snake venoms and coagulopathy
TRANSCRIPT
Snake venoms and coagulopathy
Julian White*
Toxinology Dept, Women’s and Children’s Hospital, North Adelaide SA 5006, Australia
Available online 12 April 2005
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.
Keywords: Snakebite; Coagulopathy; Antivenom; Thrombosis; Haemorrhage
1. Introduction
Interference with aspects of the human haemostatic system
is a common theme amongst snake venoms, encompassing all
four families of venomous snakes, to a greater or lesser degree
(Meier & Stocker 1995). This is reflected in the importance of
coagulopathy clinically, following snakebite in all continents
(except Antarctica, which has no snakes). However, while
coagulopathy may be important in humans envenomed by
snakes, it is not always the key venom effect responsible for
morbidity or mortality, yet may act synergistically with other
major venom effects, to the detriment of human health.
Similarly it should be remembered that humans are not a
natural prey species for any venomous snake and the effect of
any venom component in the intended prey may be rather
different to the effect in humans.
2. An overview of global snakebite
Globally venomous snakebite is estimated to affect
greater than 2.5 million humans annually, of whom more
0041-0101/$ - see front matter q 2005 S. Yamamoto. Published by Elsev
doi:10.1016/j.toxicon.2005.02.030
* Corresponding author. Fax: C61 8 81616049.
E-mail address: [email protected].
than 100,000 will die (Chippaux, 1998). The burden of
morbidity and mortality is greatest in the rural tropics
(Lalloo et al, 1995; Laing et al, 1995; Warrell et al, 1999),
but snakebite is not confined to poorer rural tropical areas.
There is evidence that some of the most dangerous
venomous snakes are invading urban areas, putting new
groups of humans at significant risk (Melgarejo & Aguiar,
1995; Revault, 1995). Even in temperate westernised
countries, snakebite from wild snakes still occurs, if
infrequently in some areas, but there is the added problem
of bites from exotic captive snakes. These latter may pose
special challenges to the health system, as few doctors in
Europe or North America are trained in how to manage such
envenoming. Information resources are available to assist in
such situations (Clinical Toxinology Resources Website;
www.toxinology.com).
There are many potential effects in humans following
envenoming by snakes, but just a few broad categories are of
major clinical significance (White, 2004a). They are; (1)
flaccid paralysis; (2) systemic myolysis; (3) coagulopathy
and haemorrhage; (4) renal damage and failure; (5)
cardiotoxicity; (6) local tissue injury at the bite site. Each
of these may cause a number of secondary effects, each with
potential morbidity and mortality. Any single species of
snake may show activity in one or more of these categories,
Toxicon 45 (2005) 951–967
www.elsevier.com/locate/toxicon
ier Ltd. All rights reserved.
Table 1
Snakes considered to cause medically significant effects on the haemostatic system
Scientific name Common name Effect
COLUBRIDAE
Dyspholidus typus Boomslang Coagulopathy and haemorrhage
Thelotornis spp. Vine snakes Coagulopathy and haemorrhage
Rhabdophis spp. Yamakagashi, red necked keelback Coagulopathy and haemorrhage
ELAPIDAE
Hoplocephalus spp. Australian broad headed snakes Coagulopathy and haemorrhage
Micropechis ikaheka New Guinea small eyed snake Anticoagulant and haemorrhage
Notechis spp. Australian tiger snakes Coagulopathy and haemorrhage
Oxyuranus spp. Australian taipans Coagulopathy and haemorrhage
Pseudechis spp. Australian mulga snakes Anticoagulant and haemorrhage
Pseudonaja spp. Australian brown snakes Coagulopathy and haemorrhage
Tropidechis carinatus Rough scaled snake Coagulopathy and haemorrhage
VIPERIDAE
Agkistrodon spp. American copperheads Coagulopathy and haemorrhage
Bitis spp. African puff adders, Gaboon vipers etc Coagulopathy and haemorrhage
Bothrops spp. Includes Bothriechis, Cerriphidion,
Ophryacus, Porthidium spp.
Central and South American pit vipers Coagulopathy and haemorrhage
Bothrops lanceolatus Martinique viper Coagulopathy; thrombosis with
DVT and pulmonary embolus
Calloselasma rhodostoma Malayan pit viper Coagulopathy and haemorrhage
Cerastes spp. North African horned vipers Coagulopathy and haemorrhage
Crotalus spp. (selected) North American rattlesnakes Coagulopathy and haemorrhage
Daboia russelii Russell’s viper Coagulopathy and haemorrhage
Echis spp. Saw scaled vipers Coagulopathy and haemorrhage
Lachesis spp. Bushmasters Coagulopathy and haemorrhage
Trimeresurus spp. Green pit vipers Coagulopathy and haemorrhage
Vipera spp. (selected) Includes Macrovipera spp. Selected European vipers Coagulopathy and haemorrhage
J. White / Toxicon 45 (2005) 951–967952
though rarely all six. In the past there has been an
assumption that a single snake species will generally
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
is entirely incorrect. Some of the worst cases of local tissue
injury are caused by elapid bites (selected Asian and African
cobras) (Warrell, 1995a; Warrell, 1995b) and some vipers
(eg South American rattlesnakes) cause minimal local
effects (Fan & Cardoso, 1995). Similarly, some vipers can
cause paralysis or myolysis, while some elapids cause
Table 2
Snakes considered to have medically significant haemorrhagins
Scientific name Common name
VIPERIDAE
Agkistrodon spp. American copperheads
Bitis spp. African puff adders, Gab
Bothrops spp. Central and South Amer
Calloselasma rhodostoma Malayan pit viper
Crotalus spp. (selected) North American rattlesna
Daboia russelii Russell’s viper
Echis spp. Saw scaled vipers
Trimeresurus spp. Green pit vipers
Vipera spp. (selected) Selected European viper
severe coagulopathy (White, 2004a; White, 2004b; White,
2004c; Warrell, 1995a; Warrell, 1995b; White, 1995a).
3. An overview of coagulopathy induced by snakebite
A brief summary of major snake groups causing coagulo-
pathy and/or haemorrhage is presented in Tables 1 and 2.
The diverse array of venom components affecting human
haemostasis is mirrored only partially in a diversity of clinical
effects. An outline of the broad effects is presented in Fig. 1.
Effect
Disintegrins and haemorrhagins
oon vipers etc Disintegrins and haemorrhagins
ican pit vipers Disintegrins and haemorrhagins
Haemorrhagins
kes Disintegrins and haemorrhagins
Haemorrhagins
Disintegrins and haemorrhagins
Disintegrins and haemorrhagins
s Disintegrins and haemorrhagins
Fig. 1. Diagrammatic representation of principle ways snake venom interacts with human haemostasis. (Illustration copyright q Dr. Julian
White).
J. White / Toxicon 45 (2005) 951–967 953
Indeed, in practical clinical terms, the range of clinical
problems presented by this venom diversity is limited. The
principal problems encountered are listed in Table 3.
Essentially these can be further reduced to the following; (1)
reduced coagulability of blood, resulting in an increased
tendency to bleed; (2) frank bleeding due to damage of the
blood vessels; (3) secondary effects of increased bleeding,
ranging from hypovolaemic shock to secondary organ
damage, such as intracerebral haemorrhage, anterior pituitary
haemorrhage or renal damage; (4) direct pathologic thrombo-
sis and its sequelae, particularly pulmonary embolism (seen
only with envenoming by Martinique vipers and related
species from the West Indies; Thomas et al 1995; Numeric
et al, 2002). Each one of these effects can cause morbidity and
even mortality. Between them they may represent as much as
half of all snakebite morbidity and mortality worldwide.
Table 3
Principal types of toxin effects on the haemostatic system (after
Markland, 1998)
Toxin type Effect
Procoagulants Factor V activating
Factor X activating
Factor IX activating
Prothrombin activating
Fibrinogen clotting
Anticoagulant Protein C activating
Factor IX/X activating protein
Thrombin inhibitor
Phospholipase A2
Fibrinolytic Fibrin(ogen) degradation
Plasminogen activation
Vessel wall interactive Haemorrhagins
Platelet activity Platelet aggregation inducers
Platelet aggregation inhibitors
Plasma protein activators SERPIN inhibitors
J. White / Toxicon 45 (2005) 951–967954
However, it should be remembered that while snakebite-
induced coagulopathy can appear severe, providing some truly
horrifying clinical laboratory results, this does not always
equate with actual major morbidity in individual patients.
Further, it should be emphasised that snakebite coagulopathy
is not entirely like other forms of coagulopathy, so that
standard treatments used for common coagulopathies are often
entirely ineffective or even dangerous if applied to snakebite
coagulopathy (White, 2004a; Warrell et al, 1976; Warrell
et al., 1977). As in most areas of medicine, a principal part of
treating the patient should be elimination of the cause of
disease, in this case neutralisation of venom using antivenom.
4. The procoagulants and coagulopathy
A wide variety of venom components can act as
procoagulants, causing in-vivo activation of the coagulation
system, but in most cases, this does not result in massive
thrombosis and consequent embolic disease, but rather
causes consumption of coagulation factors, resulting in
clinical anticoagulation (White, 2004a; Markland, 1998).
This may cause profound abnormalities of clinical labora-
tory tests, but unless there is some bleeding point, may not
result in clinically significant bleeding (White, 2004a;
Warrell et al, 1977). However, this should not be
misinterpreted as therefore of small clinical significance;
these patients are but a small step away from a catastrophic
haemorrhage.
The rapidity of development and resolution of procoa-
gulant coagulopathy is quite variable. Time from bite to
complete defibrination can be as little as 15 min for some
Australian elapid snakes, where complete resolution, with-
out antivenom treatment, may take at least many hours and
for some species, days (White, 1995a). The spontaneous
resolution of procoagulant coagulopathy is an important
phenomenon clinically, as it may muddy the diagnostic and
treatment process, if not understood.
Some of the earliest reported procoagulant actions of
snake venoms were reported for Russell’s viper, Daboia
russelii, which contains Factor V and Factor X activator.
Envenoming by these snakes is associated with marked
coagulopathy and haemorrhage, though the precise mix of
systemic effects varies markedly within this single species,
dependant on the geographic population. Thus snakes from
Sri Lanka, while causing coagulopathy and renal damage,
also cause flaccid paralysis and myolysis, clinical effects
less common in other parts of the range of this snake
(Warrell, 1989). The incidence of non-clotting blood in
Daboia bites is high; 62% in Pranchinburi (Thailand), 44%
in Tharawaddy (Burma), 59% in Anuradhapura (Sri Lanka)
(Warrell, 1989). Coagulopathy can develop rapidly, but not
always, with some cases having initially normal coagulation
at 1–2 h post bite, but severe coagulopathy with defibrina-
tion by 4–8 h post bite (Than-Than et al, 1987). In addition
to local bleeding from the bite site, venepuncture sites and
from the gums, there may be gastrointestinal bleeding, with
haematemesis and melaena, bleeding into the skin, causing
ecchymoses and discoid haemorrhages, haematuria (72% of
Burmese cases), and less commonly, bleeding into the
respiratory tract (haemoptysis), menorrhagia and intracra-
nial bleeding. The latter is likely to be fatal, although very
localised bleeding involving the anterior pituitary can occur,
in association with shock. This can result in acute and
chronic hypopituitarism, though in some cases, as with
cerebral injury, early thrombosis may be a factor (see later
comments) (Tun-Pe et al, 1987).
Australian elapids are amongst the most potent in
causing procoagulant coagulopathy, though not all species
cause this effect (Schapel et al, 1971; Herrmann et al, 1972;
White, 1987a–d, 1995a; Williams & White, 1997; Brima-
combe & Murray, 1995; Nocera et al., 1998; Sutherland &
Tibballs, 2001). The typical clinical laboratory findings are
shown in results from actual cases (Tables 4–6) (White,
1981; White, 1987c; White et al, 1983; White et al, 1983-4;
White, 1989; White et al., 1992). Spontaneous bleeding is
uncommon to rare following bites by these snakes, but any
point of vascular damage, even a needle prick, can cause
major bleeding (White, 1995b). As blood vessels develop
small areas of damage frequently, normally undergoing
repair without major adverse sequelae, patients with
procoagulant coagulopathy may develop unexpected mas-
sive haemorrhage at any time, especially intracranial, where
such uncontrolled bleeds are usually fatal, even with
antivenom treatment (White, 2004a; Warrell, 1995a;
Warrell, 1995b; Warrell et al, 1977; Sprivulis & Jelinek,
1995; Tibballs et al, 1991a; Sutherland, 1992; Sutherland &
Leonard, 1995). At least with the Australian elapids, there is
a further twist to the procoagulant coagulopathy story.
Experiments in dogs have shown that for brown snake
(Pseudonaja) envenoming, there can be a brief period of
true coagulation, with thrombus formation, as the venom
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
No.
1 2 3 4 5 6 7 8 9 10
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.
J. White / Toxicon 45 (2005) 951–967 955
first reaches the circulation and before fibrinolysis is
activated (Tibballs et al, 1991b; Tibballs et al., 1992).
The resultant thrombi can occlude critical vessels, notably
coronary vessels, resulting in cardiac arrythmias and arrest.
Table 5
Coagulation results for 6 cases of tiger snake (Notechis spp.) bite; results s
prior to antivenom therapy
PATIENT No. 1 2 3
SEX M M F
AGE 33 66 73
WBCT – O30 –
PR/INR O12 O12 1.6
APTT O150 O150 30
TCT O150 – 35.5
Fibrinogen !0.04 – 0.48
FDP – 10000 O80
D-Dimer 32–64 – –
Factor II 0.79 – –
Factor V 0.10 – –
Factor VII – – –
Factor VIII 0.46 (0.29) – –
Factor IX – – –
Factor X – – –
Protein C 10% – –
Plasminogen 52% – –
Platelets 317 200 179
Notes: All cases were bites by N. scutatus except case 5 which was a bite fr
was given prior to full coagulation studies, the results given being 4 h afte
Case 5 also occurred in a country area and results were from a sample taken
These thrombi are quickly destroyed once fibrinolysis
activates, but even a few minutes of such thrombotic
complications can be devastating for the victim. It is likely
that this brief thrombotic window is the cause of the well
elected as earliest full set indicative of coagulopathy, in most cases
4 5 6
F M F
2 10 59
O30 – –
O12 1.2 O12
O150 39 O150
– – O150
!0.1 0.69 !0.1
5000 – –
– 16–32 O16
0.37 – –
0.06 – –
0.95 – –
!0.01 – –
0.35 – –
0.55 – –
– – –
– – –
288 463 308
om N. ater. Case 3 occurred in a country area and antivenom therapy
r therapy indicating residual evidence of a corrected coagulopathy.
18 h after envenoming, again indicative of a resolved coagulopathy.
Table 6
Coagulation results for 4 cases of taipan (Oxyuranus spp.) bite;
results selected as earliest full set indicative of coagulopathy, in
most cases prior to antivenom therapy.
PATIENT
No.
1 2 3 4
SEX F F M M
AGE 29 72 10 65
PR/INR O12 2.5 7.5 O12
APTT O150 72 150 O150
TCT O150 – – O150
Fibrinogen !0.1 – – !0.01
FDP – – 1280 O1280
D-Dimer O16 O64 – O16
Factor II 0.87 – – 0.83
Factor V 0.01 – – 0.07
Factor VII – – – 0.73
Factor
VIII
(0.02) – – 0.03
Factor IX – – – 1.05
Factor X – – – 0.97
Factor XI – – – 1.19
Factor XII – – – 0.70
Protein C 8% – – !10%
Plasmino-
gen
17% – – 36%
Platelets 231 244 295 166
Notes: Cases 1,2,3 were bites by O. scutellatus and case 4 was a bite
by O. microlepidotus. Case 2 was unusual in that the coagulopathy
was mild and there was no evidence of neurotoxic paralysis or
myolysis as might be predicted for a significant taipan bite, but the
patient developed severe renal failure with renal cortical necrosis.
Case 4 is only the 3rd recorded envenoming of a human by the
inland taipan which has the most potent snake venom known and is
technically the worlds most dangerous snake. Case 3 was interstate
and little data is available.
Table 7
Serial coagulation results after a saw scaled viper, Echis ocellatus
bite (adapted from Ajzenberg et al, 1993)
Day after bite 5 9 10 42
Prothrombin time %
(nZ70–130)
!10 80 98 99
aPTT (nZ35–42) O150 29 28 32
Fibrinogen (nZ0.2–0.4 g/
100 ml)
!0.05 0.12 0.18 0.38
D-dimer (nZ!0.4 mg/ml) 114 8 3 0.5
Factor II% (nZ80–120) 14 86 ND ND
Factor V% (nZ80–120) 37 86 ND ND
Platelets (nZ150–400!
109/l)
305 ND 430 319
J. White / Toxicon 45 (2005) 951–967956
documented cases of early cardiac collapse following brown
snake bite, unhappily a cause of fatalities which no amount
of antivenom can prevent, because this is generally a pre-
hospital phenomenon (White, 2000). Potentially, of course,
if injected intravenously, most procoagulant venoms could
cause a cardiac catastrophe, as was shown many years ago
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).
The procoagulants in certain viper venoms, notably
the carpet or saw scaled vipers (Echis spp.) produce a
more devastating clinical picture than the Australian
elapids, probably because of the presence of haemor-
rhagins in the venom as well, working synergistically
with the procoagulants (Markland FS, 1998; Warrell
et al, 1976; Warrell et al., 1977; Charak et al, 1988;
Yatziv et al, 1974;). These snakes, in addition to causing
local tissue injury, exert their principle systemic effects
through these two coagulopathic actions. In consequence,
clinical manifestations of bleeding are common, such as
bleeding gums and bite sites, but even here, catastrophic
bleeding into internal organs, particularly the brain,
though well documented, appears to be uncommon
(Warrell et al, 1977; Murthy et al, 1997). Spontaneous
bleeding was seen in 66 of 115 cases of Echis
(carinatus) ocellatus bites in Nigeria, of whom 40 had
bleeding gums, 29 blood stained sputum or saliva, 10 had
epistaxis, 6 developed haematomas, 3 had haematemesis,
3 had subarachnoid bleeds and 2 melaena (Warrell et al,
1977). In this series, 2 patients died following intracra-
nial bleeding and 3 died from haemorrhagic shock. In a
series of 68 cases of Echis coloratus bites in Israel, the
majority (40) did not show active bleeding, while in 19
bleeding was minor and in only 9 was there ‘major’
bleeding (Porath et al, 1992). In this series, average
duration of coagulopathy was 2.8 days, with a maximum
of 9 days. There were no fatalities. Similarly, amongst 7
children bitten by Echis coloratus in Saudi Arabia, only
3 developed hypofibrinogenaemia and there were no
deaths (Annobil, 1993). Without antivenom treatment, a
coagulopathy can persist for many days (Table 7), with
one case taking 30 days for return of normal fibrinogen
levels (Reid Ha, 1977). Similar coagulopathy with
depletion of fibrinogen has been reported for Echis
sochureki (Weis et al, 1991) and E. pyramidum (Gillissen
et al, 1994).
5. The fibrinogen clotting toxins, fibrinolytics
and coagulopathy
Fibrinogen clotting and fibrinolytic snake venom toxins
exert a direct effect on the actual thrombus-forming protein,
fibrinogen, but in varying ways (Markland, 1998). Fibrino-
gen may be split to fibrin and then degradation products, or
it may be only partially split, leaving an ineffective form of
fibrinogen circulating, the end result being an increased
bleeding tendency through either mechanism. As with the
procoagulants, this need not cause spontaneous bleeding,
but certainly increases the risk of a major bleed and can have
Table 8
Snake species with venom components causing fibrinogen clotting action (after Markland, 1998)
Genus and species Fibrinopeptide A split
(venombin A group)
Fibrinopeptide B split
(venombin B group)
Split of both A and B
(venombin AB group)
Agkistrodon contortrix contortrix – Venzyme –
Bitis gabonica – – Gabonase
Bothrops atrox Batroxobin – –
Calloselasma rhodostoma Ancrod – –
Crotalus adamanteus Crotalase – –
Gloydius halys pallas – C –
Table 9
Snake species with fibrinolytic venom components (after Markland,
1998). This list is not complete, but rather is representative
Genus and species Fibrinolytic component
ELAPIDAE
Naja nigricollis a-chain fibrinogenase
VIPERIDAE
Agkistrodon contortrix
contortrix
a&b-chain
Agkistrodon contortrix
mokasen
a-chain fibrinogenase
Bothrops moojeni Batroxobin—plasminogen activator
J. White / Toxicon 45 (2005) 951–967 957
severe effects, if working synergistically with a haemor-
rhagin. A number of snakes utilise these mechanisms
(Table 8). Clinically, at least some of these toxins have
major effects, a classic example being the Malayan pit viper,
Calloselasma rhodostoma. This snake causes major coagu-
lopathy and bite-site tissue damage (Reid et al, 1963a). It is a
very significant cause of snakebite morbidity within its
range, in SE Asia (Warrell, 1995b; Warrell et al, 1986).
Patients develop a profound haemorrhagic defibrination
coagulopathy, with both spontaneous bleeding and incoa-
gulable blood. The onset of coagulopathy can be rapid, with
incoagulable blood as soon as 30 min post-bite (Reid et al,
1963a), but full defibrination (and incoagulable blood) may
also be delayed up to 72 h post-bite even though venom and
fibrin(ogen) degradation products may be present at
presentation (Ho et al, 1986). The duration of coagulopathy
can be lengthy, from 6–26 days (incoagulable blood for up
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
initiate the breakdown process, normally caused by
plasmin(ogen). These are mostly a- or b-fibrinogenases,
but unlike plasmin, are not serine proteases, so are not
susceptible to SERPINS (Markland, 1998). Selected
examples are listed in Table 9. The contribution of these
toxins to coagulopathy and bleeding in humans remains
uncertain, as they generally exist in venoms with a variety of
other haematologically active toxins, however in two
species without such a diversity of other components
(Naja nigricollis, Crotalus basiliscus) haemorrhagic fea-
tures are not a significant part of the clinical profile of
envenoming. In those species with coagulopathic toxins, the
combination of fibrinogen activation and direct fibrinolysis
is likely to enhance haemorrhagic potential. Similarly, those
venoms possessing plasminogen activating toxins will also
enhance haemorrhagic potential.
Cerastes cerastes Cerastase—a, b, g-chain fibrinogenaseCrotalus adamanteus Plasminogen activator
Crotalus atrox Atroxase-a, b-chain fibrinogenase;
plasminogen activator
Crotalus basiliscus a, b-chain fibrinogenase
Trimeresurus
flavoviridis
Habutoxin-plasminogen activator
(indirect)
Trimeresurus stejnegeri TSV-PA-direct plasminogen activator
Vipera lebetina l3batas3-a, b-chain fibrinogenase
6. Platelet active venoms and coagulopathy
Platelets form a vital part of the haemostatic process,
acting as the ‘front line’ in plugging any vascular defect, as
well as providing activating surfaces for the coagulation
cascade. They are metabolically active and subject to many
forms of attack. There are two principal effects likely; (1)
inhibition of platelet activity, thus reducing their effective-
ness in haemostasis; (2) promotion of platelet activity,
increasing their contribution to haemostasis, in this case
pathologic. To these must be added the possibility of
reducing availability of platelets, resulting in low circulating
numbers (thrombocytopenia), itself also a risk for increased
bleeding.
A number of snake venoms can induce one or more of
these effects, depending on concentration of venom
(Table 10). While inhibition of platelet activity can increase
the risk of bleeding, it is unclear if this is of great clinical
significance in envenomed humans. Thrombocytopenia,
however, is far more important and is a feature of
envenoming by a number of snakes, such as North American
rattlesnakes. The degree of linkage between thrombocyto-
penia and increased bleeding in snakebite is unclear.
7. Anticoagulant venoms and coagulopathy
Some snake venoms contain toxins that are direct or
indirect anticoagulants, that inhibit the clotting process, thus
Table 10
Snakes with platelet-active venom components (after Markland, 1998); this is an incomplete list, as new inhibitors especially are being
constantly described
Genus and species Platelet inhibition Platelet aggregation
ELAPIDAE
Austrelaps superba C (phospholipase A2)
Naja mossambica C (phospholipase A2)
Naja nigricollis C (a-fibrinogenases)
Ophiophagus hannah C (phospholipase A2)
Pseudechis papuanus C (phospholipase A2)
VIPERIDAE
Agkistrodon contortrix contortrix C (disintegrin-contortostatin) C (phospholipase A2)
Bitis arietans C (disintegrin; bitistatin) C (bitiscetin)
Bitis gabonica C (disintegrin-gabonin)
Bothrops atrox C (serine protease-thrombocytin; botroce-
tin)
Bothrops jararaca C (disintegrin-like-jararhagin) C (GPIb binding protein-GPIb-BP)
Calloselasma rhodostoma C (a-fibrinogenases; disintegrins-kistrin,
rhodostomin)
C (aggretin)
Cerastes cerastes C (disintegrin-cersatatin) C (thrombin-like serine protease-cerasto-
cytin)
Cerastes vipera C (thrombin-like serine protease-cerasto-
bin)
Crotalus atrox C (collagen-mediated inhibitor-catrocol-
lastatin)
Crotalus durissus terrificus C (non-enzymatic-convuluxin)
Crotalus horridus horridus C (serine protease-crotalocytin; GPIb
binding proteins-CHH-A, CHH-B)
Crotalus viridis C (collagen-mediated inhibitor-crovidisin)
Daboia russelii C (phospholipase A2)
Echis carinatus C (disintegrin-echistatin; VoWillebrand
binding inhibitor-echicetin)
Eristocophis macmahoni C (disintegrin-eristostatin)
Echis multisquamatus C (disintegrin-multisquamatin)
Lachesis muta C (lectins)
Sistrurus miliaris barbouri C (disintegrin-barbourin)
Trimeresurus albolabris C (disintegrin-albolabrin) C (alboaggregins)
Trimeresurus elegans C (disintegrin-elegantin)
Trimeresurus flavoviridis C (disintegrin-triflavin, flavoviridin) C (GPIb binding proteins-flavocetin-A &
B)
Trimeresurus gramineus C (50-nucleotidase) C (aggregoserpentin)
Trimeresurus mucrosquamatus C (trimucytin)
Trimeresurus tokarensis C (GPIb binding protein-tokaracetin)
Tropidolaemus wagleri C (triwaglerin)
J. White / Toxicon 45 (2005) 951–967958
increasing the risk of bleeding. Clinically this may be little
different in effect than the consumptive route used by
procoagulants, although, in general, anticoagulant venoms
are associated with less severe pathologic bleeding than
consumptive venoms (procoagulants etc). There will,
however, be important differences in clinical laboratory
results that can be useful diagnostically. This is especially
true of Australian elapids, where one particular group
(mulga snakes; selected Pseudechis spp.), cause antic-
oagulant coagulopathy (Table 11). The key diagnostic
distinction is the absence of significant fibrinogen consump-
tion or elevation of degradation products in purely antic-
oagulant venoms such as Pseudechis (Table 12). In many of
the other species with anticoagulant toxins, they coexist
with coagulant and haemorrhagic toxins, thus producing a
far less clear or diagnostic clinical laboratory picture.
8. Thrombotic venoms and pathologic thrombosis
While a coagulant venom, by definition, induces some
degree of clotting, in most cases this is accompanied by
active fibrinolysis, resulting in a net loss of clotting capacity.
As discussed earlier, there may be a brief window of
thrombosis prior to activation of fibrinolysis. However, two
snakes, the Martinique viper (Bothrops lanceolatus) and
Table 11
Snakes with anticoagulant action in their venom (after Markland,
1998)
Genus and species Activity
ELAPIDAE
Pseudechis australis, colletti
VIPERIDAE
Agkistrodon contortrix
contortrix
Protein C activator
Bothrops jararaca Factor IX/X inhibitor; bothro-
jaracin-thrombin inhibitor
Deinagkistrodon acutus Factor IX/X inhibitor
Echis carinatus leucogaster Factor IX/X inhibitor
Trimeresurus mucrosquamatus Anticoagulant phospholipase
J. White / Toxicon 45 (2005) 951–967 959
the Saint Lucia viper (Bothrops caribbaeus) cause clinical
thrombosis and emboli routinely following envenoming
(Thomas et al 1995; Thomas et al 1998; Numeric et al
2002). Clinically this is manifest as deep vein thrombosis in
the legs (DVT) in most cases, with a significant incidence of
emboli, especially pulmonary emboli, which can prove
lethal, but also cerebral emboli and infarction. Despite this
distinctly different clinical problem, compared to all other
snakes affecting haemostasis, antivenom is even here, the
key treatment (Thomas et al 1995; Thomas et al., 1998).
While likely due to the brief thrombotic window that
may occur in the early stages of procoagulant envenoming,
as mentioned earlier, thrombotic events can occur in
association with procoagulant venoms. In addition to
concerns re early cardiac collapse seen with Australian
Pseudonaja bites (White, 2000; Johnston et al, 2002), there
are scattered cases for other species. Sri Lankan Russell’s
viper, Daboia russelii has been reported to cause cerebral
infarction secondary to thrombosis in key cerebral arteries,
resulting in permanent left hemiplegia (Ameratunga, 1972).
Especially Burmese and to a lesser extent Indian Daboia
russelii can cause anterior pituitary infarction, resulting in
acute and chronic pituitary failure, similar to Sheehan’s
syndrome (Tun-Pe et al, 1987).
Table 12
Illustrative case of anticoagulant coagulopathy (Collett’s snake,
Pseudechis colletti)
Time after
bite
1.5 3.0 6.5 8.5 12.0
INR O12 O12 1.1 1.1 1.1
APTT (secs) 62 58 24 26 27
Fibrinogen
(g/l)
4.7 4.35 – – 4.4
XDP !0.25 !0.25 !0.25 !0.25 !0.25
Platelets 186 179 161 170 181
Antivenom
therapy
– 1 vial at
5 hrs pst
bitea
– – –
a CSL Black Snake Antivenom.
9. Venoms and vascular injury; the haemorrhagins
A number of viperid snakes have evolved toxins that act
to increase vascular permeability or damage the vascular
endothelium; the haemorrhagins. Many of these are zinc
metalloproteinases (Markland, 1998). In their own right
they can cause pathologic bleeding and cause more severe
local effects in the bitten limb than might otherwise develop.
However, when combined with toxins affecting haemo-
stasis, reducing clotting ability, such as procoagulants, the
effects can be severe indeed. The clinical effects are seen
locally in the bitten limb and throughout the body. There
may be bleeding spontaneously from tissues, observable
often as bleeding gums, but also as bleeding into
the gastrointestinal tract (GIT), with haematemesis and
melaena; bleeding into the lungs, with haemoptysis;
bleeding into the genito-urinary tract (GUT), with haema-
turia or menorrhagia. Each of these can vary from mild to
severe, capable of causing life-threatening shock. This in
turn will produce further adverse effects, accelerating the
victim’s march to doom.
There are specific organs that are at special risk.
Pathologic bleeding into the brain as a result of haemor-
rhagins and coagulopathy is generally catastrophic for the
patient. Injury will occur immediately and within a short
time is likely to become irremediable and lethal, usually
before any therapeutic interventions, even antivenom, can
take effect (Fig. 2). This is the most dreaded, though
fortunately uncommon, complication of this venom
combination. Also within the cranium, there may be far
more specific haemorrhagic targeting, with anterior pitu-
itary haemorrhage and infarction (Fig. 3). This is
particularly a feature of envenoming by Russell’s viper
from Burma (Myanmar) and, to a lesser extent, India.
While early fatality can occur, it can be survivable,
Fig. 2. CT Scan of the head of a snakebite victim, showing major
intracranial haemorrhage secondary to venom-induced coagulo-
pathy. (photo copyright q Prof. David Warrell).
Fig. 3. Anterior pituitary haemorrhage and infarction at autopsy in a
victim of Burmese Russell’s viper bite. (photo copyright q Prof.
David Warrell).
Fig. 5. Bleeding gums in a victim of venom-induced coagulopathy.
(photo copyright q Prof. David Warrell).
Fig. 4. Persistent bleeding at the bite site in a victim of venom-
induced coagulopathy. (Illustration copyright q Dr. Julian White).
J. White / Toxicon 45 (2005) 951–967960
resulting in panhypopituitarism, essentially Sheehan’s
syndrome, otherwise seen in obstetric shock. The kidneys
are also particularly vulnerable. Renal failure, due either to
effects of haemorrhagins and/or coagulopathy, or second-
ary shock (or other venom-related causes) remains a
significant clinical problem globally. Even a ‘simple’
procoagulant coagulopathy can stress or critically injure
the kidneys, which must cope with reduced blood flow
coupled with the clearance of coagulopathy degradation
products. Renal damage varies from slight, temporary,
manifest as a rise in creatinine and urea, often with either
polyuria or mild oliguria, through acute renal failure,
usually anuric, to bilateral kidney destruction, generally
manifest as bilateral renal cortical necrosis. This latter is
not recoverable and the victim, if they survive, will be left
with either severely impaired renal function, or no
significant function, such that their survival depends on
chronic haemodialysis or renal transplantation. Even
reversible acute renal failure will prove lethal if adequate
support is unavailable; few developing tropical nations can
afford to support many patients with haemodialysis. Thus
renal failure remains a significant contributor to annual
snakebite fatalities.
In addition to renal failure as a specific complication of
envenoming, it can also be part of the triad, including
thrombocytopenia and haemolytic anaemia, designated as
‘haemolytic uraemic syndrome’ (HUS). This disease has a
variety of causes and can have a significant mortality rate.
HUS has been described in association with Russell’s viper
bite, Daboia russelii (Date et al, 1986), brown snake bite,
Pseudonaja spp. (Schapel et al, 1971; Harris et al, 1976)
and boomslang bite, Dispholidus typus (Lakier & Fritz,
1969).
10. Diagnosing venom induced coagulopathy
Venom-induced coagulopathy is often easy to diagnose,
either clinically, or by clinical laboratory testing. Clinically,
clues include spontaneous bleeding from the bite site
(Fig. 4), gums (Fig. 5) and any recent trauma, including
venepuncture sites (Figs. 6 and 7). Internal bleeding may be
hidden, or manifest as haematemesis, haemoptysis, haema-
turia etc. Bleeds into crucial organs will result, generally, in
signs, ranging from the very obvious (i.e. lapse into coma
with dilating pupils as a result of intracranial bleeding), to
the easily missed (in the early stages; i.e. oliguric renal
failure).
Clinical laboratory testing can reliably determine the
presence, often the nature of any venom-induced coagulo-
pathy, if it is still active. However, few rural tropical
hospitals can perform extended coagulation studies at all, let
alone urgently. Measuring whole blood clotting time,
though considered by many laboratories as an outdated
test, remains an invaluable tool in snakebite coagulopathy. It
is a simple test, easily performed without the need for
sophisticated equipment. All that is required, apart from
Fig. 6. Persistent bleeding at an IV site in a victim of venom-
induced coagulopathy (inland taipan). (Photo copyright q Dr.
Julian White).
J. White / Toxicon 45 (2005) 951–967 961
the victim’s blood, is a glass container in which to place the
blood and measure time to clot. The time taken to clot (or
absence of a clot) is measured and, if possible, clot
consistency can be determined. A further refinement,
developed by Warrell, is the 20 min whole blood cloting
test (20minWBCT) (Warrell et al, 1977; Warrell et al.,
1986; Sano-Martins et al, 1994). This simple variant, based
on extensive clinical experience and control studies, simply
determines, if, after 20 min, a clot is present. If there is no
clot the test is strongly predictive of coagulopathy. A
simple, rapid test, it has become a standard globally for
snakebite coagulopathy. Even where a full laboratory is
available, the 20minWBCT can give a more rapid, if less
detailed answer.
If full laboratory facilities are available, then extended
coagulation studies are appropriate. These should include
Fig. 7. Extensive bleeding following failed IV insertion into the
right jugular vein in a case of severe defibrination coagulopathy
(taipan bite). The resultant haemorrhage threatened to occlude the
airway, extended to the abdomen, and resulted in a halving of
haemoglobin levels in 3 h. (Photo copyright q Dr. Julian White).
prothrombin time (PT; INR), activated partial thromboplas-
tin time (aPTT or PTTK), fibrinogen level, fibrin(ogen)
degradation products (FDP, XDP, d-dimer) and platelet
count (this latter usually as part of a whole blood count,
including red cells and white cells). As kidney damage is
common with coagulopathy, renal function should also be
tested (creatinine and urea) and urine output carefully
documented.
Whichever testing method is used, it is crucial that serial
tests be performed. Even if initial testing is normal, late
developing coagulopathy can occur, especially if effective
first aid has been used. In general, if the initial studies are
normal and the patient is otherwise well, first aid is removed
and coagulation is retested after 2–3 h and, if normal, a
further 2-3 h later. For some snakes, testing should be
extended even further.
If tests reveal a coagulopathy then antivenom treatment
should be instituted (if available), followed by further
testing to ensure an adequate response and guide the need
for more antivenom.
Apart from determining if there is a coagulopathy,
laboratory tests can illuminate the type of coagulopathy.
This can be diagnostically important, if the choice of
antivenoms are mostly ‘monovalent’, as in Australia, and if
venom detection or a dead snake are not available. In this
Australian example, there are two principle patterns of
coagulopathy; defibrination and anticoagulation. Defibrina-
tion coagulopathy will manifest as prolonged PT/INR and
aPTT, with low to absent fibrinogen and elevated degra-
dation products. This pattern is seen with envenoming by
brown snakes (Pseudonaja spp.), tiger snakes (Notechis
spp.), rough scaled snakes (Tropidechis carinatus), taipans
(Oxyuranus spp.) and broad headed snakes (Hoplocephalus
spp.). If the coagulopathy is of the anticoagulant variety,
while PT/INR and aPTT may be prolonged, fibrinogen
should be normal and degradation products undetectable.
This pattern indicates envenoming by mulga snakes and
their relatives (Pseudechis australis, P. butleri, P. collettii)
(Table 12). So important is this distinction, it is a prime
separator in Australian snakebite diagnostic algorithms
(Fig. 8). The presence of coagulopathy is also used in
diagnostic algorithms in other regions, such as South East
Asia (Fig. 9).
11. Treating venom induced coagulopathy
Coagulopathy is generally a direct effect of toxins in
venom. It follows that removal of those toxins, using
antivenom, should allow return to normal haemostasis. Of
course, antivenom cannot repair injuries caused by the
coagulopathy, such as critical organ damage, nor can it
‘switch off’ secondary phenomena activated during the
coagulopathy, such as hyperfibrinolysis. It is therefore
important to give the correct antivenom as early as possible,
once coagulopathy is detected, in sufficient amounts, and be
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) 951–967962
Fig. 9. Diagnostic algorithm for determining the type of snake involved in South East Asian snakebite. (Modified from Warrell et al, 1999).
J. White / Toxicon 45 (2005) 951–967 963
prepared to give supplementary doses if required. Equally, it
is important to avoid giving other therapies that may
exacerbate the coagulopathic process. This is rather
different to management of most other causes of coagulo-
pathy, which generally represent derangement of normal
homeostatic mechanisms. Thus for disseminated intravas-
cular coagulation (DIC), which may resemble some types of
snakebite coagulopathy, it is common practice to ‘short
circuit’ the clotting process, by giving heparin, followed
later in selected cases by warfarin or similar. The patient
may also be given supplementary clotting factors, often as
fresh frozen plasma (FFP) or cryoprecipitate (cryo).
In snakebite coagulopathy, such treatments are generally
ineffective (Porath et al, 1992) and may be potentially
dangerous (Malik GM, 1995). Heparin will not ‘switch off’
the pathologic venom-induced coagulopathy, so will not
J. White / Toxicon 45 (2005) 951–967964
help, yet may induce its own degree of pathologic changes
to clotting, thus making things worse (Warrell et al, 1976a).
Similarly, the addition of extra substrate in FFP or cryo may
only add fuel to the venom-stoked fire, especially with
procoagulants, unless all venom has been removed (White,
1987c). This, in turn, will increase levels of degradation
products that must be cleared by the kidneys and may also
accelerate the hyperfibrinolytic state which can occur. This
increases the risk of spontaneous bleeding. Further, the
degradation products are, themselves, partially anticoagu-
lant, thus potentially deepening the crisis. Conversely, if
extra clotting factors are not considered until after there is
evidence that all venom has been neutralised, then often
they will be superfluous anyway, as the liver rapidly
replenishes depleted clotting factors. Cases of defibrination
where fibrinogen has been given in the absence of
antivenom therapy have confirmed the deleterious effect
of such treatment (Reid et al, 1963b).
There is some controversy regarding rate of replenish-
ment of clotting factors. Australian experience indicates
fibrinogen can reach measurable levels following defibrina-
tion reversal with antivenom, in about 3 h (White, 1987c),
but standard teaching elsewhere is a wait of 6 h (Warrell,
1995a; Warrell, 1995b). Certainly the longer wait will give a
more definitive result, but if insufficient antivenom has been
given, it doubles the period at risk, before more antivenom is
administered. The greater delay will, at least theoretically,
reduce the likelihood of giving unnecessary extra anti-
venom, an important issue in countries where antivenom is
in short supply. Where antivenom is generally available, as
in Australia, such considerations are less important, though
giving more antivenom than is necessary will increase
treatment cost and increase the likelihood of serum sickness,
which is generally dose-related.
Repeat dosing with antivenom may be required, not just
to provide a sufficient dose to neutralise acute venom levels,
but to neutralise late release venom from bite site depots.
The late release phenomenon is well documented for some
vipers causing haemostatic disturbance. Examples include
the Malayan pit viper, Calloselasma rhodostoma, where late
release can extend coagulopathy for up to 2 weeks post-bite
(Reid et al, 1963b). Similarly, venom-induced thrombo-
cytopenia can occur late after North American rattlesnake
bite, presumed due to further venom release. These late
release phenomena have implications for designing anti-
venoms. The current US snake antivenom for viper bites is
ovine F(ab)’ based and in consequence, has a short half life.
Its rapid elimination puts the patient at risk of recurrent
envenoming, unless follow up doses are given, requiring
treatment regimes incorporating regular doses of antivenom
every few hours, or even by continuous infusion. In this
situation, it might be better to have an antivenom with at
least some F(ab)2 or even IgG component, with a much
longer half life. Of course, such an antivenom, particularly
with whole IgG, might pose greater risks of other adverse
reactions.
At least in Australia, coagulopathy is used as a
convenient guide to ongoing antivenom dosing, ‘titrating’
antivenom doses against resolution of the coagulopathy.
This technique has been used for a number of years since
initially recommended, but though generally useful in an
‘antivenom rich’ environment, is not without problems.
Firstly, some doctors have given insufficient time after a
dose to see if it is effective, before launching into further
doses. This can result in overdosage. Secondly, the problem
of intra-generic venom variability is often a mystery to
doctors, who assume all species from a genus will cause
exactly the same degree of envenoming, be equally
responsive to antivenom raised against a single species,
thus similar doses should be used. A prime example is the
brown snake (Pseudonaja spp.), a wide-ranging genus,
represented across all mainland Australia and currently the
leading cause of snakebites on that continent. The quantity
of venom produced for a given-sized snake varies based on
geographic location, even within a single species, let alone
between species. Procoagulants in the venom, though
similar, appear to have different degrees of susceptibility
to the specific antivenom. Thus envenoming may require
anything from 3 vials to 20 vials to neutralise the
coagulopathy and for some specimens, antivenom appears
poorly effective, even at very high doses. This needs to be
understood in managing a case. The initial dose should be
evaluated, depending on the geographic location, experi-
ence suggesting (currently being evaluated in a trial) that
envenoming by Western Australian brown snakes (dugite,
P. affinis; gwardar, P. nuchalis) may require substantially
more vials of antivenom, possibly a starting dose of 10 vials,
compared to 5 vials in eastern Australia.
Where available, antivenom is the treatment of choice
for all snakebite coagulopathies, but not all antivenoms are
created equal. The choice of antivenom can be critical in
obtaining the best outcome. The variation in venom activity
profile within a single species, spread over a wide
geographic range, is typified by Russell’s viper, Daboia
russelii. Antivenom produced against the venom from
snakes in one geographic region can be near useless in
treating bites by the same species from a different region.
The comparative efficacy of a given antivenom, or in some
cases, lack of efficacy, will be important in judging dosage,
together with the degree of envenoming in each case. Thus,
as discussed for Australian snakebites, the initial and
subsequent doses of antivenom must be individualised for
each snake, from each region, for each antivenom,
dynamically modified by the peculiarities of each case of
envenoming. Listing appropriate antivenoms for each snake
species is beyond the scope of this paper, but some
information may be found on the internet (www.toxinol-
ogy.com).
The issue of when to use antivenom for snakebite
coagulopathy is increasingly important, especially in those
regions where antivenom is scarce. The importance of
objectively establishing if coagulopathy is present, by
J. White / Toxicon 45 (2005) 951–967 965
measuring clotting function, such as by the simple WBCT,
before deciding to give antivenom, has been known for
many years (Swinson C, 1976). Even in areas with poor
resources, the WBCT can usually be performed and will
give a rapid indication of the presence of coagulopathy in
association with envenoming, which is essentially always an
indication to give antivenom, presuming it is available.
Similarly, repeat WBCT after antivenom may guide the
need for further antivenom. Clearly the WBCT is not useful
in all forms of snakebite coagulopathy, most notably where
the problem is pathologic thrombosis and embolism, as seen
with Bothrops lanceolatus and B. caribbaeus. It may also
fail to indicate platelet abnormalities and will not be
diagnostic for haemorrhagic problems, but in these
situations, clinical examination is likely to detect the
abnormality and so point to the requirement for antivenom.
The method of determining need for further antivenom in
such cases is less clear and must generally rely on clinical
judgement rather than laboratory diagnostic parameters.
12. Medical uses for haemostatically-active venoms
A detailed account of medical uses of snake venoms is
beyond the scope of this paper. In particular, potential
therapeutic uses will not be discussed. From the perspective
of haemostatically active components, however, there is a
long-standing role in diagnostic tests, both for coagulation
abnormalities and related diseases. Amongst the most
venerable are toxins from Russell’s viper venom (Daboia
russelii) (Marsh, 1998), long used as reagents for specific
tests of clotting function. More recently, toxins from snake
venoms have been used to develop tests for other parts of the
haemostatic system, such as Protein C, and for related
disease, such as testing for lupus anticoagulant. It seems
likely that the list of clinical tests using haemostatically-
active venom components will lengthen.
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