bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Monocyte Tissue Factor Activity by Allogeneic and Xenogeneic Endothelial Cells
Authors: Kopp Christoph , Siegel Jonathan , Anrather Josef , Winkler Hans , Grey Shane , Kaczmarek Elzbieta , Bach Fritz , Geczy Carolyn , Robson Simon 
Published: March 2018

SummaryThe regulation of tissue factor (TF) activity by the cell associated tissue factor pathway inhibitor (TFPI) during monocyte (Mo) and endothelial cell (EC) interactions is not fully understood. This report describes co-ordinate induction of TF antigen (TF-Ag) and membrane-associated TFPI-Ag on human Mo following coculture with human aortic (HAEC) or porcine aortic EC (PAEC) or after stimulation with TNFα. We show that both allo- and xenogeneic EC induce human Mo-TF antigen in short-term culture. However, the TF activity of TNFα-primed Mo is suppressed when these cells are cocultured with HAEC [by 40.3 ± 6.3% (p <0.02)] or PAEC [by 50.5 ± 10.6% (p <0.001)]. Antibody (Ab) blocking studies confirm that TFPI is the principal anticoagulant associated with this suppression of TF-activity. Our data indicate that anti-TF activity originates, at least in part, from the activated human Mo in the coculture; additionally, specific generation of TFPI by Mo is observed under the xenogeneic culture conditions. As Mo associated TF, induced by allo- or xenogeneic EC interactions, is regulated by cell-associated TFPI, we propose that infiltrating Mo may modulate the thrombotic process at sites of vascular injury in association with both allo- and xenograft rejection.Aspects of the work were presented at the American Society for Hematology meeting in Orlando, FL, December 1996.
Biochemical and Pharmacological Characterization of YM-60828, a Newly Synthesized and Orally Active Inhibitor of Human Factor Xa
Authors: Sakai Yumiko , Hisamichi Nami , Kayama Makoto , Mano Yuji , Sato Kazuo , Hirayama Fukushi , Koshio Hiroyuki , Matsumoto Yuzo , Kawasaki Tomihisa , Taniuchi Yuta 
Published: March 2018

SummaryYM-60828 was found to potently inhibit human factor Xa following oral administration. YM-60828 showed high affinity for factor Xa (Ki = 1.3 μM), but did not affect thrombin (Ki > 100 μM). YM-60828 doubled factor Xa clotting time, prothrombin time (PT) and activated partial thromboplastin time (APTT) at 0.10, 0.21, 0.24 μM, respectively. Importantly, it did not prolong thrombin time at 100 μM. YM-60828 also inhibited factor Xa in the prothrombinase complex with an IC50 value of 7.7 nM. In addition to its anticoagulant activity, YM-60828 inhibited platelet aggregation induced by various agonists (IC50 = 3 to 23 μM). Squirrel monkeys were used to study the ex vivo anticoagulant activity and pharmacokinetic properties of YM-60828. One hour after oral administration at 3 mg/kg, YM-60828 strongly prolonged PT and APTT by 4.8- and 1.9-fold, respectively, and plasma concentration reached 788 ± 167 ng/ml. Bioavailability was calculated to be 20.3%. These results strongly suggest that YM-60828 will be a valuable orally active and potent anticoagulant agent showing potential antithrombotic activity.
Activation of the Coagulant Pathway in Cigarette Smokers
Authors: Bauer K. A. , Cooper J. A. , Rosenberg R. D. , Miller G. J. 
Published: March 2018

SummaryThe effects of chronic cigarette smoking on the coagulation system were examined in 2964 men aged 50 to 61 years and clinically free of cardiovascular disease. Factor VII activity (VIIc), factor VII antigen (VIIag), prothrombin fragment 1+2 (F1.2), fibrinopeptide A (FPA) and fibrinogen were measured in all participants, and activated factor VII (VIIa), factor IX activation peptide (IX pep) and factor X activation peptide (X pep) in a large sub-sample. The levels of all indices except FPA differed significantly between non-smokers, ex-smokers and current smokers. After adjustment for other conventional cardiovascular risk factors, mean VIIc was raised slightly by 3% in ex-smokers and current smokers as compared with non-smokers, owing to increases in VIIa and VIIag. Plasma IX pep, X pep, F1.2 and fibrinogen concentration were highest in current smokers, intermediate in ex-smokers and lowest in non-smokers. These findings accord with the increased risk of arterial thrombosis in smokers.
Thrombomodulin Levels during Normal Pregnancy, at Delivery and in the Postpartum: Comparison with Tissue-type Plasminogen Activator and Plasminogen Activator Inhibitor-1
Authors: Mermillod N. , Amiral J. , Reber G. , Moerloose de 
Published: March 2018

SummarySome studies suggest that soluble thrombomodulin (TM) could be used as a marker of preeclampsia or eclampsia. However little is known about the sequential changes of TM during the course of normal pregnancy.Levels of TM were determined in 100 women with uneventful pregnancies. Samples (n = 394) were divided into five study intervals, three during pregnancy, one at delivery and one three days postpartum.As compared with TM levels (median 34.3 ng/ml, range 17.6-61) of a control group of 60 healthy non-pregnant women, TM levels were shown to increase throughout pregnancy, median (and range) values being respectively 38.5 (17.6-72.7) from 11 to 20 weeks, 45.2 (22.6-75.2) from 21 to 30 weeks and 54.3 (25.1-114.5) ng/ml from 31st week to delivery. One hour after delivery TM levels were still elevated and dropped three days postpartum to 40.5 (20.9-79.4) ng/ml. The increase of TM levels was correlated with those of tissue-type plasminogen activator and plasminogen activator inhibitor-1 antigens. The large overlap in TM levels between the study periods seems to preclude a clinical use of TM based on reference values from a control group. Our data suggest that it would be more appropriate to take into account TM baseline values in a given woman to examine her TM increase during pregnancy.
Enhancement of Fibrinolysis by Plactins: Structure-activity Relationship and Effects in Human U937 Cells and in Mice
Authors: Inoue Toshiki , Hasumi Keiji , Sugimoto Maki , Endo Akira 
Published: March 2018

SummaryPlactin D, a cyclic pentapeptide [
cyclo
(-D-Val-L-Leu-D-Leu-LPhe-D-Arg-)] produced by a fungal strain, enhances fibrinolytic activity (6). The present study deals with the structure-activity relationship of plactins and their effects in U937 cells and mice. The results obtained from 50 plactin D analogues with a single amino acid substitution demonstrated that the following substitutions were detrimental: the enantiomer for each of the five residues; a polar, an acidic or a basic residue for D-Val, L-Leu, D-Leu or L-Phe; a polar, a hydrophobic or an acidic residue for D-Arg. On the other hand, a compound with L-Leu or L-Val in place of L-Phe was seven times as active as plactin D. These results suggest an essential role of a sterically restricted arrangement of four hydrophobic residues and the adjacent basic residue. The enhancement of fibrinolysis was dependent on plasma, ranging from 2- to 3-fold when U937 cells were incubated with 15-30 μM plactin D in the presence of 6-50% plasma, while no elevation was observed when cells were incubated in the absence of plasma. Plasminogen alone could not substitute for plasma. The plactin D effect was totally abolished by anti-urokinase IgG but not by anti-tissue plasminogen activator IgG. Plactin D caused a plasma-dependent, transient increase in the cellular urokinase activity. This urokinase activation may have accounted for the increased fibrinolytic activity of plactin D-treated U937 cells. Homogenates of the lung obtained from mice 0.5 to 2 h after intravenous plactin D (5 mg/kg) showed 2- to 3-fold increased levels of fibrinolytic activity, while activities of the brain, heart, liver, spleen, kidney and aorta were not significantly affected. In conclusion, plactin D enhances fibrinolysis both in cultured mammalian cells and in experimental animals.
Platelets and Endothelial Cells Act in Concert to Delay Thrombolysis – Evidence from an In Vitro Model of the Human Occlusive Thrombus
Authors: Jerome W. G. , Handt S. , Hantgan R. R. 
Published: March 2018

SummaryThe molecular and cellular mechanisms that over a period of hours render a human thrombus progressively resistant to fibrinolysis have been probed with a novel in vitro model. The kinetics of clot formation and fibrinolysis were monitored by laser light scattering with platelet-rich model thrombi contained in cylindrical flow chambers. In selected experiments, human umbilical vein endothelial cells were also cultured to confluence on the inner walls of these “glass blood vessels”. Following an “aging” period (0.5, 2 or 4 h), each thrombus was gently perfused with a bolus of plasminogen/recombinant tissue plasminogen activator to induce fibrinolysis. Platelets delayed lysis of 2 h-aged thrombi by ~70% and (non-stimulated) endothelial cells by ~30%, compared to cell-free control clots. However, even greater lytic delays (~260%) resulted when both vascular cells were present in the same 2 h-aged thrombus. In contrast, rapid lysis was consistently achieved with R298E,R299E t-PA, a genetically engineered plasminogen activator that is insensitive to inhibition by plasminogen activator inhibitor type 1. These observations suggest platelets and endothelial cells act in concert to enrich the fibrin scaffold of an aging human thrombus in plasminogen activator inhibitor. We propose that the presence of both platelets and endothelial cells may contribute to progressive thrombolytic resistance.
Suppression of Intimal Hyperplasia by a 5-lipoxygenase Inhibitor, MK-886: Studies with a Photochemical Model of Endothelial Injury
Authors: Umemura Kazuo , Ohmura Tomohiro , Hashimoto Hisakuni , Nakashima Mitsuyoshi , Kondo Kazunao 
Published: March 2018

SummaryIntimal thickening is a major complication following percutaneous transluminal coronary angioplasty, which leads to restenosis and requires reoperation. We have investigated the effect of a 5-lipoxygenase inhibitor, MK-886, a leukotriene B4 (LTB4) receptor antagonist, ONO-4057 or a LTC4 and LTD4 receptor antagonist, ONO-1078, on intimal thickening. Photochemical reaction between green light and systemically administered Rose Bengal produced intimal thickening in the rat femoral artery. Each drug was administered orally, once a day for 7 days, starting just after the endothelial injury. Both MK-886 administration, 10 mg/kg, and ONO-4057 administration, 100 mg/kg, suppressed intimal thickening level examined three weeks after endothelial injury, while similarly administered ONO-1078 did not. In cultured rat-derived smooth muscle cells, LTB4, an active metabolite of 5-lipoxygenase whose biosynthesis in air pouch exudate was suppressed by MK-886, stimulated cell migration. Based on these observations, the 5-lipoxygenase may have a key role in intimal thickening via its metabolites such as LTB4.
Tissue Factor Pathway Inhibitor in Tetracycline-induced Pleuritis in Rabbits
Authors: Pendurthi Usha , Pueblitz Siegfried , Koenig Kathleen , Williams Todd , Rao Vijay Mohan , Idell Steven 
Published: March 2018

SummaryPleural fibrin deposition that promotes loculation and fibrosis after pleural injury is initiated by tissue factor (TF). In this study, we sought to determine if tissue factor pathway inhibitor (TFPI), an inhibitor of the TF-factor VIIa complex, was likewise expressed in tetracycline (TCN)-induced pleural injury and, if so, whether TFPI was locally elaborated. Pleural fluid TFPI activity approximated that of plasma by 24 h and doubled by 3 days after intrapleural TCN. By contrast, pleural fluid coagulation factors VII and V remained below plasma concentrations at these intervals. Immunohistochemical studies demonstrated TF, TFPI and fibrin localized in pleural and subpleural tissues and within intrapleural adhesions. TFPI activity and mRNA were also elaborated by rabbit pleural mesothelial cells and lung fibroblasts. TFPI is locally expressed and pleural fluid TFPI exceeds plasma levels during TCN-induced pleural injury. Resident cells as well as extravasation likely contribute to intrapleural TFPI. TFPI expression temporally and anatomically approximates that of TF and may limit TF-induced fibrin deposition in evolving TCN-induced pleuritis.
Adhesion of Leukocytes to Growing Arterial Thrombi
Authors: Roald Helge Einar , Lyberg Torstein , Hagberg Inger Anne 
Published: March 2018

SummarySince the role of leukocytes found present in thrombi and haemo-static plugs is not clearly understood, we have investigated the interaction between leukocytes and growing thrombi in a human ex vivo model of arterial thrombogenesis. At a wall shear rate characteristic of moderately stenosed arteries (2600 s–1), granulocytes selectively accumulated at the luminal surface of platelet thrombi. The leukocyte adhesion seemed independent of fibrin formation and was clearly correlated to thrombus growth and platelet activation. In contrast, flow cytometry revealed that the expression of adhesion molecules (CD11a, CD11b, CD11c, CD3, CD14, CD62L, HLA-DR and binding of fibrinogen) on the surface of circulating leukocytes passing the thrombi was, on short term conditions (15 min), independent of thrombus growth. The adhered granulocytes probably play a pivotal role in limiting the size of the evolving thrombi, as suggested by our electron micrographs of the arterial thrombi showing lysed and phagocytosed platelets. Thus, granulocytes might play an active role in the acute/semiacute phase of local thromboregulation.
C4b-binding Protein Inhibits the Factor V-dependent but not the Factor V-independent Cofactor Activity of Protein S in the Activated Protein C-mediated Inactivation of Factor VIIIa
Authors: van de Poel Robbert , Meijers Joost , Bouma Bonno 
Published: March 2018

SummaryActivated protein C (APC) is an important inactivator of coagulation factors Va and VIIIa. In the inactivation of factors Va and VIIIa, protein S serves as a cofactor to APC. Protein S can bind to C4b-binding protein (C4BP), and thereby loses its cofactor activity to APC. By modulating free protein S levels, C4BP is an important regulator of protein S cofactor activity. In the factor VIIIa inactivation, protein S and factor V act as synergistic cofactors to APC. We investigated the effect of C4BP on both the factor V-independent and factor V-dependent cofactor activity of protein S in the factor VIIIa inactivation using a purified system. Protein S increased the APC-mediated inactivation of factor VIIIa to 60% and in synergy with protein S, factor V at equi-molar concentrations increased this effect further to 90%. The protein S/factor V synergistic effect was inhibited by preincubation of protein S and factor V with a four-fold molar excess of C4BP. However, C4BP did not inhibit the factor V-independent protein S cofactor activity in the purified system whereas it inhibited the cofactor activity in plasma. We conclude that C4BP-bound protein S retains its cofactor activity to APC in the factor VIIIa inactivation.
Coagulation Factor VII in Middle-aged Women with and without Coronary Heart Disease
Authors: Silveira Angela , Orth-Gomér Kristina , Hamsten Anders , Schenck-Gustafsson Karin , Eriksson-Berg Margita 
Published: March 2018

SummaryEpidemiological studies of coagulation factor VII as a risk factor for coronary heart disease (CHD), mainly conducted in men, have shown discrepant results. We examined the associations of coagulation factor VII antigen (VIIag) and activated factor VII (VIIa) with manifest CHD in a community-based case-control study of women aged ≤65 years. Mean plasma concentrations of VIIag and VIIa in patients and controls were 443 ± 108 and 418 ± 89 ng/L (p <0.01) and 5.26 ± 2.21 and 4.90 ± 1.65 ng/L (NS), respectively. The odds ratio (OR) for CHD for the highest versus the lowest quartile of VIIag was 1.75 (95% CI, 1.05 to 2.92). The adjusted OR was 0.76 (95% CI, 0.28-1.98) after controlling for other cardiovascular risk factors. The corresponding ORs for VIIa were non-significant. In conclusion, the plasma concentration of VIIa was not significantly increased in a large group of women with precocious CHD, and VIIag levels, although elevated, were not independently associated with manifest disease.
Plasma Levels of Total and Free Tissue Factor Pathway Inhibitor (TFPI) as Individual Pharmacological Parameters of Various Heparins
Authors: Gastpar Robert , Alban Susanne 
Published: March 2018

SummaryThe release of circulating tissue factor pathway inhibitor (TFPI) into plasma by heparins is thought to contribute to their overall anti-thrombotic activity. In the presented study in healthy volunteers, we measured the heparin-induced increase of circulating total and free TFPI antigen and the aXa- and aIIa activity after subcutaneous (s.c.) injection of 9000 aXa-U of four different heparins: unfractionated heparin (UFH) (13.0 kDa), a medium molecular weight (MW) heparin with a narrow MW range (HF) (10.5 kDa), certoparin (6.0 kDa) and enoxaparin (4.5 kDa). Based on the administration of equi-active aXa doses, certoparin induced the highest increase in total TFPI determined as AUC (p <0.01). The lowest effect was observed for UFH (p <0.0001). However, the AUC of released free TFPI significantly increased in the order: enoxaparin < UFH < certoparin < HF, showing MW dependency with the exception of UFH. Comparing the effects of equi-gravimetric heparin doses, the MW dependency becomes even more pronounced. The mismatch of UFH may be due to its poor bioavailability, which becomes obvious from its low ex vivo aXa activity. In contrast to the TFPI releasing potency, the ex vivo aXa activity continuously decreased with increasing MW. Although the ex vivo aIIa activity of the heparins increased in the same order like the release of free TFPI, there was no clear correlation. This is attributed to the fact that the aIIa activity of heparin is not only dependent on the MW, but, in contrast to its TFPI releasing effect, also on the percentage of material with high affinity to AT. In conclusion, besides the aXaand aIIa activity, the TFPI releasing effect of heparins is an additional parameter of their individual pharmacological profile.
The NFY Transcription Factor Mediates Induction of the von Willebrand Factor Promoter by Irradiation
Authors: Bertagna Angela , Jahroudi Nadia 
Published: March 2018

SummaryIonizing irradiation in patients is proposed to cause thrombus formation. An increase in von Willebrand factor secretion in response to irradiation is a major contributing factor to thrombus formation. We have previously reported that the increased VWF secretion in response to irradiation is mediated at the transcriptional level. The VWF core promoter fragment (sequences –90 to +22) was shown to contain the necessary cis-acting element(s) to mediate the irradiation response of the VWF gene. Here we report that a CCAAT element in the VWF promoter is the cis-acting element necessary for irradiation induction and that the NFY transcription factor interacts with this element. These analyses demonstrate that inhibition of NFY’s interaction with the CCAAT element abolishes the irradiation induction of the VWF promoter. These results provide a novel role for NFY and add this factor to the small list of irradiation-responsive transcription factors. Coimmunoprecipitation experiments demonstrated that NFY is associated with the histone acetylase P/CAF in vivo and that irradiation resulted in an increased association of NFY with coactivator P/CAF. We propose that irradiation induction of the VWF promoter involves a mechanism resulting in increased recruitment of the coactivator P/CAF to the promoter via the NFY transcription factor.
Factor XIII of Blood Coagulation as a Nuclear Crosslinking Enzyme
Authors: Antal Miklós , Módis László , Sárváry Attila , Szücs Sándor , Balogh Imre , Ádány Róza , Bárdos Helga 
Published: March 2018

SummaryIntracellular localization and distribution of Factor XIII subunit A (FXIIIA) was investigated in association with monocyte-macrophage differentiation in a long term culture of human monocytes by light-and electron microscopical as well as biochemical and immunobio-chemical techniques. To allow the detection of FXIIIA in cells with well-preserved ultrustructure, immunosera against glutaraldehydederivatized recombinant FXIIIA were developed in rabbits, then characterized and used in this study. In the early phase of macrophage differentiation intranuclear accumulation of FXIIIA was detected as a transient phenomenon in cells of the 2nd day culture by optical sectioning with 0,7 m steps in laser scanning confocal microscopy and immunoblotting technique. FXIIIA could be detected by immuno-electron microscopic postembedding staining over electrodense DNA-containing areas. Fluoresceinated monodansylcadaverine incorporation assay was used to demonstrate that FXIIIA is not only present in the nuclei, but also expresses its transglutaminase activity. Our finding of the nuclear accumulation of FXIIIA in differentiating human macrophages is also unique in that a blood clotting factor has, for the first time, been localized in nuclei and has been shown to be an intracellular crosslinking enzyme. The possible role of nuclear FXIIIA in association with cellular processes involving chromatin structure remodeling, such as cell death, cell differentiation or cellular proliferation requires further in-depth investigation.
Mouse Protein Z-Dependent Protease Inhibitor cDNA
Authors: Zhang Jing , Broze George 
Published: March 2018

SummaryProtein Z-dependent protease inhibitor (ZPI) is plasma proteinase inhibitor in the serpin superfamily that produces rapid inhibition of factor Xa in the presence of phospholipids, Ca++ and protein Z (PZ). Mouse ZPI cDNA was isolated and cloned from mouse liver RNA using RT-PCR. The cDNA contains 100 nucleotides 5’ of a translation initiation codon and an open reading frame of 1344 nucleotides followed by a 163 nucleotide 3’ untranslated sequence with a poly (A) tail. The cDNA predicts a signal peptide containing 21 amino acids and a mature protein of 427 residues with 8 potential sites for N-linked glycosylation. The oligonucleotide and predicted amino acid sequences of mouse ZPI are 72% and 81% homologous with those of human ZPI. Like human ZPI, mouse ZPI contains tyrosine-serine (P1-P1’) at its reactive center in contrast to the rat molecule which contains tyrosinecysteine. By Northern analysis, mouse ZPI mRNA is 1.6 kb in size and, similar to both human and rat, it is detectable in liver, but not in heart, brain, spleen, lung, kidney, skeletal muscle or testes.