Pnolapat_relayout.qxp 30/3/09 9:04 am Page 93
Thrombosis and Haemostasis
Snake Venom and Haemostasis – An Overview
a report by
Ponlapat Rojnuckarin
Head, Division of Haematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University
Venomous snakebites are still a public health problem in tropical tissue injury is the current management problem after snakebites, and
countries. Even in metropolitan areas, such as Bangkok, green pit viper further research is needed.
(Cryptelytrops albolabris and C. macrops) bites are still prevalent. As we
are invading their territory, they are adapting to live among humans in Viper Venoms
our backyards. With some exceptions, clinical syndromes of snakebites The significance of viper venoms goes far beyond the tropical medicine
can be divided simply into two classes: elapid envenomation attacks discipline. Different snake venoms have been found to affect almost all
neuromuscular junctions, causing muscular paralysis; viper envenomation components of the haemostatic system, including the vascular wall,
targets the haemostatic system, resulting in bleeding disorders. platelets, clotting factors, clotting inhibitors and fibrinolytic components.
Therefore, viper venoms are of great interest to haematologists. Vipers In addition, there are effects on a wide variety of physiological and
(Viperinae) are members of the snake family that develops the most pathological processes, including angiogenesis, inflammation and cancer
advanced venom-injecting organs, the long sheathed fangs that can be metastasis. Consequently, snake venoms are rich sources of proteins with
folded like switchblades. Some vipers possess pit organs, infrared potential to be useful diagnostic or therapeutic agents or compounds for
detectors for locating warm-blooded prey in the dark. This specialised studying the molecular mechanisms of haemostasis. Apart from the
subfamily is termed crotalidae (Pit viper), separating them from viperidae conventional protein purifications from snake venoms, current molecular
(true viper). Vipers found in the Americas are pit vipers, while African biology permits the construction of a complementary DNA (cDNA) library
vipers are true vipers. Asia and Europe are homes to both subfamilies. of the expressed genes in venom glands. This provides us with complete
and accurate sequences of DNA and conceptually translated proteins to
Viper Bites correlate with their functions. Furthermore, cDNA is an unlimited source
Clinically, viper bites cause both local tissue damage and systemic effects: of pure recombinant proteins that can be used to investigate their
local tissue swelling, blisters from dermo-epidermal separation, ecchymoses therapeutic and/or diagnostic values. Finally, mutagenesis can be
and gangrene. Snake venom metalloprotease (SVMPs) have been performed to study the structure–function relationship and engineer
implicated in these tissue injuries, both directly and indirectly via vascular proteins with desirable activities.
damage
1
and inflammatory responses.
2
The most prominent systemic
effects of pit viper venoms are towards fibrinogen and platelets. Although The evolutionary origins of venom proteins are from non-toxic genes that
the venoms clot fibrinogen (thrombin-like effect) and activate platelets in are recruited to express in venom glands, the special organs that started
vitro, these friable clots and platelet aggregates are rapidly cleared from developing before snakes phylogenetically branched out from lizards.
11
For
circulation in vivo, resulting in hypofibrinogenaemia, termed defibrination example, snake venom serine proteases (SVSPs) are from tissue kallikrein,
syndrome, and thrombocytopenia.
3
On the other hand, true vipers, such as SVMPS/disintegrins are from a disintegrin and metalloproteinase (ADAM)
Russell’s viper and Daboia russelii, activate common pathways of proteins and a prothrombin activator, is from clotting factor X.
12
coagulation via factor X and V, causing bleeding from disseminated Subsequently, these genes acquired toxic properties following a process
intravascular coagulation. Kinetics studies in humans showed that the viper known as accelerated evolution.
13
After gene duplications and high rates of
venom is rapidly absorbed. However, the effects on blood may be delayed non-synonymous base substitutions in coding regions, a wide variety of
and prolonged as the half-life of viper venoms is over 24 hours.
4
novel functions emerged, greatly expanding the arrays of susceptible prey
Antivenoms, the specific treatment of venomous snakebites, are polyclonal with enormous geographical and seasonal variations.
antibodies derived from horses or sheep. Older versions of antivenoms may
cause potentially fatal early reactions mediated by complement activation Snake venom proteins, like other toxins, are cysteine-rich (CR) peptides.
14
In
from the immunoglobulin (Ig)-G (fragment, crystallisable) Fc portion.
5,6
an oxidising extracellular environment most form disulphide bonds. The
Current F (ab)’
2
antivenoms in Thailand, the products of Queen Saovabha conserved bonds may be helpful in supporting the original folding structures
Memorial Institute, are pure and devoid of the Fc portion. A study revealed of proteins during accelerated evolution. On the other hand, alterations of
that the incidence of reactions is low (3.5%) and unpredictable by the disulphide bond patterns may lead to novel structures and functions
intradermal test.
7
Therefore, a hypersensitivity skin test for immunoglobulin enhancing their variety. For example, a loss in a disulphide bond in the
(Ig)-E-mediated reactions is unnecessary, but close observation is essential disintegrin-like domain of SVMPS resulted in a disintegrin, the integrin-
during administration in all patients. Although antivenoms are efficacious blocking proteins unique to snake venoms.
15
In addition, changes in
in reversing coagulopathy and thrombocytopenia from viper venoms, this disulphide bonds may cause different forms of post-translational
efficacy in treating local tissue injuries is limited.
8,9
This is consistent with modifications, such as the release of disintegrin domains from the protease
animal studies showing that venom-induced local damage was rapid and domain of SVMPs.
15
Furthermore, disulphide bonds can determine the
unable to be treated even by immediate antivenom.
10
Therefore, local multimeric structures, e.g. dimer versus tetramer, of the venom CLPs. Only
© TOUCH BRIEFINGS 2008 93
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100