Procoagulant Snake Toxins: Laboratory Studies, Diagnosis, and Understanding Snakebite Coagulopathy

 

 Buy Article Permissions and Reprints

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.

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
  CrossrefPubMedGoogle Scholar
• 2 Koh D C, Armugam A, Jeyaseelan K. Snake venom components and their applications in biomedicine.  Cell Mol Life Sci. 2006;  63 3030-3041
  CrossrefPubMedGoogle Scholar
• 3 Hati R, Mitra P, Sarker S, Bhattacharyya K K. Snake venom hemorrhagins.  Crit Rev Toxicol. 1999;  29 1-19
  CrossrefPubMedGoogle Scholar
• 4 Kini R M, Rao V S, Joseph J S. Procoagulant proteins from snake venoms.  Haemostasis. 2001;  31 218-224
  PubMedGoogle Scholar
• 5 Sitprija V. Snakebite nephropathy.  Nephrology.(Carlton.). 2006;  11 442-448
  CrossrefPubMedGoogle Scholar
• 6 Mebs D, Ownby C L. Myotoxic components of snake venoms: their biochemical and biological activities.  Pharmacol Ther. 1990;  48 223-236
  CrossrefPubMedGoogle Scholar
• 7 Gutierrez J M, Rucavado A. Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage.  Biochimie. 2000;  82 841-850
  CrossrefPubMedGoogle Scholar
• 8 Hodgson W C. Pharmacological action of Australian animal venoms.  Clin Exp Pharmacol Physiol. 1997;  24 10-17
  CrossrefPubMedGoogle Scholar
• 9 Dutertre S, Lewis R J. Toxin insights into nicotinic acetylcholine receptors.  Biochem Pharmacol. 2006;  72 661-670
  CrossrefPubMedGoogle Scholar
• 10 Marsh N, Williams V. Practical applications of snake venom toxins in haemostasis.  Toxicon. 2005;  45 1171-1181
  CrossrefPubMedGoogle Scholar
• 11 Ferreira S H. A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararca.  Br J Pharmacol Chemother. 1965;  24 163-169
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 14 Liu M, Counsell C, Zhao X L, Wardlaw J. Fibrinogen depleting agents for acute ischaemic stroke.  Cochrane Database Syst Rev. 2003;  CD000091
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 16 Markland F S. Inventory of alpha- and beta- fibrinogenases from snake venoms.  Thromb Haemost. 1991;  65 438-443
  PubMedGoogle Scholar
• 17 Swenson S, Markland Jr F S. Snake venom fibrin(ogen)olytic enzymes.  Toxicon. 2005;  45 1021-1039
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 20 Kini R M. Anticoagulant proteins from snake venoms: structure, function and mechanism.  Biochem J. 2006;  397 377-387
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 24 Currie B J. Snakebite in tropical Australia, Papua New Guinea and Irian Jaya.  Emerg Med. 2001;  12 285-294
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 26 White J. Snake venoms and coagulopathy.  Toxicon. 2005;  45 951-967
  CrossrefPubMedGoogle Scholar
• 27 Isbister G K. Snake bite: a current approach to management.  Aust Prescrib. 2006;  29 125-129
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 30 Rosing J, Tans G. Structural and functional properties of snake venom prothrombin activators.  Toxicon. 1992;  30 1515-1527
  CrossrefPubMedGoogle Scholar
• 31 Joseph J S, Kini R M. Snake venom prothrombin activators homologous to blood coagulation factor Xa.  Haemostasis. 2001;  31 234-240
  PubMedGoogle Scholar
• 32 Tans G, Rosing J. Snake venom activators of factor X: an overview.  Haemostasis. 2001;  31 225-233
  PubMedGoogle Scholar
• 33 Rosing J, Govers-Riemslag J W, Yukelson L, Tans G. Factor V activation and inactivation by venom proteases.  Haemostasis. 2001;  31 241-246
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 37 Moise M A, Kashyap V S. Alfimeprase for the treatment of acute peripheral arterial occlusion.  Expert Opin Biol Ther. 2008;  8 683-689
  CrossrefPubMedGoogle Scholar
• 38 Toombs C F. Alfimeprase: pharmacology of a novel fibrinolytic metalloproteinase for thrombolysis.  Haemostasis. 2001;  31 141-147
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 40 Toombs C F. New directions in thrombolytic therapy.  Curr Opin Pharmacol. 2001;  1 164-168
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 45 Girolami A, Saggin L, Boeri G. Factor X assays using chromogenic substrate S-2222.  Am J Clin Pathol. 1980;  73 400-402
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 47 Marshall L R, Herrmann R P. Coagulant and anticoagulant actions of Australian snake venoms.  Thromb Haemost. 1983;  50 707-711
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 54 Salooja N, Perry D J. Thrombelastography.  Blood Coagul Fibrinolysis. 2001;  12 327-337
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 56 Kessels H, Willems G, Hemker H C. Analysis of thrombin generation in plasma.  Comput Biol Med. 1994;  24 277-288
  CrossrefPubMedGoogle Scholar
• 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;
  Google Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 61 Parkin J D, Ibrahim K, Dauer R J, Braitberg G. Prothrombin activation in eastern tiger snake bite.  Pathology. 2002;  34 162-166
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 65 Mosesson M W. Dysfibrinogenemia and thrombosis.  Semin Thromb Hemost. 1999;  25 311-319
  Article in Thieme ConnectPubMedGoogle Scholar
• 66 Holford N H. Clinical pharmacokinetics and pharmacodynamics of warfarin. Understanding the dose-effect relationship.  Clin Pharmacokinet. 1986;  11 483-504
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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;
  Google Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 77 Fox J W, Serrano S M. Exploring snake venom proteomes: multifaceted analyses for complex toxin mixtures.  Proteomics. 2008;  8 909-920
  CrossrefPubMedGoogle Scholar

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