bluuebunny/crossref_metadata_2025_split huggingface dataset:
DN 9693: A Phosphodiesterase Inhibitor with a Platelet Membrane Effect
Authors: Jackson C , Ball J , Peel J , Lawry J , Greaves M , Preston F E 
Published: June 2018

SummaryWe have examined the in vitro effects of DN 9693 (piperidinylimidazo-quinazolinone) on various aspects of platelet reactivity. Our results are consistent with its known function as a phosphodiesterase inhibitor in that it increased platelet cyclic AMP, particularly in conjunction with an adenylate cyclase stimulator, and exerted a profound inhibitory effect on platelet aggregation responses to a variety of agonists. DN 9693 also inhibited ristocetin-induced platelet agglutination (RIPA). We therefore examined its effect on ristocetin co-factor assays and on the binding of a monoclonal antibody (McAb) to platelet membrane glycoprotein lb (GPIb). The drug inhibited the binding of the monoclonal antibody in a dose-dependent manner. This suggests an effect of the drug on the platelet surface membrane with reduced expression of GPIb. Our results indicate that in addition to its anticipated inhibitory effect on platelet aggregation, DN 9693 may also inhibit platelet adhesion.
The Inhibitory Effect of Aspirin on Fibrinolysis Is Reversed by Iloprost, a Prostacyclin Analogue
Authors: Bertelé V , Mussoni L , Pintucci G , del Rosso G , Romano G , de Gaetano G , Libretti A 
Published: June 2018

SummaryThe reduced fibrinolytic response after aspirin intake may be due to prevention of prostacyclin production. The effect of iloprost (a stable prostacyclin analogue) was tested on the fibrinolytic activity (euglobulin lysis area on fibrin plate [E.L.A.], t-PA antigen, PAI activity and PAI-1 antigen) of plasma drawn after venous stasis test from six healthy male volunteers, who each received all the following treatments according to a single-blind randomized cross-over design: placebo, iloprost, aspirin + placebo, aspirin + iloprost. The mean E. L. A. value after venous occlusion was significantly higher than the basal level after every treatment, but aspirin. Within each treatment group the t-PA antigen levels in response to venous stasis were significantly higher than the basal ones. PAI-1 antigen levels did not change significantly before and after venous stasis either within or among the treatment groups. These data are consistent with the hypothesis that the mechanism related to aspirin’s effect on fibrinolysis is mediated by suppression of vessel wall prostacyclin production. Aspirin’s inhibitory effect on fibrinolysis was in fact prevented by replacing endogenous prostacyclin with iloprost. Iloprost enhances fibrinolytic activity reduced by aspirin, but not by promoting t-PA release or by inhibiting release of the specific inhibitor, PAI-1.
Evaluation of Fibrinolytic Capacity in Plasma during Thrombolytic Therapy with Single (scu-PA) or Two-chain Urokinase Type Plasminogen Activator (tcu-PA) by a Combined Assay System for Urokinase Type Plasminogen Activator Antigen and Function
Authors: Wojta Johann , Binder Bernd R , Huber Kurt , Hoover Richard L 
Published: June 2018

SummaryA combined assay for urokinase type plasminogen activator (u-PA) activity and antigen determination in plasma samples is described. This assay is based on binding of u-PA to an antibody immobilized on a microtiter plate followed by determination of the enzymatic activity of the bound u-PA. Thereafter bound u-PA antigen can be quantified by means of a specific peroxidase labelled monoclonal antibody against u-PA. By use of this assay system u-PA activity and antigen can be determined with lower detection limits of 0.08 IU/ml and 1.0 ng/ml, respectively, and intraassay as well as interassay coefficients of variation of 10% and 12% for activity and 5% and 7% for antigen determinations, respectively. Normal plasma levels of u-PA antigen could be determined to be 1.88 nglml ± 0.61. Furthennore, this assay system allows specific quantification of u-PA antigen and activity during thrombolytic therapy.
Effect of Physiological Concentrations of Vasopressin on Components of the Fibrinolytic System
Authors: Hariman H , Grant P J , Hughes J R , Booth N A , Davies J A , Prentice C R M 
Published: June 2018

SummaryHigh physiological concentrations of plasma vasopressin (aVP) when achieved by infusion cause an increase in plasma factor VIII coagulant activity and shortening of the euglobulin clot lysis time (ECLT). To investigate the effects of aVP on components of the fibrinolytic pathway and on thrombin generation, t healthy volunteers were infused with saline for 30 min followed by aVP for L hour and blood samples taken every 30 min for measurement of aVR ECtf tissue-type plasminogen activator (t-PA), t-PA inhibition (tPA-I), plasminogen activator inhibitor L (PAI-1 Ag), activated partial thromboplastin time (APTT), fibrinopeptide A (FPA), fibrinopeptide B 15-42 (FPBß 15-42) and crosslinked fibrin breakdown products (XL-FDP). Plasma aVP rose to a median of 75 pg/ml after 90 min and fell to 13.8 pdml 30 min later. The APTT fell from 43.5 to 35 sec (p <0.01) but there was no change in plasma FPA or in XL-FDP. Plasminogen activator activity (106/ECLT2) increased from 25 to 736 units (p <0.01) and t-PA from 200 to 1012 mlU/ml (p <0.01). tPA-I fell from 8.0 to 2.7 IU/ml at 90 min (p <0.05) but PAI-1 Ag remained unchanged. Plasma FPBß 15-42 was 2.4 and 1.2 pmol/ml before infusion with aVP and showed a small rise to 3.5 pmol/ml after 60 min (p <0.05). The results show the effects of aVP on fibrinolysis are mediated by an increase in t-PA. In the absence of thrombin generation the rise in t-PA was not accompanied by changes in XL-FDP.
In Vivo Measurements of Fibrin Formation and Fibrinolysis in Operable Breast Cancer
Authors: McCulloch P , Douglas J , Lowe G D O , Murray G , George W D 
Published: June 2018

SummaryFibrin formation and fibrinolysis were estimated in 89 breast cancer patients by measurement in plasma of Fibrin Fragment Bβ 15-42 and Fibrinopeptide A (FPA), serum Fibrin(ogen) Degradation Products (FDPs) and plasminogen activator by Fibrin Plate Lysis Assay. Results were compared with (a) 26 patients with benign breast diseases; and (b) 45 healthy factory workers. FPA, FDP and Bβ 15-42 Levels were elevated in both breast cancer patients and benign disease patients, but there were no significant differences between these two groups. Cancer stage, patient age and smoking habits did not affect these results, but Oestrogen Receptor (ER) positive patients had higher Bβ 15-42 values than ER negative patients (p = 0.017). These results show that fibrin formation is enhanced preoperatively in patients with either benign or malignant breast disease. The fibrinolytic response to activated coagulation may be relatively deficient in breast cancer. The roles of malignancy, stress and other factors in the causation of these abnormalities require further assessment.
Plasminogen Activators and Plasminogen Activator Inhibitors in Liver Deficiencies Caused by Chronic Alcoholism or Infectious Hepatitis
Authors: Tran-Thang Chiên , Fasel-Felley Josette , Pralong Gerard , Hofstetter Jean-René , Bachmann Fedor , Kruithof Egbert K O 
Published: June 2018

SummaryPlasma concentrations of tissue-type plasminogen activator (t-PA), urokinase (u-PA), plasminogen activator inhibitor 1 (PAI-1) and PAI-2 were studied in 53 patients with liver deficiency caused by chronic alcoholism (n = 40), viral hepatitis (n = 10) or malignant disease of the liver (n = 3) and compared to that of a control group (n = 20) of healthy subjects. u-PA and PAI-1 levels were significantly increased in all patients with chronic alcoholism, whereas high t-PA was only observed in combination with disturbed liver function tests or with liver cirrhosis (two and sixfold above control values, respectively). A good correlation was observed between t-PA and gamma glutamyl transferase (r = 0.615; p <0.001). In patients with infectious hepatitis or with malignant disease of the liver t-PA was normal whereas u-PA and PAI-1 were increased.PAI-2 levels were close to or below the detection limit (15 ng/ml) in the control group and in most patients. However, in two patients with alcohol induced cirrhosis PAI-2 levels were approximately 45 ng/ml and in one patient with hepatocarcinoma even 66 ng/ml. Thus, in liver disease, marked elevations of t-PA, u-PA and PAI-1 levels may occur, with increased PAI-1 as an early marker of liver defects and t-PA a marker of severe liver defects.
Synthesis of Vitamin K-Dependent Proteins by Cultured Human Tumor Cells
Authors: Al-Mondhiry Hamid , Wallin Reidar 
Published: June 2018

SummaryThe observation that warfarin inhibits the growth and metastasis of certain types of clinical and experimental tumors suggests a role for vitamin K in tumor biology. We have investigated synthesis of vitamin K-dependent proteins in four malignant (lung epidermoid carcinoma, melanoma, colon adenocarcinoma, and breast adenocarcinoma) and three normal (colon epithelium, breast epithelium, and fibroblasts) cell lines of human origin grown in tissue cultures. Our results show the following: 1) Vitamin K-dependent carboxylase activity is present in all of the malignant and normal cell lines studied. 2) The malignant as well as normal cell lines synthesize a family of vitamin K-dependent proteins. Microsomal precursors of these proteins with apparent molecular mass of 74, 62, and 34 kDa are common to all malignant and normal cell lines whereas precursors of higher and lower molecular mass seem to be synthesized by some but not all tumor cell lines. 3) The 74 kDa precursor synthesized by colon carcinoma and breast carcinoma was positively identified as a precursor of protein S.
Binding and Degradation of Tissue-Type Plasminogen Activator by the Human Hepatoma Cell Line Hep G2
Authors: Otter M , Van Berkel Th J C , Rijken D C 
Published: June 2018

SummaryIn this study, binding and degradation of tissue-type plasminogen activator (t-PA) by the human hepatoma cell line Hep G2 was investigated. Binding at 4° C was time-dependent and reached a maximum after ca. 2 hours. Scatchard analysis of saturation experiments showed about 170,000 high affinity binding sites for t-PA per cell with an apparent Kd of 90 nM. These binding sites were calcium-dependent. Part of the binding to the hepatoma cells was non-saturable, owing to a large amount of low affinity binding sites which are at least partially located on the extracellular matrix of the cells. Competition with mannose- and galactose-terminated glycoproteins had no effect on total binding of 125I-t-PA. Degradation products of 125I-t-PA were found in the supernatant after a short lag phase and then increased linearly for at least 5 hours at 37° C. Degradation could be inhibited by chloroquine, NH4Cl and NaN3. We conclude that the human hepatoma cell line Hep G2 has a specific binding mechanism for t-PA which is not mediated by known carbohydrate receptor systems. Binding is followed by cellular uptake and degradation in the lysosomes.
Elevated Plasminogen Activator Inhibitor (PAI), a Cause of Thrombophilia? – A Study in 203 Patients with Familial or Sporadic Venous Thrombophilia
Authors: Engesser L , Brommer E J P , Kluft C , Briët E 
Published: June 2018

SummaryTwo hundred and three patients with venous thrombophilia were investigated in order to find out whether an elevated plasma concentration of plasminogen activator inhibitor (PAI) could be a cause of their tendency to thrombosis. The patients were studied in an asymptomatic period about 3 months after their last thromboembolic episode. PAI activity was found to be elevated in 19 patients (9%), and a corresponding elevation of PAI-1 antigen was observed.In 16 out of the 19 patients with elevated PAI activity, followup could be performed after an additional asymptomatic period of about 1 year: in eight patients the elevation of PAI was transient and in eight it was persistent. Out of the eight patients with a persistent elevation of PAI, seven had a positive family history of thrombosis. Investigation of these families excluded a hereditary elevation of PAI activity in two families. In only two other families was elevated PAI activity also found among family members. The occurrence of elevated PAI activity, however, did not coincide with the occurrence of thrombosis in these individuals: except for the probands, all investigated family members who had a history of thrombosis had a normal PAI activity.We therefore conclude that, at least in our material, familial thrombophilia can not be attributed to an inherited, persistent elevation of the blood level of PAI.
DDAVP Induces Systemic Release of Urokinase-Type Plasminogen Activator
Authors: Levi Marcel , ten Cate Jan W , Dooijewaard Gerard , Sturk Augueste , Brommer Emile J P , Agnelli Giancarlo 
Published: June 2018

SummaryThe desamino-d-arginine vasopressin (DDAVP) induced enhancement of endogenous fibrinolysis is generally attributed to the release of tissue-type plasminogen activator (t-PA) from the vessel wall.The observation of concurrent release of urokinase-type plasminogen activator (u-PA), which eventually might cooperate in the enhanced fibrinolytic activity, has not been reported thusfar.In a preliminary study in two healthy human volunteers we found a 1.8-fold increase of urokinase-antigen (UK-antigen) and a 1.7-fold increase of plasmin-activatable pro-urokinase (pro-UK) activity to DDAVP intravenously. The plasma-peak levels coincided with the maximal t-PA level. These responses following infusion of DDAVP were subsequently confirmed in a randomized double blind cross-over study in six human volunteers. We conclude that u-PA is released by DDAVP concurrently with t-PA and that it is presumably from the same origin as t-PA i.e. endothelial cells. u-PA and t-PA may therefore cooperate in the enhanced fibrinolytic activity upon DDAVP infusion.
Effect of Heparin and/or Antithrombin III on the Generation of Endotoxin-Induced Plasminogen Activator Inhibitor
Authors: Gómez C , Páramo J A , Colucci M , Rocha E 
Published: June 2018

SummaryIt has been experimentally shown that endotoxin induces a significant increase in the blood levels of a plasminogen activator inhibitor (PAI). We evaluated the effect of different doses of heparin (5 to 20IU kg−1 h−1), antithrombin III (10 to 40 U kg−1 h−1 and 240 U/kg as bolus) and of a combination of the two on: 1) the elevation of PAI activity, 2) fibrin deposition in kidneys and 3) mortality in rabbits infused with E. coli lipopoly-saccharide. Our results show that heparin plus AT III is able to significantly reduce the generation of endotoxin-induced PAI activity in rabbits' circulation. Low dose of heparin and a bolus injection of AT III both cause a decrease in the generation of PAI at 2 but not at 6 hours of endotoxin infusion. Moreover, fibrin deposits in kidneys of animals receiving heparin plus AT III or a bolus injection of AT III were significantly reduced as compared to control rabbits. The association between low levels of PAI and decreased fibrin deposits is strengthened by the significant correlation (p < 0.05) found between these two parameters. Finally, the plasma levels of PAI activity at 2 and 6 hours of endotoxin infusion in surviving animals were lower than those observed in animals that died within 2 hours after the end of treatment. We conclude that heparin plus AT III partially prevents the endotoxin-induced generation of PAI activity which seems to correlate with the reduced presence of fibrin deposits in kidneys and with a reduced mortality.
Coated Pits and Vesicles Transfer Plasma Components to Platelet Granules
Authors: Behnke O 
Published: June 2018

SummaryElectron microscopy of mammalian blood platelets after contrast enhancement with tannic acid after an initial fixation in glutaraldehyde and osmium reveals numerous coated pits (c.p.) and vesicles (c.v.), indicating a process of receptor-mediated endocytosis. The c.p. may be located at any site of the plasma membrane or the canalicular, surface connected membrane system. C.v. fuse with platelet granules without losing their coat. Evidence for a continuous transfer of ambient fluid to granules via c. p. and c.v. was obtained by the use of fluid-phase markers.It is proposed that the endocytic process may play a role in blood platelet activation.
Stability of Plasminogen Activator Inhibitor 1 (PAI-1)
Authors: Lindahl Tomas L , Sigurdardottir Olöf , Wiman Björn 
Published: June 2018

SummaryThe stability of PAI-activity has been studied at different conditions. The inactivation followed first order kinetics. Lowering the temperature and decreasing the pH both, increased the stability of PAI-1 dramatically. Addition of the PAI-1 binding protein, vitronectin, to reactivated PAI-1, about doubled the halflife of PAI-1 at all conditions studied. In the presence of chloramine T, the inactivation of reactivated PAI-1 was very rapid. In this case the protective effect of purified vitronectin, human plasma or fetal calf serum, but not of bovine serum albumin, was pronounced. The stability of the spontaneously active high Mr form of PAI-1 (partially purified or in plasma), constituting a complex between PAI-1 and vitronectin, was quite similar to reactivated PAI-1 in the presence of vitronectin. Addition of pure vitronectin, human plasma or fetal calf serum to such material had no further stabilizing effect. Reactivated PAI-1, which was inactivated by incubation at physiological conditions could again be fully reactivated, in contrast to chloramine T-oxidized PAI-1, which was irreversibly inactivated.
Stimulation of Plasmin Catalyzed Conversion of SingleChain to Two-Chain Urokinase-Type Plasminogen Activator by Sulfated Polysaccharides
Authors: Rydzewski Andrzej , Takada Yumiko , Takada Akikazu 
Published: June 2018

SummaryInfluence of heparin, chondroitin sulfate C and dextran sulfate (MW 3,500 and 7,000) on plasmin catalyzed conversion of singlechain (scu-PA) to two-chain (u-PA) urokinase-type plasminogen activator and generation of plasmin in mixtures of scu-PA and Glu-plasminogen (Glu-plg) was investigated. Conversion of scu-PA to u-PA catalyzed by plasmin was enhanced by chondroitin sulfate C and heparin, maximally by 10-fold and 3-fold, respectively. Sulfated polysaccharides potentiated generation of plasmin in mixtures of Glu-plg and scu-PA, as well as enhanced plasminogenolytic activity of u-PA. The possible role of these interactions is discussed.
A Second Plasma Inhibitor of Activated Protein C: α1-Antitrypsin
Authors: van der Meer Felix J M , van Tilburg Nico H , van Wijngaarden Aat , van der Linden Irma K , Briët Ernest , Bertina Rogier M 
Published: June 2018

SummaryInactivation of activated protein C (APC) in normal human plasma was studied in the absence and presence of heparin. In the absence of heparin APC inactivation followed pseudo-first order kinetics. In the presence of heparin the neutralization of APC was found to be biphasic. Up to 500 nM APC could be readily inactivated in normal plasma, indicating that the concentration of the APC inhibitor must be higher than previously assumed. Plasma deficient in the protein C inhibitor (PCI-I, as described by Suzuki and coworkers) and deficient in p2-glycoprotein I still possessed APC neutralizing capacity, presumably through the formation of complexes of APC with another plasma protein as was demonstrated by immunoblotting with anti-protein C antibodies. Together these data made us to conclude that a second inhibitor of APC (PCI-II) must be present in normal human plasma. This second inhibitor should be heparin independent, have a relatively high plasma concentration and form complexes with APC.Subsequently, we purified this PCI-II by isolating APC-PCI-II complexes from plasma deficient of vitamin K dependent proteins, PCI-I and β2-glycoprotein-I, to which purified human APC had been added. Purified PCI-II has a molecular weight of 50,000 daltons and aminoacid analysis revealed that PCI-II is identical with α1-antitrypsin (α1-AT). The second order rate constant for the reaction between purified α1-AT and APC was found to be 269 M−1 min−1 in the absence of calcium and 602 M−1 min−1 in the presence of calcium.Finally, the analysis of the kinetics of APC inactivation in the plasma of a patient congenitally deficient in α1-AT (3% α1-AT antigen) revealed that there probably is a third inhibitor of APC in plasma, different from PCI-I and from α1-AT.
Impaired Fibrinolytic Capacity and Tissue Plasminogen Activator Release in Patients with Restenosis after Percutaneous Transluminal Coronary Angioplasty (PTCA)
Authors: Kirschstein W , Simianer S , Dempfle C E , Keller H , Stegaru B , Rentrop P , Heene D L 
Published: June 2018

SummaryTo assess the role of the fibrinolytic system in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we determined the components of this system in a retrospective study, including 16 patients with restenosis (gr. A) and 19 patients with long-term success (gr. B). In both groups at baseline fibrinolytic activity (FA) is unchanged, whereas tissue plasminogen activator antigen (tPA-Ag) is significantly increased (gr. A: 147.0%; gr. B: 139.8%; p <0.01). Fibrinolytic capacity (FC) and tPA-Ag release are significantly reduced in the restenosis group (FC: 46.5%, p <0.05; tPA-Ag release: 48.3%, p <0.01) compared to normal controls as well as to gr. B (FC: 84.3%, p <0.05; tPA-Ag release: 79.0%, p <0.05).Relating to the contact activation system, F XII (79.5%, p <0.05) is significantly, and F XI (82.3%) is clearly reduced in gr. A. Protein C (PC) is significantly elevated in gr. B (117.5%, p <0.05). There is a negative correlation between plasminogen activator inhibitor (PAI 1) and HDL-cholesterol (r = 0.37, p <0.05).It appears, that there is a typical pattern of defective fibrinolysis in patients with restenosis after PTCA and that this might be a pathogenetic factor in the development of restenosis.
The Effect of n-3 Fatty Acids on Lipids and Haemostasis in Patients with Type lla and Type IV Hyperlipidaemia
Authors: Berg Schmidt E , Ernst E , Varming K , Pedersen J O , Dyerberg J 
Published: June 2018

SummaryPlasma lipids and haemostasis were investigated in 17 patients with hyperlipidaemia before and after 6 weeks supplementation with 6 g n-3 fatty acids. Nine of the patients had type IIa and 8 had type IV hyperlipidaemia. No effect on plasma cholesterol, LDL- or HDL-cholesterol were seen, but plasma triglycerides decreased after n-3 supplementation. Apolipoprotein B increased and apolipoprotein A1 decreased after the oil supplement. The bleeding time was prolonged, but platelet aggregation was unaltered by n-3 fatty acids. Protein C activity increased in type II a and decreased in type IV after the supplement. Fibrinolysis was markedly depressed while von Willebrand factor antigen was reduced after intake of n-3 fatty acids.