subjects.

scholarly journals Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Zuo ◽  
Mark Warnock ◽  
Alyssa Harbaugh ◽  
Srilakshmi Yalavarthi ◽  
Kelsey Gockman ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Ex Vivo ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Bleeding Complications ◽  
Clot Lysis ◽  
Thrombosis Prophylaxis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

AbstractPatients with coronavirus disease-19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. However, bleeding complications have also been observed in some patients. Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies. 118 hospitalized COVID-19 patients and 30 healthy controls were included in the study. We measured plasma antigen levels of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) and performed spontaneous clot-lysis assays. We found markedly elevated tPA and PAI-1 levels in patients hospitalized with COVID-19. Both factors demonstrated strong correlations with neutrophil counts and markers of neutrophil activation. High levels of tPA and PAI-1 were associated with worse respiratory status. High levels of tPA, in particular, were strongly correlated with mortality and a significant enhancement in spontaneous ex vivo clot-lysis. While both tPA and PAI-1 are elevated among COVID-19 patients, extremely high levels of tPA enhance spontaneous fibrinolysis and are significantly associated with mortality in some patients. These data indicate that fibrinolytic homeostasis in COVID-19 is complex with a subset of patients expressing a balance of factors that may favor fibrinolysis. Further study of tPA as a biomarker is warranted.

Demonstration of three distinct high molecular weight complexes between plasminogen activator inhibitor type 1 and tissue type plasminogen activator.

2021 ◽  
Author(s):  
Tae Ito ◽  
Yuko Suzuki ◽  
Hideto Sano ◽  
Naoki Honkura ◽  
Francis J Castellino ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Type Plasminogen Activator ◽  
Sds Page ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Pai 1

Background: Details of the molecular interaction between tissue type plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) remain unknown. Methods and Results: Three distinct forms of high molecular weight complexes are demonstrated. Two of the forms were detected by mass spectrometry. The high molecular mass detected by MALDI-TOF MS spectrometry was 107,029 Da, which corresponds to the sum of molecular masses of the intact tPA (65,320 Da) and the intact PAI-1 (42,416 Da). The lower molecular mass was 104,367 Da and is proposed to lack the C-terminal bait peptide of PAI-1 (calculated mass, 3,804 Da) which was detected as a 3,808 Da fragment. When the complex was analyzed by SDS-PAGE, only a single band was observed. However, after treatment by SDS and Triton X-100, two distinct forms of the complex with different mobilities were shown by SDS-PAGE. The higher molecular weight band demonstrated specific tPA activity on fibrin autography, whereas the lower molecular weight band did not. Peptide sequence analysis of these two bands, however, unexpectedly revealed the existence of the C-terminal cleavage peptide in both bands and its amount was less in the upper band. In the upper band, the sequences corresponding to the regions at the interface between two molecules in its Michaelis intermediate were diminished. Thus, these two bands corresponded to distinct nonacyl-enzyme complexes, wherein only the upper band liberated free tPA under the conditions employed. Conclusion: These data suggest that under physiological conditions a fraction of the tPA-PAI-1 population exists as non-acylated-enzyme inhibitor complex.

scholarly journals The interaction of plasminogen activator inhibitor 1 with plasminogen activators (tissue-type and urokinase-type) and fibrin: localization of interaction sites and physiologic relevance

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 401-409 ◽  
Author(s):  
J Keijer ◽  
M Linders ◽  
AJ van Zonneveld ◽  
HJ Ehrlich ◽  
JP de Boer ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Regulatory Protein ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activators ◽  
Tissue Type ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Interaction Sites ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Plasminogen activator inhibitor 1 (PAI-1), an essential regulatory protein of the fibrinolytic system, harbors interaction sites for plasminogen activators (tissue-type [t-PA] and urokinase-type [u-PA]) and for fibrin. In this study, anti-PAI-1 monoclonal antibodies (MoAbs) were used to identify interaction sites of PAI-1 with these components. The binding sites of 18 different MoAbs were established and are located on five distinct “linear” areas of PAI-1. MoAbs, binding to two distinct areas of PAI-1, are able to prevent the inhibition of t-PA by PAI-1. In addition, two interaction sites for fibrin were identified on PAI-1. The area located between amino acids 110 and 145 of PAI-1 contains a binding site for both components and its significance is discussed in the context of the t-PA inhibition by fibrin-bound PAI-1. Subsequently, the MoAbs were used to assess the role of platelet-PAI-1 in clot-lysis. An in vitro clot-lysis system was used to demonstrate that clot-lysis resistance is dependent on the presence of activated platelets and that PAI-1 is a major determinant for lysis-resistance. We propose that, upon activation of platelets, PAI-1 is fixed within the clot by binding to fibrin and retains its full capacity to inhibit t-PA and u-PA.

Relationship of lipoprotein(a) to variables of coagulation and fibrinolysis in a healthy population

1991 ◽  
Vol 37 (11) ◽  
pp. 1950-1954 ◽  
Author(s):  
J Heinrich ◽  
M Sandkamp ◽  
R Kokott ◽  
H Schulte ◽  
G Assmann
Keyword(s):  
Plasminogen Activator ◽  
Premenopausal Women ◽  
Plasminogen Activator Inhibitor ◽  
Significant Negative Correlation ◽  
Serum Lipoprotein ◽  
Tissue Type ◽  
Healthy Population ◽  
Lipoprotein A ◽  
Activator Inhibitor Type ◽  
Pai 1

Abstract In the Prospective Cardiovascular Münster (PROCAM) study, serum lipoprotein(a) [Lp(a)] and its relationship to pro- and anticoagulatory as well as fibrinolytic indices were determined in a large group of employees: 864 men (m) and 373 women (f), ages 16-65 years. Univariate statistical analysis showed Lp(a) concentration to be associated with fibrinogen concentrations in both sexes (m: r = 0.08, P less than 0.05; f: r = 0.20, P less than 0.001), but not with euglobulin fibrinolysis activity, tissue-type plasminogen activator, plasminogen activator inhibitor type 1 (PAI-1), or the split products of cross-linked fibrin (d-dimer). In women only, Lp(a) was significantly correlated with antithrombin III (r = 0.15, P less than 0.01) and Protein C (r = 0.17, P less than 0.01). Further sex-related differences were seen in the relationship between Lp(a) and age (m: r = 0.05; f: r = 0.23, P less than 0.001) and body mass index (m: r = 0.01; f: r = 0.19, P less than 0.001), primarily as a consequence of remarkable differences of Lp(a) concentrations between postmenopausal (mean = 79.4 mg/L) and premenopausal women (mean = 51.5 mg/L, P = 0.001). Multiple-regression analysis demonstrated a significant negative correlation of Lp(a) to PAI-1 (m: beta = -0.12, P less than 0.01; f: beta = -0.14, P less than 0.05) and a positive correlation to cholesterol (m: beta = 0.18, P less than 0.001; f: beta = 0.17, P less than 0.01) and systolic blood pressure (m: beta = 0.08, P less than 0.05; f: beta = 0.11, P less than 0.05).

scholarly journals Is There a Tendency for Thrombosis in Gestational Diabetes Mellitus?

2016 ◽  
Vol 8 (02) ◽  
pp. 101-105 ◽  
Author(s):  
Suheyla Gorar ◽  
Bulent Alioglu ◽  
Esranur Ademoglu ◽  
Seyit Uyar ◽  
Handan Bekdemir ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Study Groups ◽  
Tissue Type ◽  
Coagulation System ◽  
Significant Difference ◽  
Pai 1

ABSTRACT Context: Impact of gestational diabetes mellitus (GDM) on the coagulation system, dynamics involved at a pathophysiological level and the exact mechanism remain unclear. Aims: To evaluate the association between diabetes-related parameters and hemostatic factors to search for a tendency of thrombosis in GDM. Settings and Design: Nineteen pregnant women who had GDM, 16 healthy pregnant and 13 healthy nonpregnant controls admitted to the Endocrinology outpatient clinics were enrolled in the study. Subjects and Methods: Fasting and postprandial glucose, hemoglobin A1c and insulin levels, and insulin resistance; fructosamine, thrombin activatable fibrinolysis inhibitor (TAFI), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor Type-1 (PAI-1), tissue-type plasminogen activator (t-PA), fibrinogen, plasminogen and hemoglobin levels, platelet counts, prothrombin time (PT), and activated partial thromboplastin time (aPTT) were studied. Statistical Analysis Used: One-way analysis of variance, Kruskal–Wallis, and post hoc Tukey honestly significant difference or Conover’s nonparametric multiple comparison tests for comparison of the study groups. Results: PT and aPTT were significantly lower in GDM patients compared to controls (P < 0.05), whereas fibrinogen and plasminogen levels were significantly higher in this group compared to both nonpregnant and healthy pregnant controls (P < 0.05 for each). TAFI, TFPI, PAI-1, and tissue t-PA levels were not significantly different among groups. Conclusions: Our findings indicate tendency to develop thrombosis in GDM similar to diabetes mellitus; but more comprehensive studies with larger sample size are needed to determine the relationship between GDM and hemostasis.

Cellular Degradation of Free and Inhibitor-bound Tissue-type Plasminogen Activator

2000 ◽  
Vol 83 (02) ◽  
pp. 290-296 ◽  
Author(s):  
Chantal Camani ◽  
Olivier Gavin ◽  
Egbert Kruithof
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Density Lipoprotein Receptor ◽  
Activator Inhibitor Type ◽  
Pai 1

SummaryThe low density lipoprotein receptor-related protein (LRP) is a multiligand clearance receptor that removes free tissue-type plasminogen activator (t-PA) or complexes of t-PA with plasminogen activator inhibitor type 1 (PAI-1) from the blood circulation or the pericellular space. Co-receptors are essential for LRP-mediated clearance of several ligands (e.g. glycosaminoglycans for thrombin/protease nexin and lipoprotein lipase, and the urokinase receptor for urokinase/PAI-1 complexes). The present study was undertaken to investigate whether LRP-mediated t-PA clearance requires a co-receptor as well.In five cell lines from different organs and species degradation of t-PA and t-PA/PAI-1 was mediated by LRP (or LRP-like receptors). No degradation of t-PA and t-PA/PAI-1 occurred in THP-1 or U-937 human monocyte-like cells, despite the presence of functional LRP. As glycosaminoglycans can bind t-PA and PAI-1 we investigated whether they are involved in t-PA/PAI-1 degradation. Pre-treatment of COS cells or HT1080 cells with chlorate, an inhibitor of glycosaminoglycan sulfation, did not decrease t-PA/PAI-1 degradation. Furthermore, CHO cells genetically deficient in glycosaminoglycans efficiently degraded t-PA/PAI-1. Thus it is unlikely that glycosaminoglycans are co-receptors for degradation of t-PA or t-PA/PAI-1.This study indicates that THP-1 and U-937 cells lack a critical component (co-receptor?) for the LRP-mediated degradation of t-PA. Abbreviations: LRP, low density lipoprotein receptor-related protein; PAI-1, plasminogen activator inhibitor type 1; RAP, receptor-associated protein; t-PA, tissue-type plasminogen activator; u-PA, urokinase; u-PAR, urokinase receptor.

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