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).

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.

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.

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.

Characterization of the Interaction of a Complex of Tissue-type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 with Rat Liver Cells

1995 ◽  
Vol 74 (05) ◽  
pp. 1298-1304 ◽  
Author(s):  
J Kuiper ◽  
M Otter ◽  
A H Voorschuur ◽  
A J van Zonneveld ◽  
D C Rijken ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Liver Cells ◽  
Tissue Type ◽  
Type Plasminogen Activator ◽  
Parenchymal Liver ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Pai 1

SummaryThe present study was undertaken in order to determine the recognition site for tissue-type plasminogen activator-plasminogen activator inhibitor type 1 [t-PA-PAI-1] complexes in rat liver in vivo and in vitro. After intravenous injection into rats t-PA-PAI-1 complexes were rapidly removed from the plasma and the liver took up 80% of the injected dose. Within the liver parenchymal and endothelial liver cells contributed mainly to the uptake of t-PA-PAI-1, and were responsible for 62% and 24% of the liver uptake, respectively. The interaction of t-PA- PAI-1 with isolated rat parenchymal liver cells was of high affinity (Kd 17 nM). A well-known antagonist of the α2-macroglobulin receptor (α2MR/low-density lipoprotein receptor-related protein (LRP), GST-39kDa protein (GST-39kDaP) efficiently inhibited the binding (IC50 0.7 nM) of t-PA-PAI-1 to rat parenchymal liver cells. The interaction of t-PA-PAI-1 with LRP on rat parenchymal liver cells was not Ca2+-dependent and is most probably mediated by a specific determinant on PAI-1, since an anti-PAI-1 monoclonal antibody inhibited the binding of t-PA-PAI-1, where as free t-PA did not. The binding of t-PA-PAI-1 to rat hepatocytes could not be inhibited by a complex of plasmin and α2-antiplasmin nor by various other ligands of LRP like β-VLDL and lactoferrin. Binding of t-PA-PAI-1 to rat parenchymal liver cells was followed by internalization and subsequent degradation in the lysosomal compartment.It is concluded that parenchymal and endothelial liver cells mediate the removal of t-PA-PAI-1 complexes from the circulation. LRP on rat parenchymal liver cells is responsible for the uptake and degradation of t-PA-PAI-1 and may therefore be important for the regulation of the t-PA levels in the circulation.

scholarly journals A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 528-532 ◽  
Author(s):  
J Dieval ◽  
G Nguyen ◽  
S Gross ◽  
J Delobel ◽  
EK Kruithof
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Bleeding Tendency ◽  
Plasminogen Activator Inhibitor Type ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor ◽  
Pai 1

Abstract A 36-year-old patient was investigated for a lifelong history of epistaxis and delayed bleeding after minor surgeries. Deficiencies or abnormalities of the coagulation system, of platelet function, or of factor XIII and alpha-2-antiplasmin were excluded. Consistently, however, over a period of 7 years, a high basal euglobulin fibrinolytic activity was observed that was characterized by a high tissue-type plasminogen activator (t-PA) activity, normal t-PA antigen, and undetectable plasminogen activator inhibitor type-1 (PAI-1) antigen and activity. The high specific activity of t-PA (640,000 IU/mg) and the minimal amounts of t-PA/PAI-1 complexes detected by fibrin zymography suggest that in this patient all t-PA was active. This is in striking contrast to normal plasma, where the majority of t-PA is complexed to PAI-1. Thus, in this patient, a severe deficiency of PAI-1 is associated with a delayed type bleeding tendency. Our observation underscores the importance of plasma PAI-1 for the stabilization of the hemostatic plug.

Standardization of methods for measuring plasminogen activator inhibitor activity in human plasma.

1989 ◽  
Vol 35 (5) ◽  
pp. 787-793 ◽  
Author(s):  
W L Chandler ◽  
S C Loo ◽  
S V Nguyen ◽  
G Schmer ◽  
J R Stratton
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Type Plasminogen Activator ◽  
Analytical Recovery ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor ◽  
Pai 1

Abstract We have standardized the measurement of plasminogen activator inhibitor type 1 (PAI-1) activity in plasma. One-chain tissue-type plasminogen activator (t-PA; EC 3.4.21.31; final activity, 5 int. units/mL) was incubated with plasma (final dilutions 1:4 to 1:40) in phosphate buffer (pH 7.4, ionic strength = 0.15) for 15 min at 37 degrees C, followed by acidification and measurement of residual t-PA activity by an amidolytic method. The PAI-1 activity assay was 98% specific for PAI-1 activity in samples from both pregnancy and nonpregnancy, and varied linearly with added plasma volume when the percent inhibition of t-PA was between 8% and 50%. For the standardized method, analytical recovery was 93 +/- 5%, the detection limit was 1.6 arbitrary units per milliliter (1 arb. unit of PAI-1 activity = inhibition of 1 int. unit of t-PA activity), and total imprecision was 10.2 (SD 0.7) arb. units/mL (CV = 7%, n = 20). The average PAI-1 activity in 10 healthy individuals drawn between 0800 and 1000 hours was 23.9 +/- 15.4 arb. units/mL. Compared with the standardized assay, two of three previously described assays underestimated PAI-1 activity in plasma by 77% and 85%, respectively.

PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1: STUDIES ON STRUCTURE AND REGULATION

1987 ◽  
Author(s):  
P A Andreasen ◽  
A Riccio ◽  
L R Lund ◽  
K G Welinder ◽  
F Blasi ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Amino Terminal ◽  
Plasminogen Activator Inhibitor Type ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Activator Inhibitor ◽  
Pai 1

Human plasminogen activator inhibitor type-1 is an Mr∼54,000 protein which specifically inhibits urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activators. During inhibition, u-PA and t-PA convert PAI-1 to an inactive form with Mr∼50,000. We have determined the amino-terminal amino acid sequence of native and converted PAI-1, and isolated and partly sequenced PAI-1 cDNA. The data show that the conversion of PAI-1 consists of cleavage of an Arg-Met bond 33 residues from the carboxy-terminus, thus localizing the reactive center of the inhibitor to that position, and identifying PAI-1 as an "arg-serpin". PAI-1 activity is known to be influenced by a number of agents; we have studied the mechanisms of the stimulation of PAI-1 activity by transforming growth factor-β (TGF-β) and the synthetic glucocorticoid dexame-thasone in human WI-38 lung fibroblasts and HT-1080 fibrosarcoma cells. Bytheuse of PAI-1 cDNA, TGF-β was found to course a rapid increase in PAI-1 mRNA level in WI-38 cells, reaching a maximal 50-fold enhancement after 8 hours. Dexamethasone caused a 10-fold increase in PAI-1 mRNA in HT-1080 cells, which was detectable after 4 hours and became maximal after 16 hours. In both cases, the 3.4 as well as the 2.4 Kb-PAI-1-mRNA species were increased. Quantitative studies on the effect of these agents on PAI-1 protein levels in cell extracts and culture media by ELISA gave results consistent with the effects on PAI-1 mRNA. These studies suggest that TGF-β and glucocorticoids may exert important controls over plasminogen activation-mediated extracellular proteolysis through an enhancement of PAI-1 gene transcription.

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