Professional Documents
Culture Documents
Snake Venoms and Coagulopathy
Snake Venoms and Coagulopathy
www.elsevier.com/locate/toxicon
Abstract
Snakebite affects around 2.5 million humans annually, with greater than 100,000 deaths. Coagulopathy is a significant cause
of both morbidity and mortality in these patients, either directly, or indirectly. This paper reviews clinical aspects of snakebite
coagulopathy, including types of coagulopathy (procoagulant, fibrinogen clotting, fibrinolytic, platelet-active, anticoagulant,
thrombotic, haemorrhagic), diagnosis and treatment. Examples of clinical laboratory findings in selected types of snakebite
coagulopathy are presented. Where available, antivenom is the most effective treatment, while standard treatments for other
forms of coagulopathy, such as factor replacement therapy and heparin, are either ineffective or dangerous in snakebite
coagulopathy, except in specific situations.
q 2005 S. Yamamoto. Published by Elsevier Ltd. All rights reserved.
Table 1
Snakes considered to cause medically significant effects on the haemostatic system
though rarely all six. In the past there has been an severe coagulopathy (White, 2004a; White, 2004b; White,
assumption that a single snake species will generally 2004c; Warrell, 1995a; Warrell, 1995b; White, 1995a).
cause either local effects or systemic effects and that vipers
cause local and/or haemorrhagic effects, while elapids cause
purely systemic, non-haemorrhagic effects. This assumption 3. An overview of coagulopathy induced by snakebite
is entirely incorrect. Some of the worst cases of local tissue
injury are caused by elapid bites (selected Asian and African A brief summary of major snake groups causing coagulo-
cobras) (Warrell, 1995a; Warrell, 1995b) and some vipers pathy and/or haemorrhage is presented in Tables 1 and 2.
(eg South American rattlesnakes) cause minimal local The diverse array of venom components affecting human
effects (Fan & Cardoso, 1995). Similarly, some vipers can haemostasis is mirrored only partially in a diversity of clinical
cause paralysis or myolysis, while some elapids cause effects. An outline of the broad effects is presented in Fig. 1.
Table 2
Snakes considered to have medically significant haemorrhagins
Fig. 1. Diagrammatic representation of principle ways snake venom interacts with human haemostasis. (Illustration copyright q Dr. Julian
White).
Indeed, in practical clinical terms, the range of clinical damage, such as intracerebral haemorrhage, anterior pituitary
problems presented by this venom diversity is limited. The haemorrhage or renal damage; (4) direct pathologic thrombo-
principal problems encountered are listed in Table 3. sis and its sequelae, particularly pulmonary embolism (seen
Essentially these can be further reduced to the following; (1) only with envenoming by Martinique vipers and related
reduced coagulability of blood, resulting in an increased species from the West Indies; Thomas et al 1995; Numeric
tendency to bleed; (2) frank bleeding due to damage of the et al, 2002). Each one of these effects can cause morbidity and
blood vessels; (3) secondary effects of increased bleeding, even mortality. Between them they may represent as much as
ranging from hypovolaemic shock to secondary organ half of all snakebite morbidity and mortality worldwide.
954 J. White / Toxicon 45 (2005) 951–967
Table 4
Coagulation results for 10 cases of brown snake (Pseudonaja spp.) bite; results selected as earliest full set indicative of coagulopathy, in most
cases prior to antivenom therapy
PATIENT 1 2 3 4 5 6 7 8 9 10
No.
SEX M M M F M M M M M M
AGE 15 3 2 42 15 7 27 69 21 16
WBCT O30 O30 O30 – – 20 – O30 – –
PR/INR O12 O12 O12 4.9 1.76 – O12 O12 1.7 O12
APTT O150 O150 O150 O94 60 74 O150 O150 32 O150
TCT – – O150 – – – O150 O150 27 O150
Fibrinogen !0.1 0.2 !0.1 – 0.27 – !0.1 !0.1 0.6 !0.1
FDP 500 16000 O5000 O1380 620 2000 – – – –
D-Dimer – O64 – – – – O16 O16 O16 O16
Factor II 0.59 0.56 0.54 – – – – – – –
Factor V 0.11 0.08 0.15 – – – – – – –
Factor VII – – 0.44 – – – – – – –
Factor VIII 0.14 0.03 0.08 – – – – – – –
Factor IX – – 1.0 – – – – – – –
Factor X – – 0.5 – – – – – – –
Protein C 36% 11% – – – – – – – –
Plasminogen 46% 43% – – – – – – – –
Platelets 171 242 250 272 305 265 175 201 301 214
Notes: Case 9 results are 4 h post antivenom therapy, on arrival in Adelaide post retreival from a country town. Case 5 was clinically a very mild
case of envenomation and these results by themselves, though indicative of a very mild coagulopathy and envenoming, would not necessarily
have justified antivenom therapy, however the patient also developed evidence of renal impairment and therefore was treated with antivenom.
There was also evidence of impaired renal function in cases 7 and 9.
first reaches the circulation and before fibrinolysis is These thrombi are quickly destroyed once fibrinolysis
activated (Tibballs et al, 1991b; Tibballs et al., 1992). activates, but even a few minutes of such thrombotic
The resultant thrombi can occlude critical vessels, notably complications can be devastating for the victim. It is likely
coronary vessels, resulting in cardiac arrythmias and arrest. that this brief thrombotic window is the cause of the well
Table 5
Coagulation results for 6 cases of tiger snake (Notechis spp.) bite; results selected as earliest full set indicative of coagulopathy, in most cases
prior to antivenom therapy
PATIENT No. 1 2 3 4 5 6
SEX M M F F M F
AGE 33 66 73 2 10 59
WBCT – O30 – O30 – –
PR/INR O12 O12 1.6 O12 1.2 O12
APTT O150 O150 30 O150 39 O150
TCT O150 – 35.5 – – O150
Fibrinogen !0.04 – 0.48 !0.1 0.69 !0.1
FDP – 10000 O80 5000 – –
D-Dimer 32–64 – – – 16–32 O16
Factor II 0.79 – – 0.37 – –
Factor V 0.10 – – 0.06 – –
Factor VII – – – 0.95 – –
Factor VIII 0.46 (0.29) – – !0.01 – –
Factor IX – – – 0.35 – –
Factor X – – – 0.55 – –
Protein C 10% – – – – –
Plasminogen 52% – – – – –
Platelets 317 200 179 288 463 308
Notes: All cases were bites by N. scutatus except case 5 which was a bite from N. ater. Case 3 occurred in a country area and antivenom therapy
was given prior to full coagulation studies, the results given being 4 h after therapy indicating residual evidence of a corrected coagulopathy.
Case 5 also occurred in a country area and results were from a sample taken 18 h after envenoming, again indicative of a resolved coagulopathy.
956 J. White / Toxicon 45 (2005) 951–967
Table 6
Table 7
Coagulation results for 4 cases of taipan (Oxyuranus spp.) bite;
Serial coagulation results after a saw scaled viper, Echis ocellatus
results selected as earliest full set indicative of coagulopathy, in
bite (adapted from Ajzenberg et al, 1993)
most cases prior to antivenom therapy.
Day after bite 5 9 10 42
PATIENT 1 2 3 4
No. Prothrombin time % !10 80 98 99
(nZ70–130)
SEX F F M M
aPTT (nZ35–42) O150 29 28 32
AGE 29 72 10 65
Fibrinogen (nZ0.2–0.4 g/ !0.05 0.12 0.18 0.38
PR/INR O12 2.5 7.5 O12
100 ml)
APTT O150 72 150 O150
D-dimer (nZ!0.4 mg/ml) 114 8 3 0.5
TCT O150 – – O150
Factor II% (nZ80–120) 14 86 ND ND
Fibrinogen !0.1 – – !0.01
Factor V% (nZ80–120) 37 86 ND ND
FDP – – 1280 O1280
Platelets (nZ150–400! 305 ND 430 319
D-Dimer O16 O64 – O16
109/l)
Factor II 0.87 – – 0.83
Factor V 0.01 – – 0.07
Factor VII – – – 0.73 bleeding gums and bite sites, but even here, catastrophic
Factor (0.02) – – 0.03
bleeding into internal organs, particularly the brain,
VIII
Factor IX – – – 1.05
though well documented, appears to be uncommon
Factor X – – – 0.97 (Warrell et al, 1977; Murthy et al, 1997). Spontaneous
Factor XI – – – 1.19 bleeding was seen in 66 of 115 cases of Echis
Factor XII – – – 0.70 (carinatus) ocellatus bites in Nigeria, of whom 40 had
Protein C 8% – – !10% bleeding gums, 29 blood stained sputum or saliva, 10 had
Plasmino- 17% – – 36% epistaxis, 6 developed haematomas, 3 had haematemesis,
gen 3 had subarachnoid bleeds and 2 melaena (Warrell et al,
Platelets 231 244 295 166 1977). In this series, 2 patients died following intracra-
Notes: Cases 1,2,3 were bites by O. scutellatus and case 4 was a bite nial bleeding and 3 died from haemorrhagic shock. In a
by O. microlepidotus. Case 2 was unusual in that the coagulopathy series of 68 cases of Echis coloratus bites in Israel, the
was mild and there was no evidence of neurotoxic paralysis or majority (40) did not show active bleeding, while in 19
myolysis as might be predicted for a significant taipan bite, but the bleeding was minor and in only 9 was there ‘major’
patient developed severe renal failure with renal cortical necrosis. bleeding (Porath et al, 1992). In this series, average
Case 4 is only the 3rd recorded envenoming of a human by the duration of coagulopathy was 2.8 days, with a maximum
inland taipan which has the most potent snake venom known and is of 9 days. There were no fatalities. Similarly, amongst 7
technically the worlds most dangerous snake. Case 3 was interstate
children bitten by Echis coloratus in Saudi Arabia, only
and little data is available.
3 developed hypofibrinogenaemia and there were no
deaths (Annobil, 1993). Without antivenom treatment, a
documented cases of early cardiac collapse following brown
coagulopathy can persist for many days (Table 7), with
snake bite, unhappily a cause of fatalities which no amount
one case taking 30 days for return of normal fibrinogen
of antivenom can prevent, because this is generally a pre-
levels (Reid Ha, 1977). Similar coagulopathy with
hospital phenomenon (White, 2000). Potentially, of course,
depletion of fibrinogen has been reported for Echis
if injected intravenously, most procoagulant venoms could
sochureki (Weis et al, 1991) and E. pyramidum (Gillissen
cause a cardiac catastrophe, as was shown many years ago
et al, 1994).
for tiger snake (Notechis) venom, with massive coagulation
of blood in the heart causing immediate and irremediable
cardiac standstill in animals as large as sheep (Fairley,
1929). 5. The fibrinogen clotting toxins, fibrinolytics
The procoagulants in certain viper venoms, notably and coagulopathy
the carpet or saw scaled vipers (Echis spp.) produce a
more devastating clinical picture than the Australian Fibrinogen clotting and fibrinolytic snake venom toxins
elapids, probably because of the presence of haemor- exert a direct effect on the actual thrombus-forming protein,
rhagins in the venom as well, working synergistically fibrinogen, but in varying ways (Markland, 1998). Fibrino-
with the procoagulants (Markland FS, 1998; Warrell gen may be split to fibrin and then degradation products, or
et al, 1976; Warrell et al., 1977; Charak et al, 1988; it may be only partially split, leaving an ineffective form of
Yatziv et al, 1974;). These snakes, in addition to causing fibrinogen circulating, the end result being an increased
local tissue injury, exert their principle systemic effects bleeding tendency through either mechanism. As with the
through these two coagulopathic actions. In consequence, procoagulants, this need not cause spontaneous bleeding,
clinical manifestations of bleeding are common, such as but certainly increases the risk of a major bleed and can have
J. White / Toxicon 45 (2005) 951–967 957
Table 8
Snake species with venom components causing fibrinogen clotting action (after Markland, 1998)
Genus and species Fibrinopeptide A split Fibrinopeptide B split Split of both A and B
(venombin A group) (venombin B group) (venombin AB group)
Agkistrodon contortrix contortrix – Venzyme –
Bitis gabonica – – Gabonase
Bothrops atrox Batroxobin – –
Calloselasma rhodostoma Ancrod – –
Crotalus adamanteus Crotalase – –
Gloydius halys pallas – C –
severe effects, if working synergistically with a haemor- forms of attack. There are two principal effects likely; (1)
rhagin. A number of snakes utilise these mechanisms inhibition of platelet activity, thus reducing their effective-
(Table 8). Clinically, at least some of these toxins have ness in haemostasis; (2) promotion of platelet activity,
major effects, a classic example being the Malayan pit viper, increasing their contribution to haemostasis, in this case
Calloselasma rhodostoma. This snake causes major coagu- pathologic. To these must be added the possibility of
lopathy and bite-site tissue damage (Reid et al, 1963a). It is a reducing availability of platelets, resulting in low circulating
very significant cause of snakebite morbidity within its numbers (thrombocytopenia), itself also a risk for increased
range, in SE Asia (Warrell, 1995b; Warrell et al, 1986). bleeding.
Patients develop a profound haemorrhagic defibrination A number of snake venoms can induce one or more of
coagulopathy, with both spontaneous bleeding and incoa- these effects, depending on concentration of venom
gulable blood. The onset of coagulopathy can be rapid, with (Table 10). While inhibition of platelet activity can increase
incoagulable blood as soon as 30 min post-bite (Reid et al, the risk of bleeding, it is unclear if this is of great clinical
1963a), but full defibrination (and incoagulable blood) may significance in envenomed humans. Thrombocytopenia,
also be delayed up to 72 h post-bite even though venom and however, is far more important and is a feature of
fibrin(ogen) degradation products may be present at envenoming by a number of snakes, such as North American
presentation (Ho et al, 1986). The duration of coagulopathy rattlesnakes. The degree of linkage between thrombocyto-
can be lengthy, from 6–26 days (incoagulable blood for up penia and increased bleeding in snakebite is unclear.
to 8 days; reduced coagulability thereafter) in the absence of
antivenom therapy (Reid et al, 1963a,b).
The fibrinolytic toxins act on fibrin or fibrinogen to 7. Anticoagulant venoms and coagulopathy
initiate the breakdown process, normally caused by
plasmin(ogen). These are mostly a- or b-fibrinogenases, Some snake venoms contain toxins that are direct or
but unlike plasmin, are not serine proteases, so are not indirect anticoagulants, that inhibit the clotting process, thus
susceptible to SERPINS (Markland, 1998). Selected
examples are listed in Table 9. The contribution of these Table 9
Snake species with fibrinolytic venom components (after Markland,
toxins to coagulopathy and bleeding in humans remains
1998). This list is not complete, but rather is representative
uncertain, as they generally exist in venoms with a variety of
other haematologically active toxins, however in two Genus and species Fibrinolytic component
species without such a diversity of other components ELAPIDAE
(Naja nigricollis, Crotalus basiliscus) haemorrhagic fea- Naja nigricollis a-chain fibrinogenase
tures are not a significant part of the clinical profile of VIPERIDAE
envenoming. In those species with coagulopathic toxins, the Agkistrodon contortrix a&b-chain
combination of fibrinogen activation and direct fibrinolysis contortrix
is likely to enhance haemorrhagic potential. Similarly, those Agkistrodon contortrix a-chain fibrinogenase
venoms possessing plasminogen activating toxins will also mokasen
Bothrops moojeni Batroxobin—plasminogen activator
enhance haemorrhagic potential.
Cerastes cerastes Cerastase—a, b, g-chain fibrinogenase
Crotalus adamanteus Plasminogen activator
Crotalus atrox Atroxase-a, b-chain fibrinogenase;
6. Platelet active venoms and coagulopathy plasminogen activator
Crotalus basiliscus a, b-chain fibrinogenase
Trimeresurus Habutoxin-plasminogen activator
Platelets form a vital part of the haemostatic process,
flavoviridis (indirect)
acting as the ‘front line’ in plugging any vascular defect, as Trimeresurus stejnegeri TSV-PA-direct plasminogen activator
well as providing activating surfaces for the coagulation Vipera lebetina l3batas3-a, b-chain fibrinogenase
cascade. They are metabolically active and subject to many
958 J. White / Toxicon 45 (2005) 951–967
Table 10
Snakes with platelet-active venom components (after Markland, 1998); this is an incomplete list, as new inhibitors especially are being
constantly described
increasing the risk of bleeding. Clinically this may be little the other species with anticoagulant toxins, they coexist
different in effect than the consumptive route used by with coagulant and haemorrhagic toxins, thus producing a
procoagulants, although, in general, anticoagulant venoms far less clear or diagnostic clinical laboratory picture.
are associated with less severe pathologic bleeding than
consumptive venoms (procoagulants etc). There will,
however, be important differences in clinical laboratory 8. Thrombotic venoms and pathologic thrombosis
results that can be useful diagnostically. This is especially
true of Australian elapids, where one particular group While a coagulant venom, by definition, induces some
(mulga snakes; selected Pseudechis spp.), cause antic- degree of clotting, in most cases this is accompanied by
oagulant coagulopathy (Table 11). The key diagnostic active fibrinolysis, resulting in a net loss of clotting capacity.
distinction is the absence of significant fibrinogen consump- As discussed earlier, there may be a brief window of
tion or elevation of degradation products in purely antic- thrombosis prior to activation of fibrinolysis. However, two
oagulant venoms such as Pseudechis (Table 12). In many of snakes, the Martinique viper (Bothrops lanceolatus) and
J. White / Toxicon 45 (2005) 951–967 959
Table 12
Illustrative case of anticoagulant coagulopathy (Collett’s snake,
Pseudechis colletti)
Fig. 8. Diagnostic algorithm for determining the type of snake involved in Australian snakebite. (Illustration copyright q Dr. Julian White).
J. White / Toxicon 45 (2005) 951–967 963
Fig. 9. Diagnostic algorithm for determining the type of snake involved in South East Asian snakebite. (Modified from Warrell et al, 1999).
prepared to give supplementary doses if required. Equally, it circuit’ the clotting process, by giving heparin, followed
is important to avoid giving other therapies that may later in selected cases by warfarin or similar. The patient
exacerbate the coagulopathic process. This is rather may also be given supplementary clotting factors, often as
different to management of most other causes of coagulo- fresh frozen plasma (FFP) or cryoprecipitate (cryo).
pathy, which generally represent derangement of normal In snakebite coagulopathy, such treatments are generally
homeostatic mechanisms. Thus for disseminated intravas- ineffective (Porath et al, 1992) and may be potentially
cular coagulation (DIC), which may resemble some types of dangerous (Malik GM, 1995). Heparin will not ‘switch off’
snakebite coagulopathy, it is common practice to ‘short the pathologic venom-induced coagulopathy, so will not
964 J. White / Toxicon 45 (2005) 951–967
help, yet may induce its own degree of pathologic changes At least in Australia, coagulopathy is used as a
to clotting, thus making things worse (Warrell et al, 1976a). convenient guide to ongoing antivenom dosing, ‘titrating’
Similarly, the addition of extra substrate in FFP or cryo may antivenom doses against resolution of the coagulopathy.
only add fuel to the venom-stoked fire, especially with This technique has been used for a number of years since
procoagulants, unless all venom has been removed (White, initially recommended, but though generally useful in an
1987c). This, in turn, will increase levels of degradation ‘antivenom rich’ environment, is not without problems.
products that must be cleared by the kidneys and may also Firstly, some doctors have given insufficient time after a
accelerate the hyperfibrinolytic state which can occur. This dose to see if it is effective, before launching into further
increases the risk of spontaneous bleeding. Further, the doses. This can result in overdosage. Secondly, the problem
degradation products are, themselves, partially anticoagu- of intra-generic venom variability is often a mystery to
lant, thus potentially deepening the crisis. Conversely, if doctors, who assume all species from a genus will cause
extra clotting factors are not considered until after there is exactly the same degree of envenoming, be equally
evidence that all venom has been neutralised, then often responsive to antivenom raised against a single species,
they will be superfluous anyway, as the liver rapidly thus similar doses should be used. A prime example is the
replenishes depleted clotting factors. Cases of defibrination brown snake (Pseudonaja spp.), a wide-ranging genus,
where fibrinogen has been given in the absence of represented across all mainland Australia and currently the
antivenom therapy have confirmed the deleterious effect leading cause of snakebites on that continent. The quantity
of such treatment (Reid et al, 1963b). of venom produced for a given-sized snake varies based on
There is some controversy regarding rate of replenish- geographic location, even within a single species, let alone
ment of clotting factors. Australian experience indicates between species. Procoagulants in the venom, though
fibrinogen can reach measurable levels following defibrina- similar, appear to have different degrees of susceptibility
tion reversal with antivenom, in about 3 h (White, 1987c), to the specific antivenom. Thus envenoming may require
but standard teaching elsewhere is a wait of 6 h (Warrell, anything from 3 vials to 20 vials to neutralise the
1995a; Warrell, 1995b). Certainly the longer wait will give a coagulopathy and for some specimens, antivenom appears
more definitive result, but if insufficient antivenom has been poorly effective, even at very high doses. This needs to be
given, it doubles the period at risk, before more antivenom is understood in managing a case. The initial dose should be
administered. The greater delay will, at least theoretically, evaluated, depending on the geographic location, experi-
reduce the likelihood of giving unnecessary extra anti- ence suggesting (currently being evaluated in a trial) that
venom, an important issue in countries where antivenom is envenoming by Western Australian brown snakes (dugite,
in short supply. Where antivenom is generally available, as P. affinis; gwardar, P. nuchalis) may require substantially
in Australia, such considerations are less important, though more vials of antivenom, possibly a starting dose of 10 vials,
giving more antivenom than is necessary will increase compared to 5 vials in eastern Australia.
treatment cost and increase the likelihood of serum sickness, Where available, antivenom is the treatment of choice
which is generally dose-related. for all snakebite coagulopathies, but not all antivenoms are
Repeat dosing with antivenom may be required, not just created equal. The choice of antivenom can be critical in
to provide a sufficient dose to neutralise acute venom levels, obtaining the best outcome. The variation in venom activity
but to neutralise late release venom from bite site depots. profile within a single species, spread over a wide
The late release phenomenon is well documented for some geographic range, is typified by Russell’s viper, Daboia
vipers causing haemostatic disturbance. Examples include russelii. Antivenom produced against the venom from
the Malayan pit viper, Calloselasma rhodostoma, where late snakes in one geographic region can be near useless in
release can extend coagulopathy for up to 2 weeks post-bite treating bites by the same species from a different region.
(Reid et al, 1963b). Similarly, venom-induced thrombo- The comparative efficacy of a given antivenom, or in some
cytopenia can occur late after North American rattlesnake cases, lack of efficacy, will be important in judging dosage,
bite, presumed due to further venom release. These late together with the degree of envenoming in each case. Thus,
release phenomena have implications for designing anti- as discussed for Australian snakebites, the initial and
venoms. The current US snake antivenom for viper bites is subsequent doses of antivenom must be individualised for
ovine F(ab)’ based and in consequence, has a short half life. each snake, from each region, for each antivenom,
Its rapid elimination puts the patient at risk of recurrent dynamically modified by the peculiarities of each case of
envenoming, unless follow up doses are given, requiring envenoming. Listing appropriate antivenoms for each snake
treatment regimes incorporating regular doses of antivenom species is beyond the scope of this paper, but some
every few hours, or even by continuous infusion. In this information may be found on the internet (www.toxinol-
situation, it might be better to have an antivenom with at ogy.com).
least some F(ab)2 or even IgG component, with a much The issue of when to use antivenom for snakebite
longer half life. Of course, such an antivenom, particularly coagulopathy is increasingly important, especially in those
with whole IgG, might pose greater risks of other adverse regions where antivenom is scarce. The importance of
reactions. objectively establishing if coagulopathy is present, by
J. White / Toxicon 45 (2005) 951–967 965
measuring clotting function, such as by the simple WBCT, Date, A., Pulimood, R., Jacob, C.K., Kirubakaran, M.G.,
before deciding to give antivenom, has been known for Shastry, J.C.M., 1986. Haemolytic uraemic syndrome compli-
many years (Swinson C, 1976). Even in areas with poor cating snake bite. Nephron 42, 89–90.
resources, the WBCT can usually be performed and will Fairley, N.H., 1929. The present position of snakebite and the snake
give a rapid indication of the presence of coagulopathy in bitten in Australia. Med J Aust 1, 296–313.
Fan, H.W., Cardoso, J.L., 1995. Clinical toxicology of snakebite in
association with envenoming, which is essentially always an
South America. In: Meier, J., White, J. (Eds.), Handbook of
indication to give antivenom, presuming it is available.
Clinical Toxicology of Animal Venoms and Poisons. CRC
Similarly, repeat WBCT after antivenom may guide the Press, Boca Raton, pp. 667–688.
need for further antivenom. Clearly the WBCT is not useful Gillissen, A., Theakston, R.D.G., Barth, J., May, B., Krieg, M.,
in all forms of snakebite coagulopathy, most notably where Warrell, D.A., 1994. Neurotoxicity, haemostatic disturbances
the problem is pathologic thrombosis and embolism, as seen and haemolytic anaemia after a bite by a Tunisian saw-scaled or
with Bothrops lanceolatus and B. caribbaeus. It may also carpet viper (Echis pyramidum-complex); failure of antivenom
fail to indicate platelet abnormalities and will not be treatment. Toxicon 32, 937–944.
diagnostic for haemorrhagic problems, but in these Harris, A.R.C., Hurst, P.E., Saker, B.M., 1976. Renal failure after
situations, clinical examination is likely to detect the snake bite. Med J Aust 2, 409–411.
abnormality and so point to the requirement for antivenom. Herrmann, R.P., Davey, M.G., Skidmore, P.H., 1972. The
The method of determining need for further antivenom in coagulation defect after envenomation by the bite of the dugite
such cases is less clear and must generally rely on clinical (Demansia nuchalis affinis) a Western Australian brown snake.
judgement rather than laboratory diagnostic parameters. Med J Aust 2, 183–186.
Ho, M., Warrell, D.A., Looareesuwan, S., Phillips, R.E.,
Chanthavanich, P., Karbwang, J., Supanaranond, W.,
Viravan, C., Hutton, R.A., Vejcho, S., 1986. Clinical signifi-
12. Medical uses for haemostatically-active venoms cance of venom antigen levels in patients envenomed by the
Malayan pit viper (Calloselasma rhodostoma). Am J Trop Med
A detailed account of medical uses of snake venoms is Hyg 35, 579–587.
beyond the scope of this paper. In particular, potential Johnston, M.A., Fatovich, D.M., Haig, A.D., Daly, F.F.S., 2002.
therapeutic uses will not be discussed. From the perspective Successful resuscitation after cardiac arrest following massive
brown snake envenomation. Med J Aust 177, 646–649.
of haemostatically active components, however, there is a
Laing, G.D., Lee, L., Smith, D.C., Landon, J., Theakston, R.D.G.,
long-standing role in diagnostic tests, both for coagulation
1995. Experimental assessment of a new, low cost antivenom
abnormalities and related diseases. Amongst the most for treatment of carpet viper (Echis ocellatus) envenoming.
venerable are toxins from Russell’s viper venom (Daboia Toxicon 33, 307–313.
russelii) (Marsh, 1998), long used as reagents for specific Lakier, J.B., Fritz, V.U., 1969. Consumptive coagulopathy caused
tests of clotting function. More recently, toxins from snake by boomslang bite. S Afr Med J 43, 1052–1055.
venoms have been used to develop tests for other parts of the Lalloo, D., Trevett, A.J., Saweri, A., Naraqui, S.,
haemostatic system, such as Protein C, and for related Theakston, R.D.G., Warrell, D.A., 1995. The epidemiology of
disease, such as testing for lupus anticoagulant. It seems snake bite in Central Province and National Capitol
likely that the list of clinical tests using haemostatically- District, Papua New Guinea. Trans R Soc Trop Med Hyg 89,
active venom components will lengthen. 178–182.
Malik, G.M., 1995. Snake bites in adults from the Asir region of
southern Saudi Arabia. Am J Trop Med Hyg 52, 314–317.
Markland, F.S., 1998. Snake venoms and the haemostatic system.
References Toxicon 36, 1749–1800.
Marsh, N.A., 1998. Use of snake venom fractions in the coagulation
laboratory. Blood Coagulation and Fibrinolysis 9, 395–404.
Ajzenberg, N., Cherin, P., Diallo, D., Bridley, F., Brivet, F.,
Dreyfus, M., 1993. In vivo effect of Echis carinatus venom Meier, J., Stocker, K.F., 1995. Biology and distribution of
observed in a woman in Mali. Thromb Haemostasis 70, 1063– venomous snakes of medical importance and the composition
1066. of snake venoms. In: Meier, J., White, J. (Eds.), Handbook of
Ameratunga, B., 1972. Middle cerebral occlusion following Clinical Toxicology of Animal Venoms and Poisons. CRC
Russell’s viper bite. J Trop Med Hyg 75, 95–97. Press, Boca Raton, pp. 367–412.
Annobil, S.H., 1993. Complications of Echis colorata snake bites in Melgarejo, AR, Aguiar, AS, (1995) Poisonous snakes, ecological
the Asir region of Saudi Arabia. Ann Trop Paediat 13, 39–44. disturbs and public health. 1st International Congress on
Brimacombe, J., Murray, A., 1995. Envenomation by ingram’s Envenomations and Their Treatments. Paris.
brown snake (Pseudonaja ingrami). Anaesth Intens Care 23, Murthy, J.M.K., Kishore, L.T., Naidu, K.S., 1997. Cerebral
231–233. infarction after envenomation by viper. J Comput Assist
Charak, B.S., Charak, K.S., Pal, V.R., Parikh, P.M., Gupta, V.K., Tomogr 21, 35–37.
1988. Coagulopathies in viper bites. J Postgrad Med 34, 80–83. Nocera, A., Gallagher, J., White, J., 1998. Severe tiger snake
Chippaux, J.P., 1998. Snake bites: appraisal of the global situation. envenomation in a wilderness environment. Med J Aust 168,
Bull. World Health. Organ 76, 515–524. 69–71.
966 J. White / Toxicon 45 (2005) 951–967
Numeric, P., Moravie, V., Didier, M., Chatot-Henrey, D., Cirille, S., Tibballs, J., Sutherland, S.K., Kerr, S., 1991. Studies on Australian
Bucher, B., Thomas, L., 2002. Multiple cerebral infarctions snake venoms, part II: the haematological effects of brown
following a snakebite by Bothrops caribbaeus. Am J Trop Med snake (Pseudonaja) species in the dog. Anaesth Intens Care 19,
Hyg 67, 287–288. 338–342.
Porath, A., Gilon, D., Schulchynska-Castel, H., Shalev, O., Tibballs, J., Sutherland, S.K., Rivera, R.A., Masci, P.P., 1992. The
Keynan, A., Benbassat, J., 1992. Risk indicators after cardiovascular and haematological effects of purified prothrom-
envenomation in humans by Echis coloratus (Mid-east saw bin activator from the common brown snake (Pseudonaja
scaled viper). Toxicon 30, 25–32. textilis) and their antagonism with heparin. Anaesth Intens Care
Reid, H.A., 1977. Prolonged defibrination syndrome after bite by 20, 28–32.
the carpet viper Echis carinatus. B M J 2, 1326. Tun-Pe, Phillips, R.E., Warrell, D.A., Moore, R.A., Tin-Nu-Swe,
Reid, H.A., Thean, P.C., Chan, K.E., Baharom, A.R., 1963. Clinical Myint-Lwin, Burke, C.W., 1987. Acute and chronic pituitary
effects of bites by Malayan viper (Ancistrodon rhodostoma). failure resembling Sheehan’s syndrome following bites by
Lancet, March 1963;, 617–621. Russell’s viper in Burma. Lancet 2, 763–767.
Reid, H.A., Chan, K.E., Thean, P.C., 1963. Prolonged coagulation Warrell, D.A., 1995. Clinical Toxicology of Snakebite in Africa and
defect (defibrination syndrome) in Malayan pit viper bite. the Middle East. In: Meier, J., White, J. (Eds.), Handbook of
Lancet, March 1963;, 621–626. Clinical Toxicology of Animal Venoms and Poisons. CRC
Revault, P, (1995) Ecology of Echis ocellatus and peri-urban bites Press, Boca Raton, pp. 433–492.
in Ouagadougou (Burkino Faso). 1st International Congress on Warrell, D.A., 1995. Clinical Toxicology of Snakebite in Asia. In:
Envenomations and Their Treatments. Paris. Meier, J., White, J. (Eds.), Handbook of Clinical Toxicology of
Sano-Martins, I.S., Fan, H.W., Castro, S.C.B., Tomy, S.C., Animal Venoms and Poisons. CRC Press, Boca Raton, pp. 493–
Franca, F.O.S., Jorge, M.T., Kamiguti, A.S., Warrell, D.A., 594.
Theakston, R.D.G., 1994. BIASG Reliability of the Warrell, D.A., 1989. Snake venoms in science and clinical
simple 20 min whole blood clotting test (WBCT20) as an medicine: Russell’s viper; biology, venom and treatment of
indicator of low plasma fibrinogen concentration in bites. Trans R Soc Trop Med Hyg 83, 732–740.
patients envenomed by Bothrops snakes. Toxicon 32, Warrell, D.A., Pope, H., Prentice, C.R.M., 1976. Disseminated
1045–1050. intravascular coagulation caused by the carpet viper (Echis
Schapel, G.J., Utley, D., Wilson, G.C., 1971. Envenomation by the carinatus); trial of heparin. Brit J Haem 33, 335–342.
Australian common brown snake Pseudonaja (Demansia) Warrell, D.A., Davidson, N.M., Greenwood, B.M., Ormerod, L.D.,
textilis textilis. Med J Aust 1, 142–144. Pope, H., Watkins, B.J., Prentice, C.R.M., 1977. Poisoning by
Sprivulis, P., Jelinek, G.A., 1995. Fatal intracranial haematomas in bites of the saw scaled or carpet viper (Echis carinatus) in
two patients with brown snake envenomation. Med J Aust 162, Nigeria. Q J Med 46, 33–62.
215–216. Warrell, D.A., Looareesuwan, S., Theakston, R.D.G., Phillips, R.E.,
Sutherland, S.K., 1992. Deaths from snake bite in Australia, 1981- Chanthavanich, P., Virivan, C., Spanaranond, W., Karbwang, J.,
1991. Med J Aust 157, 740–746. Ho, M., Hutton, R.A., Vejcho, S., 1986. Randomised compari-
Sutherland, S.K., Leonard, R.L., 1995. Snakebite deaths in Australia tive trial of three monospecific antivenoms for bites by the
1992-1994 and a management update. Med J Aust 163, Malayan pit viper (Calloselasma rhodostoma) in southern
616–618. Thailand; clinical and laboratory correlations. Am. J Trop
Sutherland, S.K., Tibballs, J., 2001. Australian Animal Toxins. Med Hyg 35, 1235–1247.
Oxford University Press, Melbourne. Warrell, D.A., Bhetwal, B.B., Chugh, K.S., Lalloo, D.G.,
Swinson, C., 1976. Control of antivenom treatment in Echis Looareesuwan, S., Win, M.M., Sjostrom, L.,
carinatus (carpet viper) poisoning. Trans. R Soc Trop Med Hyg Theakston, R.D.G., Watt, G., White, J., 1999. Asian snakes
70, 85–87. and snakebite. Southeast Asian J Trop Med Public Health 30
Than-Than, Khin-Ei-Han, Hutton, R.A., Myint-Lwin, Tin-Nu-Swe, (suppl. 1), 1–85.
Phillips, R.E., Warrell, D.A., 1987. Brit J Haematol 65, Weis, J.R., Whatley, R.E., Glenn, J.L., Rodgers, G.M., 1991.
193–198. Prolonged hypofibrinogenemia and protein C activation after
Thomas, L., Tyburn, B., Bucher, B., Pecout, F., Ketterle, J., envenoming by Echis carinatus sochureki. Am J Trop Med Hyg
Rieux, D., Smadja, D., Garnier, D., Plumelle, Y., 1995. 44, 452–460.
Prevention of thromboses in human patients with Bothrops White, J., 1981. Ophidian envenomation; a South Australian
lanceolatus envenoming in Martinique; failure of anticoagulants perspective. Rec Adelaide Child Hosp 2, 311–421.
and efficacy of a monospecific antivenom. Am J Trop Med Hyg White, J., 1987a. Elapid snakes: venom production and bite
52, 419–426. mechanism. In: Covacevich, J., Davie, P., Pearn, J. (Eds.),
Thomas, L., Tyburn, B., Ketterle, J., Biao, H., Moravie, V., Toxic Plants and Animals: a guide for Australia, 504. Queens-
Rouvel, C., Plumelle, Y., Bucher, B., Canonge, D., Marie- land Museum, p. 504.
Nelly, C.A., Lang, J., 1998. Prognostic significance of White, J., 1987b. Elapid snakes: venom toxicity and actions. In:
clinical grading of patients envenomed by Bothrops lanceo- Covacevich, J., Davie, P., Pearn, J. (Eds.), Toxic Plants and
latus in Martinique. Trans Roy Soc Trop Med Hyg 92, Animals: a guide for Australia. Queensland Museum, p. 504.
542–545. White, J., 1987c. Elapid snakes: aspects of envenomation. In:
Tibballs, J., Henning, R.D., Sutherland, S.K., Kerr, A.R., 1991. Covacevich, J., Davie, P., Pearn, J. (Eds.), Toxic Plants and
Fatal cerebral haemorrhage after tiger snake (Notechis scutatus) Animals: a guide for Australia. Queensland Museum,
envenomation. Med J Aust 154, 275–276. p. 504.
J. White / Toxicon 45 (2005) 951–967 967
White, J., 1987d. Elapid snakes: management of bites. In: White, J., Fassett, R., 1983. Acute renal failure and coagulopathy
Covacevich, J., Davie, P., Pearn, J. (Eds.), Toxic Plants and after snakebite. Med J Aust 2, 142–143.
Animals: a guide for Australia. Queensland Museum, p. 504. White, J., Williams, V., 1989. Severe envenomation with
White, J., 1995. Clinical Toxicology of Snakebite in Australia and convulsion following multiple bites by a common
New Guinea. In: Meier, J., White, J. (Eds.), Handbook of brown snake Pseudonaja textilis. Aust Paediatr J 25,
Clinical Toxicology of Animal Venoms and Poisons. CRC 109–111.
Press, Boca Raton, pp. 595–618. White, J., Tomkins, D., Steven, I., Williams, V., 1983. 4) Tiger
White, J., 1995. Poisonous and Venomous Animals—the Phys- snake bite. Rec Adelaide Child Hosp 3, 169–173.
ician’s View. In: Meier, J., White, J. (Eds.), Handbook of White, J., Duncan, B., Wilson, C., Williams, V., Lloyd, J., 1992.
Clinical Toxicology of Animal Venoms and Poisons. CRC Coagulopathy following Australian elapid snakebite; a review
Press, Boca Raton, pp. 9–26. of 20 cases. In: Gopalakrishnakone, P., Tan, C.K. (Eds.), Recent
White, J., 2000. Why do people still die from brown-snake bites?. Advances In Toxinology Research. National University of
Emerg Med 12, 204–206. Singapore, Singapore, pp. 337–344.
White, J., 2004a. Overview of venomous snakes of the world. In: Williams, V., White, J., 1997. Snake venom and snakebite in
Dart, R. (Ed.), Medical Toxicology. Lippincott, Williams and Australia. In: Thorpe, R.S., Wuster, W., Malhotra, A. (Eds.),
Wilkins, pp. 1543–1559. Evolution and Snakebite; Venomous Snakes. Zoological
White, J., 2004b. Elapid snakes. In: Dart, R. (Ed.), Medical Society of London, London, pp. 205–217.
Toxicology. Lippincott, Williams and Wilkins, pp. 1566–1578. Yatziv, S., Manny, N., Ritchie, J., Russell, A., 1974. The induction
White, J., 2004c. Viperid snakes. In: Dart, R. (Ed.), Medical of afibrinogenaemia by Echis colorata snake bite. J Trop Med
Toxicology. Lippincott, Williams and Wilkins, pp. 1579–1591. Hyg 77, 136–138.