Elsevier

Toxicon

Volume 45, Issue 8, 15 June 2005, Pages 951-967
Toxicon

Snake venoms and coagulopathy

https://doi.org/10.1016/j.toxicon.2005.02.030Get rights and content

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.

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.

Section snippets

An overview of global snakebite

Globally venomous snakebite is estimated to affect greater than 2.5 million humans annually, of whom more 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 and

An overview of coagulopathy induced by snakebite

A brief summary of major snake groups causing coagulopathy and/or haemorrhage is presented in Table 1, Table 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. 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

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 laboratory tests, but unless there is some bleeding point, may not result in clinically significant bleeding (White,

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). Fibrinogen 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

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 effectiveness in haemostasis; (2) promotion of platelet activity, increasing their contribution to haemostasis, in this case pathologic. To these

Anticoagulant venoms and coagulopathy

Some snake venoms contain toxins that are direct or indirect anticoagulants, that inhibit the clotting process, thus 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

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 the Saint Lucia viper (Bothrops caribbaeus) cause clinical thrombosis and emboli routinely following envenoming (Thomas et al., 1995, Thomas et al., 1998

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 haemostasis, reducing clotting ability, such as procoagulants, the effects can be severe indeed. The clinical

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 (Fig. 6, Fig. 7). Internal bleeding may be hidden, or manifest as haematemesis, haemoptysis, haematuria 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

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

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

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    Copyright © 2005 S. Yamamoto. Published by Elsevier Ltd. All rights reserved.