Skip to main content
SpringerLink
Log in
Book cover

Toxins and Hemostasis pp 485–499Cite as

Snake Venom Prothrombin Activators – The History

  • Chapter
  • First Online:

Abstract

Snake venom prothrombin activators have been shown to be excellent tools in diagnostic coagulation assays and in studying the mechanism of prothrombin activation. In this review we give an historical overview of the discovery of snake venom prothrombin activators and of their mechanisms of action on prothrombin. Based on the effects of the accessory components of the human prothrombin-activating complex (calcium ions, phospholipids and factor Va), venom prothrombin activators can be divided into four groups comprising activators that are metalloproteinases which either do not require accessory components (group A) or which require calcium ions for expressing activity (group B). The other activators are serine proteases that share homology with blood coagulation factor Xa and which require phospholipids plus calcium ions for optimal activity (Group C) or the activity of which is greatly enhanced by calcium ions, phospholipids and factor Va (group D).

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Bergstrom, K., Egberg, N., 1978. Determination of vitamin K sensitive coagulation factors in plasma: studies on three methods using synthetic chromogenic substrates. Thromb. Res. 12, 531–547.

    Article  CAS  PubMed  Google Scholar 

  • Bos, M.H., Boltz, M., St. Pierre, L., Masci, P.P., de Jersey, J., Lavin, M.F., Camire, R.M., 2009. Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations. Blood 114, 686–692.

    Article  CAS  PubMed  Google Scholar 

  • Bradlow, B.A., Atkinson, P.M., Gomperts, E.D., Gaillard, M.C., 1980. Studies on the coagulant effects of boomslang (Dispholidus typus) venom. Clin. Lab. Haemat. 2, 317–331.

    CAS  Google Scholar 

  • Briet, E., Noyens, C.M., Roberts, H.R., Griffith, M.J., 1982. Cleavage and activation of human prothrombin by Echis carinatus venom. Thromb. Res. 27, 591–600.

    Article  CAS  PubMed  Google Scholar 

  • Davie, E.W., Fujikawa, K., Kisiel, W., 1991. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 30, 10363–10370.

    Article  CAS  PubMed  Google Scholar 

  • Denson, K.W., 1969. Coagulant and anticoagulant action of snake venoms. Toxicon 7, 5–11.

    Article  CAS  PubMed  Google Scholar 

  • Denson, K.W., 1976. Clot-inducing substances present in snake venoms with particular reference to Echis carinatus. Thromb. Res. 8, 351–360.

    Article  CAS  PubMed  Google Scholar 

  • Denson, K.W., Borrett, R., Biggs, R., 1971. The specific Assay of prothrombin using the Taipan snake venom. Br. J. Haematol. 21, 219–226.

    Article  CAS  PubMed  Google Scholar 

  • Doyle, M.F., Mann, K.G., 1990. Multiple active forms of thrombin. IV. Relative activities of meizothrombins. J. Biol. Chem. 265, 10693–10701.

    CAS  PubMed  Google Scholar 

  • Eagle, H., 1937. The coagulation of blood by snake venoms and its physiologic significance. J. Exp. Med. 65, 613–639.

    Article  CAS  PubMed  Google Scholar 

  • Esmon, C.T., Jackson, C.M., 1974a. The conversion of prothrombin to thrombin III The factor Xa catalyzed activation of prothrombin. J. Biol. Chem. 249, 7782–7790.

    CAS  PubMed  Google Scholar 

  • Esmon, C.T., Jackson, C.M. 1974b. Conversion of prothrombin to thrombin. IV. The function of the fragment 2 region during activation in the presence of factor V. J. Biol. Chem. 249, 7791–7797.

    CAS  PubMed  Google Scholar 

  • Esmon, C.T., Owen, W.G., Jackson, C.M. 1974a. The conversion of prothrombin to thrombin II differentiation between thrombin- and factor Xa-catalyzed proteolysis. J. Biol. Chem. 249, 606–611.

    CAS  PubMed  Google Scholar 

  • Esmon, C.T., Owen, W.G., Jackson, C.M., 1974b. The conversion of prothrombin to thrombin V The activation of prothrombin by factor Xa in the presence of phospholipid. J. Biol. Chem. 249, 7798–7807.

    CAS  PubMed  Google Scholar 

  • Esmon, C.T., Owen, W.G., Jackson, C.M., 1974c. A plausible mechanism for prothrombin activation by factor Xa, factor Va, phospholipid and calcium ions. J. Biol. Chem. 249, 8045–8047.

    CAS  PubMed  Google Scholar 

  • Filippovich, I., Sorokina, N., St. Pierre, L., Flight, S., de Jersey, J., Perry, N., Masci, P.P., Lavin, M.F., 2005. Cloning and functional expression of venom prothrombin activator protease from Pseudonaja textilis with whole blood procoagulant activity. Br. J. Haematol. 131, 237–246.

    Article  CAS  PubMed  Google Scholar 

  • Franza, B.R., Jr., Aronson, D.L., Finlayson, J.S., 1975. Activation of human prothrombin by a procoagulant fraction from the venom of Echis carinatus. Identification of a high molecular weight intermediate with thrombin activity. J. Biol. Chem. 250, 7057–7068.

    CAS  PubMed  Google Scholar 

  • Govers-Riemslag, J.W., Johnsen, L., Petrovan, R.J., Rosing, J., Tans, G., 1998. A kinetic assay to determine prothrombin binding to membranes. Thromb. Res. 92, 239–247.

    Article  CAS  PubMed  Google Scholar 

  • Govers-Riemslag, J.W., Knapen, M.J., Tans, G., Zwaal, R.F., Rosing, J., 1987. Structural and functional characterization of a prothrombin activator from the venom of Bothrops neuwiedi. Biochim. Biophys. Acta 916, 388–401.

    Article  CAS  PubMed  Google Scholar 

  • Gowda, D.C., Jackson, C.M., Hensley, P., Davidson, E.A., 1994. Factor X-activating glycoprotein of Russell’s viper venom. J. Biol. Chem. 269, 10644–10650.

    CAS  PubMed  Google Scholar 

  • Guillin, M.C., Bezeaud, A., Menache, D., 1978. The mechanism of activation of human prothrombin by an activator isolated from dispholidus types venom. Biochim. Biophys. Acta 537, 160–168.

    Article  CAS  PubMed  Google Scholar 

  • Hackeng, T.M., Tans, G., Koppelman, S.J., de Groot, P.G., Rosing, J., Bouma, B.N., 1996. Protein C activation on endothelial cells by prothrombin activation products generated in situ: meizothrombin is a better protein C activator than α-thrombin. Biochem. J. 319, 399–405.

    CAS  PubMed  Google Scholar 

  • Hjort, P., Rapaport, S.I., Owren, P.A., 1955. A simple, specific one-stage prothrombin assay using Russell’s viper venom in cephalin suspension. J. Lab. Clin. Med. 46, 89–97.

    CAS  PubMed  Google Scholar 

  • Hofmann, H., Bon, C., 1987a. Blood coagulation induced by the venom of Bothrops atrox. 1. Identification, purification, and properties of a prothrombin activator. Biochemistry 26, 772–780.

    Article  CAS  PubMed  Google Scholar 

  • Hofmann, H., Bon, C., 1987b. Blood coagulation induced by the venom of Bothrops atrox. 2. Identification, purification, and properties of two factor X activators. Biochemistry 26, 780–787.

    Article  CAS  PubMed  Google Scholar 

  • Jobin, F., Esnouf, M.P., 1966. Coagulant activity of tiger snake (Notechis scutatus scutatus) venom. Nature 211, 873–875.

    Article  CAS  PubMed  Google Scholar 

  • Joseph, J.S., Chung, M.C., Jeyaseelan, K., Kini, R.M., 1999. Amino acid sequence of trocarin, a prothrombin activator from Tropidechis carinatus venom: its structural similarity to coagulation factor Xa. Blood 94, 621–631.

    CAS  PubMed  Google Scholar 

  • Kini, R.M., 2005. The intriguing world of prothrombin activators from snake venom. Toxicon 45, 1133–1145.

    Article  CAS  PubMed  Google Scholar 

  • Kini, R.M., Rao, V.S., Joseph, J.S., 2001. Procoagulant proteins from snake venoms. Haemostasis 31, 218–224.

    CAS  PubMed  Google Scholar 

  • Kirchhof, B.R., Vermeer, C., Hemker, H.C., 1978. The determination of prothrombin using synthetic chromogenic substrates; choice of a suitable activator. Thromb. Res. 13, 219–232.

    Article  CAS  PubMed  Google Scholar 

  • Kornalik, F., Blomback, B., 1975. Prothrombin activation induced by Ecarin – a prothrombin converting enzyme from Echis carinatus venom. Thromb. Res. 6, 57–63.

    Article  CAS  PubMed  Google Scholar 

  • Kornalik, F., Schieck, A., Habermann, E., 1969. Isolation, biochemical and pharmacologic characterization of a prothrombin-activating principle from Echis carinatus venom. Naunyn Schmiedebergs Arch. Pharmakol. 264, 259–260.

    Article  CAS  PubMed  Google Scholar 

  • Krishnaswamy, S., Church, W.R., Nesheim, M.E., Mann, K.G., 1987. Activation of human prothrombin by human prothrombinase. Influence of factor Va on the reaction mechanism. J. Biol. Chem. 262, 3291–3299.

    CAS  PubMed  Google Scholar 

  • Krishnaswamy, S., Mann, K.G., Nesheim, M.E., 1986. The prothrombinase-catalyzed activation of prothrombin proceeds through the intermediate meizothrombin in an ordered, sequential reaction. J. Biol. Chem. 261, 8977–8984.

    CAS  PubMed  Google Scholar 

  • Lanchantin, G.F., Friedmann, J.A., Hart, D.W., 1973. Two forms of human thrombin. Isolation and characterization. J. Biol. Chem. 248, 5956–5966.

    CAS  PubMed  Google Scholar 

  • Lavin, M.F., Masci, P.P., 2009. Prothrombinase complexes with different physiological roles. Thromb. Haemost. 102, 421–423.

    CAS  PubMed  Google Scholar 

  • Macfarlane, R.G., 1948. Normal and abnormal blood coagulation: a review. J. Clin. Pathol. 1, 113–143.

    Article  CAS  PubMed  Google Scholar 

  • Marsh, N., Williams, V., 2005. Practical applications of snake venom toxins in haemostasis. Toxicon 45, 1171–1181.

    Article  CAS  PubMed  Google Scholar 

  • Martin, C.J., 1893. On some effects upon the blood produced by the injection of the venom of the Australian black snake (Pseudechis porphyriacus). J. Physiol. 15, 380–400.

    CAS  PubMed  Google Scholar 

  • Masci, P.P., Whitaker, A.N., de Jersey, J., 1988. Purification and characterization of a prothrombin activator from the venom of the Australian brown snake, Pseudonaja textilis textilis. Biochem. Int. 17, 825–835.

    CAS  PubMed  Google Scholar 

  • Mellanby, J., 1909. The coagulation of blood: Part II. The actions of snake venoms, peptone and leech extract. J. Physiol. 38, 441–503.

    CAS  PubMed  Google Scholar 

  • Minh Le, T.N., Reza, M.A., Swarup, S., Kini, R.M., 2005. Gene duplication of coagulation factor V and origin of venom prothrombin activator in Pseudonaja textilis snake. Thromb. Haemost. 93, 420–429.

    Google Scholar 

  • Morita, T., 1998. Proteases which activate factor X. in: Bailey, G. (Ed.), Enzymes from Snake Venoms. Alaken Inc., Fort Collins, CO, pp. 179–209.

    Google Scholar 

  • Morita, T., Iwanaga, S., 1978. Purification and properties of prothrombin activator from the venom of echis carinatus. J. Biochem. 83, 559–570.

    CAS  PubMed  Google Scholar 

  • Morita, T., Iwanaga, S., Suzuki, T., 1976. The mechanism of activation of bovine prothrombin by an activator isolated from Echis carinatus venon and characterization of the new active intermediates. J. Biochem. 79, 1089–1108.

    CAS  PubMed  Google Scholar 

  • Nishida, S., Fujita, T., Kohno, N., Atoda, H., Morita, T., Takeya, H., Kido, I., Paine, M.J., Kawabata, S., Iwanaga, S., 1995. cDNA cloning and deduced amino acid sequence of prothrombin activator (ecarin) from Kenyan Echis carinatus venom. Biochemistry 34, 1771–1778.

    Article  CAS  PubMed  Google Scholar 

  • Novoa, E., Seegers, W.H., 1980. Mechanisms of α-thrombin and β-thrombin-E formation: use of ecarin for isolation of meizothrombin 1. Thromb. Res. 18, 657–668.

    Article  CAS  PubMed  Google Scholar 

  • Owen, W.G., Jackson, C.M., 1973. Activation of prothrombin with Oxyuranus scutellatus scutellatus (Taipan snake) venom. Thromb. Res. 3, 705–714.

    Article  CAS  Google Scholar 

  • Petrovan, R.J., Govers-Riemslag, J.W., Nowak, G., Hemker, H.C., Rosing, J., Tans, G., 1997. Purification and characterization of multisquamase, the prothrombin activator present in Echis multisquamatus venom. Thromb. Res. 88, 309–316.

    Article  CAS  PubMed  Google Scholar 

  • Petrovan, R.J., Govers-Riemslag, J.W., Nowak, G., Hemker, H.C., Tans, G., Rosing, J., 1998. Autocatalytic peptide bond cleavages in prothrombin and meizothrombin. Biochemistry 37, 1185–1191.

    Article  CAS  PubMed  Google Scholar 

  • Petrovan, R.J., Rapaport, S.I., Le, D.T., 1999. A novel clotting assay for quantitation of plasma prothrombin (factor II) using Echis multisquamatus venom. Am. J. Clin. Pathol. 112, 705–711.

    CAS  PubMed  Google Scholar 

  • St. Pierre, L., Masci, P.P., Filippovich, I., Sorokina, N., Marsh, N., Miller, D.J., Lavin, M.F., 2005. Comparative analysis of prothrombin activators from the venom of Australian elapids. Mol. Biol. Evol. 22, 1853–1864.

    Article  Google Scholar 

  • Pirkle, H., McIntosh, M., Theodor, I., Vernon, S., 1972. Activation of prothrombin with taipan snake venom. Thromb. Res. 1, 559–568.

    Article  CAS  Google Scholar 

  • Platonova, T.N., Sushko, E.A., Petrov, A.V., Solov’ev, D.A., 1995. Determination of the general prothrombin level and detection of its functionally inactive forms using the enzyme ecamulin purified from Echis multisquamatus venom. Ukr. Biokhim. Zh. 67, 75–80.

    CAS  PubMed  Google Scholar 

  • Rabiet, M.J., Blashill, A., Furie, B., Furie, B.C., 1986. Prothrombin fragment 1 X 2 X 3, a major product of prothrombin activation in human plasma. J. Biol. Chem. 261, 13210–13215.

    CAS  PubMed  Google Scholar 

  • Rao, V.S., Joseph, J.S., Kini, R.M., 2003a. Group D prothrombin activators from snake venom are structural homologues of mammalian blood coagulation factor Xa. Biochem. J. 369, 635–642.

    Article  CAS  PubMed  Google Scholar 

  • Rao, V.S., Kini, R.M., 2002. Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: its structural and functional similarity to mammalian coagulation factor Xa-Va complex. Thromb. Haemost. 88, 611–619.

    CAS  PubMed  Google Scholar 

  • Rao, V.S., Swarup, S., Kini, R.M., 2003b. The nonenzymatic subunit of pseutarin C, a prothrombin activator from eastern brown snake (Pseudonaja textilis) venom, shows structural similarity to mammalian coagulation factor V. Blood 102, 1347–1354.

    Article  CAS  PubMed  Google Scholar 

  • Rao, V.S., Swarup, S., Kini, R.M., 2004. The catalytic subunit of pseutarin C, a group C prothrombin activator from the venom of Pseudonaja textilis, is structurally similar to mammalian blood coagulation factor Xa. Thromb. Haemost. 92, 509–521.

    CAS  PubMed  Google Scholar 

  • Reza, A., Swarup, S., Kini, R.M., 2005. Two parallel prothrombin activator systems in Australian rough-scaled snake, Tropidechis carinatus. Structural comparison of venom prothrombin activator with blood coagulation factor X. Thromb. Haemost. 93, 40–47.

    CAS  PubMed  Google Scholar 

  • Reza, M.A., Minh Le, T.N., Swarup, S., Kini, R.M., 2006. Molecular evolution caught in action: gene duplication and evolution of molecular isoforms of prothrombin activators in Pseudonaja textilis (brown snake). J. Thromb. Haemost. 4, 1346–1353.

    Article  CAS  PubMed  Google Scholar 

  • Rhee, M.J., Morris, S., Kosow, D.P., 1982. Role of meizothrombin and meizothrombin-(des F1) in the conversion of prothrombin to thrombin by the echis carinatus venom coagulant. Biochemistry 21, 3437–3443.

    Article  CAS  PubMed  Google Scholar 

  • Rosing, J., Tans, G., 1988. Meizothrombin, a major product of factor Xa-catalyzed prothrombin activation. Thromb. Haemost. 60, 355–360.

    CAS  PubMed  Google Scholar 

  • Rosing, J., Tans, G., 1992. Structural and functional properties of snake venom prothrombin activators. Toxicon 30, 1515–1527.

    Article  CAS  PubMed  Google Scholar 

  • Rosing, J., Tans, G., Govers-Riemslag, J.W., Zwaal, R.F., Hemker, H.C., 1980. The role of phospholipids and factor Va in the prothrombinase complex. J. Biol. Chem. 255, 274–283.

    CAS  PubMed  Google Scholar 

  • Rosing, J., Zwaal, R.F., Tans, G., 1986. Formation of meizothrombin as intermediate in factor Xa-catalyzed prothrombin activation. J. Biol. Chem. 261, 4224–4228.

    CAS  PubMed  Google Scholar 

  • Schieck, A., Habermann, E., Kornalik, F., 1972. The prothrombin-activating principle from Echis carinatus venom. II. Coagulation studies in vitro and in vivo. Naunyn Schmiedebergs Arch. Pharmacol. 274, 7–17.

    Article  CAS  PubMed  Google Scholar 

  • Seegers, W.H., Teng, C.M., Ghosh, A., Novoa, E., 1981. Three aspects of prothrombin activation related to protein M, ecarin, acutin, meizothrombin 1 and prethrombin 2. Ann. N. Y. Acad. Sci. 370, 453–467.

    Article  CAS  PubMed  Google Scholar 

  • Solovjev, D.A., Platonova, T.N., Ugarova, T.P. 1996. Isolation and characteristics of ekamulin – a prothrombin activator from multiscaled viper (Echis multisquamatus) venom. Biokhimiia 61, 1094–1105.

    PubMed  Google Scholar 

  • Solovjev, D.A., Platonova, T.N., Ugarova, T.P., 1996. Purification and characterization of ecamulin – a prothrombin activator from the venom of multi-scaled viper (Echis multisquamatus). Ukr. Biokhim. Zh. 68, 18–19.

    CAS  PubMed  Google Scholar 

  • Speijer, H., Govers-Riemslag, J.W., Zwaal, R.F., Rosing, J., 1986. Prothrombin activation by an activator from the venom of Oxyuranus scutellatus (Taipan snake). J. Biol. Chem. 261, 13258–13267.

    CAS  PubMed  Google Scholar 

  • Tans, G., Govers-Riemslag, J.W., van Rijn, J.L., Rosing, J., 1985. Purification and properties of a prothrombin activator from the venom of Notechis scutatus scutatus. J. Biol. Chem. 260, 9366–9372.

    CAS  PubMed  Google Scholar 

  • Tans, G., Janssen-Claessen, T., Hemker, H.C., Zwaal, R.F., Rosing, J., 1991. Meizothrombin formation during factor Xa-catalyzed prothrombin activation. Formation in a purified system and in plasma. J. Biol. Chem. 266, 21864–21873.

    CAS  PubMed  Google Scholar 

  • Tans, G., Nicolaes, G.A., Thomassen, M.C., Hemker, H.C., van Zonneveld, A.J., Pannekoek, H., Rosing, J., 1994. Activation of human factor V by meizothrombin. J. Biol. Chem. 269, 15969–15972.

    CAS  PubMed  Google Scholar 

  • van Rijn, J.L., Govers-Riemslag, J.W., Zwaal, R.F., Rosing, J., 1984. Kinetic studies of prothrombin activation: effect of factor Va and phospholipids on the formation of the enzyme-substrate complex. Biochemistry 23, 4557–4564.

    Article  PubMed  Google Scholar 

  • Walker, F.J., Owen, W.G., Esmon, C.T., 1980. Characterization of the prothrombin activator from the venom of Oxyuranus scutellatus scutellatus (Taipan venom). Biochemistry 19, 1020–1023.

    Article  CAS  PubMed  Google Scholar 

  • Welton, R.E., Burnell, J.N., 2005. Full length nucleotide sequence of a factor V-like subunit of oscutarin from Oxyuranus scutellatus scutellatus (coastal Taipan). Toxicon 46, 328–336.

    Article  CAS  PubMed  Google Scholar 

  • Yamada, D., Morita, T., 1997. Purification and characterization of a Ca2+-dependent prothrombin activator, multactivase, from the venom of Echis multisquamatus. J. Biochem. 122, 991–997.

    Article  CAS  PubMed  Google Scholar 

  • Yamada, D., Morita, T., 1999. CA-1 method, a novel assay for quantification of normal prothrombin using a Ca2+-dependent prothrombin activator, carinactivase-1. Thromb. Res. 94, 221–226.

    Article  CAS  PubMed  Google Scholar 

  • Yamada, D., Sekiya, F., Morita, T., 1996. Isolation and characterization of carinactivase, a novel prothrombin activator in Echis carinatus venom with a unique catalytic mechanism. J. Biol. Chem. 271, 5200–5207.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, P.O. Box 616, Maastricht, 6200, MD, The Netherlands

    Jan Rosing & Guido Tans

Authors
  1. Jan Rosing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guido Tans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan Rosing .

Editor information

Editors and Affiliations

  1. , Department of Biological Sciences, National University of Singapore, Science Drive 4 14, Singapore, 117543, Singapore

    R. Manjunatha Kini

  2. , Department of Haematology, University of Berne, Inselspital, Bern, CH-3010, Switzerland

    Kenneth J Clemetson

  3. , Biochemistry and Molecular Biology, University of Southern California, Health Sciences Campus/9270, Los Angeles, 90089, USA

    Francis S. Markland

  4. , Medical Technology, University of Delaware, 305G Willard Hall Educ Bld, Newark, 19716, Delaware, USA

    Mary Ann McLane

  5. , Biochemistry, Meiji Pharmaceutical University, Nishio Kiyose 2-522-1, Tokyo, 204-8588, Japan

    Takashi Morita

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Rosing, J., Tans, G. (2010). Snake Venom Prothrombin Activators – The History. 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_28

Download citation

Publish with us

Policies and ethics

Search

Navigation