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Article: Inhibition of extrinsic and intrinsic thrombin generation by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma.

Gast, A / Tschopp, T B

Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis

1995 Volume 6, Issue 6, Page(s) 553–560

Abstract: To further define the anticoagulant activity of Ro 46-6240, a novel, synthetic, thrombin inhibitor, we compared its effect on extrinsic and intrinsic thrombin generation in human platelet-poor plasma with that of recombinant hirudin and standard heparin. ...

Abstract	To further define the anticoagulant activity of Ro 46-6240, a novel, synthetic, thrombin inhibitor, we compared its effect on extrinsic and intrinsic thrombin generation in human platelet-poor plasma with that of recombinant hirudin and standard heparin. The time course of thrombin generation was followed with a chromogenic substrate assay. The total amount of active thrombin formed was quantified by calculating the area under the thrombin generation curve. Ro 46-6240 and r-hirudin delayed thrombin formation in a concentration-dependent manner in both activation systems whereas heparin showed this effect only in the intrinsic system. Heparin was the most potent inhibitor of extrinsic and intrinsic thrombin generation with IC50 values of 20 and 27 nM, respectively. Ro 46-6240 was nearly as potent as r-hirudin for inhibiting extrinsic thrombin generation (IC50 418 vs 229 nM) and intrinsic thrombin generation (IC50 463 vs 343 nM) despite a much lower affinity of Ro 46-6240 for thrombin (Ki apparent: 0.3 nM) in a purified buffer system. The similar potency of the small active-site thrombin inhibitor compared to the larger hirudin may be explained by different kinetic mechanisms for inhibition of thrombin and by a higher accessibility to the phospholipid surface where thrombin generation takes place. In conclusion, our results show that a specific small thrombin inhibitor efficiently inhibits and delays thrombin generation in human coagulating plasma. This reduced thrombin generation might be caused by inhibition of thrombin-mediated feedback reactions during blood coagulation.
MeSH term(s)	Antithrombins/pharmacology ; Binding Sites ; Chromogenic Compounds/metabolism ; Dipeptides/metabolism ; Heparin/pharmacology ; Hirudins/pharmacology ; Humans ; Hydrolysis ; Kinetics ; Naphthalenes/pharmacology ; Piperidines/pharmacology ; Recombinant Proteins/pharmacology ; Thrombin/antagonists & inhibitors ; Thrombin/metabolism
Chemical Substances	Antithrombins ; Chromogenic Compounds ; Dipeptides ; Hirudins ; Naphthalenes ; Piperidines ; Recombinant Proteins ; S 2238 (64815-81-2) ; Heparin (9005-49-6) ; Thrombin (EC 3.4.21.5) ; napsagatran (VL5IZU8PF8)
Language	English
Publishing date	1995-09
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	1033551-1
ISSN	0957-5235
ISSN	0957-5235
DOI	10.1097/00001721-199509000-00009
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Zs.A 2920: Show issues

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Article: Aspirin inhibits platelet aggregation on, but not adhesion to, collagen fibrils: an assessment of platelet adhesion and deposited platelet mass by morphometry and 51Cr-labeling.

Tschopp, T B

Thrombosis research

1977 Volume 11, Issue 5, Page(s) 619–632

MeSH term(s)	Animals ; Aspirin/pharmacology ; Chromium Radioisotopes ; Collagen/metabolism ; Isotope Labeling ; Platelet Adhesiveness/drug effects ; Platelet Aggregation/drug effects ; Rabbits
Chemical Substances	Chromium Radioisotopes ; Collagen (9007-34-5) ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	1977-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/0049-3848(77)90020-2
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Zs.A 863: Show issues

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Article: Fischöl bei Thrombose und Arteriosklerose.

Tschopp, T B / Muggli, R

Schweizerische medizinische Wochenschrift

1990 Volume 120, Issue 11, Page(s) 372–378

Abstract: In the past few years interest in the use of fish oil as a dietetic approach in the management of thromboarteriosclerotic diseases has increased. This is based on epidemiological studies which indicate that people living mainly on a fish diet have a low ... ...

Title translation	Fish oil in thrombosis and arteriosclerosis.
Abstract	In the past few years interest in the use of fish oil as a dietetic approach in the management of thromboarteriosclerotic diseases has increased. This is based on epidemiological studies which indicate that people living mainly on a fish diet have a low incidence of coronary heart disease (CHD). The beneficial effect is attributed to the high content of polyunsaturated n-3 fatty acids (PUFA), especially eicosapentaenoic acid (C20:5n-3) (EPA), in the marine diet. These fatty acids are built into the phospholipids of various cell membranes, changing their biological reactivity. EPA and docosahexaenoic acid (C22:6n-3) are also metabolized into specific eicosanoids (e.g. prostaglandin I3, thromboxane A3 and leukotriene B5). In contrast to the mediators originating from the n-6 fatty acids, these n-3 autocoids exhibit stronger antiaggregant, vasodilatory and anti-inflammatory activities. When given to volunteers, n-3 PUFAs inhibit platelet aggregation and lower plasma triglycerides. However, first clinical studies in patients with angina pectoris are equivocal. Furthermore, restenosis of coronary arteries in patients after PTCA was not clearly reduced. Therefore, more prospective clinical studies are needed to establish the efficacy of these fish oils before their use in thromboarteriosclerotic CHD can be recommended.
MeSH term(s)	Animals ; Arteriosclerosis/prevention & control ; Fatty Acids/metabolism ; Fish Oils/pharmacology ; Fish Oils/therapeutic use ; Humans ; Lipids/blood ; Platelet Aggregation/drug effects ; Thrombosis/prevention & control
Chemical Substances	Fatty Acids ; Fish Oils ; Lipids
Language	German
Publishing date	1990-03-17
Publishing country	Switzerland
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	200461-6
ISSN	0036-7672
ISSN	0036-7672
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Article: Aggregation of cat platelets in vitro.

Tschopp, T B

Thrombosis et diathesis haemorrhagica

1970 Volume 23, Issue 3, Page(s) 601–620

MeSH term(s)	Adenine Nucleotides/pharmacology ; Animals ; Blood Platelets/drug effects ; Blood Platelets/metabolism ; Blood Specimen Collection ; Cats ; Densitometry ; Epinephrine/pharmacology ; Platelet Adhesiveness/drug effects ; Serotonin/metabolism ; Species Specificity
Chemical Substances	Adenine Nucleotides ; Serotonin (333DO1RDJY) ; Epinephrine (YKH834O4BH)
Language	English
Publishing date	1970-06-30
Publishing country	Germany
Document type	Journal Article
ZDB-ID	204356-7
ISSN	0340-5338 ; 0563-4954
ISSN	0340-5338 ; 0563-4954
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Article: Active site-blocked factors VIIa and IXa differentially inhibit fibrin formation in a human ex vivo thrombosis model.

Kirchhofer, D / Tschopp, T B / Baumgartner, H R

Arteriosclerosis, thrombosis, and vascular biology

1995 Volume 15, Issue 8, Page(s) 1098–1106

Abstract: The role of tissue factor/factor VIIa (FVIIa) and factor VIIIa/factor IXa (FVIIIa/FIXa) complexes in thrombus formation was examined in a human ex vivo blood flow system by use of active site-blocked FVIIa (FVIIai) and FIXa (FIXai) as selective ... ...

Abstract	The role of tissue factor/factor VIIa (FVIIa) and factor VIIIa/factor IXa (FVIIIa/FIXa) complexes in thrombus formation was examined in a human ex vivo blood flow system by use of active site-blocked FVIIa (FVIIai) and FIXa (FIXai) as selective inhibitors. Blood was drawn directly from the veins of volunteers into a mixing device where FVIIai and FIXai were mixed with flowing blood. The blood then entered parallel-plate chambers containing coverslips coated with human fibrillar collagen or tissue factor-expressing cell layers of tumor necrosis factor-alpha-stimulated human endothelial cells, human smooth muscle cells, and J82 cells. Exposure of stimulated endothelial cells to blood flowing at a venous shear rate of 65/s led to fibrin deposition, which was inhibited by infusion of FVIIai (IC50, 3 nmol/L), as quantified by micro-densitometry of fibrin-stained coverslips. Whereas FIXai (600 nmol/L) was only a weak inhibitor, FVIIai (60 nmol/L) reduced fibrinopeptide A (FPA) plasma levels from 504 +/- 79 to 171 +/- 27 ng/mL and concomitantly inhibited platelet thrombus deposition. Similarly, experiments with smooth muscle cells and J82 cells showed that FVIIai but not FIXai efficiently reduced FPA levels. Conversely, with tissue factor-free collagen, ,hich induces platelet-dependent fibrin formation, infusion of FIXai but not of FVIIai inhibited fibrin deposition (IC50, 8 nmol/L) and reduced FPA levels from 55 +/- 8 to 9 +/- 5 ng/mL. However, FIXai did not affect the number of platelet thrombi deposited on collagen.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH term(s)	Amino Acid Sequence ; Binding Sites ; Blood Coagulation ; Blood Platelets/physiology ; Cells, Cultured ; Collagen/metabolism ; Endothelium, Vascular/metabolism ; Factor VIIa/antagonists & inhibitors ; Factor XIa/antagonists & inhibitors ; Fibrin/metabolism ; Fibrinopeptide A/metabolism ; Humans ; In Vitro Techniques ; Molecular Sequence Data ; Peptides/chemistry ; Platelet Activation ; Rheology ; Thrombosis/enzymology ; Time Factors ; beta-Thromboglobulin/metabolism
Chemical Substances	Peptides ; beta-Thromboglobulin ; Fibrinopeptide A (25422-31-5) ; Fibrin (9001-31-4) ; Collagen (9007-34-5) ; Factor VIIa (EC 3.4.21.21) ; Factor XIa (EC 3.4.21.27)
Language	English
Publishing date	1995-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/01.atv.15.8.1098
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Article: Thrombin plays a key role in late platelet thrombus growth and/or stability. Effect of a specific thrombin inhibitor on thrombogenesis induced by aortic subendothelium exposed to flowing rabbit blood.

Gast, A / Tschopp, T B / Baumgartner, H R

Arteriosclerosis and thrombosis : a journal of vascular biology

1994 Volume 14, Issue 9, Page(s) 1466–1474

Abstract: Thrombin is involved in the pathogenesis of venous and arterial thrombosis. This study addressed the question of the relative importance of thrombin in the early and late phases of thrombogenesis. The effect of Ro 46-6240 (1.43 mg/kg bolus and 0.1 mg/kg ... ...

Abstract	Thrombin is involved in the pathogenesis of venous and arterial thrombosis. This study addressed the question of the relative importance of thrombin in the early and late phases of thrombogenesis. The effect of Ro 46-6240 (1.43 mg/kg bolus and 0.1 mg/kg per minute i.v.), a novel, selective thrombin inhibitor on thrombogenesis induced by rabbit aorta subendothelium, was measured ex vivo in a perfusion chamber model after a short (5-minute) and long (30-minute) exposure time to rabbit native blood. The role of the perfusion time was assessed at shear rates of 100/s, 650/s, and 2600/s. These shear rates mimic blood flow conditions found in veins, arteries, and small or stenosed arteries, respectively. Fibrin deposition and platelet thrombus formation on subendothelium were evaluated by microscopic morphometry. In the presence of Ro 46-6240, fibrin deposition was abolished at both perfusion times and at all shear rates. In the 5-minute experiments, thrombus height was reduced by Ro 46-6240 at shear rates of 100/s (85%) and 650/s (35%) but not at a shear rate of 2600/s, whereas thrombus area was not affected at any shear rate. In contrast, both thrombus height and thrombus area were reduced (60% to 90%) by Ro 46-6240 in the 30-minute perfusion groups at all wall shear rates. The antithrombotic effect of Ro 46-6240 after 30-minute perfusion was confirmed by the minimal increase in the pressure difference between the entrance and the exit of the perfusion chamber compared with the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
MeSH term(s)	Animals ; Aorta/physiopathology ; Blood Flow Velocity ; Blood Platelets/physiology ; Endothelium, Vascular/physiopathology ; Female ; Fibrin/metabolism ; Male ; Naphthalenes/pharmacology ; Piperidines/pharmacology ; Rabbits ; Thrombin/antagonists & inhibitors ; Thrombin/physiology ; Thrombosis/physiopathology
Chemical Substances	Naphthalenes ; Piperidines ; Fibrin (9001-31-4) ; Thrombin (EC 3.4.21.5) ; napsagatran (VL5IZU8PF8)
Language	English
Publishing date	1994-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1063375-3
ISSN	1049-8834
ISSN	1049-8834
DOI	10.1161/01.atv.14.9.1466
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Article: Platelet adhesion and mural platelet thrombus formation on aortic subendothelium of rats, rabbits, and guinea pigs correlate negatively with the vascular PGI2 production.

Tschopp, T B / Baumgartner, H R

The Journal of laboratory and clinical medicine

1981 Volume 98, Issue 3, Page(s) 402–411

Abstract: This study investigates whether PGI2 produced locally by the vessel wall affects the interaction of platelets with subendothelium. Aortic endothelium was removed by a balloon catheter. Subsequent platelet deposition on subendothelium was assessed by ... ...

Abstract	This study investigates whether PGI2 produced locally by the vessel wall affects the interaction of platelets with subendothelium. Aortic endothelium was removed by a balloon catheter. Subsequent platelet deposition on subendothelium was assessed by morphometry. After 10 min exposure, surface coverage with adherent platelets in rats, rabbits, and guinea pigs amounted to 63% +/- 4, 82% +/- 3, and 97% +/- 1 (means +/- S.E.) (n greater than 5), and with microthrombi to 0 +/- 0, 6% +/- 2 and 15% +/- 4, respectively. Conversely, as measured by bioassay, excised aortic segments of rats, rabbits, and guinea pigs produced 135 +/- 14, 34 +/- 4, and less than 15 pmol of PGI2 per 10 mg of aorta per 30 min incubation in buffer, respectively (n = 4). In a second set of experiments, native blood from the aorta of a rabbit was circulated (30 ml/min) through a rat's de-endothelialized abdominal aorta and back into the vena cava of the rabbit. After a 5 min exposure at an approximate gamma w of 3000 sec-1, adhesion and aggregation of rabbit platelets on subendothelium of untreated rats amounted to 6% +/- 2 and 0 +/- 0, respectively. In contrast, on subendothelium of rats pretreated with 50 mg/kg ASA, which inhibits generation of PGI2 by greater than 80%, platelet adhesion and aggregation amounted to 55% +/- 11 and 19% +/- 7, respectively (n = 6, 2 alpha less than 0.01). The deposited thrombus volume per surface area differed by 3 orders of magnitude between the two groups. We conclude that platelet adhesion and aggregation on subendothelium correlate negatively with the generation of PGI2. Thus the smooth muscle cells of the media can produce sufficient amounts of PGI2 to locally influence the thrombogenicity of a de-endothelialized artery.
MeSH term(s)	Animals ; Aorta/metabolism ; Aorta/physiology ; Aspirin/pharmacology ; Blood Coagulation ; Blood Platelets/physiology ; Blood Vessels/metabolism ; Endothelium/physiology ; Epoprostenol/antagonists & inhibitors ; Epoprostenol/biosynthesis ; Epoprostenol/pharmacology ; Guinea Pigs ; Male ; Muscle, Smooth, Vascular/cytology ; Platelet Adhesiveness ; Platelet Aggregation ; Prostaglandins/biosynthesis ; Rabbits/blood ; Rats
Chemical Substances	Prostaglandins ; Epoprostenol (DCR9Z582X0) ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	1981-09
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	80208-6
ISSN	1532-6543 ; 0022-2143
ISSN (online)	1532-6543
ISSN	0022-2143
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Article: Activated clotting time as an appropriate test to compare heparin and direct thrombin inhibitors such as hirudin or Ro 46-6240 in experimental arterial thrombosis.

Carteaux, J P / Gast, A / Tschopp, T B / Roux, S

Circulation

1995 Volume 91, Issue 5, Page(s) 1568–1574

Abstract: Background: Specific thrombin inhibitors are considered to be more potent antithrombotics than heparin. However, the relation between the systemic anticoagulation generated by thrombin inhibitors and their antithrombotic effect is not well defined. In a ...

Abstract	Background: Specific thrombin inhibitors are considered to be more potent antithrombotics than heparin. However, the relation between the systemic anticoagulation generated by thrombin inhibitors and their antithrombotic effect is not well defined. In a guinea pig carotid thrombosis model, the activated clotting time (ACT), the activated partial thromboplastin time (aPTT), and thrombin-generation tests were evaluated for their ability to predict the arterial antithrombotic effect of direct thrombin inhibitors such as hirudin and Ro 46-6240 compared with heparin. Methods and results: Thrombosis of the carotid artery was induced by subendothelial damage in guinea pigs, and the subsequent cyclic flow variations were monitored. The effects of pretreatment with intravenous heparin, hirudin, and Ro 46-6240 were tested. After doubling the baseline aPTT, 1 IU.kg-1.min-1 heparin was inactive, whereas either hirudin or Ro 46-6240 (30 micrograms.kg-1.min-1) prevented thrombus formation by 80%. Heparin (10 IU.kg-1.min-1) induced the same antithrombotic effect but with indefinite aPTT prolongation. However, for similar prolongation of the ACT, the three compounds had equivalent antithrombotic effects. Thrombin generation was predictive of the antithrombotic effect of the thrombin inhibitors but not of heparin. Conclusions: The arterial antithrombotic effect of direct thrombin inhibitors, when compared with those of heparin, should be evaluated by the ACT and not the aPTT or thrombin-generation assays. For a "therapeutic" aPTT prolongation, thrombin inhibitors induce higher systemic anticoagulation than does heparin and thus might unduly have higher bleeding liability.
MeSH term(s)	Animals ; Antithrombins/therapeutic use ; Carotid Artery Thrombosis/blood ; Carotid Artery Thrombosis/prevention & control ; Guinea Pigs ; Heparin/therapeutic use ; Hirudin Therapy ; Humans ; In Vitro Techniques ; Male ; Naphthalenes/therapeutic use ; Partial Thromboplastin Time ; Piperidines/therapeutic use ; Predictive Value of Tests ; Rabbits ; Whole Blood Coagulation Time
Chemical Substances	Antithrombins ; Naphthalenes ; Piperidines ; Heparin (9005-49-6) ; napsagatran (VL5IZU8PF8)
Language	English
Publishing date	1995-03-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/01.cir.91.5.1568
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Article: Role of collagen-adherent platelets in mediating fibrin formation in flowing whole blood.

Kirchhofer, D / Tschopp, T B / Steiner, B / Baumgartner, H R

Blood

1995 Volume 86, Issue 10, Page(s) 3815–3822

Abstract: Activated platelets provide assembly sites for coagulation enzyme complexes and in this way can mediate coagulation during hemostasis and thrombosis. In this study, we examined the procoagulant activity of platelets adhering directly to fibrillar ... ...

Abstract	Activated platelets provide assembly sites for coagulation enzyme complexes and in this way can mediate coagulation during hemostasis and thrombosis. In this study, we examined the procoagulant activity of platelets adhering directly to fibrillar collagen, a main thrombogenic constituent of subendothelium. For this purpose, we used a human ex-vivo thrombosis model in which collagen-coated coverslips were exposed to flowing nonanticoagulated blood (shear rate, 65/s) for 5.5 minutes, which led to the deposition of adherent platelets, platelet thrombi, and fibrin. To examine the procoagulant activity of adherent platelets only, a selective antagonist of the platelet GPIIb-IIIa complex, Ro 44-9883, was infused via a mixing device, resulting in a complete abrogation of platelet thrombus formation but leaving the collagen-adherent platelet layer intact. This platelet layer generated increased postchamber fibrinopeptide A (FPA) levels (203 +/- 33 ng/mL) as compared with control experiments without infusion of inhibitor (95 +/- 13 ng/mL). Concomitantly, fibrin deposition measured by morphometric analysis of cross-sections was also increased, as was the platelet adhesion to collagen. An immunochemical staining of fibrin fibers further showed that the adherent platelets formed the nuclei for fibrin fiber formation. This increase in fibrin deposition was mediated by the intrinsic factor X (F.X) activation complex on adherent single platelets, because almost complete inhibition of FPA generation (9 ng/mL) and fibrin deposition (0.4% +/- 0.2% coverage) was achieved upon coinfusion of the GP IIb-IIIa antagonist and active site-inhibited F.IXa. The large platelet thrombi that were deposited in control experiments contained no significant amounts of immunodetectable fibrin except at the thrombus base, where adherent platelets anchored the thrombi to the collagen surface. These results suggest that the collagen-adherent platelets are important promoters of coagulation during the initial phase of thrombogenesis by providing assembly sites for the F.X activation complex.
MeSH term(s)	Acetates/pharmacology ; Anticoagulants/pharmacology ; Blood Coagulation/drug effects ; Blood Coagulation/physiology ; Blood Platelets/physiology ; Collagen/metabolism ; Enzyme Activation ; Factor Xa/metabolism ; Fibrin/biosynthesis ; Fibrinopeptide A/metabolism ; Hemorheology ; Humans ; In Vitro Techniques ; Macromolecular Substances ; Perfusion ; Platelet Adhesiveness ; Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors ; Thrombosis ; Tyrosine/analogs & derivatives ; Tyrosine/pharmacology
Chemical Substances	Acetates ; Anticoagulants ; Macromolecular Substances ; Platelet Glycoprotein GPIIb-IIIa Complex ; Fibrinopeptide A (25422-31-5) ; Tyrosine (42HK56048U) ; Fibrin (9001-31-4) ; Collagen (9007-34-5) ; lamifiban (9XOE28082S) ; Factor Xa (EC 3.4.21.6)
Language	English
Publishing date	1995-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article: Endothelial cells stimulated with tumor necrosis factor-alpha express varying amounts of tissue factor resulting in inhomogenous fibrin deposition in a native blood flow system. Effects of thrombin inhibitors.

Kirchhofer, D / Tschopp, T B / Hadváry, P / Baumgartner, H R

The Journal of clinical investigation

1994 Volume 93, Issue 5, Page(s) 2073–2083

Abstract: TNF-alpha induces changes in endothelial cell functions, such as upregulation of tissue factor, resulting in endothelial procoagulant activity which may play a role in disseminated intravascular coagulation. The procoagulant activity of TNF-alpha- ... ...

Abstract	TNF-alpha induces changes in endothelial cell functions, such as upregulation of tissue factor, resulting in endothelial procoagulant activity which may play a role in disseminated intravascular coagulation. The procoagulant activity of TNF-alpha-stimulated endothelial cell monolayers was studied in a human ex vivo native (nonanticoagulated) blood flow system using the three thrombin inhibitors recombinant hirudin, Ro 46-6240, and heparin. Under venous blood flow conditions (shear rate 65 s-1) recombinant hirudin, Ro 46-6240, and heparin inhibited fibrin deposition on the endothelial cells by 50% at concentrations of 14, 28, and 412 ng/ml, respectively. The highest tested concentrations of the thrombin inhibitors reduced the postchamber fibrinopeptide A levels from 713 +/- 69 to < 70 ng/ml. Surprisingly, even at relatively high inhibitor concentrations, some local fibrin deposits were found on TNF-alpha-stimulated cells, suggesting that some endothelial cells possess higher procoagulant activity than others. Therefore, the surface expression pattern of tissue factor, the primary initiator of coagulation in this system, was examined by immunogold-silver staining. The results showed that the tissue factor density on the cell surface varied strongly among TNF-alpha-stimulated endothelial cells. Using TNF receptor-selective agonistic mutants of TNF-alpha, it was demonstrated further that the heterogenous surface expression of tissue factor was mediated entirely by the 55-kD TNF receptor and did not involve the 75-kD TNF receptor. We conclude that in this system TNF-alpha induces heterogenous tissue factor expression which may lead to a high local thrombin concentration, such that even in the presence of thrombin inhibitors focal fibrin deposition occurs.
MeSH term(s)	Blood Circulation ; Blood Coagulation/physiology ; Blood Platelets/cytology ; Cell Membrane/chemistry ; Dose-Response Relationship, Drug ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Fibrin/metabolism ; Fibrinopeptide A/analysis ; Heparin/pharmacology ; Hirudins/pharmacology ; Humans ; Immunohistochemistry ; Leukocytes/cytology ; Naphthalenes/pharmacology ; Piperidines/pharmacology ; Thrombin/antagonists & inhibitors ; Thromboplastin/biosynthesis ; Thromboplastin/isolation & purification ; Tumor Necrosis Factor-alpha/pharmacology ; Umbilical Veins/cytology
Chemical Substances	Hirudins ; Naphthalenes ; Piperidines ; Tumor Necrosis Factor-alpha ; Fibrinopeptide A (25422-31-5) ; Fibrin (9001-31-4) ; Heparin (9005-49-6) ; Thromboplastin (9035-58-9) ; Thrombin (EC 3.4.21.5) ; napsagatran (VL5IZU8PF8)
Language	English
Publishing date	1994-05
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI117202
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