Abstract
The coagulation cascade involves the regulated sequence of proteolytic activation of a series of zymogens culminating in conversion of fibrinogen to fibrin and clot formation. These reactions are mainly performed by enzymatic complexes comprised of a serine protease, a protein cofactor and membranes containing anionic phospholipids. A number of specific coagulation inhibitors from exogenous sources have been identified from salivary glands of blood-sucking arthropods and herein named sialogenins (from the Greek sialo, saliva; gen, origin, source; and ins for proteins) with anticlotting activity.
Anti-clotting sialogenins target components of the extrinsic (e.g. ixolaris, penthalaris, NAPc2) or intrinsic Xase (e.g. nitrophorin 2, nitrophorin 7) complexes resulting in inhibition of the initiation, propagation or consolidation steps of blood coagulation cascade. In addition, these molecules act in a redundant and synergistic manner in order to keep hemostatic tonus as low as possible so as to facilitate blood-feeding. These molecules may also attenuate inflammatory events associated with vascular injury. Finally, anti-clotting sialogenins have potential therapeutic applications and are valuable tools in pharmacology and cell biology.
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References
Andersen, J.F., Gudderra, N.P., Francischetti, I.M., Valenzuela, J.G., Ribeiro, J.M., 2004. Recognition of anionic phospholipid membranes by an antihemostatic protein from a blood-feeding insect. Biochemistry 43, 6987–6994.
Andersen, J.F., Montfort, W.R., 2000. The crystal structure of nitrophorin 2. A trifunctional antihemostatic protein from the saliva of Rhodnius prolixus. J. Biol. Chem. 275, 30496–30503.
Bauer, K.A., Kass, B.L., ten Cate, H., Hawiger, J.J., Rosenberg, R.D., 1990. Factor IX is activated in vivo by the tissue factor mechanism. Blood 76, 731–736.
Baugh, R.J., Broze, G.J., Jr., Krishnaswamy, S., 1998. Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J. Biol. Chem. 273, 4378–4386.
Belting, M., Ahamed, J., Ruf, W., 2005. Signaling of the tissue factor coagulation pathway in angiogenesis cancer. Arterioscler. Thromb. Vasc. Biol. 25, 1545–1550.
Bergum, P.W., Cruikshank, A., Maki, S.L., Kelly, C.R., Ruf, W., Vlasuk, G.P., 2001. Role of zymogen and activated factor X as scaffolds for the inhibition of the blood coagulation factor VIIa-tissue factor complex by recombinant nematode anticoagulant protein c2. J. Biol. Chem. 276, 10063–10071.
Broze, G.J., Jr., 1995. Tissue factor pathway inhibitor and the revised theory of coagulation. Annu. Rev. Med. 46, 103–112.
Buddai, S.K., Toulokhonova, L., Bergum, P.W., Vlasuk, G.P., Krishnaswamy, S., 2002. Nematode anticoagulant protein c2 reveals a site on factor Xa that is important for macromolecular substrate binding to human prothrombinase. J. Biol. Chem. 277, 26689–26698.
Bunnett, N.W., 2006. Protease-activated receptors: how proteases signal to cells to cause inflammation and pain. Semin. Thromb. Hemost. 32(Suppl 1), 39–48.
Camerer, E., Huang, W., Coughlin, S.R., 2000. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc. Natl. Acad. Sci. U.S.A. 97, 5255–5260.
Carneiro-Lobo, T.C., Konig, S., Machado, D.E., Nasciutti, L.E., Forni, M.F., Francischetti, I.M., Sogayar, M.C., Monteiro, R.Q., 2009. Ixolaris, a tissue factor inhibitor, blocks primary tumor growth and angiogenesis in a glioblastoma model. J. Thromb. Haemost. 7, 1855–1864.
Champagne, D.E., Nussenzveig, R.H., Ribeiro, J.M., 1995. Purification, partial characterization, and cloning of nitric oxide-carrying heme proteins (nitrophorins) from salivary glands of the blood-sucking insect Rhodnius prolixus. J. Biol. Chem. 270, 8691–8695.
Coughlin, S.R., 2005. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800–1814.
Davie, E.W., Fujikawa, K., Kisiel, W., 1991. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30, 10363–10370.
Duggan, B.M., Dyson, H.J., Wright, P.E., 1999. Inherent flexibility in a potent inhibitor of blood coagulation, recombinant nematode anticoagulant protein c2. Eur. J. Biochem. 265, 539–548.
Esmon, C.T., 2003. The protein C pathway. Chest 124, 26S–32S.
Fluture, A., Giugliano, G.R., Giugliano, R.P., 2007. Recombinant nematode anticoagulant protein c2 in non-ST segment elevation acute coronary syndrome and beyond. Future Cardiol. 3, 365–375.
Francischetti, I.M., 2008. Does activation of the blood coagulation cascade have a role in malaria pathogenesis? Trends Parasitol. 24, 258–263.
Francischetti, I.M., Mather, T.N., Ribeiro, J.M., 2004. Penthalaris, a novel recombinant five-Kunitz tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick vector of Lyme disease, Ixodes scapularis. Thromb. Haemost. 91, 886–898.
Francischetti, I.M., Sa-Nunes, A., Mans, B.J., Santos, I.M., Ribeiro, J.M., 2009. The role of saliva in tick feeding. Front. Biosci. 14, 2051–2088.
Francischetti, I.M., Seydel, K.B., Monteiro, R.Q., 2008. Blood coagulation, inflammation, and malaria. Microcirculation 15, 81–107.
Francischetti, I.M., Valenzuela, J.G., Andersen, J.F., Mather, T.N., Ribeiro, J.M., 2002. 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. Blood 99, 3602–3612.
Furie, B., Furie, B.C., 2003. Real time in vivo imaging of tissue factor-induced thrombus formation. Pathophysiol. Haemost. Thromb. 33(Suppl 1), 26–27.
Gailani, D., Broze, G.J., Jr., 1991. Factor XI activation in a revised model of blood coagulation. Science 253, 909–912.
Geisbert, T.W., Hensley, L.E., Jahrling, P.B., Larsen, T., Geisbert, J.B., Paragas, J., Young, H.A., Fredeking, T.M., Rote, W.E., Vlasuk, G.P., 2003. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 362, 1953–1958.
Giesen, P.L., Rauch, U., Bohrmann, B., Kling, D., Roque, M., Fallon, J.T., Badimon, J.J., Himber, J., Riederer, M.A., Nemerson, Y., 1999. Blood-borne tissue factor: another view of thrombosis. Proc. Natl. Acad. Sci. U.S.A. 96, 2311–2315.
Gudderra, N.P., Ribeiro, J.M., Andersen, J.F., 2005. Structural determinants of factor IX(a) binding in nitrophorin 2, a lipocalin inhibitor of the intrinsic coagulation pathway. J. Biol. Chem. 280, 25022–25028.
Hembrough, T.A., Swartz, G.M., Papathanassiu, A., Vlasuk, G.P., Rote, W.E., Green, S.J., Pribluda, V.S., 2003. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Res. 63, 2997–3000.
Isawa, H., Yuda, M., Yoneda, K., Chinzei, Y., 2000. The insect salivary protein, prolixin-S, inhibits factor IXa generation and Xase complex formation in the blood coagulation pathway. J. Biol. Chem. 275, 6636–6641.
Kalafatis, M., Swords, N.A., Rand, M.D., Mann, K.G., 1994. Membrane-dependent reactions in blood coagulation: role of the vitamin K-dependent enzyme complexes. Biochim. Biophys. Acta 1227, 113–129.
Knipp, M., Yang, F., Berry, R.E., Zhang, H., Shokhirev, M.N., Walker, F.A., 2007a. Spectroscopic and functional characterization of nitrophorin 7 from the blood-feeding insect Rhodnius prolixus reveals an important role of its isoform-specific N-terminus for proper protein function. Biochemistry 46, 13254–13268.
Knipp, M., Zhang, H., Berry, R.E., Walker, F.A., 2007b. Overexpression in Escherichia coli and functional reconstitution of the liposome binding ferriheme protein nitrophorin 7 from the bloodsucking bug Rhodnius prolixus. Protein Expr. Purif. 54, 183–191.
Koh, C.Y., Kini, R.M., 2009. Molecular diversity of anticoagulants from haematophagous animals. Thromb. Haemost. 102, 437–453.
Krishnaswamy, S., 2005. Exosite-driven substrate specificity and function in coagulation. J. Thromb. Haemost. 3, 54–67.
Lee, A., Agnelli, G., Buller, H., Ginsberg, J., Heit, J., Rote, W., Vlasuk, G., Costantini, L., Julian, J., Comp, P., van Der Meer, J., Piovella, F., Raskob, G., Gent, M., 2001. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 104, 74–78.
Levi, M., van der Poll, T., Buller, H.R., 2004. Bidirectional relation between inflammation and coagulation. Circulation 109, 2698–2704.
Lorand, L., 2005. Factor XIII and the clotting of fibrinogen: from basic research to medicine. J. Thromb. Haemost. 3, 1337–1348.
Mahajan, A.L., Tenorio, X., Pepper, M.S., Baetens, D., Montandon, D., Schlaudraff, K.U., Pittet, B., 2006. Progressive tissue injury in burns is reduced by rNAPc2. Burns 32, 957–963.
Mann, K.G., Butenas, S., Brummel, K., 2003. The dynamics of thrombin formation. Arterioscler. Thromb. Vasc. Biol. 23, 17–25.
Marshall, J.C., 2001. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit. Care Med. 29, S99–S106.
Monroe, D.M., Hoffman, M., Roberts, H.R., 2002. Platelets and thrombin generation. Arterioscler. Thromb. Vasc. Biol. 22, 1381–1389.
Monteiro, R.Q., Rezaie, A.R., Bae, J.S., Calvo, E., Andersen, J.F., Francischetti, I.M., 2008. Ixolaris binding to factor X reveals a precursor state of factor Xa heparin-binding exosite. Protein Sci. 17, 146–153.
Monteiro, R.Q., Rezaie, A.R., Ribeiro, J.M., Francischetti, I.M., 2005. Ixolaris: a factor Xa heparin-binding exosite inhibitor. Biochem. J. 387, 871–877.
Moons, A.H., Peters, R.J., Bijsterveld, N.R., Piek, J.J., Prins, M.H., Vlasuk, G.P., Rote, W.E., Buller, H.R., 2003. Recombinant nematode anticoagulant protein c2, an inhibitor of the tissue factor/factor VIIa complex, in patients undergoing elective coronary angioplasty. J. Am. Coll. Cardiol. 41, 2147–2153.
Moons, A.H., Peters, R.J., Cate, H., Bauer, K.A., Vlasuk, G.P., Buller, H.R., Levi, M., 2002. Recombinant nematode anticoagulant protein c2, a novel inhibitor of tissue factor-factor VIIa activity, abrogates endotoxin-induced coagulation in chimpanzees. Thromb. Haemost. 88, 627–631.
Murakami, M.T., Rios-Steiner, J., Weaver, S.E., Tulinsky, A., Geiger, J.H., Arni, R.K., 2007. Intermolecular interactions and characterization of the novel factor Xa exosite involved in macromolecular recognition and inhibition: crystal structure of human Gla-domainless factor Xa complexed with the anticoagulant protein NAPc2 from the hematophagous nematode Ancylostoma caninum. J. Mol. Biol. 366, 602–610.
Naito, K., Fujikawa, K., 1991. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J. Biol. Chem. 266, 7353–7358.
Nazareth, R.A., Tomaz, L.S., Ortiz-Costa, S., Atella, G.C., Ribeiro, J.M., Francischetti, I.M., Monteiro, R.Q., 2006. Antithrombotic properties of Ixolaris, a potent inhibitor of the extrinsic pathway of the coagulation cascade. Thromb. Haemost. 96, 7–13.
Opal, S.M., Esmon, C.T., 2003. Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Crit. Care 7, 23–38.
Osterud, B., Rapaport, S.I., 1977. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc. Natl. Acad. Sci. U.S.A. 74, 5260–5264.
Rak, J., Milsom, C., May, L., Klement, P., Yu, J., 2006. Tissue factor in cancer and angiogenesis: the molecular link between genetic tumor progression, tumor neovascularization, and cancer coagulopathy. Semin. Thromb. Hemost. 32, 54–70.
Rao, L.V., Pendurthi, U.R., 2005. Tissue factor-factor VIIa signaling. Arterioscler. Thromb. Vasc. Biol. 25, 47–56.
Rezaie, A.R., 2000. Heparin-binding exosite of factor Xa. Trends Cardiovasc. Med. 10, 333–338.
Rezaie, A.R., 2002. Insight into the molecular basis of coagulation proteinase specificity by mutagenesis of the serpin antithrombin. Biochemistry 41, 12179–12185.
Rezaie, A.R., Yang, L., 2003. Thrombomodulin allosterically modulates the activity of the anticoagulant thrombin. Proc. Natl. Acad. Sci. U.S.A. 100, 12051–12056.
Ribeiro, J.M., Francischetti, I.M., 2003. Role of arthropod saliva in blood feeding: sialome and post-sialome perspectives. Annu. Rev. Entomol. 48, 73–88.
Ribeiro, J.M., Hazzard, J.M., Nussenzveig, R.H., Champagne, D.E., Walker, F.A., 1993. Reversible binding of nitric oxide by a salivary heme protein from a bloodsucking insect. Science 260, 539–541.
Ribeiro, J.M., Schneider, M., Guimaraes, J.A., 1995. Purification and characterization of prolixin S (nitrophorin 2), the salivary anticoagulant of the blood-sucking bug Rhodnius prolixus. Biochem. J. 308(Pt 1), 243–249.
Rickles, F.R., Edwards, R.L., 1983. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 62, 14–31.
Riewald, M., Kravchenko, V.V., Petrovan, R.J., O’Brien, P.J., Brass, L.F., Ulevitch, R.J., Ruf, W., 2001. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1. Blood 97, 3109–3116.
Riewald, M., Ruf, W., 2003. Science review: role of coagulation protease cascades in sepsis. Crit. Care 7, 123–129.
Rios-Steiner, J.L., Murakami, M.T., Tulinsky, A., Arni, R.K., 2007. Active and exo-site inhibition of human factor Xa: structure of des-Gla factor Xa inhibited by NAP5, a potent nematode anticoagulant protein from Ancylostoma caninum. J. Mol. Biol. 371, 774–786.
Roberts, H.R., Hoffman, M., Monroe, D.M., 2006. A cell-based model of thrombin generation. Semin. Thromb. Hemost. 32 Suppl 1, 32–38.
Ruf, W., 2004. Protease-activated receptor signaling in the regulation of inflammation. Crit. Care Med. 32, S287–292.
Sanders, N.L., Bajaj, S.P., Zivelin, A., Rapaport, S.I., 1985. Inhibition of tissue factor/factor VIIa activity in plasma requires factor X an additional plasma component. Blood 66, 204–212.
Slofstra, S.H., Spek, C.A., ten Cate, H., 2003. Disseminated intravascular coagulation. Hematol. J. 4, 295–302.
Stassens, P., Bergum, P.W., Gansemans, Y., Jespers, L., Laroche, Y., Huang, S., Maki, S., Messens, J., Lauwereys, M., Cappello, M., Hotez, P.J., Lasters, I., Vlasuk, G.P., 1996. Anticoagulant repertoire of the hookworm Ancylostoma caninum. Proc. Natl. Acad. Sci. U.S.A. 93, 2149–2154.
Steinhoff, M., Buddenkotte, J., Shpacovitch, V., Rattenholl, A., Moormann, C., Vergnolle, N., Luger, T.A., Hollenberg, M.D., 2005. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr. Rev. 26, 1–43.
Sun, J., Yamaguchi, M., Yuda, M., Miura, K., Takeya, H., Hirai, M., Matsuoka, H., Ando, K., Watanabe, T., Suzuki, K., Chinzei, Y., 1996. Purification, characterization and cDNA cloning of a novel anticoagulant of the intrinsic pathway, (prolixin-S) from salivary glands of the blood sucking bug, Rhodnius prolixus. Thromb. Haemost. 75, 573–577.
Taylor, F.B., Jr., Wada, H., Kinasewitz, G., 2000. Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIC) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human model of endotoxemia: toward a better definition of DIC. Crit. Care Med. 28, S12–19.
ten Cate, H., Bauer, K.A., Levi, M., Edgington, T.S., Sublett, R.D., Barzegar, S., Kass, B.L., Rosenberg, R.D., 1993. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J. Clin. Invest. 92, 1207–1212.
ten Cate, H., Biemond, B.J., Levi, M., Wuillemin, W.A., Bauer, K.A., Barzegar, S., Buller, H.R., Hack, C.E., ten Cate, J.W., Rosenberg, R.D., 1996. Factor XIa induced activation of the intrinsic cascade in vivo. Thromb. Haemost. 75, 445–449.
Vlasuk, G.P., Bradbury, A., Lopez-Kinninger, L., Colon, S., Bergum, P.W., Maki, S., Rote, W.E., 2003. Pharmacokinetics and anticoagulant properties of the factor VIIa-tissue factor inhibitor recombinant nematode anticoagulant protein c2 following subcutaneous administration in man. Dependence on the stoichiometric binding to circulating factor X. Thromb. Haemost. 90, 803–812.
Vlasuk, G.P., Rote, W.E., 2002. Inhibition of factor VIIa/tissue factor with nematode anticoagulant protein c2: from unique mechanism to a promising new clinical anticoagulant. Trends Cardiovasc. Med. 12, 325–331.
Vu, T.K., Hung, D.T., Wheaton, V.I., Coughlin, S.R., 1991. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64, 1057–1068.
Weichsel, A., Andersen, J.F., Champagne, D.E., Walker, F.A., Montfort, W.R., 1998. Crystal structures of a nitric oxide transport protein from a blood-sucking insect. Nat. Struct. Biol. 5, 304–309.
Yuda, M., Higuchi, K., Sun, J., Kureishi, Y., Ito, M., Chinzei, Y., 1997. Expression, reconstitution and characterization of prolixin-S as a vasodilator – a salivary gland nitric-oxide-binding hemoprotein of Rhodnius prolixus. Eur. J. Biochem. 249, 337–342.
Zacharski, L.R., 2002. Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy. Cancer Lett. 186, 1–9.
Zhang, Y., Ribeiro, J.M., Guimaraes, J.A., Walsh, P.N., 1998. Nitrophorin-2: a novel mixed-type reversible specific inhibitor of the intrinsic factor-X activating complex. Biochemistry 37, 10681–10690.
Zhao, J., Aguilar, G., Palencia, S., Newton, E., Abo, A., 2009. rNAPc2 inhibits colorectal cancer in mice through tissue factor. Clin. Cancer Res. 15, 208–216.
Acknowledgements
This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank NIAID intramural editor Brenda Rae Marshall for assistance.
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Monteiro, R.Q., Andersen, J.F., Francischetti, I.M. (2010). Hematophagy and Inhibition of the Extrinsic and Intrinsic Tenase Complexes. In: Kini, R., Clemetson, K., Markland, F., McLane, M., Morita, T. (eds) Toxins and Hemostasis. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9295-3_14
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