Plasma Levels Of Plasminogen Activator Research Articles

Commentary on “Elevated plasma levels of plasminogen activator inhibitor‐1 are associated with risk of future incident venous thromboembolism”: A new role for plasminogen activator inhibitor‐1—An inhibitor of fibrinolysis predicts future venous thromboembolic events and links them to obesity

Commentary on “Elevated plasma levels of plasminogen activator inhibitor‐1 are associated with risk of future incident venous thromboembolism”: A new role for plasminogen activator inhibitor‐1—An inhibitor of fibrinolysis predicts future venous thromboembolic events and links them to obesity

Elevated plasma levels of plasminogen activator inhibitor‐1 are associated with risk of future incident venous thromboembolism

BackgroundPlasminogen activator inhibitor‐1 (PAI‐1), the main inhibitor of fibrinolysis, is frequently elevated in obesity and could potentially mediate the risk of venous thromboembolism (VTE) in obese subjects. However, whether PAI‐1 is associated with VTE remains uncertain. ObjectiveTo investigate the association between plasma PAI‐1 levels and risk of future incident VTE and whether PAI‐1 could mediate the VTE risk in obesity. MethodsA population‐based nested case‐control study, comprising 383 VTE cases and 782 age‐ and sex‐matched controls, was derived from the Tromsø Study cohort. PAI‐1 antigen levels were measured in samples collected at cohort inclusion. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE across PAI‐1 tertiles. ResultsThe VTE risk increased dose‐dependently across PAI‐1 tertiles (P for trend <.001) in the age‐ and sex‐adjusted model. The OR of VTE for the highest versus lowest tertile was 1.73 (95% CI 1.27–2.35), and risk estimates were only slightly attenuated with additional stepwise adjustment for body mass index (BMI; OR 1.59, 95% CI 1.16–2.17) and C‐reactive protein (CRP; OR 1.54, 95% CI 1.13–2.11). Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. In obese subjects (BMI of ≥30 kg/m2 vs. <25 kg/m2), PAI‐1 mediated 14.9% (95% CI 4.1%‐49.4%) of the VTE risk in analysis adjusted for age, sex, and CRP. ConclusionOur findings indicate that plasma PAI‐1 is associated with increased risk of future incident VTE and has the potential to partially mediate the VTE risk in obesity.

Development of Hypertension and Cardiac Hypertrophy is associated with Endothelial Cell Dysfunction in Npr1 Gene‐disrupted Mice

Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones that elicit natriuretic, diuretic, vasorelaxant, and antiproliferative responses, all of which contribute to lowering blood pressure and blood volume. ANP and BNP bind to guanylyl cyclase ‐A/natriuretic peptide receptor ‐A (GC‐A/NPRA), which is considered to be the major natriuretic peptide receptor that synthesizes the intracellular second messenger cGMP. The objective of the present study was to examine the effect of Npr1 (coding for NPRA) gene‐disruption on the process of endothelial cell dysfunction in the development of hypertension and cardiac hypertrophy. We used six‐month old mice having different copies of Npr1 gene (0‐copy, 1‐copy, and 2‐copy). The blood pressure and echocardiographic measurements were performed in each group. Blood was collected by direct cardiac puncture and cardiac tissues were harvested and snap frozen in liquid nitrogen. The 0‐copy (Npr1−/−) mice showed 35–45 mmHg higher systolic blood pressure (SBP) as compared to 2‐copy (Npr1+/+) mice. Echocardiographic measurements of Npr1 gene‐disrupted 1‐copy (Npr1+/−) and 0‐copy mice showed significant increased LVEDD (27% in 0‐copy and 10% in 1‐copy mice), intraventricular septal wall thickness (IVSTDD, 30% in 0‐copy and 15% in 1‐copy mice), and reduced fractional shortening by 24% in 0‐copy and 12% in 1‐copy mice as compared with control mice. There was also a significant increase in plasma levels of plasminogen activator inhibitor‐1 (PAI‐1; 2.2‐fold), soluble intracellular adhesion molecule (sICAM; 1.8‐fold), soluble vascular cell adhesion molecule (sVCAM; 30%). In the present study, increased plasma levels of sICAM, sVCAM, and PAI‐1 suggested the involvement of endothelial cell dysfunction in producing cardiac hypertrophy in Npr1 null mutant mice. Our results implicate that ANP/NPRA signaling promotes inhibitory effect on the agents, which cause endothelial dysfunction in the heart leading to cardiac hypertrophy and cardiac remodeling.Support or Funding InformationThis work was supported by NIH grant (HL062147).

Activation of autophagy is involved in the protective effect of 17β-oestradiol on endotoxaemia-induced multiple organ dysfunction in ovariectomized rats.

Oestrogens have been reported to attenuate acute inflammation in sepsis. In this study, the effects of long‐term oestrogen replacement with 17β‐oestradiol (E2) on endotoxaemia‐induced circulatory dysfunction and multiple organ dysfunction syndrome were evaluated in ovariectomized (Ovx) rats. E2 (50 μg/kg, s.c., 3 times/week) was administered for 8 weeks, followed by the induction of endotoxaemia by intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg/4 hrs). Oestrogen deficiency induced by ovariectomy for 9 weeks augmented the LPS‐induced damage, including endotoxic shock, myocardial contractile dysfunction, renal dysfunction and rhabdomyolysis. Cardiac levels of NF‐κB p65, iNOS and oxidized glutathione, free radical production in skeletal muscles, myoglobin deposition in renal tubules, and plasma levels of plasminogen activator inhibitor‐1, TNF‐α, and IL‐6 were more pronounced in the Ovx + LPS group than in the Sham + LPS group. Long‐term treatment of E2 prevented this amplified damage in Ovx rats. Six hours after LPS initiation, activation of the autophagic process, demonstrated by increases in Atg12 and LC3B‐II/LC3B‐I ratios, and induction of haem oxygenase (HO)‐1 and heat‐shock protein (HSP) 70 protein expression in myocardium were increased significantly in the Ovx + E2 + LPS group. These results suggest that activation of autophagy and induction of HO‐1 and HSP70 contribute to the protective effect of long‐term E2 replacement on multiple organ dysfunction syndrome in endotoxaemia.

Critical Role of Activated Protein C in Early Coagulopathy and Later Organ Failure, Infection and Death in Trauma Patients

Recent studies have identified an acute traumatic coagulopathy that is present on admission to the hospital and is independent of iatrogenic causes. We have previously reported that this coagulopathy is due to the association of severe injury and shock and is characterized by a decrease in plasma protein C (PC) levels. Whether this early coagulopathy and later propensity to infection, multiple organ failure and mortality are associated with the activation of PC pathway has not been demonstrated and constitutes the aim of this study. This was a prospective cohort study of 203 major trauma patients. Serial blood samples were drawn on arrival in the emergency department, and at 6, 12, and 24 hours after admission to the hospital. PT, PTT, Va, VIIIa, PC aPC t-PA, and D-dimer levels were assayed. Comprehensive injury, resuscitation, and outcome data were prospectively collected. A total of 203 patients were enrolled. Patients with tissue hypoperfusion and severe traumatic injury showed a strong activation of the PC which was associated with a coagulopathy characterized by inactivation of the coagulation factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen activator and high D-dimers. Elevated plasma levels of activated PC were significantly associated with increased mortality, organ injury, increased blood transfusion requirements, and reduced ICU ventilator-free days. Finally early depletion of PC after trauma is associated with a propensity to posttraumatic ventilator-associated pneumonia. Acute traumatic coagulopathy occurs in the presence of tissue hypoperfusion and severe traumatic injury and is mediated by activation of the PC pathway. Higher plasma levels of aPC upon admission are predictive of poor clinical outcomes after major trauma. After activation, patients who fail to recover physiologic plasma values of PC have an increased propensity to later nosocomial lung infection.

THROMBOLYSIS ENHANCING ACTIVITY OF A LOW MOLECULAR WEIGHT DERMATAN SULFATE (DESMIN 370) IN EXPERIMENTAL PULMONARY EMBOLISM IN RATS

The effect of Desmin 370 (D370), a low molecular weight dermatan sulfate, on the extent of lysis of radiolabelled pulmonary emboli in rats was evaluated. 125I-fibrin labelled blood clots were embolized into the lungs via a jugular vein, and the degree of lysis was calculated, at predetermined intervals, by the residual radioactivity in the lungs. A single i.v. injection of D370 (50 mg/kg) caused a significant increase in the rate of lysis, which was visible at 30 min and persisted for the whole experimental period (2 h). This effect was prevented by ε-aminocaproic acid (1 g/kg). At comparable antithrombotic dosages, heparin (2 mg/kg) also produced a significant enhancement of thrombolysis while hirudin (2 mg/kg) was totally ineffective. Heparin, however, produced a much more pronounced anticoagulant effect than D370. No changes in the plasma levels of plasminogen activator and plasminogen activator inhibitor activities were observed after treatment with D370. Moreover, the dermatan sulfate failed to enhance the blood fibrinolytic activity measured by a solid phase 125I-fibrin assay. These results extend previous data indicating that D370 may be efficient also in the therapy of thrombosis and provide direct evidence that this effect occurs, at least in part, via degradation of thrombus associated fibrin. © 1997 Elsevier Science Ltd

Factor XII dependent fibrinolytic activity is decreased in the acute phase of myocardial or cerebral infarction

Summary A factor XII dependent plasminogen activator has been described in human blood. In vitro its activity in plasma is mainly generated via kallikrein. Clinical data suggest long-term depression after myocardial infarction and relation to reinfarction. We were interested in FXII dependent plasminogen activator plasma levels during the acute phase of coronary or cerebral artery occlusion before therapeutic intervention. Plasma was obtained from 41 consecutive patients with myocardial infarction and from 40 patients with cerebral infarction immediately on admission to the hospital. Measurement was performed in dextran sulphate euglobulin fractions in the presence of neutralizing antibodies towards t-PA and u-PA. Plasma levels of FXII dependent fibrinolytic activity were found highly significantly reduced both in myocardial (18.3 (8.1–26.3); p=0.003 Blood activator units/ml; median value; (25–75 interpercentile range)) and in cerebral infarction (14.4 (7.6–25.6); p

Plasminogen Activators and Plasminogen Activator Inhibitor 1 in Urinary Tract Cancer

The plasminogen activation system is considered to play an important role in cancer growth and metastasis. Both plasminogen activators (PAs) and their fast-acting inhibitors are produced in tumor cells and their surrounding tissues. In order to clarify the influence of the existence of malignant tumor in urinary tract on the systemic fibrinolytic activity, we designed a study in which we compared the plasma levels of PAs and their inhibitors between before and after radical resection of tumors. Fourteen patients with renal cell carcinoma and 14 patients with transitional cell carcinoma participated in the study. In both groups, plasma levels of tissue-type plasminogen activator and urokinase-type plasminogen activator before the operation were higher than those 15 days after operation. The plasma level of plasminogen activator inhibitor 1 (PAI-1), however, did not change after the operation in the renal cell carcinoma group, and it decreased slightly in the transitional cell carcinoma group although it was not significant. When these values of the groups with or without metastasis were compared to other organs or lymph nodes, the PAI-1 level before operation was significantly higher in the group with metastasis than that without metastasis. In the three groups divided by the degree of atypia, PAI-1 level in the most atypical group was the highest. These results suggest that the fibrinolytic system in the plasma of cancer patients may play an important role in tumor growth and metastasis.

Antithrombotic and thrombolytic activity of sulodexide in rats.

We evaluated the ability of sulodexide, an extracted glycosaminoglycan, to prevent thrombus formation and to reduce a stabilized thrombus in a rat venous thrombosis model (vena cava ligature). Injection of sulodexide 10 min before induction of venous stasis, prevented thrombus formation in a dose-dependent manner (median effective dose 0.55 mg/kg). When given to rats with 6-h-old thrombi, sulodexide caused a marked reduction in thrombus size which reached 70% after 2 h with the highest dose tested (2 mg/kg). The effect of sulodexide on established thrombi appears to be due, at least in part, to a fibrinolysis-mediated mechanism, since it was significantly inhibited by epsilon-aminocaproic acid, a well-known antifibrinolytic drug. Treatment with sulodexide did not noticeably affect plasma levels of plasminogen activator and its specific inhibitor. We also showed that fluorescein-labelled sulodexide, when given to animals with 6-h-old thrombi, was present within the thrombi harvested 2 h later, but was then absent from blood. The fluorescence was mainly located in areas filled with amorphous material, that was identified as fibrin by staining with phosphotungstic acid-hematoxylin. No fluorescein-labelled material could be detected in rats treated with fluorescein alone. These findings indicate that, besides preventing venous thrombus formation, sulodexide is able to promote thrombus dissolution by a mechanism that is partly related to local fibrinolysis stimulation.

Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat.

The effects of both clot-bound and circulating plasminogen activator inhibitor-1 (PAI-1) on endogenous fibrinolysis were investigated in a rat model of pulmonary embolism. Iodine-125 fibrin(ogen)-labeled blood-clot homogenates were delivered through the left jugular vein to the lung microvasculature, and the subsequent extent of the clot lysis was monitored by measuring the release of 125I-fibrin degradation products (FDPs) into the blood. Clots that had incorporated activated PAI-1 ex vivo were subsequently protected from dissolution in vivo in a dose-responsive manner (half-maximal concentration [IC50] = 4.3 micrograms/ml). PAI-1-containing clots also resisted lysis, as measured by the release of the specific FDP D-dimer. Plasma levels of plasminogen activator (PA) and PAI activity were unaltered by administration of PAI-1-containing clots, and the clot-protective effects of clot-bound PAI-1 were reversed by exogenous tissue-type plasminogen activator administration. Clot lysis was also inhibited in a dose-responsive manner (IC50 = 58 micrograms/kg) by intravenous bolus delivery of activated PAI-1 to the circulation. The clot-protective effects of circulating PAI-1 were correlated with dose-dependent increases in plasma PAI-1 antigen and activity levels and decreases in plasma PA levels (IC50 = 37 micrograms/ml). There was no evidence of any accumulation of circulating PAI-1 in the lungs. Latent PAI-1, whether delivered with or delivered after the clot homogenates, did not affect the clot-lytic process. Activated and latent PAI-1 was cleared from the circulation in a monophasic manner, with a half-life of approximately 32 and 7 minutes, respectively. The results indicate that both clot-bound and circulating PAI-1 are potent inhibitors of fibrinolysis in vivo. Clot-bound PAI-1 may inhibit PAs in the immediate vicinity of the clots, whereas circulating PAI-1 may act systemically by controlling overall levels of PAs present in the blood.

Changes of the Plasma Levels of Plasminogen Activator in Various Tumors

Changes of the Plasma Levels of Plasminogen Activator in Various Tumors

Regulation of anterior chamber fibrinolysis

Levels of plasminogen activator (PA), plasminogen (Plg), and antiplasmin activity (APli) were compared in feline aqueous humor obtained from normal eyes, eyes inflamed by chronic mycobacterial-induced uveitis (CMIU), opposite eyes, and in plasma. Fibrin-agar plate microassays were utilized to visually confirm the extent of differences in in vitro fibrinolysis, per se. Chromogenic peptide (S2251) microassays were utilized to quantify differences. Normal AH showed much more available PA than did plasma. However, when APli activity was first neutralized their levels of total PA were comparable. Available PA activity in both normal and CMIU AH was considerably amplified in the presence of trace amounts of free plasmin. Plasma failed to show this response. AH levels of circulating Plg and APli in normal eyes were far below plasma levels. During CMIU, total PA levels remained approximately normal while levels of Plg and APli were greatly increased. The net effect of these concurrent rises was that antiplasmin activity (APli) prevailed over free plasmin formation; i.e., in vitro fibrinolysis was suppressed. Plasma levels of PA, Plg and APli did not change during CMIU. Changes in the normal PA+Plg/APli balance induced by CMIU suggested a hypothetical model of AH fibrinolysis wherein exclusion of APli from the normal anterior chamber and the high levels attained during CMUI are posited as key determinants of AH fibrinolytic capability.