In the United States, it is estimated that approximately 150,000 to 300,000 companion animals are bitten by snakes annually,1,2 and approximately 99% of those bites are from snakes of the Crotalinae (formerly known as Crotalidae) subfamily,3 which includes pit vipers such as rattlesnakes, cottonmouths, and copperheads.4 A recent search of the veterinary literature did not reveal any specific data regarding the number of companion animals bitten by snakes in southern California, but it has been reported that approximately 800 humans are bitten by snakes in that region every year.5 Furthermore, it is estimated that approximately 20% to 25% of snake bites are dry bites, or bites during which no venom is injected.1,5,6 Southern California harbors a single family of venomous snakes, the Viperidae,5 which includes the subfamily Crotalinae. Rattlesnakes are found throughout the continental United States and account for most snakebite fatalities.1 In southern California, life-threatening spontaneous hemorrhage has been reported in human patients following rattlesnake envenomation, although only 1 or 2 human deaths are attributed to rattlesnake bites each year.6
Hematologic methods traditionally used to evaluate patients for snakebite envenomation include PT, aPTT, platelet count, fibrinogen and D-dimer concentrations, and microscopic assessment of erythrocytes for morphological changes.7,8 Those methods have limitations in that they require blood clot initiation, amplification, and propagation to be individually tested.7 Thromboelastography uses continuous detection of changes in the viscoelastic properties of blood from clot formation to dissolution to yield a more comprehensive assessment of hemostasis.8,9
In veterinary medicine, thromboelastography has been used to evaluate the coagulation status of dogs with protein-losing enteropathy,9 hyperadrenocorticism,10 immune-mediated hemolytic anemia,11 parvoviral enteritis,12 neoplasia,13 and disseminated intravascular coagulation.14 In human medicine, investigators of a retrospective study15 of 51 children bitten by snakes in southern Africa used thromboelastography as a means to predict severe bleeding diathesis. Thromboelastography has also been used to determine the coagulation status of dogs following natural envenomation by African puff adders (Bitis arietans) and snouted cobras (Naja annulifera)16 and by pit viper species native to north-central Florida.7 Results of those studies7,16 indicate that dogs develop hypocoagulable thromboelastographic tracings following envenomation by puff adders and pit vipers and that a hypocoagulable thromboelastographic tracing was positively associated with risk of death.7
Treatment of patients with snake envenomation generally includes fluid therapy and analgesic and antivenin administration.17–19 Antivenin administration is indicated for patients with rapid progression of local clinical signs (eg, swelling, pain, and ecchymosis), substantial coagulation abnormalities, neuromuscular paralysis, and cardiovascular collapse.2 Thromboelastography provides a measure of a patient's overall coagulation status20 and might be useful for identifying patients with coagulopathies that require antivenin treatment prior to the manifestation of clinical signs.
The purpose of the study reported here was to validate that dogs become hypocoagulable following rattlesnake envenomation. We hypothesized that dogs bitten by rattlesnake species native to southern California would be in a hypocoagulable state when initially examined and that the severity of envenomation would be positively associated with the severity of thromboelastographic abnormalities in those dogs.
Materials and Methods
Animals
The study had a prospective observational design. Data were collected over an 18-month period from March 9, 2013, to September 18, 2014, at the VCA West Los Angeles Animal Hospital. Dogs eligible for study enrollment included those that were observed to have been bitten by a rattlesnake and those that were suspected to have been bitten by a rattlesnake and had clinical signs consistent with envenomation. Dogs that were previously treated for rattlesnake envenomation at another facility were excluded from the study.
Data collection and patient management
Data collected for each dog included signalment, location of wound or wounds, number of hours between observed or suspected bite and veterinary examination, and physical examination and diagnostic test results. The care of each dog was overseen by 1 of 3 diplomates of the American College of Veterinary Emergency and Critical Care. Each patient was managed at the discretion of the primary attending clinician in accordance with common standards of care and with the owner's consent. All dogs received analgesics with or without fluid therapy and antivenin.a The primary clinician determined the course of treatment for each dog on the basis of its clinical condition and the owner's financial means. All dogs enrolled in the study were concurrently enrolled in another study in which antivenin was provided to study subjects at no charge; thus, owner finances did not affect the decision of whether antivenin was administered. Antivenin was administered in 1-vial aliquots, and the number of vials administered ranged from 1 to 9 vials.
Blood sample collection
A blood sample (approx 1.8 mL) was collected by cephalic, jugular, or saphenous venipuncture from each dog prior to initiation of treatment for thromboelastography and coagulation analysis. Immediately following collection, the blood sample was transferred to a blood collection tubeb that contained 3.2% trisodium citrate solution as an anticoagulant. The tubes were gently inverted several times to ensure mixing of the anticoagulant with the blood samples. For 13 of the 14 study dogs, an additional blood sample (approx 1.8 mL) was collected and transferred into a blood collection tubec that contained EDTA as an anticoagulant for an automated platelet count.
SSS
Each dog was assigned an SSS as described.7,21,22 Briefly, the SSS provides a semiquantitative assessment of the patient's respiratory, cardiovascular, gastrointestinal, hematologic, and nervous systems and local wound severity. Each category was assigned a number from 0 to 3, with the exception of the hematologic system and local wound severity categories, which were assigned a number from 0 to 4. The numbers assigned to each category were summed to calculate the SSS. Thus, the SSS could range from 0 to 20. This SSS has been validated in human patients with snake envenomation21 and previously used to evaluate dogs with snake envenomation.7,22 All SSSs were assigned retrospectively by the principle investigator (BAL) on the basis of clinical examination and hematologic findings recorded by the primary clinician in the medical record of each dog.
Thromboelastography
Thromboelastography was performed on all blood samples within 30 minutes after collection on site at the VCA West Los Angeles Animal Hospital by means of an automated hemostasis analyzerd and analyzed with the manufacturer's analytical software.e Briefly, each blood sample was activated with kaolinf in accordance with instructions provided by the manufacturer of the hemostasis analyzer. Then, 340 μL of the kaolin-activated blood sample was mixed with 20 μL of calcium chloridef and placed in a prewarmed thromboelastography cup.g The analysis was run at 37°C until MA was achieved, and the R, K, α, and MA were recorded. Clot strength was calculated as 5,000 × MA/(100 - MA). All thromboelastographic variables were determined in duplicate, and the means were calculated and used for analyses. The thromboelastographic variables for the envenomated dogs were compared with those obtained for 10 healthy (control) dogs of various signalments that were owned by employees of the VCA West Los Angeles Animal Hospital. Those 10 dogs were intended to represent a standard population of healthy dogs and were selected on the basis of no known history of major medical issues and unremarkable physical examination results.
Coagulation analyses
All coagulation analyses except platelet counts were performed on site at the VCA West Los Angeles Animal Hospital. Prothrombin time and aPTTh were determined for 5 of the 14 envenomated dogs. Platelet counts were determined by automated means at an off-site diagnostic laboratoryi for 13 dogs. Platelet counts, PT, and aPTT were not determined for the remaining envenomated dogs because the primary attending clinician did not deem that information necessary or owing to owner financial constraints.
Statistical analysis
Descriptive statistics were generated to summarize signalment, envenomation site, and SSS information. Data distributions for all thromboelastographic variables (R, K, α, MA, and G) were assessed for normality by means of Kolmogorov-Smirnov analysis. Analysis of variance was used to compare thromboelastographic variables between envenomated dogs and healthy control dogs. Kendall rank correlation (τ) was used to evaluate the strength of association between SSS and each thromboelastographic variable and between SSS and platelet count. Mann-Whitney U tests were used for comparisons between continuous variables (eg, thromboelastographic variables) and categorical variables (SSS, sex, and snakebite location). Comparisons between categorical variables were performed with χ2 tests or Fisher exact tests when cell counts were ≤ 5. All analyses were performed with statistical software,j and values of P ≤ 0.05 were considered significant.
Results
Dogs
Fourteen dogs met the inclusion criteria and were enrolled in the study. Six dogs were enrolled subsequent to an observed snakebite, whereas the remaining 8 dogs were enrolled on the basis of exposure risk and clinical signs consistent with a snakebite. The study population consisted of 4 mixed-breed dogs and 1 each of American Eskimo, Cairn Terrier, Long-coated Chihuahua, Golden Retriever, Jack Russell Terrier, Korean Jindo, Pitbull Terrier, Shiba Inu, Toy Poodle, and Weimaraner; no breed was overrepresented in the population. There were 6 spayed females, 1 sexually intact female, 6 neutered males, and 1 sexually intact male. The median age of the study dogs was 5 years (range, 2 to 14 years; mean, 6.5 years).
Clinical and hematologic findings
The median duration between observed or suspected envenomation and veterinary examination was 1.5 hours (range, 30 minutes to 14 hours; mean, 2.8 hours). All dogs had regional swelling at the observed or suspected envenomation site. Twelve dogs had visible puncture wounds in the swollen region. Ten dogs were bitten on the muzzle, and the remaining 4 dogs were bitten either on a thoracic (n = 2) or pelvic (2) limb. All 14 envenomated dogs survived to be discharged from the hospital.
For the 5 dogs for which PT and aPTT were determined, the median PT was 15 seconds (range, 10 to 31 seconds; mean ± SD, 16.6 ± 9 seconds [reference range, 12 to 17 seconds]) and the median aPTT was 88 seconds (range, 75 to 97 seconds; mean ± SD, 86.8 ± 9 seconds [reference range, 71 to 102 seconds]). Only 1 of those 5 dogs had a prolonged PT (31 seconds), but its aPTT (88 seconds) was within the reference range. That was also the only dog with an observed snakebite for which PT and aPTT were determined. All thromboelastographic variables for those 5 dogs were within the respective reference ranges.
Of the 13 dogs for which the platelet count was determined, 7 had thrombocytopenia (platelet count reference range, 170,000 to 400,000 platelets/μL). All samples were assessed for and verified free of platelet clumping by a medical technologist in accordance with standard operating procedures established by the diagnostic laboratory where the platelet counts were determined. Thus, the thrombocytopenia reported for those 7 dogs was believed to be a real finding and not the result of platelet clumping in the evaluated blood samples. The platelet count for sexually intact dogs was significantly (P = 0.030) lower than that for neutered dogs.
SSS
The median SSS was 3 (range, 1 to 11). The SSS was negatively correlated with platelet count (P = 0.024) and positively correlated with the number of antivenin vials administered to the patient (P = 0.025).
Thromboelastographic variables
Thromboelastographic variables for the envenomated dogs and healthy control dogs were summarized (Table 1). Thromboelastographic results suggested that envenomated dogs were in a hypocoagulable state relative to the healthy dogs. The mean G value for the envenomated dogs (3.5 Kd/s) was significantly (P = 0.001) less than that for the healthy dogs (6.0 Kd/s), and 12 of the 14 envenomated dogs had G values that were less than the 25th percentile for the healthy dogs. The thromboelastographic tracings for 3 of the 14 envenomated dogs had an MA ≤ 20 mm. Therefore, the K could not be reported for those 3 dogs, and those results were treated as missing and excluded from the analysis. None of the envenomated dogs had evidence of hypercoagulability. For all 14 envenomated dogs, there was a significant (P = 0.033 for both analyses) positive correlation between age and both MA and G. Neuter status was significantly (P ≤ 0.029 for all analyses) correlated with R, K, α, MA, and G, with sexually intact dogs having lower values for those variables than neutered dogs. None of the thromboelastographic variables were significantly associated with SSS or the number of antivenin vials administered. However, the dog with the highest SSS received the most vials (n = 9) of antivenin and had the lowest G value (0.1 Kd/s) among all 14 envenomated dogs.
Summary statistics for thromboelastographic variables and platelet counts determined for 14 dogs with observed or suspected rattlesnake envenomation and 10 healthy control dogs.
| Envenomated dogs | Control dogs | |||
|---|---|---|---|---|
| Variable | Mean (IQR) | Median (range) | Mean (IQR) | Median (range) |
| R (min) | 5.9 (3.1) | 3.8 (2.1–25) | 3.7 (1.3) | 3.4 (2.2–5.8) |
| K (min)* | 22.1 (4.0)*† | 4.5 (2.2–7.9) | 2.4 (1.6) | 1.8 (1.1–4.4) |
| α (°) | 36.7 (23.8)* | 38.1 (2.8–61.2) | 62.2 (16.1) | 66.2 (37.9–75) |
| MA (mm) | 36.8 (20.4)* | 40.1 (2.6–58.2) | 53.1 (10.3) | 52.6 (38.7–66.7) |
| G (Kd/s) | 3.5 (3.1)* | 3.4 (0.1–6.9) | 6 (2.4) | 5.6 (3.2–10.0) |
| Platelet count (× 103 platelets/μL):‡ | 161.7 (110.2)§ | 153 (48–270) | — | — |
Value differs significantly (P ≤ 0.05) from the corresponding value for the control dogs.
Represents mean for only 11 dogs because the K could not be reported for 3 dogs that had thromboelastographic tracings with an MA ≤ 20 mm.
Reference range, 170,000 to 400,000 platelets/μL.
Platelet count was determined for only 13 of the 14 envenomated dogs.
— = Not determined.
Discussion
Results of the present study indicated that dogs bitten by rattlesnakes native to southern California were in a hypocoagulable state at initial examination relative to healthy dogs that were not bitten by rattlesnakes. Twelve of the 14 envenomated dogs had G values less than the 25th percentile for the G values of healthy dogs. The G value is calculated from the MA; it provides an assessment of the global strength of a blood clot and can be used to classify dogs as being in a hypocoagulable, normal coagulable, or hypercoagulable state.7,14
The hemostatic findings for the envenomated dogs of the present study were consistent with those for dogs bitten by pit viper species native to north-central Florida7 and African puff adders.16 However, unlike those other studies,7,16 all envenomated dogs of the present study survived to be discharged from the hospital, and an abnormal thromboelastographic tracing could not be used as a prognostic indicator. Clinical signs of snake envenomation include puncture wounds, signs of acute pain, marked swelling and edema, and ecchymosis at and near the bite site.4 Six of the 14 dogs of the present study were observed to be bitten by a rattlesnake, whereas the remaining 8 dogs were suspected to have been bitten by a rattlesnake on the basis of exposure risk and clinical signs. The rattlesnakes that bit the envenomated dogs of this study were not available for evaluation; thus, speciation of those snakes was not possible. Although we cannot comment directly on the snake species that caused the envenomations for the dogs of this study, all dogs were bitten in the local area surrounding the VCA West Los Angeles Animal Hospital; therefore, it was presumed that Viperidae native to the region were responsible for all envenomations.
The SSS system used in the present study was adapted from a snakebite scoring system used in human medicine21 and has been used in other studies1,7,16,17 to assess severity of snake envenomation in dogs. The SSS takes into account a number of factors associated with the respiratory, cardiovascular, gastrointestinal, hematologic, and nervous systems and local wound severity, and envenomation-induced changes in those factors can be delayed and not evident in patients that are examined immediately after being bitten. Thus, the SSS may not initially reflect the severity of envenomation, but it can be serially repeated to evaluate disease progression. For the dogs of the present study, the SSS was assigned to each dog once on the basis of information recorded in the medical record by the attending clinician at the time of the initial physical examination, and that score was used for comparison with the thromboelastographic variables. Although the dog with the highest SSS (ie, most severe disease) had the lowest G value (ie, was in the most hypocoagulable state), SSS was not significantly correlated with any thromboelastographic variable. It is possible that a significant correlation between SSS and thromboelastographic variables would have been identified had the SSS been serially evaluated for the dogs of this study.
Life-threatening spontaneous hemorrhage following crotalid (rattlesnake) envenomation develops as a result of abnormal functioning of coagulation factors in addition to local effects of metalloproteinases that damage extracellular matrix proteins, particularly type IV collagen, which leads to weakened adhesion of endothelial cells to the basement membrane and compromises the integrity of blood vessels.22 The hypocoagulable state identified for the envenomated dogs of the present study and other studies7,16 was likely initiated by several venom constituents such as phospholipase A2, protein C, antithrombin, and factor V denaturation.7,23,24 Collectively, those constituents cause thrombocytopenia, consumptive coagulopathy, and hemorrhage. Results of another study23 suggest that venom-induced platelet dysfunction can cause systemic hemorrhage without evidence of coagulation factor abnormalities.
Use of thromboelastography may provide a more comprehensive assessment of global hemostasis and might be a more valuable tool than assessment of PT and aPTT or platelet count alone for assessment of envenomation severity in dogs. The design of the present study allowed evaluation of thromboelastographic variables for all envenomated dogs; however, some owners could not afford additional diagnostic testing such as determination of PT, aPTT, and platelet count. In fact, PT and aPTT were determined for only 5 of the 14 envenomated dogs of the present study, and the results for those 5 dogs were all within the respective reference ranges, with the exception of 1 dog that had an abnormally prolonged PT. All thromboelastographic variables for those 5 dogs were also within the respective reference ranges. The 3 dogs with the lowest G values were also thrombocytopenic, but PT and aPTT results were not available for those dogs; thus, we could not assess whether the thromboelastographic results were consistent with clinically detectable prolonged coagulation. It should also be noted that the blood samples that underwent thromboelastography in the present study were anticoagulated with citrate and activated with kaolin as recommended by the manufacturer of the automated hemostasis analyzer in an effort to standardize the procedure and minimize variation in the results. Results of other studies25,26 suggest that kaolin activation of citrated blood samples prior to thromboelastography might cause the results to appear more hypercoagulable than those yielded following analysis of native (unactivated) citrated blood samples. Therefore, it is possible that the results of the present study might have been more pronounced had native blood samples been analyzed.
Although 12 of the 14 dogs of the present study were examined within 3 hours after observed or suspected evenomation, the duration between envenomation and examination was not standardized and varied greatly, ranging from 30 minutes to 14 hours. One dog had been treated for snake envenomation on 2 different occasions prior to the snake bite that initiated enrollment in the present study. During the present study, that dog was examined within 8 hours after evenomation and appeared to have normal coagulation (ie, its PT, aPTT, platelet count, and thromboelastographic variables were all within the respective reference ranges). Investigators of another study23 postulate that preexisting antibodies from natural envenomation or vaccination may not prevent local tissue effects but may provide protective effects against other systemic venom-induced signs such as hypocoagulability. Given that the dog had been previously exposed to venom, it possibly had antibodies that prevented the development of coagulation abnormalities despite the presence of local effects. The dog with the next to lowest G value (0.7 Kd/s) in the present study was initially examined 14 hours after envenomation and did not have any known previous exposure to rattlesnake envenomation. Variation in the duration between envenomation and examination could have had a substantial effect on thromboelastographic findings. In the present study, all blood samples underwent thromboelastography within 30 minutes after collection to limit the time of incubation with active venom. Future investigations should focus on the duration between envenomation and thromboelastographic analysis to determine whether dogs that go untreated for a prolonged period are in a more hypocoagulable state than dogs that receive immediate treatment. That could be evaluated in vitro, whereby blood samples incubated with known aliquots of venom undergo thromboelastography at different time points.
In a study7 of 38 dogs that were bitten by pit viper species native to north-central Florida, all dogs had thromboelastographic tracings that were suggestive of normal coagulation or hypocoagulation at initial examination, similar to the dogs of the present study. In that study,7 the prevalence rate of hypocoagulability (as determined on the basis of an abnormally decreased G value) was 39% (15/38 dogs) at initial examination and decreased to 19% (6/31) immediately after antivenin administration and to 14% (4/29) at 12 hours after antivenin administration. Although thromboelastographic tracings were not repeated for the dogs of the present study after treatment initiation, we believe that the number of dogs that would have been classified as hypocoagulable would likewise have decreased owing to the lack of progression of clinical signs in the study population. Collectively, the results of the present study and that other study7 suggest that thromboelastographic tracings will be indicative of hypocoagulability for many dogs envenomated by most, if not all, pit viper species.
Findings of the present study supported results of other studies7,16 that indicate thromboelastography is a useful tool for assessment of global hemostasis in envenomated dogs at initial examination. In the present study, 12 of 14 envenomated dogs had G values that were less than the 25th percentile for the healthy control dogs, which suggested they were in a hypocoagulable state. Moreover, only 1 of 5 envenomated dogs for which PT and aPTT results were available had a prolonged PT, but the aPTT and all thromboelastographic variables were within the respective reference range for that dog. Thus, it appeared that thromboelastography might be better than PT and aPTT for detection of coagulation disorders in dogs following observed or suspected rattlesnake bites. Although SSS was not significantly correlated with the number of antivenin vials administered or any of the thromboelastographic variables assessed for the envenomated dogs of this study, we believe thromboelastography might provide an objective measure of the coagulation status for envenomated dogs and aid in the identification of dogs that are in a hypocoagulable state and in need of antivenin treatment prior to the onset of progressive clinical signs. Serial measurement of thromboelastographic variables for envenomated dogs may also be useful for assessment of the response to treatment and the effects of treatment on coagulation status and clinical outcome. Additional research is necessary to determine whether thromboelastographic evidence of hypocoagulability can be used as a predictor of disease severity or risk of death for dogs that are bitten by rattlesnakes.
Acknowledgments
The authors thank Dr. Terri Rieser for technical assistance.
ABBREVIATIONS
| α | Clot formation angle |
| aPTT | Activated partial thromboplastin time |
| G | Clot strength |
| IQR | Interquartile range (75th percentile minus 25th percentile) |
| K | Clot formation time |
| MA | Maximum amplitude |
| PT | Prothrombin time |
| R | Reaction time |
| SSS | Snakebite severity score |
Footnotes
VenomVet, MT Venom LLC, Canoga Park, Calif.
Vacutainer with sodium citrate, Becton Dickinson, Franklin Lakes, NJ.
Vacutainer with EDTA, Becton Dickinson, Franklin Lakes, NJ.
Haemoscope Thromboelastic Analyzer, Haemoscope Corp, Niles, Ill.
TEG Analytical Software, version 4.2.3, Haemoscope Corp, Niles, Ill.
Haemoscope Corp, Niles, Ill.
Disposable cups and pins, Haemoscope Corp, Niles, Ill.
Coag Dx Analyzer, Idexx, Westbrook, Me.
Antech Diagnostics, Irvine, Calif.
Statsview, version 5.0, SAS Institute Inc, Cary, NC.
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