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Haematological effects and complications of snake envenoming
PII: S0887-7963(14)00097-2
DOI: doi: 10.1016/j.tmrv.2014.09.005
Reference: YTMRV 50420
Please cite this article as: Berling I, Isbister GK, Haematological effects and
complications of snake envenoming, Transfusion Medicine Reviews (2014), doi:
10.1016/j.tmrv.2014.09.005
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1
Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Newcastle, NSW,
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Australia
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School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
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Corresponding author:
Dr Ingrid Berling
E-mail: Ingrid.berling@gmail.com
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Abstract
Haematological abnormalities are the most common effects of snake envenoming globally.
Venom induced consumption coagulopathy (VICC) is the commonest and most important.
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Other haematological abnormalities are an anticoagulant coagulopathy and thrombotic
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microangiopathy. VICC is venom induced activation of the clotting pathway by procoagulant
toxins, resulting in clotting factor consumption and coagulopathy. The type of procoagulant
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toxin differs between snakes and can activate prothrombin, factor X, factor V or consume
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fibrinogen. The most useful investigation in VICC is a prothrombin time/international
normalised ratio (INR). The D-Dimer may assist in early diagnosis but fibrinogen levels often
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add little in the clinical setting. Bedside investigations would be ideal but point of care testing
INR and whole blood clotting tests (WBCT) have been shown to be unreliable in VICC. The
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often fatal. The role of antivenom in VICC is controversial and may only be beneficial for
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some types of snakes including Echis spp. where the duration of abnormal clotting is reduced
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from over a week to 24-48 hours. In contrast, antivenom does not appear to speed the
recovery of VICC in Australian snake envenoming. Other treatments for VICC include factor
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replacement, observation and prevention of trauma, and heparin. An Australian study showed
that fresh frozen plasma speeds recovery of VICC but early use may increase consumption.
Introduction
subtropical regions such as South Asia, South-East Asia and Sub-Sahara Africa [1]. It is
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estimated that annually there are more than 400,000 snake envenomings and 20,000 deaths
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worldwide [1]. One of the most common and clinically significant complications of snake
envenoming is coagulopathy, which can result in life-threatening haemorrhage and death [2].
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Venom-induced consumption coagulopathy (VICC) is the most frequent type of
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coagulopathy associated with snake envenoming globally, but less clinically significant
coagulopathies are also recognised with certain snakes, such as the Australian black snakes
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[3, 4]. More recently there has been a recognition of a thrombotic microangiopathic
patients envenomed from a snake bite. This review will focus on describing the underlying
mechanisms of coagulopathy in snake bite, how this differs between snake species, and the
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Snake is the common term used for the ‘serpentes’ family of reptiles. Only about 20% of
snakes are venomous and therefore medically important. Venomous snakes have specialised
venom producing glands and teeth (fangs) for effective venom delivery. Venomous snakes
come from the families Elapidae, Viperidae, Colubridae and Atractaspididae, although most
of the burden of snake envenoming is due to bites by vipers and elapids. As a general rule
vipers mainly cause coagulopathy compared to elapids that mainly cause neurotoxicity
VICC is the broad, simple descriptive term used to describe any coagulopathy that results
from the consumption of clotting factors due to a procoagulant toxin in a snake venom. It is
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caused by the bites of a range of snakes including Viperid snakes, Elapidae snakes and some
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Colubrid snakes[2]. Previously the coagulopathy associated with snake envenoming was
often referred to as a disseminated intravascular coagulation (DIC). However the term DIC is
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not appropriate for snakebite coagulopathy [5]. DIC results from widespread immune,
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endothelial, cellular and clotting cascade activation and has a very high mortality, whereas
VICC is characterised by the activation of the clotting pathway due to procoagulant toxins in
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the snake venom. They are referred to as procoagulant toxins because in vitro they result in
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rapid clot formation, but in vivo lead to severe factor consumption and therefore a risk of
bleeding. The toxins differ between snake species and activate various parts of the clotting
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pathway by targeting different clotting factors. Despite these differences, all procoagulant
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toxins cause a similar clinical picture of clotting factor consumption and coagulopathy. The
clinical severity of VICC is dependent on which clotting factors are consumed. For example a
milder VICC appears to occur when there is only fibrinogen consumption, whereas a more
severe form of VICC is usually associated with multiple factor consumption, such as is seen
with Australian elapid envenoming which results in FII, FV, FVIII and fibrinogen
consumption.
The toxins in snake venom that produce VICC are classically categorised by where they act
on the clotting pathway, with the most important ones being prothrombin activators, factor V
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and X activators and thrombin-like enzymes (TLEs), the latter also referred to as
Prothrombin Activators
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Two large important groups of snakes contain prothrombin activators: most of the
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Australasian elapids (brown snake [Pseudechis spp.], tiger snakes [Notechis spp.], rough-
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scaled snake [Tropidechis carinatus], broad-headed snakes [Hoplocephalus spp.] and taipans
[Oxyuranus spp.]) and the Echis genus which includes carpet vipers and the saw-scaled viper
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[6]. Prothrombin activators can be classified into four groups (A-D) depending on their
structure, function and co-factor requirements [6]. Australian snakes contain the group C and
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D prothrombin activators which are serine proteases. Group C prothrombin activators are
found in the brown snake and taipan and resemble the human prothrombinase or factor XaVa
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complex which converts prothrombin to thrombin. Group D toxins are found in tiger snake,
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rough-scale snake and broad-headed snakes and contain a toxin similar to human factor FXa,
without the FVa cofactor [7]. Group A and B toxins are found in the Echis species of snakes
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and directly activated prothrombin but convert it to meizothrombin rather than the fully
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deficiencies due to the positive and negative feedback loops activated when prothrombin (II)
is converted to thrombin (IIa) (see Figure 1) [7]. This leads to activation of FV to FVa and
FVIII to FVIIIa regardless of whether the initial toxin contained a FVa-like complex.
Thrombin also activates fibrinogen to fibrin consuming all of the fibrinogen. Measurements
of factor levels post envenoming have shown severe deficiencies of factor V and factor VIII,
undetectable fibrinogen levels, consistent with complete VICC [7]. A partial VICC has been
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recognised in patients with low, but recordable fibrinogen levels where the pathway has not
been completely activated and not all of the fibrinogen has been converted to fibrin [7, 9].
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Russell’s viper (Daboia genus) venom contains factor V and X activators [6]. The more
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important toxin is the factor X activator which converts factor X to Xa resulting in the
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formation of the prothrombinase complex and subsequent conversion of fibrinogen to fibrin
(see Figure 1). Because the factor X activator toxin acts so earlier in the coagulation pathway
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(before the common pathway), it results in positive and negative feedback loops leading to
indirect consumption of factors V and VIII. There is also direct activation and consumption
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of factor V. This again results in an unrecordable prothrombin time/INR and undetectable
fibrinogen.
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Thrombin-like Enzymes
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Thrombin-like enzymes (TLEs) are different to the prothrombin activators and factor Xa/Va
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activator toxins because they simply consume fibrinogen rather than activating the clotting
pathway. For this reason, TLEs only produce an isolated deficiency of fibrinogen and
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uncommonly affect other clotting factors. They usually cause a milder form of VICC, but
they will result in an unrecordable prothrombin time/INR and bleeding complications if there
is undetectable fibrinogen [10]. There are over 67 different TLE toxins that have been
identified, the majority being zinc metalloproteinase that cleave the alpha chain of fibrinogen
resulting in consumption of fibrinogen without the production of (or conversion to) fibrin
[11]. Other TLEs cleave the beta chain and a few cleave both chains, but they do not result in
intact fibrin. Ancrod is the best known of the TLEs and was for a while tested for use in
cerebrovascular disease until it was shown that there were too many bleeding complications
The clinical outcome for patients who develop VICC is not only dependent on the severity of
the coagulopathy, but other factors such as trauma, platelet count and function, and vascular
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injury are important. Arguably the most important issue in patients with VICC is whether
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physical trauma occurs and anything that potentially causes vessel damage and the release of
tissue factor may result in haemorrhage. This may result in significant morbidity or death in
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the case of intracranial or major organ haemorrhage. Table 2 lists the clinical effects of snake
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bite associated with coagulopathy and bleeding. Bleeding can range from minor, such as
oozing at the bite site or cannula insertion site, to major life threatening haemorrhage
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requiring blood transfusion. Intracranial haemorrhage can be seen after an associated head
injury, but spontaneous bleeds also occur, often in the setting of hypertension. Thoracic
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cavity bleeding or bleeding into other body compartments can occur after trauma.
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The metalloproteinase prothrombin activator toxin ecarin found in Echis species not only
activates the clotting pathway, but also acts as a haemorrhagin [7]. These haemorrhagins are
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proteolytic enzymes that cause damage to the blood vessel wall, affecting the basement
membrane and creating a ‘shear-stress’ like injury which in turn increases the risk of bleeding
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associated with VICC. This explains why spontaneous and more severe bleeding is reported
with Echis envenoming compared to Australian elapid envenoming, despite the prothrombin
The duration of VICC depends on the type of toxin and the administration of antivenom.
VICC resulting from Australian elapid envenoming appears to resolve over 24 to 48 hours
independent of antivenom treatment, and the time to recovery appears to depend only on the
production of new clotting factors [8]. On the other hand, Echis induced VICC has been
shown to continue for days if not treated with antivenom [4]. However, after Echis
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demonstrating that once the toxin is neutralised there is normal recovery of clotting factors.
An understanding of the expected natural course of VICC determined by the type of snake
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and procoagulant toxin may influence the need for antivenom, duration of hazard reduction
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for trauma and decision to use factor replacement.
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Investigation of VICC
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The diagnosis of VICC can be made based on a history of snakebite and evidence of
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coagulopathy due to factor consumption. This can be confirmed by an abnormal (often
unrecordable) INR, or prothrombin time (PT), low or undetectable fibrinogen and an elevated
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D-dimer (at least 10 times the upper limit of normal) [7]. This definition captures all forms of
VICC, from the milder TLE induced fibrinogen consumption to the more severe multi-factor
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consumption, seen with prothrombin activator venoms. Fibrinogen is the most consistently
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consumed factor in all types of snake bites causing VICC because it is the common point of
The D-dimer is a marker of fibrin degradation from normally formed cross-linked fibrin clot.
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Therefore, D-dimer levels are expected to be markedly increased in VICC resulting from
procoagulant toxins that activate the clotting pathway high up. In this case normal fibrin is
formed from fibrinogen, cross-linked by factor XIII and degraded by plasmin. In the case of
Australian elapids the D-dimer is 100 to 1000 times the upper limit of normal [7]. For
Russell’s viper envenoming the D-dimer is elevated by 10 to 100 times the upper limit. For
the TLEs which consume fibrinogen without the production of fibrin, there is no formation of
cross-linked fibrin and so there is only a modest elevation of the D-dimer [10, 15]. The
reason for an abnormal D-dimer with TLEs is unclear but may be due to the D-dimer assay
being less specific with large concentrations of non-cross linked fibrinogen degradation
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products or to some associated endogenous activation of the clotting pathway. A less specific
marker of fibrin(ogen) degradation products, FnDP/FgD or FDP assay, will be 100 times
normal in VICC due to TLEs, compared to only a modest increase in the D-dimer [10].
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However, these FDP assays are no longer available in diagnostic laboratories which is
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unfortunate for regions where snakes with TLEs occur.
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Serial measurement of fibrinogen levels has been used in many studies to demonstrate
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recovery of the coagulopathy and is a useful outcome for research into VICC [13, 16].
Clinically, the measurement of fibrinogen in VICC will confirm that there has been
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consumption but will not usually add much additional information to a PT/INR or D-dimer.
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Fibrinogen is the slowest of all factors to recover and effective clotting appears to occur with
only minimal fibrinogen recovery to 0.5 to 1.0g/L when the PT/INR has almost normalised
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[7]. This means that fibrinogen is not a good clinical marker of recovery. The PT/INR is a
more useful marker of recovery of VICC because it measures the functional recovery of the
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clotting pathway and clinicians better understand the risk of bleeding associated with elevated
INRs.
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Bedside assessment of clotting function in VICC is ultimately the best investigation, but there
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continues to be no reliable and accurate bedside test for the diagnosis of VICC. The whole
blood clotting test (WBCT) is the most commonly used bedside clotting test worldwide. This
test works on the principle that blood taken from a patient with VICC is incoagulable and so
will not clot in a glass tube within a defined time frame, usually 20 minutes. Although widely
used, there is no standardised procedure for the WBCT and hence the test is fraught with
error, misinterpretation and high false negative rates in a busy clinical environment, which is
prone to interruption and distraction. Various studies have used time end-points of 10, 15, 20
and 30 minutes and there is no universally agreed tube for collection or defined volume of
Russell’s vipers showed a sensitivity of only 40%, which contributed to delays in antivenom
administration [17]. However, it has been suggested that when performed under strict
procedural guidelines the WBCT may be more accurate and further studies are required to
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confirm this.
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Modern point of care (POC) INR testing devices have also been used in patients with VICC.
Unfortunately POC INR machines have also been unreliable and have been shown to have a
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high false negative rate in Australian snakebites and cannot be recommended for use. In a
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small study of 15 patients the POC INR was normal in 3 of 7 patients with VICC where a
laboratory INR was unrecordable [18]. The reason for this lies in the difference between the
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assays from formal laboratories and POC machines (see figure 2). A standard laboratory
calculating the time to clot formation, usually identifying a clot by either spectrophotometry
(visual absorbance) or fibrometery (mechanical method) [14]. Hence, in a patient with VICC
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In contrast, POC INR machines do not assesses or measure clot formation, but use thrombin
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cleavage as a marker of clotting function. This is achieved by adding tissue factor to a blood
sample (similar to the laboratory method) to trigger clot formation, and then adding an
VICC where factor deficiencies prevent clot formation, there still remains active thrombin,
due to activation by the prothrombin activator. Therefore, the substrate in POC machines is
still able to be cleaved, and activated, incorrectly indicating clot formation. This means that
in patients with VICC a POC INR will often give a normal INR result when in fact the
PT/INR is unrecordable when repeated in the laboratory [18, 19]. Table 3 summaries the
Treatment
The aim of treatment in VICC is to prevent major haemorrhage and complications of this.
This is achieved by neutralising the procoagulant toxins and allowing the recovery of clotting
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factors to a level where minor trauma does not result in haemorrhage. In patients with active
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bleeding clotting replacement may be used to speed the recovery of VICC.
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Antivenom
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Antivenom has been shown to be highly efficacious in binding venom (toxins) and
neutralising toxic effects, both in vitro and in vivo [20]. However, binding and neutralisation
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of the toxins will only prevent VICC if given before it develops (very early). For some toxin
types it appears to stop further consumption in patients who have already developed VICC.
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Antivenom will not speed the recovery of clotting function beyond this.
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The clinical benefit of antivenom in VICC appears to vary for different snakes. Antivenom
has been shown to have little impact on the clinical course of VICC in Australasian elapid
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envenoming. In contrast, there is clear evidence that antivenom improves recovery in Echis
species envenoming [13, 21] and other viper envenoming. In an Australian study, the
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recovery of PT/INR was compared between patients who had antivenom administered within
6 hours of the bite and patients who received antivenom more than 6 hours after the bite
[21]. There was no significant difference in the improvement of PT/INR between the two
groups, where one would assume if antivenom was having an effect then there would be
faster improvement in the group treated earlier. This compared to a group treated with fresh
frozen plasma (FFP) in addition to antivenom, in which there was a clear benefit with
improvement to an INR <2 within 10 to 12 hours compared to 24 hours without FFP. This
positive result with FFP strengthens the negative finding in the time to antivenom study [21].
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The natural duration of VICC from Echis envenoming differs from Australasian elapids, with
a prolonged duration of coagulopathy. A recent study from Africa compared the time to
recovery of clotting times and fibrinogen in 60 patients, 47 who received antivenom and 13
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who did not [13]. The recovery time to a fibrinogen level more than 1 g/L was 7.5 days in the
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untreated group compared to 40 hours in the antivenom group which was highly statistically
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significant (P<0.0001). There was a similar benefit on the PT and the activated partial
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thromboplastin time (aPTT). Although this was not a randomised controlled trial the large
treatment effect and objective laboratory outcomes provides strong evidence for the benefit of
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antivenom in VICC due to Echis envenoming.
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There have been no placebo randomised control studies comparing the effectiveness of
antivenom in VICC and these would be difficult to undertake for ethical reasons. Rather,
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there has been numerous randomised controlled trials of antivenom in VICC which have
compared one antivenom to another, different doses or repeat dosing of antivenom and
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antivenom to antivenom and heparin or immunoglobulin [16, 22-45]. Further research into
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the effectiveness of antivenom for each individual snake group is needed because there are
A major consideration in treating snake envenoming is that VICC rarely occurs as an isolated
envenoming syndrome, but rather, the patient will usually develop either local injury,
effective for other clinical effects the reason for antivenom may not always simply be the
presence of VICC. For example, although the administration of antivenom may not change
the clinical course of VICC in Australasian elapid envenoming, early use of antivenom may
prevent neurotoxicity and death due to respiratory paralysis in taipan bites or myotoxicity in
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tiger snake envenoming [46]. In this case the early presence of abnormal clotting tests are an
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Fresh Frozen Plasma
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Once the procoagulant toxins have been neutralised, clotting function will take 24 to 48 hours
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to recover. During this period the patient is at risk of haemorrhage and arguably the most
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important intervention is to prevent trauma. For recovery of clotting function to occur more
administration resulted in a more rapid recovery in the PT/INR [47]. The study was too small
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death, and the administration of FFP did not decrease the hospital length of stay. Further
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larger studies, including studies of different snakes, are required to develop a better
understanding of the potential benefits and risks of FFP. Until further evidence is available
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The Australian FFP trial, FFP given within 6 hours of the bite was associated with ongoing
reductions in fibrinogen, despite prior neutralisation with antivenom. The clinical impact of
this remains uncertain, but it does appear that FFP could still "add fuel to the fire" if the
clotting pathway remains activated downstream of the (neutralised or inactive) venom effect
for a period of time after the initial envenoming until a degree of equilibrium is restored [47].
Unfortunately formal studies on the use of other factor replacement products, including
lacking. The use of cryoprecipitate make senses for snakes producing isolated fibrinogen
deficiencies, but patients can recover adequate clotting function from low levels of
fibrinogen. The advantage of FFP is that it contains all of the major clotting factors, including
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factors V and VIII which appear to be more important in the recovery of VICC at least in
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Australian elapids [7].
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Heparin
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Heparin has been suggested as a treatment for VICC for many years based on the idea that an
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anticoagulant may counter the procoagulant toxins. There are surprisingly six studies that
have investigated the effectiveness of heparin in VICC, but they are of low quality with small
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numbers, unclear outcomes and positive and negative results [27, 34, 36, 38, 42, 48]. These
studies do not provide sufficient evidence for or against the use of heparin.
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Anticoagulant Coagulopathy
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coagulopathy. The Australian black snake (Pseudechis) genus venom has been shown to
inhibit clotting in vitro and cause a mild to moderate elevation of the aPTT [11]. In a series of
coagulopathy evidenced by an aPTT median rise of 82s (IQR 55-91s) [3]. Four of these
patients had a small INR rise (<3.0) with the rest having an INR within the normal limits.
Fibrinogen and D-dimer levels were normal. No patients developed any significant clinical
bleeding, supporting the idea that this is not a significant coagulopathy. A similar
anticoagulant coagulopathy was also found in red-bellied black snake (P. porphyriacus) bites.
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identifying envenoming early. This means that antivenom can be given early based on this. In
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the case of black snake envenoming which can cause myotoxicity, the early administration of
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antivenom has been shown to prevent myotoxicity [3, 4].
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The occurrence of anticoagulant coagulopathies in other snakes remains unclear, mainly
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because the 20 minute WBCT is unlikely to be abnormal except in the most severe cases.
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Anticoagulant toxins have been identified in a number of snakes, including cobras (Naja
spp.) and the southern copperhead (Agkistrodon genus). The venom of the southern
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copperhead contains a protein C activator [6], but does not appear to have any clinical effects
in humans.
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Thrombotic Microangiopathy
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acute kidney injury which continues beyond the resolution of VICC and has been noted in a
number of different snake species, including Australasian elapids and many viper species [5,
42, 49-51]. From the information available in published cases, it is difficult to define where
involvement is unusual.
In the full blown syndrome which occurs in less than 5% of cases patients develop severe
thrombocytopenia and acute anuric renal failure requiring renal replacement therapy for 2 to
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6 weeks. [5]. However, the majority of cases are less severe and snake bite induced
having a brief period of thrombocytopenia and a moderate rise in creatinine without oliguria.
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Treatment is supportive in all cases with renal replacement therapy being the most important
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intervention in severe cases. Plasmapheresis has been used in a number of more severe cases
but does not appear to change the natural course of the thrombocytopenia, anaemia or renal
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injury [49]. The lack of benefit of plasmapheresis is probably due to the underlying cause
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being different and not related to ADAMTS-13 function or antibodies like in TTP. An
beneficial for any toxin-related injury resulting in the neutralisation and removal of the toxin
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Conclusion
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Haematological effects are arguably the most important clinical consequences of snakebite
and range from the procoagulant coagulopathy VICC to thrombotic microangiopathy. These
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haematological syndromes seen with snake envenoming are unique and an understanding of
the mechanisms is essential to accurate investigation and safe treatment. The most important
complication is major haemorrhage which is often fatal so early intervention and treatment of
Conflict of Interest
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Acknowledgements
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Geoff Isbister is funded by an NHMRC Clinical Career Development Award.
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Figure Legend:
Figure 1: A schematic representation of where each type of procoagulant toxin acts on the
clotting pathway. Square shapes are inactivate factors and hexagonal shapes are activated
clotting factors. The blue arrows indicate conversion of inactive to active factors and the red
arrows indicate inactivation of the activated clotting factor.
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Figure 2: A schematic representation of the clotting pathway and the difference between
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point of care (POC) international normalised ratio (INR) testing and a laboratory INR.
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Table 1: A list of snakes grouped by mechanism of coagulopathy, including clotting factor studies in
human cases
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Activators Echis coloratus Painted carpet viper
Echis ocellatus West African carpet
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Echis pyramidum viper
Northeast African carpet
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viper
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Prothrombin Pseudonaja spp. Brown snake Fibrinogen, FII, FV, FVIII
VENOM INDUCED CONSUMPTION COAGULOPATHY
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Hoplocephalus Coastal taipan
spp.
Oxyuranus
scutellatus
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FX activator Vipera aspis European asp/Asp viper Fibrinogen
Trimeresurus viper
albolabris Large-eyed pit viper
Trimeresurus Bushmasters
macrops Western diamondback
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Protein C Agkistrodon Southern Copperhead Unknown
activator
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Haematuria
Epistaxis
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Gastrointestinal haemorrhage Vomiting frank blood
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PR bleeding
Falling Hb
Intracranial haemorrhage Falling GCS
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Focal Neurology
Can occur spontaneously, although often in the setting
of hypertension
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Traumatic haemorrhage Bleeding from lacerations/wounds
Intracranial bleeding post fall/collapse/syncope
Mediastinal bleeding chest wound/fractured ribs
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Long bone cavity bleeding post fractures
Major haemorrhage Falling Hb requiring blood replacement
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Table 3. The range of laboratory and bedside investigation used for the diagnosis and
monitoring of VICC.
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WBCT (bedside) Non-standardised test with a low sensitivity [17], but may be of
use if performed under strict guidelines with a 5mL glass tube.
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Prothrombin time (PT) Most useful diagnostic test in VICC.
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or international Unrecordable prothrombin time (INR) indicates complete VICC
normalised ratio (INR) while an INR < 3 occurs with partical VICC. [7] An INR is
- laboratory based useful initially to make the diagnosis and also subsequently to
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monitor the recovery of VICC.
INR (Point of care) Not to be used in VICC. False negative results in snake bite due
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to assay method used [18].
aPTT Will be abnormal or unrecordable in VICC but adds no further
information to the PT/INR. Useful in anticoagulant
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coagulopathy where it will be elevated while the INR is often
normal. However, low phospholipid containing reagents must be
used because high phospholipid content will be insensitive [52].
D-dimer Will be abnormal with any form of VICC but much higher with
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