Hematophagy and Inhibition of the Extrinsic and Intrinsic Tenase Complexes
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.
KeywordsTissue Factor Coagulation Cascade Tissue Factor Expression Primary Tumor Growth Coagulation Inhibitor
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.
Because J.F.A. and I.M.B.F. are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license.
- 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.PubMedCrossRefGoogle Scholar
- 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.Google Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedGoogle Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.PubMedGoogle Scholar