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DOI: 10.1055/s-0029-1214152
Procoagulant Snake Toxins: Laboratory Studies, Diagnosis, and Understanding Snakebite Coagulopathy
Publication History
Publication Date:
23 March 2009 (online)
ABSTRACT
Procoagulant toxins are important hemotoxins that have been investigated both as laboratory reagents and potential therapeutic agents. In human envenomation by some elapid and many viperid snakes, these toxins result in venom-induced consumption coagulopathy. Overall, the coagulant activity of the various venoms is difficult to characterize, and many studies simply characterize toxin conversion of isolated substrates, such as the effect of a snake toxin on purified fibrinogen, or on multiple single substrates. As the full effects of toxins on the coagulation pathway are rarely examined, even in vitro, our understanding of the pathophysiology of envenoming is limited. Although prothrombin activators cause a single effect in vitro, there may be complete consumption of fibrinogen, factor V, and factor VIII in vivo due to the downstream effects of the thrombin that is formed. Laboratory diagnosis is a key part of the treatment of snakebite coagulopathy. Assessing which assays are the most informative in snake envenoming, based on the pathophysiology of snakebite coagulopathy, will optimize diagnosis and timing of appropriate coagulation tests. A better understanding of the coagulation effects arising from human envenoming will also improve treatment with antivenom and define the role of adjuvant therapies such as factor replacement.
KEYWORDS
Snake venom - coagulopathy - envenomation - snakebite - hemotoxin
REFERENCES
- 1 Kuruppu S, Smith A I, Isbister G K, Hodgson W C. Neurotoxins from Australo-Papuan elapids: a biochemical and pharmacological perspective. Crit Rev Toxicol. 2008; 38 73-86
- 2 Koh D C, Armugam A, Jeyaseelan K. Snake venom components and their applications in biomedicine. Cell Mol Life Sci. 2006; 63 3030-3041
- 3 Hati R, Mitra P, Sarker S, Bhattacharyya K K. Snake venom hemorrhagins. Crit Rev Toxicol. 1999; 29 1-19
- 4 Kini R M, Rao V S, Joseph J S. Procoagulant proteins from snake venoms. Haemostasis. 2001; 31 218-224
- 5 Sitprija V. Snakebite nephropathy. Nephrology.(Carlton.). 2006; 11 442-448
- 6 Mebs D, Ownby C L. Myotoxic components of snake venoms: their biochemical and biological activities. Pharmacol Ther. 1990; 48 223-236
- 7 Gutierrez J M, Rucavado A. Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage. Biochimie. 2000; 82 841-850
- 8 Hodgson W C. Pharmacological action of Australian animal venoms. Clin Exp Pharmacol Physiol. 1997; 24 10-17
- 9 Dutertre S, Lewis R J. Toxin insights into nicotinic acetylcholine receptors. Biochem Pharmacol. 2006; 72 661-670
- 10 Marsh N, Williams V. Practical applications of snake venom toxins in haemostasis. Toxicon. 2005; 45 1171-1181
- 11 Ferreira S H. A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararca. Br J Pharmacol Chemother. 1965; 24 163-169
- 12 Han T S, Teichert R W, Olivera B M, Bulaj G. Conus venoms - a rich source of peptide-based therapeutics. Curr Pharm Des. 2008; 14 2462-2479
- 13 Hennerici M G, Kay R, Bogousslavsky J, Lenzi G L, Verstraete M, Orgogozo J M. Intravenous ancrod for acute ischaemic stroke in the European Stroke Treatment with Ancrod Trial: a randomised controlled trial. Lancet. 2006; 368 1871-1878
- 14 Liu M, Counsell C, Zhao X L, Wardlaw J. Fibrinogen depleting agents for acute ischaemic stroke. Cochrane Database Syst Rev. 2003; CD000091
- 15 Serrano S M, Maroun R C. Snake venom serine proteinases: sequence homology vs. substrate specificity, a paradox to be solved. Toxicon. 2005; 45 1115-1132
- 16 Markland F S. Inventory of alpha- and beta- fibrinogenases from snake venoms. Thromb Haemost. 1991; 65 438-443
- 17 Swenson S, Markland Jr F S. Snake venom fibrin(ogen)olytic enzymes. Toxicon. 2005; 45 1021-1039
- 18 Lalloo D G, Trevett A J, Owens D et al.. Coagulopathy following bites by the Papuan taipan (Oxyuranus scutellatus canni). Blood Coagul Fibrinolysis. 1995; 6 65-72
- 19 Warrell D A, Davidson N M, Greenwood B M et al.. Poisoning by bites of the saw-scaled or carpet viper (Echis carinatus) in Nigeria. Q J Med. 1977; 46 33-62
- 20 Kini R M. Anticoagulant proteins from snake venoms: structure, function and mechanism. Biochem J. 2006; 397 377-387
- 21 Johnstone I B, Martin C A. Comparative effects of the human protein C activator, Protac, on the activated partial thromboplastin clotting times of plasmas, with special reference to the dog. Can J Vet Res. 2000; 64 117-122
- 22 Gold B S, Barish R A, Dart R C. North American snake envenomation: diagnosis, treatment, and management. Emerg Med Clin North Am. 2004; 22 423-443,ix
- 23 Thorson A, Lavonas E J, Rouse A M, Kerns W P. Copperhead envenomations in the Carolinas. J Toxicol Clin Toxicol. 2003; 41 29-35
- 24 Currie B J. Snakebite in tropical Australia, Papua New Guinea and Irian Jaya. Emerg Med. 2001; 12 285-294
- 25 Isbister G K, Hooper M R, Dowsett R, Maw G, Murray L, White J. Collett's snake (Pseudechis colletti) envenoming in snake handlers. QJM. 2006; 99 109-115
- 26 White J. Snake venoms and coagulopathy. Toxicon. 2005; 45 951-967
- 27 Isbister G K. Snake bite: a current approach to management. Aust Prescrib. 2006; 29 125-129
- 28 Madaras F, Smith I L, Parkin J D. Purification and characterisation of coagulation inhibitors from the King Brown venom. , [abstract] Clin Exp Pharmacol Physiol. 1983; 10 490
- 29 Senis Y A, Kim P Y, Fuller G L et al.. Isolation and characterization of cotiaractivase, a novel low molecular weight prothrombin activator from the venom of Bothrops cotiara. Biochim Biophys Acta. 2006; 1764 863-871
- 30 Rosing J, Tans G. Structural and functional properties of snake venom prothrombin activators. Toxicon. 1992; 30 1515-1527
- 31 Joseph J S, Kini R M. Snake venom prothrombin activators homologous to blood coagulation factor Xa. Haemostasis. 2001; 31 234-240
- 32 Tans G, Rosing J. Snake venom activators of factor X: an overview. Haemostasis. 2001; 31 225-233
- 33 Rosing J, Govers-Riemslag J W, Yukelson L, Tans G. Factor V activation and inactivation by venom proteases. Haemostasis. 2001; 31 241-246
- 34 Zhang Y, Wisner A, Xiong Y, Bon C. A novel plasminogen activator from snake venom. Purification, characterization, and molecular cloning. J Biol Chem. 1995; 270 10246-10255
- 35 Sanchez E F, Felicori L F, Chavez-Olortegui C et al.. Biochemical characterization and molecular cloning of a plasminogen activator proteinase (LV-PA) from bushmaster snake venom. Biochim Biophys Acta. 2006; 1760 1762-1771
- 36 Segers K, Rosing J, Nicolaes G A. Structural models of the snake venom factor V activators from Daboia russelli and Daboia lebetina. Proteins. 2006; 64 968-984
- 37 Moise M A, Kashyap V S. Alfimeprase for the treatment of acute peripheral arterial occlusion. Expert Opin Biol Ther. 2008; 8 683-689
- 38 Toombs C F. Alfimeprase: pharmacology of a novel fibrinolytic metalloproteinase for thrombolysis. Haemostasis. 2001; 31 141-147
- 39 Filippovich I, Sorokina N, Masci P P et al.. A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties. Br J Haematol. 2002; 119 376-384
- 40 Toombs C F. New directions in thrombolytic therapy. Curr Opin Pharmacol. 2001; 1 164-168
- 41 St Pierre L, Masci P P, Filippovich I et al.. Comparative analysis of prothrombin activators from the venom of Australian elapids. Mol Biol Evol. 2005; 22 1853-1864
- 42 Filippovich I, Sorokina N, St Pierre L et al.. Cloning and functional expression of venom prothrombin activator protease from Pseudonaja textilis with whole blood procoagulant activity. Br J Haematol. 2005; 131 237-246
- 43 Rao V S, Kini R M. Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: its structural and functional similarity to mammalian coagulation factor Xa-Va complex. Thromb Haemost. 2002; 88 611-619
- 44 Rao V S, Joseph J S, Kini R M. Group D prothrombin activators from snake venom are structural homologues of mammalian blood coagulation factor Xa. Biochem J. 2003; 369 635-642
- 45 Girolami A, Saggin L, Boeri G. Factor X assays using chromogenic substrate S-2222. Am J Clin Pathol. 1980; 73 400-402
- 46 Girolami A, Patrassi G, Toffanin F, Saggin L. Chromogenic substrate (S-2238) prothrombin assay in prothrombin deficiencies and abnormalities. Lack of identity with clotting assays in congenital dysprothrombinemias. Am J Clin Pathol. 1980; 74 83-87
- 47 Marshall L R, Herrmann R P. Coagulant and anticoagulant actions of Australian snake venoms. Thromb Haemost. 1983; 50 707-711
- 48 Sprivulis P, Jelinek G A, Marshall L. Efficacy and potency of antivenoms in neutralizing the procoagulant effects of Australian snake venoms in dog and human plasma. Anaesth Intensive Care. 1996; 24 379-381
- 49 Isbister G K, O'Leary M A, Schneider J J, Brown S G, Currie B J. Efficacy of antivenom against the procoagulant effect of Australian brown snake (Pseudonaja sp.) venom: in vivo and in vitro studies. Toxicon. 2007; 49 57-67
- 50 O'Leary M A, Schneider J J, Krishnan B P et al.. Cross-neutralisation of Australian brown and tiger snake venoms with commercial antivenoms: cross-reactivity or antivenom mixtures?. Toxicon. 2007; 50 206-213
- 51 Barnett R N, Pinto C L. Reproducibility of prothrombin time determinations between technologists. Comparison of the fibrometer and tilt-tube methods. Tech Bull Regist Med Technol. 1966; 36 146-149
- 52 He S, Antovic A, Blomback M. A simple and rapid laboratory method for determination of haemostasis potential in plasma. II. Modifications for use in routine laboratories and research work. Thromb Res. 2001; 103 355-361
- 53 Dambisya Y M, Lee T L, Gopalakrishnakone P. Anticoagulant effects of Pseudechis australis (Australian king brown snake) venom on human blood: a computerized thromboelastography study. Toxicon. 1995; 33 1378-1382
- 54 Salooja N, Perry D J. Thrombelastography. Blood Coagul Fibrinolysis. 2001; 12 327-337
- 55 Lincz L F, Lonergan A, Scorgie F E et al.. Endogenous thrombin potential for predicting risk of venous thromboembolism in carriers of factor V Leiden. Pathophysiol Haemost Thromb. 2006; 35 435-439
- 56 Kessels H, Willems G, Hemker H C. Analysis of thrombin generation in plasma. Comput Biol Med. 1994; 24 277-288
- 57 Isbister G K, Woods D, Alley S, O'Leary M A, Seldon M, Lincz L. Endogenous thrombin potential as a novel method for the characterization of procoagulant snake venoms. Presented at: Haematology Society of Australia and New Zealand Annual Conference October 2008 Perth, Australia;
- 58 Isbister G K, Brown S GA, Duffull S B. Failure of antivenom in venom induced consumption coagulopathy: in silica and empirical evidence. , [abstract] Clin Toxicol. 2008; 46 1
- 59 O'Leary M A, Isbister G K, Schneider J J, Brown S G, Currie B J. Enzyme immunoassays in brown snake (Pseudonaja spp.) envenoming: detecting venom, antivenom and venom-antivenom complexes. Toxicon. 2006; 48 4-11
- 60 Tanos P P, Isbister G K, Lalloo D G, Kirkpatrick C M, Duffull S B. A model for venom-induced consumptive coagulopathy in snake bite. Toxicon. 2008; 52 769-780
- 61 Parkin J D, Ibrahim K, Dauer R J, Braitberg G. Prothrombin activation in eastern tiger snake bite. Pathology. 2002; 34 162-166
- 62 Isbister G K, Williams V, Brown S G, White J, Currie B J. Clinically applicable laboratory end-points for treating snakebite coagulopathy. Pathology. 2006; 38 568-572
- 63 Bush S P, Wu V H, Corbett S W. Rattlesnake venom-induced thrombocytopenia response to Antivenin (Crotalidae) Polyvalent: a case series. Acad Emerg Med. 2000; 7 181-185
- 64 Warrell D A, Looareesuwan S, Theakston R D et al.. Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations. Am J Trop Med Hyg. 1986; 35 1235-1247
- 65 Mosesson M W. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost. 1999; 25 311-319
- 66 Holford N H. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship. Clin Pharmacokinet. 1986; 11 483-504
- 67 Yeung J M, Little M, Murray L M, Jelinek G A, Daly F F. Antivenom dosing in 35 patients with severe brown snake (Pseudonaja) envenoming in Western Australia over 10 years. Med J Aust. 2004; 181 703-705
- 68 Ferguson L A, Morling A, Moraes C, Baker R. Investigation of coagulopathy in three cases of tiger snake (Notechis ater occidentalis) envenomation. Pathology. 2002; 34 157-161
- 69 Jelinek G A, Smith A, Lynch D et al.. The effect of adjunctive fresh frozen plasma administration on coagulation parameters and survival in a canine model of antivenom-treated brown snake envenoming. Anaesth Intensive Care. 2005; 33 36-40
- 70 Porath A, Gilon D, Schulchynska-Castel H, Shalev O, Keynan A, Benbassat J. Risk indicators after envenomation in humans by Echis coloratus (mid-east saw scaled viper). Toxicon. 1992; 30 25-32
- 71 Caruso N, Isbister G K, Brown S GA. Clotting factor replacement and recovery from snake venom induced consumption coagulopathy – an exploratory analysis. Presented at: Australasian College for Emergency Medicine Winter Symposium June 2007 Launceston, Tasmania, Australia;
- 72 Paul V, Pudoor A, Earali J, John B, Anil Kumar C S, Anthony T. Trial of low molecular weight heparin in the treatment of viper bites. J Assoc Physicians India. 2007; 55 338-342
- 73 Warrell D A, Pope H M, Prentice C R. Disseminated intravascular coagulation caused by the carpet viper (Echis carinatus): trial of heparin. Br J Haematol. 1976; 33 335-342
- 74 Paul V, Prahlad K A, Earali J, Francis S, Lewis F. Trial of heparin in viper bites. J Assoc Physicians India. 2003; 51 163-166
- 75 Swe T N, Lwin M, Han K E, Tun T, Pe T. Heparin therapy in Russell's viper bite victims with disseminated intravascular coagulation: a controlled trial. Southeast Asian J Trop Med Public Health. 1992; 23 282-287
- 76 Masci P P, Mirtschin P J, Nias T N, Turnbull R K, Kuchel T R, Whitaker A N. Brown snakes (Pseudonaja genus): venom yields, prothrombin activator neutralization and implications affecting antivenom usage. Anaesth Intensive Care. 1998; 26 276-281
- 77 Fox J W, Serrano S M. Exploring snake venom proteomes: multifaceted analyses for complex toxin mixtures. Proteomics. 2008; 8 909-920
Geoffrey K IsbisterM.B.B.S. F.A.C.E.M. M.D.
Department of Clinical Toxicology, Calvary Mater Newcastle Hospital
Edith St., Waratah, NSW 2298, Australia
Email: geoff.isbister@gmail.com