User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis

Primary tabs

download
  • Open access
  • PDF
  • 1.54 M
Decrem, Yves Rath, Géraldine [UCL] Blasioli, Virginie Cauchie, Philippe Robert, Severine Feron, Olivier [UCL] Dogne, Jean-Michel [UCL] Dessy, Chantal [UCL] Vanhamme, Luc [UCL] Godfroid, Edmond

Blood coagulation starts immediately after damage to the vascular endothelium. This system is essential for minimizing blood loss from an injured blood vessel but also contributes to vascular thrombosis. Although it has long been thought that the intrinsic coagulation pathway is not important for clotting in vivo, recent data obtained with genetically altered mice indicate that contact phase proteins seem to be essential for thrombus formation. We show that recombinant Ixodes ricinus contact phase inhibitor (Ir-CPI), a Kunitz-type protein expressed by the salivary glands of the tick Ixodes ricinus, specifically interacts with activated human contact phase factors (FXIIa, FXIa, and kallikrein) and prolongs the activated partial thromboplastin time (aPTT) in vitro. The effects of Ir-CPI were also examined in vivo using both venous and arterial thrombosis models. Intravenous administration of Ir-CPI in rats and mice caused a dose-dependent reduction in venous thrombus formation and revealed a defect in the formation of arterial occlusive thrombi. Moreover, mice injected with Ir-CPI are protected against collagen- and epinephrine-induced thromboembolism. Remarkably, the effective antithrombotic dose of Ir-CPI did not promote bleeding or impair blood coagulation parameters. To conclude, our results show that a contact phase inhibitor is an effective and safe antithrombotic agent in vivo.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès libre
Publication date 2009
Language Anglais
Journal information "The Journal of Experimental Medicine" - Vol. 206, no. 11, p. 2381-95 (2009)
Peer reviewed yes
Publisher Rockefeller Univ Press (New York)
issn 0022-1007
e-issn 1540-9538
Publication status Publié
Affiliations UCL - MD/MINT - Département de médecine interne
UCL - MD/FARM - Ecole de pharmacie
UCL - MD/ESP - Ecole de santé publique
UCL - MD/FSIO - Département de physiologie et pharmacologie
MESH Subject Venous Thrombosis - pathology - prevention & control ; Thrombosis - pathology - prevention & control ; Thrombin - biosynthesis ; Sequence Analysis, Protein ; Recombinant Proteins - isolation & purification - pharmacology ; Rats ; Protein Binding - drug effects ; Partial Thromboplastin Time ; Mice ; Male ; Kallikreins - metabolism ; Ixodes - chemistry ; Humans ; Fibrinolysis - drug effects ; Fibrinolysin - metabolism ; Factor XIa - metabolism ; Factor XIIa - metabolism ; Disease Models, Animal ; Blood Coagulation Factor Inhibitors - chemistry - pharmacology ; Blood Coagulation - drug effects ; Animals
Links
  1. De La Cadena, J. Lab. Clin. Med., 109, 601 (1987)
  2. Bauer, Blood., 76, 731 (1990)
  3. Dunn J T, Kaplan A P, Formation and structure of human Hageman factor fragments., 10.1172/jci110656
  4. Dunn, J. Biol. Chem., 257, 1779 (1982)
  5. Francischetti I. M. B., Ixolaris, a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick, Ixodes scapularis: identification of factor X and factor Xa as scaffolds for the inhibition of factor VIIa/tissue factor complex, 10.1182/blood-2001-12-0237
  6. FUKUMURA DAI, JAIN RAKESH K., Imaging angiogenesis and the microenvironment , 10.1111/j.1600-0463.2008.01148.x
  7. Gailani D., Broze G., Factor XI activation in a revised model of blood coagulation, 10.1126/science.1652157
  8. GAILANI D., RENNÉ T., The intrinsic pathway of coagulation: a target for treating thromboembolic disease?, 10.1111/j.1538-7836.2007.02446.x
  9. Ghebrehiwet B, Randazzo B P, Dunn J T, Silverberg M, Kaplan A P, Mechanisms of activation of the classical pathway of complement by Hageman factor fragment., 10.1172/jci110898
  10. Hemker H. Coenraad, Giesen Peter, Al Dieri Raed, Regnault Véronique, de Smedt Eric, Wagenvoord Rob, Lecompte Thomas, Béguin Suzette, Calibrated Automated Thrombin Generation Measurement in Clotting Plasma, 10.1159/000071636
  11. Ingerman-Wojenski, Thromb. Haemost., 51, 154 (1984)
  12. Bonnefoy A., Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13, 10.1182/blood-2004-12-4856
  13. Josso, Thromb. Diath. Haemorrh. Suppl., 17, 35 (1965)
  14. Kaplan A. P., A PREALBUMIN ACTIVATOR OF PREKALLIKREIN: II. DERIVATION OF ACTIVATORS OF PREKALLIKREIN FROM ACTIVE HAGEMAN FACTOR BY DIGESTION WITH PLASMIN, 10.1084/jem.133.4.696
  15. Kaplan Allen P., Joseph Kusumam, Silverberg Michael, Pathways for bradykinin formation and inflammatory disease, 10.1067/mai.2002.121316
  16. Kettner Charles, Shaw Elliott, Synthesis of peptides of arginine chloromethyl ketone. Selective inactivation of human plasma kallikrein, 10.1021/bi00615a027
  17. Kisiel Walter, Fujikawa Kazuo, Davie Earl W., Activation of bovine factor VII (proconvertin) by factor XIIa (activated Hageman factor), 10.1021/bi00638a009
  18. Kleinschnitz Christoph, Stoll Guido, Bendszus Martin, Schuh Kai, Pauer Hans-Ulrich, Burfeind Peter, Renné Christoph, Gailani David, Nieswandt Bernhard, Renné Thomas, Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis, 10.1084/jem.20052458
  19. Kurachi Kotoku, Davie Earl W., Activation of human factor XI (plasma thromboplastin antecedent) by factor XIIa (activated Hageman factor), 10.1021/bi00645a030
  20. Laskowski M, Kato I, Protein Inhibitors of Proteinases, 10.1146/annurev.bi.49.070180.003113
  21. Leboulle, Am. J. Trop. Med. Hyg., 66, 225 (2002)
  22. MACFARLANE R. G., An Enzyme Cascade in the Blood Clotting Mechanism and its Function as a Biochemical Amplifier, 10.1038/202498a0
  23. Macfarlane R. G., Biggs R., A Thrombin Generation Test: The Application in Haemophilia and Thrombocytopenia, 10.1136/jcp.6.1.3
  24. Boudjeltia K Zouaoui, Cauchie Ph, Remacle Cl, Guillaume M, Brohée D, Hubert JL, Vanhaeverbeek M, 10.1186/1472-6750-2-8
  25. Makale Milan, Chapter 8 Noninvasive Imaging of Blood Vessels, Methods in Enzymology (2008) ISBN:9780123743138 p.175-199, 10.1016/s0076-6879(08)02808-5
  26. Mandle, Blood., 54, 850 (1979)
  27. Mann K. G., Brummel K., Butenas S., What is all that thrombin for?, 10.1046/j.1538-7836.2003.00298.x
  28. Mans, Mol. Biol. Evol., 19, 1695 (2002)
  29. Meijers Joost C.M., Tekelenburg Winnie L.H., Bouma Bonno N., Bertina Rogier M., Rosendaal Frits R., High Levels of Coagulation Factor XI as a Risk Factor for Venous Thrombosis, 10.1056/nejm200003093421004
  30. Moreau Marie Eve, Garbacki Nancy, Molinaro Giuseppe, Brown Nancy J., Marceau François, Adam Albert, The Kallikrein-Kinin System: Current and Future Pharmacological Targets, 10.1254/jphs.srj05001x
  31. Osterud B., Rapaport S. I., Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation., 10.1073/pnas.74.12.5260
  32. Pauer, Thromb. Haemost., 92, 503 (2004)
  33. Pedicord D. L., Seiffert D., Blat Y., Feedback activation of factor XI by thrombin does not occur in plasma, 10.1073/pnas.0705566104
  34. Bouma, J. Biol. Chem., 252, 6432 (1977)
  35. Peternel Luka, Drevenšek Gorazd, Černe Manica, Štalc Anton, Stegnar Mojca, Budihna Metka V., Evaluation of two experimental venous thrombosis models in the rat, 10.1016/j.thromres.2004.10.007
  36. Pitney W. R., Dacie J. V., A Simple Method of Studying the Generation of Thrombin in Recalcified Plasma: Application in the Investigation of Haemophilia, 10.1136/jcp.6.1.9
  37. Prasa, Thromb. Haemost., 77, 498 (1997)
  38. Prasa, Thromb. Haemost., 78, 1215 (1997)
  39. Radcliffe, Blood., 50, 611 (1977)
  40. Renné Thomas, Gailani David, Role of Factor XII in hemostasis and thrombosis: clinical implications, 10.1586/14779072.5.4.733
  41. Renné Thomas, Pozgajová Miroslava, Grüner Sabine, Schuh Kai, Pauer Hans-Ulrich, Burfeind Peter, Gailani David, Nieswandt Bernhard, Defective thrombus formation in mice lacking coagulation factor XII, 10.1084/jem.20050664
  42. Renné Thomas, Nieswandt Bernhard, Gailani David, The intrinsic pathway of coagulation is essential for thrombus stability in mice, 10.1016/j.bcmd.2005.12.014
  43. Revak Susan D., Cochrane Charles G., Griffin John H., The Binding and Cleavage Characteristics of Human Hageman Factor during Contact Activation, 10.1172/jci108741
  44. Ribeiro José M. C., Francischetti Ivo M. B., ROLE OFARTHROPODSALIVA INBLOODFEEDING: Sialome and Post-Sialome Perspectives, 10.1146/annurev.ento.48.060402.102812
  45. Robert Séverine, Bertolla Carine, Masereel Bernard, Dogné Jean-Michel, Pochet Lionel, Novel 3-Carboxamide-coumarins as Potent and Selective FXIIa Inhibitors, 10.1021/jm8002697
  46. BROSSARD M., WIKEL S. K., Tick immunobiology, 10.1017/s0031182004004834
  47. Robert Séverine, Ghiotto Jérémie, Pirotte Bernard, David Jean-Louis, Masereel Bernard, Pochet Lionel, Dogné Jean-Michel, Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs?, 10.1016/j.phrs.2008.12.003
  48. Silverberg, Blood., 60, 64 (1982)
  49. Silverberg, J. Biol. Chem., 255, 7281 (1980)
  50. Steen, Toxicon., 47, 1 (2006)
  51. Tankersley Donald L., Finlayson J. S., Kinetics of activation and autoactivation of human factor XII, 10.1021/bi00297a016
  52. von dem Borne, Blood., 86, 3035 (1995)
  53. Westrick R. J., Winn M. E., Eitzman D. T., Murine Models of Vascular Thrombosis, 10.1161/atvbaha.107.142810
  54. Yarovaya G. A., Blokhina T. B., Neshkova E. A., 10.1023/a:1013991828598
  55. Zingali Russolina B., Jandrot-Perrus Martine, Guillin Marie Claude, Bon Cassian, Bothrojaracin, a new thrombin inhibitor isolated from Bothrops jararaca venom: Characterization and mechanism of thrombin inhibition, 10.1021/bi00091a034
  56. Cochrane C. G., ACTIVATION OF HAGEMAN FACTOR IN SOLID AND FLUID PHASES: A CRITICAL ROLE OF KALLIKREIN, 10.1084/jem.138.6.1564
  57. Colman R W, Surface-mediated defense reactions. The plasma contact activation system., 10.1172/jci111326
  58. Colman Robert W., Are hemostasis and thrombosis two sides of the same coin?, 10.1084/jem.20060217
  59. Davie E. W., Ratnoff O. D., Waterfall Sequence for Intrinsic Blood Clotting, 10.1126/science.145.3638.1310
Bibliographic reference Decrem, Yves ; Rath, Géraldine ; Blasioli, Virginie ; Cauchie, Philippe ; Robert, Severine ; et. al. Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis. In: The Journal of Experimental Medicine, Vol. 206, no. 11, p. 2381-95 (2009)
Permanent URL http://hdl.handle.net/2078.1/36134