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Thromb Haemost 2005; 93(01): 97-105
DOI: 10.1160/TH04-02-0091
Platelets and Blood Cells
Schattauer GmbH

Regulation of tissue factor-induced coagulation and platelet aggregation in flowing whole blood

Marijke J. E. Kuijpers
1   The Departments of Biochemistry, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
,
Cécile M. A. Nieuwenhuys
2   Human Biology, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
,
Marion A. H. Feijge
1   The Departments of Biochemistry, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
,
Willem Kloots
3   Unilever Health Institute, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
,
Peter L. A. Giesen
4   Synapse, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
,
Johann C. Jerling
3   Unilever Health Institute, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
*   Present address: Potchefstroom Institute of Nutrition, School of Physiology, Nutrition and Consumer Science, Potchefstroom University for Christian Higher Education, South Africa.
,
Mirjam G. A. oude Egbrink
5   Physiology CARIM, University of Maastricht, Maastricht, The Netherlands
,
Johan W. M. Heemskerk
1   The Departments of Biochemistry, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
2   Human Biology, Unilever Research Vlaardingen, Vlaardingen, The Netherlands
› Author AffiliationsFinancial support: Support was obtained from the Netherlands Foundation for Scientific Research (902–68–241) and AstraZeneca R&D.
Further Information

Publication History

Received 12 February 2004

Accepted after resubmission 13 October 2004

Publication Date:
14 December 2017 (online)

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Summary

Photochemically induced thrombosis (a thrombin-dependent process) was measured in rats treated with moderate doses of anticoagulants, but which appeared to be unchanged. We considered the possibility that platelet-inhibiting agents, which also indirectly inhibit coagulation, would act as more potent antithrombotic agents.Inhibitors used as such were prostaglandin E1 (PGE1), which elevates cyclic AMP levels, and the P2Y12 ADP-receptor antagonist,AR-C69931MX. Effects of these agents were investigated in an ex vivo model system, in which whole blood under coagulant conditions was perfused over fibrinogen at defined wall shear rate. Perfusion of blood (rat or human) in the presence of tissue factor resulted in deposition of activated platelets and subsequent aggregate formation, along with exposure of procoagulant phosphatidylserine (PS) on the platelet surface and formation of fibrin fibers. In the presence of PGE1 aggregation was completely inhibited,but platelet adhesion and PS exposure were only party reduced, while fibrin formation was hardly affected. Treatment with AR-C69931MX caused similar, but less complete effects.These results indicate that in tissue factor- triggered blood under conditions of flow:(i) the platelet procoagulant response is independent of aggregate formation; (ii) the platelet-inhibiting effect of PGE1 and AR-C69931MX is sufficient to suppress aggregation, but not platelet adhesion and coagulation. These platelet inhibitors thus maintain their aggregation- inhibiting effect at sites of thrombin formation.

Keywords

Coagulation - platelets - prostaglandin - thrombin - thrombus
 

  • References

  • 1 Giesen PL, Rauch U, Bohrmann B. et al Bloodborne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999; 96: 2311-15.
    CrossrefPubMedGoogle Scholar
  • 2 Plow EF, Cierniewski CS, Xiao Z. et al α IIbβ 3 and its antagonism at the new millennium. Thromb Haemost 2001; 86: 34-40.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Walsh PN. Roles of platelets and factor XI in the initiation of blood coagulation by thrombin. Thromb Haemost 2001; 86: 75-82.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Smeets EF, Heemskerk JWM, Comfurius P. et al Thapsigargin amplifies the platelet procoagulant response caused by thrombin. Thromb Haemost 1993; 70: 1024-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Heemskerk JWM, Vuist WMJ, Feijge MAH. et al Collagen but not fibrinogen surfaces induce bleb formation, exposure of phosphatidylserine, and procoagulant activity of adherent platelets. Blood 1997; 90: 2615-25.
    PubMedGoogle Scholar
  • 6 Bevers EM, Comfurius P, van Rijn JL. et al Generation of prothrombin-converting activity and the exposure of phosphatidylserine at the outer surface of platelets. Eur J Biochem 1982; 122: 429-36.
    CrossrefPubMedGoogle Scholar
  • 7 Swords NA, Mann KG. The assembly of the prothrombinase complex on adherent platelets. Arterioscler Thromb 1993; 13: 1602-12.
    CrossrefPubMedGoogle Scholar
  • 8 Zwaal RFA, Schroit AJ. Pathophysiological implications of membrane phospholipid asymmetry in blood cells. Blood 1997; 89: 1121-32.
    CrossrefPubMedGoogle Scholar
  • 9 Briedé JJ, Heemskerk JWM, van 't Veer C. et al Contribution of platelet-derived factor Va to thrombin generation on immobilized collagen- and fibrinogenadherent platelets. Thromb Haemost 2001; 85: 509-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Rosing J, Bevers EM, Comfurius P. et al Impaired factor X and prothrombin activation associated with decreased phospholipid exposure in platelets from a patient with a bleeding disorder. Blood 1985; 65: 1557-61.
    PubMedGoogle Scholar
  • 11 Weiss HJ. Scott syndrome: a disorder of platelet coagulant activity. Semin Hematol 1994; 31: 312-9.
    PubMedGoogle Scholar
  • 12 Reverter JC, Béguin S, Kessels H. et al Inhibition of platelet-mediated, tissue-factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and 'clinical restenosis'. J Clin Invest 1996; 98: 863-74.
    CrossrefPubMedGoogle Scholar
  • 13 Béguin S, Kumar R. Thrombin, fibrin and platelets: a resonance loop in which von Willebrand factor is a necessary link. Thromb Haemost 1997; 78: 590-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Keularts IML, Béguin S, de Zwaan C. et al Treatment with a GPIIb-IIIa antagonist inhibits thrombin generation in platelet-rich plasma from patients. Thromb Haemost 1998; 80: 370-1.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Béguin S, Kumar R, Keularts I. et al Fibrin-dependent platelet procoagulant activity requires GPIb receptors and von Willebrand factor. Blood 1999; 93: 564-70.
    PubMedGoogle Scholar
  • 16 Vanschoonbeek K, Feijge MAH, Van Kampen RJ. et al Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma. J Thromb Haemost 2004; 2: 476-84.
    CrossrefPubMedGoogle Scholar
  • 17 Léon C, Ravanat C, Freund M. et al Differential involvement of the P2Y1 and P2Y12 receptor in platelet procoagulant activity. Arterioscler Thromb Vasc Biol 2003; 23: 1941-7.
    CrossrefPubMedGoogle Scholar
  • 18 Daniel JL, Dangelmaier C, Jin J. et al Molecular basis for ADP-induced platelet activation. I: evidence for three distinct ADP receptors on human platelets. J Biol Chem 1998; 273: 2024-9.
    CrossrefPubMedGoogle Scholar
  • 19 Hechler B, Eckly A, Ohlmann P. et al The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol 1998; 103: 858-66.
    CrossrefPubMedGoogle Scholar
  • 20 Hérault JP, Dol F, Gaich C. et al Effect of clopidogrel on thrombin generation in platelet-rich plasma in the rat. Thromb Haemost 1999; 81: 957-60.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Ingall AH, Dixon J, Bailey A. et al Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy. J Med Chem 1999; 42: 213-20.
    CrossrefPubMedGoogle Scholar
  • 22 Hollopeter G, Jantzen HM, Vincent D. et al Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-8.
    CrossrefPubMedGoogle Scholar
  • 23 Matsuno H, Uematsu T, Nagashima S. et al Photochemically induced thrombosis model in rat femoral artery and evaluation of effects of heparin and tissue-type plasminogen activator with use of this model. J Pharmacol Meth 1991; 25: 303-17.
    CrossrefPubMedGoogle Scholar
  • 24 Inamo J, Belougne E, Doutremepuich C. Importance of photo activation of rose bengal for platelet activation in experimental models of photochemically induced thrombosis. Thromb Res 1996; 83: 229-35.
    CrossrefPubMedGoogle Scholar
  • 25 Nieuwenhuys CMA, Béguin S, Offermans RF. et al Hypocoagulant and lipid-lowering effects of dietary n-3 polyunsaturated fatty acids with unchanged platelet activation in rats. Arterioscler Thromb Vasc Biol 1998; 18: 1480-9.
    CrossrefPubMedGoogle Scholar
  • 26 Nieuwenhuys CMA, Feijge MAH, Béguin S. et al Monitoring hypocoagulant conditions in rat plasma: factors determining the endogenous thrombin potential of tissue factor-activated plasma. Thromb Haemost 2000; 84: 1045-51.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Jerling JC, Curiel-Martos A, Kroner C. et al Fish oil inhibits photochemically induced thrombosis in the guinea pig in a dose dependent manner. Thromb Res 2003; 111: 11-17.
    CrossrefPubMedGoogle Scholar
  • 28 Nieuwenhuys CMA, Hornstra G. The effects of purified eicosapentaenoic and docosahexaenoic acids on arterial thrombosis tendency and platelet function in rats. Biochim Biophys Acta 1998; 1390: 313-22.
    CrossrefPubMedGoogle Scholar
  • 29 Hemker HC, Giesen PLA, Ramjee M. et al The thrombogram: monitoring thrombin generation in platelet rich plasma. Thromb Haemost 2000; 83: 589-91.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Heemskerk JWM, Willems GM, Rook MB. et al Ragged spiking of free calcium in ADP-stimulated human platelets: regulation of puff-like calcium signals in vitro and ex vivo. J Physiol 2001; 535: 625-35.
    CrossrefPubMedGoogle Scholar
  • 31 Fungaloi P, Waterman P, Nigri G. et al Photochemically modulated endothelial cell thrombogenicity via the thrombomodulin-tissue factor pathways. Photochem Photobiol 2003; 78: 475-80.
    CrossrefPubMedGoogle Scholar
  • 32 Heemskerk JWM, Feijge MAH, Sage SO. et al Indirect regulation of Ca2+ entry by cAMP-dependent and cGMP-dependent protein kinases and phospholipase C in rat platelets. Eur J Biochem 1994; 223: 543-51.
    CrossrefPubMedGoogle Scholar
  • 33 Keularts IML, van Gorp RM, Feijge MAH. et al α 2A-adrenergic receptor stimulation potentiates calcium release in platelets by modulating cAMP levels. J Biol Chem 2000; 275: 1763-72.
    CrossrefPubMedGoogle Scholar
  • 34 Van Willigen G, Akkerman JWN. Regulation of glycoprotein IIb/IIIa exposure on platelets stimulated with alpha-thrombin. Blood 1992; 79: 82-90.
    PubMedGoogle Scholar
  • 35 Pasquet JM, Dachary-Prigent J, Nurden AT. Calcium influx is a determining factor of calpain activation and microparticle formation in platelets. Eur J Biochem 1996; 239: 647-54.
    CrossrefPubMedGoogle Scholar
  • 36 Butenas S, Cawthern KM, van 't Veer C. et al Antiplatelet agents in tissue factor-induced blood coagulation. Blood 2001; 97: 2314-22.
    CrossrefPubMedGoogle Scholar
  • 37 Gianetti J, De Caterina M, De Cristofaro T. et al Intravenous prostaglandin E 1 reduces soluble vascular cell adhesion molecule-1 in peripheral arterial obstructive disease. Am Heart J 2001; 142: 733-9.
    CrossrefPubMedGoogle Scholar
  • 38 Weiss T, Fischer D, Hausmann D. et al Endothelial function in patients with peripheral vascular disease: influence of prostaglandin E 1 . Prostaglandins Leukotr Essent Fatty Acids 2002; 67: 277-81.
    CrossrefPubMedGoogle Scholar
  • 39 Makino H, Aoki M, Hashiya N. et al Increase in peripheral blood flow by intravenous administration of prostaglandin E 1 in patients with peripheral arterial disease, accompanied by up-regulation of hepatocyte growth factor. Hypertens Res 2004; 27: 85-91.
    CrossrefPubMedGoogle Scholar