Coagulopathy Following Snake Bite

1. Q J Med 2001; 94:551–559
Coagulopathy following lethal and non-lethal
envenoming of humans by the South American rattlesnake
(Crotalus durissus) in Brazil
I.S. SANO-MARTINS, S.C. TOMY, D. CAMPOLINA 1 , M.B. DIAS 1 ,
S.C.B. DE CASTRO, M.C.C. DE SOUSA- E-SILVA, C.F.S. AMARAL 2 ,
N.A. REZENDE 2 , A.S. KAMIGUTI 3 , D.A. WARRELL 4 and R.D.G. THEAKSTON 5
From the Laboratorio de Fisiopatologia, Instituto Butantan, Sao Paulo, Brazil,
´ ˜
1
Hospital Joao XXIII, Minas Gerais, Belo Horizonte, Brazil, 2Departamento de Medicina
˜
Interna, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, 3University
Department of Haematology, Royal Liverpool Hospital, Liverpool, UK, 4Centre for Tropical
Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK and
5
Liverpool School of Tropical Medicine, Liverpool, UK
Received 16 May 2001 and in revised form 3 August 2001
Summary
The South American tropical rattlesnake (Crotalus attributed to venom-induced haemostatic dis-
durissus subspp) is responsible for ;10% of bites turbances. However, envenoming by C. durissus is
from venomous snakes in Brazil. We studied frequently associated with haemostatic disorders,
24 victims of bites by this species over 3 years, which are probably attributable mainly to the
in south-eastern Brazil, particularly investigating action of the thrombin-like enzyme, with possible
haemostatic alterations. Thirteen patients were additional effects secondary to the powerful
defined as moderately envenomed and 11 as myotoxic activity of the venom.
severe. There were two deaths, which were not
Introduction
The Crotalus durissus complex, comprising the in combination with crotamine exerts a neurotoxic
South American tropical rattlesnakes, is responsible effect on peripheral nerves10 and a myonecrotic
for approximately 10% of cases of envenoming by effect on muscle.11 The crotamine content of
snakes in Brazil; the majority of these are caused C. durissus venoms varies between different popu-
by the cascavel, Crotalus durissus terrificus. The lations of snakes in Brazil and Argentina. Crotamine
venom of this species possesses neurotoxic,1 was absent from populations in north and eastern
myotoxic2 and thrombin-like activities.3 Brazil, present in north-western Sao Paulo State
˜
The principal toxins present in the venom include and adjacent areas of Parana and Minas Gerais, and
´
crotoxin,4 crotamine,5 convulxin,6 a thrombin-like in Ceara there were mixed populations, some
´
enzyme7 and gyroxin.8,9 The high toxicity of secreting crotamine and some not.12 An intriguing
the whole venom is attributable to crotoxin, a possible clinical correlation with the presence of
phospholipase A2 complex, which is the principal crotamine is the ‘broken neck’ sign resulting from
component of the venom.4 Experimentally, crotoxin paralysis of the cervical flexor muscles, possibly
Address correspondence to Dr Ida S. Sano-Martins, Instituto Butantan, Laboratorio de Fisiopatologia, Av. Vital Brazil,
´
1500, 05503 900, Sao Paulo (SP), Brazil. e-mail: lusiada@uol.com.br
˜
ß Association of Physicians 2001

2. 552 I.S. Sano-Martins et al.
through direct action of crotamine. This feature a massive rise in serum myoglobin and creatine
has been reported from various parts of Latin kinase (CK) levels, accompanied by myoglobin-
America.13 Convulxin causes convulsions and uria.2,20–23 Pain throughout the whole body,
respiratory and circulatory disturbances in mice, possibly explained by rhabdomyolysis, was the
dogs, cats and guinea pigs; it also causes in vitro main symptom remembered by one of the first
platelet aggregation in the platelet rich plasma of recorded victims of cascavel bite. Father Luis
many mammalian species.6 Gyroxin, when injected Rodrigues was bitten near Bahia in north-eastern
intravenously, induces episodes of opisthotonos Brazil at Christmas-time in 1560. He suffered
and rotation of the animal’s body in the longitudinal terrible symptoms for the next 20 days.24
axis.8,9 These signs are not observed in human In the fatal case described in Londrina, Sao Paulo
˜
victims. A thrombin-like enzyme, first isolated and State there were clinical, electrocardiographic,
characterized by Raw et al.,7 is responsible for biochemical and histological features suggestive
the coagulant action of the venom. More recently, of venom-induced myocardial damage.25
a comparative study of the biological activities of Blood coagulation disturbances have been
the venoms of three different Brazilian subspecies described in about 50% of patients bitten by
of C. durissus (C. d. terrificus, C. d. collilineatus C. durissus subspp.26 Amaral et al.27 reported
and C. d. cascavella) proved that most of these patients with afibrinogenaemia but without
activities were common to all these subspecies.14 thrombocytopenia. Spontaneous bleeding has
In most respects, Rosenfeld’s clinical descrip- only been rarely observed in human patients. The
tions of envenoming by Crotalus durissus ssp in aim of the present study was therefore to examine
Brazil have not been bettered.15 Local symptoms at in detail the haemostatic disorders in patients
the site of the bite include pain, paraesthesiae bitten by this species, and to assess the ability
such as formication or anaesthesia, but little or no of antivenom to reverse them.
swelling and no local necrosis. Rosenfeld denied
erythema, but we have observed this (Figure 1),
for example in patients 3 and 13 (below). There is
a similar lack of effect when the venom is injected Methods
subcutaneously, intramuscularly or intradermally
in experimental animals.16 This contrasts with bites
Patients
by many Crotalus species in North and Central Twenty-four patients were admitted to Hospital
America, which commonly cause severe local Joao XXIII, Belo Horizonte, Minas Gerais State,
˜
necrosis.17,18 Brazil. There were three females and 21 males, ages
Systemic envenoming usually starts with the ranging from 11 to 74 years. All had been bitten by
development of symmetrical ptosis, external oph- C. durissus subspecies (of which C. d. terrificus
thalmoplegia and facial weakness, resulting in the is the most prevalent subspecies in Minas Gerais)
characteristic myopathic/neurotoxic facies. Paresis between January 1993 and November 1995.
of the pupils may impair visual accommodation Diagnosis of Crotalus durissus bite was based on
(responsible for patients’ complaints of difficulties identification of the snake brought with the
with vision), loss of pupillary reflexes and mydriasis. patient (four patients, C. d. terrificus in each case);
Rosenfeld regarded mydriasis as a fatal prognostic detection of specific venom antigen in serum
sign.15 Rarely, respiratory muscle involvement may (11 patients) or on clinical features considered
lead to respiratory failure.19 The venom induces diagnostic at admission (nine patients). All of these
generalized rhabdomyolysis, causing myalgias, last nine patients showed characteristic signs of
a b
Figure 1. Extensive erythema and some swelling 3 h after a bite by Crotalus durissus terrificus in Sao Paulo State.
˜

3. Envenoming by C. durissus 553
systemic envenoming by C. durissus (e.g. ptosis, Haematological tests
myalgia, diplopia or paraesthesia). As none of these
signs occur following bites by any other venomous Blood (2.5 ml) was mixed with 25 ml of 10%
snake in this region, it is reasonable to include potassium EDTA and 50 ml Crotalus antivenom.
these cases in the study. The patients were divided Erythrocytes, leukocytes and platelets were counted
into two entirely arbitrary groups—‘severe’ and using an automated cell counter (Coulter T 890).
‘moderate’ envenoming—based on their presenting Differential leukocyte counts were carried out on
symptoms and signs. ‘Moderate envenoming’ was blood films stained with panchromatic stain.
defined as disturbance of visual accommodation,
ptosis or neurotoxic facies,15 mild myalgia, slight Biochemical tests
or absent urinary pigment with normal urine
Blood was sampled for creatinine, urea and creatine
output, and altered or normal coagulation time.
kinase (CK, normal values: 10–120 U/L) enzyme
‘Severe envenoming’ was defined by the pres-
activity determinations using Labtest kits. Serum
ence of obvious neurotoxic signs, intense myalgia
myoglobin concentration was measured using the
accompanied by pigmented urine with the presence
Rapitex-myoglobin kit (Behring).
or absence of oliguria/anuria and normal or altered
coagulation time.28 Patients who had been treated
with antivenom before admission to the hospital Venom antigen levels
were excluded from the study. Informed consent to
Enzyme-linked immunosorbent assay (ELISA) was
participate in the clinical study was obtained from
used for detection and measurement of C. durissus
the patients or, if young children were involved,
venom in admission serum samples according
from their parents. The study was approved by the
to the technique described by Chavez-Olortegui
´ ´
Ethics Committee of Hospital Joao XXIII.
˜
et al.32 A 96-well Microtitre plate (Hemobag
Produtos Cirurgicos) was coated overnight with
´
Blood coagulation 100 ml of a 5 mg/ml solution of anti-C. durissus
IgG in carbonate buffer. After blocking and
Venous blood was sampled on admission, at 6, 12
washing, 50 ml serum diluted 1 : 2 in dilution
and 24 h after the end of antivenom therapy,
buffer was added (1 h, room temperature). The
and then daily until discharge from hospital. For
plates were washed and incubated with peroxidase
coagulation and fibrinolysis assays, 9.0 ml blood
coupled with anti-C. durissus IgG (1 h, room
was mixed with 0.8 ml 16 mM trisodium citrate
temperature). The wells were washed, and the
containing 0.2 ml Instituto Butantan Crotalus
assay was completed and stopped by the addition
monospecific antivenom29 to neutralize any venom
of 20 ml of a 1 : 20 dilution of sulphuric acid.
present in the sample at the time of collection. The
A reference curve was obtained using dilutions
citrated blood was centrifuged at 2000 g for 15 min
of known concentrations (4–500 ng/ml) of crude
at 4 8C and the platelet-poor plasma was frozen
venom from C. durissus terrificus. The baseline for
in 0.5 ml aliquots at À20 8C until tested. Control
the assay was established according to the recom-
samples, collected from people with no history of
mendations of Theakston33 and Ho et al.34 A cut-off
snakebite living in the same region as the victims
was established by testing sera from 103 controls of
were treated as described above.
the same socio-economic group as the patients. The
Standardized reagents purchased from Diag-
mean"SD OD at 492 nm was 0.037"0.016 for
nostics Stago (France) were used to measure
the whole venom assay. Using the mean plus 2 SD
prothrombin time (PT) and the activated partial
as the negative cut-off value for the assays, which
thromboplastin time (APTT). Levels of coagulation
corresponded to a whole venom concentration
factors (factors II, VII, VIII, IX, X, XI, XII) were
of 20 ng/ml, two of the 103 normal sera were
estimated using deficient plasmas, protein C (PC)
positive for whole venom, resulting in a specificity
(Staclot protein C assay), cross-linked fibrin frag-
of 98.1%.
ment (D-dimer, DD) using immunoassay by latex
agglutination, a2-antiplasmin (a2-AP) (Stachrom
Antiplasmin) and serum fibrin(ogen) degradation
products (FnDP/FgDP) using immunoassay (latex Results
agglutination). Thrombin-antithrombin antigen (TAT)
was determined using an EIA kit system from
Clinical observations
Behring (Enzygnost-TAT). Factor V was estimated The time between bite and admission to hospital in
using the standardized technique of Denson30 the 24 envenomed patients ranged from 2 to 60 h.
and fibrinogen levels were measured using the In 13/24 (54%) a tourniquet had been applied,
method of Ratnoff and Menzie.31 7/22 (32%) had paraesthesiae, 18/22 (82%) had

4. 554 I.S. Sano-Martins et al.
ptosis, and 10/19 (53%) suffered from myalgia. patients; thrombocytopenia was observed only in
Only 1/24 (4%) had respiratory insufficiency on the two fatal cases.
admission. The basic information and clinical Twelve hours after antivenom treatment, fibrino-
symptoms for each patient are shown in Table 1. gen and FnDP/FgDP levels were within the normal
haemostatic range. Fibrinogen levels increased,
and this was paralleled by a decrease in FnDP/
Laboratory findings FgDP levels and normalization of DD levels in
On admission and before antivenom therapy, 10/22 the plasma. Simultaneous consumption of a2-
(45%) patients had a PT-10% and 12/22 (55%) antiplasmin indicated secondary activation of the
had a prolonged APTT, with three patients having fibrinolytic system. All these levels had returned
totally incoagulable blood (Table 1). Assays of to normal by the time the patient was discharged
clotting and fibrinolytic factors showed fibrinogen from hospital (Figure 2).
and factor V consumption, consumption of a2-AP As expected, the increased levels of myoglobin
and consequent increase of FnDP/FgDP and D-DD in serum, highest on admission, decreased rapidly
and the formation of thrombin-antithrombin com- following antivenom therapy (Figure 3a). Serum CK
plex in some patients (Table 2). Only 3/5 patients levels were significantly elevated compared with
studied had decreased levels of protein C (0%, the normal range (10–120 U/l) from admission to
26%, 49%). 24 h after the start of antivenom (Figure 3b).
There were no gross alterations in the haem- However, the differences in CK levels on admission
atological picture, although a slight polymorpho- and 12 and 24 h after antivenom were not
nuclear leukocytosis was recorded in the majority significant (p)0.05).
of cases (Table 2). Interestingly, there was no Admission venom levels were measured in 19/24
alteration in the platelet count in the majority of patients. The mean venom antigen level in the
Table 1 Clinical features and relevant laboratory findings on admission in 24 patients envenomed by Crotalus durissus
Patient Age Time Dose Paraesthesiae Ptosis Myalgia Tourniquet Classification PT (%) APTT (s) Venom
(years) after AV (ml) antigenaemia
bite on admission
(h) (ng/ml)
1S 39 7 100 À À À q Moderate 64 36 0
2 26 4 200 q q q À Severe -10 ‘ 750
3*a,b,c 15 27 200 ND ND ND À Severe -10 ND 325
4 11 2 100 q q À q Moderate 75 36 162
5S 53 2 150 À q À q Moderate -10 ND 63
6 19 3 100 q q À q Moderate 62 30 172
7 14 9 200 À q À À Severe -10 ‘ 97
8 19 6.5 200 À q q À Severe 45 36 ND
9 27 60 200 À q q À Severe ND 55 ND
10 11 3 200 À q q q Severe 36 34 417
11 13 3 200 À q q À Severe -10 )60 250
12 74 4 100 À q q q Moderate 16.5 35 ND
13*c 50 18 200 ND ND ND q Severe 55 44 ND
14 24 2 100 À À À q Moderate 70 38 0
15 68 7.5 100 À q ND À Moderate 37 )80 0
16 21 5 200 À q q À Severe -5 ‘ 76
17 40 5 200 q q q q Moderate -5 )120 25
18 47 24 100 q q q q Moderate -10 )120 0
19 12 20 100 À q À À Moderate 5 120 0
20 26 7 200 q q ND q Severe -10 )120 95
21 56 5.5 200 q q q q Severe ND )180 0
22S 64 6 100 À À À À Moderate 46 39 0
23S 45 2.5 100 À À À q Moderate 95 29 0
24 24 4 150 À q ND À Moderate 85 32 ND
*Fatal case; adeveloped acute renal and respiratory failure; bshowed gingival bleeding on admission; cdeveloped
thrombocytopenia; Sdead snake brought with patient to the hospital. ND, not done; AV, Instituto Butantan Crotalus
antivenom; PT, prothrombin time; APTT, activated partial thromboplastin time.

5. Envenoming by C. durissus 555
Table 2 Haematological variables in patients on admis- with gingival bleeding, and oedema and redness
sion to hospital (before antivenom therapy) following at the site of the bite. He was tachycardic
bites by Crotalus durissus (120 bpm) and tachypnoeic (28 breaths/min) with
nasal flaring and audible rhonchi. Blood pressure
Parameters Patients Controls
was 100/60 mmHg. His blood was incoagulable,
with a grossly prolonged prothrombin time, fibrino-
Mean"SD n Mean"SD n
gen 0.023 g/l, platelets 1663109/l, leukocytes
Fibrinogen (g/l) 0.60"0.70 17 2.50"0.36 11 12.33109/l (83% polymorphs), CK 96 000 U/l
FII (%) 60"22 16 96"13 8 (3.9% CKMB), haemoglobin 115 g/l, haematocrit
FV (%) 33"38 13 120"37 4 35%. The venom antigen level was 325 ng/ml.
FVII (%) 87"33 16 102"21 11 Urine was strongly positive for blood, haemoglobin
FVIII (%) 71"42 17 117"35 15 or myoglobin. Twenty ampoules of Crotalus anti-
FIX (%) 75"33 16 98"27 14 venom (Anticrotalico, Instituto Butantan) was given
´
FX (%) 80"39 7 86"21 7 27 h after the bite. Two hours after admission,
FXI (%) 95"55 10 140"39 8 the patient’s respiration had become shallow and
FXII (%) 88"28 16 112"9 13
he was intubated, transferred to the intensive care
FnDP/FgDP (mg/ml) 564"501 15 4"0 11
D-dimer (mg/ml) 37.3"33.5 17 0.5"0 11
unit and mechanically ventilated, but he may have
a2-antiplasmin (%) 36"27 15 100"5 3 aspirated at this time. There was radiographic evid-
TAT (mg/l) 73.0"25.4 7 5.3"1.3 3 ence of right basal consolidation. There was evid-
Platelets3109/l 278"80 17 237"16 20 ence of renal impairment (urea 760 mg/l, creatinine
Erythrocytes31012/l 4.8"0.4 15 5.5"1.0* 20 mg/l) and mild metabolic acidosis. Despite
Haemoglobin (g/l) 144"15 15 155"25* treatment with intravenous fluids, furosamide and
Haematocrit (%) 44"4 15 47"7* dopamine, urine output was only 500 ml in 24 h,
Leucocytes3109/l 12.8"6.1 15 7.5"3.5* and the patient became more comatose with neck
Neutrophils3109/l 10.6"6.4 15 2.0 –7.5* rigidity and extensor plantar responses. A brain scan
Basophils3109/l 0 15 0.02–0.1* showed no evidence of intracranial haemorrhage.
Eosinophils3109/l 0.16"0.23 15 0.04 –0.40*
At 42 h after the bite, 12 h after antivenom treat-
Lymphocytes3109/l 1.5"0.7 15 1.5–4.0*
Monocytes3109/l 0.2"0.2 15 0.2–0.8*
ment, blood urea had risen to 1450 mg/l, creatinine
to 36 mg/l, potassium to 7 mequiv/l and the
FnDP/FgDP, fibrin(ogen) degradation products; TAT, leukocyte count to 16.33109/l (77% polymorphs).
thrombin-antithrombin III complex. *Data from Dacie The prothrombin ratio had improved to 42%,
and Lewis.35 activated partial prothrombin time (APPT) 50/32
seconds. Following initiation of peritoneal dialysis,
the patient’s level of consciousness improved. The
11 moderately envenomed patients was 38.4 ng/ml pupils were equal in size and reacted to light. The
"20.0 ng/ml (SEM) and in the eight severely platelet count had fallen to 853109/l. Eighty hours
envenomed patients it was 251.2 ng/ml"86.9 after the bite, the patient remained oliguric on
ng/ml (SEM) (Table 1). The difference between peritoneal dialysis. Diffuse consolidation developed
these levels was statistically significant (p ¼ 0.022). in both lungs, with progressive deterioration in
The majority of the severely envenomed patients respiratory and haemodynamic function. He died
(6/9, 67%) had an intense coagulopathy (PT-10%) 110 h after the bite. The key features of this
on admission, whereas only 4/13 (31%) of the fatal progression were early shock, coagulopathy
moderately envenomed patients had evidence of with spontaneous bleeding, renal failure, respiratory
severe coagulopathy (PT-10%) on admission failure, rhabdomyolysis and finally, progressive
(Table 1). respiratory failure compounded by aspiration
pneumonia, adult respiratory distress syndrome
and possibly pulmonary haemorrhage.
Patient 13 was a 50-year-old man bitten on the
Severe coagulopathy in two fatal cases
dorsum of the foot. On admission to Hospital Joao ˜
Among the 24 patients, there were two deaths XXIII 15 h after the bite, there was redness and
(8.3%). A 15-year-old boy (patient 3) was bitten on swelling at the site of the bite, blurring of vision,
the back of the hand and, 8 h later, was admitted bilateral ptosis, diplopia and passage of red urine.
to a local hospital, prostrated, sweating, hypo- The blood was incoagulable, with prolonged pro-
tensive and in urinary retention. Urethral catheter- thrombin time and APPT and thrombocytopenia
ization yielded 1000 ml of cloudy urine. He was (783109/l). Clotting factors V, VIII, VII and X were
transferred to Hospital Joao XXIII, arriving 25 h
˜ grossly depleted but with normal levels of factors II,
after the bite. He was comatose and dehydrated, IX, XI and XII, indicating disseminated intravascular

6. 556 I.S. Sano-Martins et al.
Figure 2. Plasma concentration of (a) fibrinogen, (b) fibrin/fibrinogen degradation products (FnDP/FgDP), (c) cross-linked
fragment D (DD), (d) a2-antiplasmin in patients on admission and following treatment with antivenom. Bars represent the
mean"SEM. Numbers over bars ¼ number of patients.
Figure 3. Plasma levels of (a) myoglobin and (b) creatine phosphokinase on admission and following antivenom
administration in patients bitten by Crotalus durissus. Bars show the mean"SEM. Numbers over bars ¼ number of patients.
coagulation. CK was 14 400 U/l (5% CKMB), evidence of renal impairment, falling levels of CK
haemoglobin 147 g/l, haematocrit 46%, leukocytes and an increase in platelet count. His vision and
14.83109/l (85% polymorphs). The urine was ptosis improved. On the fourth day of admission
strongly positive for blood, haemoglobin or myo- (107 h after the bite), the patient developed visual
globin, but there was no evidence of renal impair- and auditory hallucinations with paranoia. There
ment. He was treated with 20 ampoules of Crotalus was no biochemical or haemostatic abnormality.
antivenom (Anticrotalico, Instituto Butantan) 18 h
´ Ten days after the bite, the patient suffered a fatal
after the bite and remained haemodynamically cardiac arrest while taking a bath. Permission for
stable, with normal urine output, no biochemical autopsy was not granted by his family.

7. Envenoming by C. durissus 557
Discussion involved. Alternatively, the thrombin-like enzyme
in C. durissus venom may be different from that
In this study, the severity of envenoming correlated present in Bothrops venoms, and act more like
with venom antigenaemia and haemostatic abnor- physiological thrombin. The thrombin-like enzyme
malities on admission to hospital. The four highest of Bothrops jararaca venom is not capable of
venom antigen levels were found in the severely clotting rabbit fibrinogen,37 whereas C. d. terrificus
envenomed patients. However, in patient 21, venom clots both human (Minimum Coagu-
in whom a negative admission venom level was lant Dose, MCD, 21.5 mg/ml) and rabbit (MCD
recorded, it is likely that the blood sample was 33.3 mg/ml) fibrinogen.14 This suggests that the
taken before release of the tourniquet. It is pos- thrombin-like component of the major Brazilian
sible that only after release of the tourniquet subspecies of C. durissus venom has an action
were the clinical signs observed, probably due to similar to physiological thrombin. In C. durissus
the release of the venom, previously retained by envenoming, all the changes in the coagulation
the tourniquet, into the circulation. system, with the exception of fibrinogen levels,
Both the fatal cases recorded here had profound are milder than in Bothrops envenoming, as we
haemostatic abnormalities including thrombo- reported previously.38
cytopenia. Among 12 cases of fatal envenoming The venom of C. durissus includes a powerful
by C. durissus in the State of Sao Paulo, 10 (83%)
˜ myotoxin which causes rhabdomyolysis in patients2
presented with coagulopathy.36 However, the likely and damages the microvasculature of smooth
cause of death in patient 3 in the present study was muscle, especially that of endothelial cells lining
respiratory complications of probable respiratory the capillaries and arterioles.22 The changes in
muscle weakness that required intubation and vascular smooth muscle may be due directly to
mechanical ventilation. Other life-threatening the toxic effect of the venom components or
effects of envenoming identified in this study were indirectly to the ischaemia39 described in patients
hypotension and shock, rhabdomyolysis, possible envenomed by South American rattlesnakes.26 It
myocardial damage (patient 13), renal failure and is possible that endothelial cells thus stimulated
spontaneous haemorrhage. may release various constituents that can activ-
Alterations of the whole-blood clotting time ate the coagulation system. The generation of
have been observed in 48% (104/216) of patients intravascular thrombin in C. durissus envenoming
bitten by C. durissus, and incoagulability in 38% could therefore be a consequence of the secondary
(86/216).26 Some patients present with no detect- activation of the coagulation system as suggested
able fibrinogen.27 In this study, consumption in this study.
coagulopathy, characterized principally by the Ontogenic variations in snake venoms may be
consumption of fibrinogen, factor V and protein C, important.40 In the genus Bothrops, the venoms of
was observed with slight depletion of factors II the young snakes of the majority of species contain
and VIII; however, levels of other coagulation larger amounts of both factor II and factor X
factors were generally within the normal range. activators than those of adult snakes.41 This results
The coagulopathy was accompanied by an increase in relatively more severe haemostatic disorders
in levels of FnDP/FgDP and DD, and a significant following envenoming by young snakes.42 In
consumption of a2-antiplasmin, indicating a sec- young Crotalus atrox, a direct thrombin-like
ondary activation of the endogenous fibrinolytic clotting action on fibrinogen was observed in 2–8-
system; this is consistent with evidence that month-old specimens; from 11 months onwards,
the venoms of C. d. terrificus, C. d. collilineatus the venoms of the same individual snakes no longer
and C. d. cascavella do not have fibrinolytic clotted fibrinogen directly.43 However, these
activity in vitro.14 An increase in levels of the age-related differences have not been described
thrombin-antithrombin complex was also observed, in envenoming by the South American rattle-
indicating the formation of intravascular thrombin. snake,44 and there is no reference in the literature
The decrease in fibrinogen levels soon after demonstrating ontogenic differences in coagulant
the bite can be explained by the thrombin-like activity of the venoms of either C. d. terrificus or
enzyme in the venom. However, the alterations in C. d. collilineatus.
the levels of some coagulation factors (II, V, VIII and Venom-induced systemic haemorrhage is rarely
protein C) and the formation of DD and thrombin- reported following envenoming by C. durissus
antithrombin complex, characteristic of physio- subspecies; slight bleeding at the site of the bite is
logical thrombin action, are difficult to explain as usual.45 However, according to Jorge and Ribeiro,26
a direct effect of C. durissus venom, since no activ- about 4.8% (12/249) patients had systemic bleed-
ator of factors II or X is present.14 It is possible ing; gingival haemorrhage, epistaxis, and vaginal
that another, not yet identified, activator may be bleeding. The figures in our study agree, with only

8. 558 I.S. Sano-Martins et al.
one (4.2%) of our 24 patients having signs of (Crotalus durissus terrificus) envenomation in Brazil.
Toxicon 1985; 23:631–6.
spontaneous systemic haemorrhage, despite the
prevalence of severe coagulopathy. Various 3. Nahas L, Denson KWE, Macfarlane RG. A study of the
coagulant action of eight snake venom. Thromb Diath
snake venoms possess activators and inhibitors of
Haemorrh 1964; 2:355–67.
platelets.46 In patients envenomed by Bothrops
4. Slotta KH, Fraenkel-Conrat H. Estudos quımicos sobre
´
species, thrombocytopenia is very common,
os venenos ofıdicos. 4. Purificacao e cristalizacao do
´ ¸˜ ¸˜
and is frequently associated with a bleeding veneno da cobra cascavel. Mem Ins Butantan 1938;
tendency47 and platelet dysfunction.48 However, 12:505–12.
in C. durissus envenoming, thrombocytopenia is 5. Moura-Goncalves J, Vieira A. Estudo sobre veneno de
¸
rarely recorded;27 our results support this observa- serpentes brasileiras. I. Analise eletroforetica. An Acad Bras
´ ´
tion. Although it is well known that convulxin is a Cienc 1950; 22:141–50.
ˆ
potent platelet-aggregating agent6,49 and that cro- 6. Prado-Franceschi J, Vital Brazil O. Convulxin, a new toxin
toxin can also cause platelet aggregation,50 in our from the venom of the South American rattlesnake Crotalus
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