Bleeding Following Rattlesnake Envenomation in Patients With Preenvenomation Use of Antiplatelet or Anticoagulant Medications

Authors

  • Michael Levine MD,

    Corresponding author
    1. The Department of Medical Toxicology, Phoenix, AZ
    2. The Department of Emergency Medicine, Section of Medical Toxicology, University of Southern California, Los Angeles, CA
    3. The Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, AZ
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  • Anne-Michelle Ruha MD,

    1. The Department of Medical Toxicology, Phoenix, AZ
    2. The Center for Toxicology and Pharmacology Education and Research, University of Arizona College of Medicine, Phoenix, AZ
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  • Angela Padilla-Jones RN,

    1. The Banner Research Institute, Phoenix, AZ
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  • Richard Gerkin MD,

    1. The Department of Medical Education, Banner Good Samaritan Medical Center, Phoenix, AZ
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  • Stephen H. Thomas MD

    1. The Department of Emergency Medicine, University of Oklahoma, School of Community Medicine, Tulsa, OK
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  • Presented at the North American Congress of Clinical Toxicology, Denver, CO, October 2010.
  • The authors have no relevant financial information or potential conflicts of interest to disclose.

Abstract

Objectives

Rattlesnake envenomations commonly produce coagulopathy and thrombocytopenia, yet clinically significant bleeding is uncommon. It is unknown if patients who use antiplatelet or anticoagulant medications prior to envenomation are at increased risk for bleeding after envenomation.

Methods

This was a retrospective cohort study of patients age 14 years and older who were admitted to a single academic medical center for rattlesnake envenomation. Patients who reported use of antiplatelet or anticoagulant medications prior to envenomation were compared to patients not on those medications. Severity and timing of bleeding was compared between groups, as was a composite endpoint of major bleeding at any time, shock, readmission, or death.

Results

A total of 319 patients met inclusion criteria; 31 (9.7%) were documented to be taking antiplatelet or anticoagulant medications including aspirin, clopidogrel, and/or warfarin. Seventeen of the 319 patients developed bleeding associated with envenomation (major = 9; minor = 4; trivial = 4), with major bleeding occurring in five patients on antiplatelet or anticoagulant medications versus four patients not on antiplatelet or anticoagulant medications (p < 0.001). Seven of the 17 presented with early bleeding. This early bleeding occurred in three of 31 (9.7%) patients on antiplatelet or anticoagulant medications and four of 288 (1.4%) patients not on antiplatelet or anticoagulant medications (relative risk [RR] = 6.9; 95% confidence interval [CI] = 1.6 to 29.4; p = 0.022). Clinical outcome data were available for 300 of the 319 (94%) subjects following discharge. Late bleeding (bleeding after discharge from the index hospitalization) occurred in nine subjects, one of whom also had early bleeding (major = 2, minor = 3, trivial = 4). Three of these nine subjects with late bleeding were on antiplatelet or anticoagulant medications, compared with six not on antiplatelet or anticoagulant medications (p = 0.042). Both cases of late major bleeding occurred in patients on antiplatelet or anticoagulant medications. Therefore, among patients with follow-up data available, the overall rate of bleeding (early and late) was seven of 28 (25%) in patients taking antiplatelet or anticoagulant medications and 10 of 273 (3.7%) in patients not taking antiplatelet or anticoagulant medications (p < 0.001). The use of antiplatelet or anticoagulant medications was also associated with an increased risk of reaching the composite endpoint of major bleeding, shock, readmission, or death (6 of 31, or 19.4% vs. 14 of 288, or 4.9%; RR = 3.98; 95% CI = 1.65 to 9.62; p = 0.008).

Conclusions

The risk of developing bleeding following rattlesnake envenomation is increased in patients who use antiplatelet or anticoagulant medications. This risk is greatest early after envenomation during the index hospitalization. However, risk of late, major bleeding appears also to be greatest in patients on antiplatelet or anticoagulant medications. Extra vigilance should be taken in patients on antiplatelet or anticoagulant medications and a careful risk/benefit analysis should be undertaken before continuing these medications in the weeks following the envenomation.

Resumen

Objetivos

Las mordeduras de serpiente producen frecuentemente coagulopatía y trombocitopenia, aunque la hemorragia clínicamente significativa es poco común. Se desconoce si los pacientes en tratamiento con fármacos antiagregantes o anticoagulantes (FAA) tienen un riesgo incrementado de hemorragia.

Metodología

Estudio de cohorte retrospectivo de pacientes de 14 años o más que ingresaron por mordeduras de serpiente en un único centro médico universitario. Los pacientes que recibían FAA previamente a la mordedura se compararon con los pacientes que no los tomaban. La gravedad y el tiempo de la hemorragia se compararon entre los grupos mediante un resultado compuesto por hemorragia mayor en cualquier momento, shock, reingreso o muerte.

Resultados

Trescientos diecinueve pacientes cumplieron los criterios de inclusión; 31 (9,7%) en tratamiento con FAA que incluían aspirina, clopidogrel y/o warfarina. Diecisiete de los 319 pacientes desarrollaron hemorragia asociada con la mordedura (mayor = 9; menor = 4; trivial = 4). Ocurrió una hemorragia mayor en cinco pacientes con FAA vs. cuatro pacientes sin FAA (p < 0,001). Siete de 17 presentaron una hemorragia precoz. Esta hemorragia precoz ocurrió en tres de 31 pacientes con FAA (9,7%) y en cuatro de 288 pacientes sin FAA (1,4%, riesgo relativo 6,9; IC 95% = 1,6 a 29,4; p = 0,022). Los datos de los resultados clínicos estuvieron disponibles en 300 de los 319 (94%) sujetos tras el alta. La hemorragia tardía (hemorragia tras el alta del ingreso índice) ocurrió en nueve sujetos (mayor = 2, menor = 3, trivial = 4), uno de los cuales también tuvo sangrado precoz. Tres de estos nueve sujetos con hemorragia tardía eran pacientes en tratamiento con FAA, comparados con 6 sin FAA (p = 0,042). Los dos casos de hemorragia mayor tardía ocurrieron en pacientes con FAA. Por tanto, en los pacientes con datos de seguimiento disponible, la frecuencia global de hemorragia (precoz y tardía) fue 7 de 28 (25%) en los pacientes que tomaban FAA, y de 10 de 273 en pacientes que no tomaban FAA (p < 0,001). El uso de FAA también se asoció con un incremento del riesgo de alcanzar el resultado compuesto de sangrado mayor, shock, reingreso o muerte (6 de 31 [19,4%] vs. 14 de 288 [4,9%]; RR = 3,98; IC 95% = 1,65 a 9,62; p = 0,008).

Conclusiones

El riesgo de desarrollar hemorragia tras la mordedura de serpiente se incrementó en los pacientes con FAA. Este riesgo es sobre todo precoz tras la mordedura. Sin embargo, el riesgo de hemorragia mayor tardía parece ser también ser mayor en los pacientes con FAA. Se debería llevar a cabo una vigilancia extra en los pacientes con FAA y un análisis cuidadoso del riesgo-beneficio antes de continuar con estas medicaciones en las semanas posteriores a la mordedura.

Rattlesnakes are responsible for the greatest morbidity and mortality due to venomous snakebite in the United States. The most common effect of rattlesnake envenomation is localized tissue swelling, but a significant number of patients also develop thrombocytopenia and/or coagulopathy.[1, 2] Even when severe, these hematologic effects are usually not associated with bleeding.

Hemorrhage following rattlesnake envenomation, although uncommon, has been reported. Life-threatening or fatal bleeding has occurred in the settings of intravascular envenomation, preexisting alcoholic liver disease and Mallory-Weiss tear, and hematologic recurrence following treatment with Crotalidae polyvalent immune Fab antivenom (FabAV).[3-7] However, large cohort studies of patients with rattlesnake envenomation rarely describe bleeding events. Risk factors that might predispose a patient to development of bleeding following rattlesnake envenomation have not been described.

The primary purpose of this study was to determine if patients on antiplatelet or anticoagulant medications are more likely to develop bleeding following rattlesnake envenomation compared to those patients without preenvenomation use of these medications. A secondary aim of the study was to determine if patients on antiplatelet/anticoagulant medications were more likely to reach a composite endpoint of major bleeding, shock, readmission, or death compared with those not taking antiplatelet/anticoagulant medications.

Methods

Study Design

This study was a retrospective cohort study involving all patients 14 years of age or older who were admitted to a single academic medical center in Phoenix, Arizona, with a diagnosis of rattlesnake envenomation between January 1, 2001, and March 31, 2010. The medical toxicology service maintains a log-book of all consecutive patient encounters. Subjects were identified via a review of this logbook. The study was approved by the institutional review board.

Study Setting and Population

The medical records of all eligible patients were reviewed to determine study eligibility. Subjects were considered eligible if they were treated with FabAV (CroFab). Subjects were excluded if they did not receive antivenom or if they received an antivenom other than FabAV. For individuals with multiple separate envenomations, only admissions related to the first envenomation were included in the study. For all patients who met inclusion criteria, toxicology clinic and poison center records were also obtained to document follow-up information.

Study Protocol

Data abstracted from the hospital medical records included age, sex, medical history, medication history, bite characteristics, laboratory studies, treatment rendered, and outcome. Presence of bleeding, time of onset of bleeding, and severity of bleeding were documented, as were the clinical parameters of the presence of hypotension or shock. Toxicology outpatient clinic records and records from the regional poison control center were reviewed for outcome data after discharge, including laboratory studies, readmission, and documentation of bleeding.

The data were collected onto a predesigned data abstraction form and then entered into a spreadsheet (Excel 2000, version 9.0, Microsoft Corp., Redmond, WA) by two investigators (ML, APJ). Before data abstraction, each reviewer received standardized training in systematic chart review. Ten percent of the records were randomly selected for additional review by both reviewers.

Study Definitions

Patients who reported occasional use of aspirin were considered to not use aspirin. Patients who reported use of ibuprofen or other nonsteroidal anti-inflammatory drugs were not considered to be taking antiplatelet agents. Patients reporting daily use of aspirin, clopidogrel, ticlopidine, enoxaparin, or warfarin were considered to be users of antiplatelet/anticoagulant medications.

Early bleeding was defined as bleeding that was present at presentation to the hospital or in the hospital, but before completion of antivenom therapy. Late bleeding was defined as bleeding that occurred after completion of initial antivenom treatment and discharge from the hospital (e.g., bleeding beginning after the index hospitalization). Shock was defined clinically as a combination of hypotension and end-organ dysfunction. This clinical definition includes both anaphylactic reactions due to the envenomation itself and hypovolemia as a result of bleeding from the envenomation. If a patient had bleeding after control (no further swelling; laboratory abnormalities beginning to improve), but before discharge, he or she would be considered to have bleeding at “any time,” but not early nor late bleeding. The length of stay was defined based on total number of calendar days in a hospital, rather than 24-hour blocks.

Major bleeding was defined as fatal bleeding, bleeding associated with hemodynamic instability, bleeding requiring an invasive therapeutic intervention (e.g., endoscopy), bleeding requiring the transfusion of one or more units of packed red blood cells, or bleeding into an enclosed space (e.g., retroperitoneal or intracranial). Minor bleeding was defined as any bleeding resulting in an admission or prolonged observation, but not requiring the administration of blood products or performance of any procedures. Trivial bleeding was defined as bleeding not requiring any intervention or prolonged observation and included persistent oozing from puncture wounds and self-limited bleeding not requiring intervention (e.g., epistaxis or hemorrhoid bleeding).

A plasma fibrinogen measurement less than the lower limit of detection (e.g., less than 30 mg/dL) was considered to be zero for calculations. Similarly, a prothrombin time (PT) above the upper limit of detection (e.g., more than 120 seconds) was considered to be 120 seconds for calculations.

Outcomes

The primary outcome parameter was the development of early or late bleeding among those patients with preenvenomation use of antiplatelet/anticoagulant medications compared with those patients not on antiplatelet/anticoagulant medications. A secondary objective was to determine if patients on antiplatelet/anticoagulant medications were more likely to reach the composite endpoint of major bleeding at any time, shock, readmission, or death, compared with those not taking antiplatelet/anticoagulant medications.

Data Analysis

Continuous variables are reported as medians and interquartile ranges (IQRs), as they were not normally distributed. Categorical variables are reported as percentages. The Kruskal-Wallis test or Mann-Whitney U-test was used to compare continuous variables, while categorical variables were assessed using a chi-square test or Fisher's exact test, as appropriate. Relative risks (RRs) were calculated along with their 95% confidence intervals (CI) for predictors of bleeding outcomes. A two-tailed p-value of <0.05 was considered significant. All p-values reported are nominal with no adjustment for multiple comparisons. The kappa statistic was calculated for each categorical variable abstracted. Data analysis was performed using SPSS Version 20 (IBM SPSS, Armonk, NY).

Results

During the study period, 464 patients were evaluated for a rattlesnake envenomation. A total of 139 patients were excluded because they met prespecified exclusion criteria. An additional six records (1.3%) could not be located, resulting in a final study population of 319 patients (Figure 1).

Figure 1.

Final study population.

Outcome data (e.g., late bleeding, hospital readmission) were available for 301 of the 319 (94.4%) subjects. Complete laboratory results (PT and platelet counts) after discharge were available for 140 (44%), as many patients during the early phase of the study period followed up with their primary care providers for laboratory studies and the results were not always conveyed to the poison center. Nonetheless, outcome data (e.g., bleeding or no bleeding) were available for the majority of the patients without complete laboratory follow-up data. There was no statistically significant difference in availability of follow-up laboratory studies in those with or without preenvenomation use of antiplatelet/anticoagulant medications. There was 100% agreement for each categorical variable abstracted, and thus all kappa values were 1.0

The median age of all subjects was 44 years (IQR = 31 to 55 years). The majority (255 of 319; 79.9%) were men. Thirty-one patients (10.3%) reported using antiplatelet/anticoagulant medications. Subjects taking antiplatelet/anticoagulant medications were older than those not taking them; the median ages were 62 years (IQR = 55 to 71 years) versus 43 years (IQR = 30 to 52 years; p < 0.001). There was no statistically significant association between the location of the bite (e.g., upper extremity vs. lower extremity) and the preenvenomation use of antiplatelet/anticoagulant medications. Laboratory characteristics of the subjects are presented in Table 1.

Table 1. Laboratory and Treatment Characteristics of Subjects
CharacteristicNo AAMs (n = 288)Any AAMs (n = 31)p-value
  1. Values represent median with corresponding interquartile range (IQR) unless otherwise noted.

  2. AAMs = antiplatelet or anticoagulant medications; NS = nonsignificant; PT = prothrombin time.

  3. a

    Represents first blood work obtained in the ED.

  4. b

    Among the six patients on warfarin, the initial PT was significantly higher compared with those not on warfarin; 19.6 seconds vs. 13.1 seconds; p = 0.038.

Age (yr)43 (30–52)62 (55–71)0.0001
Male234 (81%)21 (67%)0.096
ED laboratory valuesa
PT (seconds)b13.1 (11.6–14.4)13.5 (11.4–22.5)NS
Fibrinogen (mg/dL)249 (187–308)269 (216–358)NS
Platelets (×109/L)196 (116–256)168 (60–216)0.017
Hemoglobin (g/dL)15.3 (14.2–16.1)15.3 (13–15.9)NS
Inpatient laboratory values
Maximal PT (seconds)14 (12.6–17.4)16.7 (12.9–34.4)0.056
Nadir fibrinogen (mg/dL)214 (127–253)213 (122–286)NS
Nadir platelets (×109/L)163 (97–214)137 (33–181)0.016
Nadir hemoglobin (g/dL)13.5 (12.5–14.6)12 (10.5–13.9)0.001
Vials of antivenom to achieve control6 (6–10)8 (4–16)NS
Total number of vials of antivenom12 (12–16)14 (10–22)NS
Length of stay (days)3 (2–3)3 (2–5)0.053

Of the 31 subjects on antiplatelet/anticoagulant medications, 25 (81%) used aspirin with or without other agents. Seven (23%) had preenvenomation use of clopidogrel with or without other agents. Five of the subjects taking clopidogrel were also taking aspirin, including one who was taking both aspirin and warfarin in addition to the clopidogrel. Six subjects were taking warfarin at the time of their envenomations. Of these six, two subjects, both of whom were previously mentioned, were on other agents with the warfarin. No patients were taking ticlopidine or low-molecular-weight heparins at the time of envenomation (see Table 2).

Table 2. Anticoagulant and Antiplatelet Use Among Subjects
Drug/Drug CombinationsNumber
Any aspirin25
Aspirin alone19
Any clopidogrel7
Clopidogrel alone2
Any warfarin6
Warfarin alone4
Combination therapy 
Aspirin + warfarin1
Aspirin + clopiodgrel4
Aspirin + clopidogrel + warfarin1

The median numbers of vials of antivenom to achieve initial control in those taking antiplatelet/anticoagulant medications versus those not taking them were 8 (IQR = 4 to 16) and 6 (IQR = 6 to 10), respectively (p = 0.253). The median number of total vials of antivenom administered for those taking antiplatelet/anticoagulant medications was 14 (IQR = 10 to 22) and those not taking them it was 12 (IQR = 12 to 16; p = 0.350). Blood products were administered more frequently to subjects with preenvenomation use of antiplatelet/anticoagulant medications (3 or 31; 9.7%) compared to those without (3 of 288; 1%; RR = 9.26, 95% CI = 2.0 to 43.5).

Early bleeding, during the time of initial hospital admission, occurred in three of the 31 (9.7%) patients taking antiplatelet/anticoagulant medications and in four of 288 (1.4%) patients not taking them (p = 0.022; RR = 6.9; 95% CI = 1.6 to 29.4).

Follow-up outcome data were available for 301 patients. In these patients, bleeding at any time occurred in seven of 28 (25%) of those on antiplatelet/anticoagulant medications, compared with 10 of 273 (3.7%) in those not on antiplatelet/anticoagulant medications (p < 0.001). The use of antiplatelet/anticoagulant medications was associated with a 6.8-fold risk of any bleeding (95% CI = 2.82 to 16.4).

Table 3 describes bleeding severity in patients with available outcome data. The risk of nontrivial bleeding occurring at any time was 11.4 times greater among those taking antiplatelet/anticoagulant medications (95% CI = 4.12 to 31.3; p < 0.001). Major bleeding occurred in five of 28 (17.9%) patients on antiplatelet/anticoagulant medications and in four of 273 (1.5%) patients not on them (p < 0.001). The RR of major bleeding with use of antiplatelet/anticoagulant medications was 12.2 (95% CI = 3.47 to 43.5). Six subjects on antiplatelet/anticoagulant medications (19.4%) met the composite endpoint of major bleeding, shock, readmission related to the envenomation, or death. Fourteen (4.9%) patients not on antiplatelet/anticoagulant medications also reached the composite endpoint. The use of antiplatelet/anticoagulant medications was thus associated with an RR of reaching the composite endpoint of 3.98 (p = 0.008, 95% CI = 1.65 to 9.62). Any bleeding (trivial, minor, or major) on initial admission was strongly associated with an increased risk of reaching the composite endpoint (RR = 19.2; 95% CI = 10.5 to 34.5).

Table 3. Classification of Bleeding for Patients With Follow-up Data Available (N = 300)
AAM UseMajor BleedingMinor BleedingTrivial BleedingNo Bleeding
  1. Data are reported as n (%).

  2. AAM = antiplatelet or anticoagulant medication.

No AAM3 (1.10)2 (0.74)4 (1.47)263 (96.69)
AAM5 (17.90)2 (7.14)0 (0)21 (75.00)
Total8 (2.67)4 (1.33)4 (1.33)284 (94.67)

Major bleeding was not present on admission, but developed during the index hospitalization, in two individuals, one on antiplatelet/anticoagulant medications and one not on them. A 71-year-old woman with a history of hypertension, atrial fibrillation, coronary artery disease, and prior cerebrovascular accident was on aspirin, clopidogrel, and warfarin. The initial PT was 19.6 seconds, with a fibrinogen of 182 mg/dL and platelets of 251 × 10[9]/L. She developed progressive anemia, although no clear source of bleeding was identified. Based on progressive increasing lower extremity edema, it was presumed she had bleeding into the soft tissues in her leg. She was transfused 2 units of packed red blood cells. She made a complete recovery. A 52-year-old woman, not on antiplatelet/anticoagulant medications, was bitten in the lower extremity. This patient presented in shock without overt bleeding. Initial laboratory studies included thrombocytopenia (42 × 10[6]/L) without coagulopathy. She developed ischemic colitis, a lower gastrointestinal hemorrhage, and acute renal failure. She ultimately recovered.

Late bleeding occurred in nine subjects: three on antiplatelet/anticoagulant medications and six not on antiplatelet/anticoagulant medications. Of those late events, all but two were considered minor or trivial and occurred in patients not taking antiplatelet/anticoagulant medications. Two bleeding events were considered major, and both occurred in patients taking antiplatelet/anticoagulant medications. One patient, a 91-year-old woman with a history of dementia and coronary artery disease, who was on aspirin, was bitten in the lower extremity. An initial platelet count of 68 × 10[9]/L was present, with an initial PT of 14.6 seconds and a hemoglobin of 13 mg/dL. A fibrinogen was not measured at presentation. The patient developed a coagulopathy. She did not exhibit early bleeding and the nadir hemoglobin during the index hospitalization was 10.7 mg/dL. She received a total of six vials of antivenom for initial control with subsequent improvement in laboratory parameters. No maintenance dosing was administered, as she had an anaphylactic reaction to the initial loading dose, which manifested as lip and tongue edema. Because she had worsening delirium during the hospitalization, the family decided to sign the patient out against medical advice, despite the worsening laboratory parameters. Her laboratory values at the time of discharge, on hospital day 7, included a PT of 79.7 seconds, platelets of 124 × 10[9]/L, a nondetectable fibrinogen, and a hemoglobin of 10.7 mg/dL. The patient was readmitted to a hospital 3 days after discharge with a lower gastrointestinal hemorrhage. At the time of readmission, the PT was greater than 165 seconds, and the hemoglobin was 8.9 mg/dL with numerically normal platelets. The hemoglobin continued to decrease over 3 days until reaching a nadir of 4.9 mg/dL. At that time, the PT was 22.9 seconds, and the platelets were 167 × 10[9]/L. She refused blood due to religious beliefs (Jehovah's Witness). The patient ultimately recovered. Prior to discharge, hemoglobin was 6.2 mg/dL, platelets were 142 × 10[9]/L, and PT was 15.3 seconds.

The second patient with late major bleeding was a 47-year-old man with a history of coronary artery disease, who was on aspirin and clopidogrel for a previously placed drug-eluting coronary stent. He was bitten in the lower extremity. An initial PT was 10.6 seconds, with platelets of 94 × 10[9]/L. The initial hemoglobin was 15.2 mg/dL. A fibrinogen was not measured at presentation. The patient developed a coagulopathy (PT 21.4 seconds, fibrinogen <30 mg/dL). Initial control was achieved after 12 vials of antivenom, with an additional six vials administered as maintenance dosing. The nadir hemoglobin was 13.4 mg/dL. Due to concern for possible stent occlusion off clopidogrel, the patient was advised to resume the aspirin and clopidogrel following discharge. At a scheduled follow-up visit 3 days after discharge, a coagulopathy (PT 120 seconds, fibrinogen <30 mg/dL) was noted. His platelets were 130 × 10[9]/L. The hemoglobin was 7.9 mg/dL, and the patient reported flank pain. He was readmitted to the hospital and a computerized tomography scan of the abdomen and pelvis revealed a retroperitoneal hematoma. The patient was transfused packed red blood cells and given additional antivenom. He made a full recovery.

One patient, with a history of liver disease, anemia, and thrombocytopenia who did not have a history of use of antiplatelet/anticoagulant medications, died. This patient was bitten in the upper extremity and presented comatose with hypotension and gastrointestinal hemorrhage. Initial laboratory studies revealed a coagulopathy (PT 56 seconds) and thrombocytopenia (10 × 10[9]/L). Initial hemoglobin was 13.1 g/dL but persistent hemorrhage led to a nadir hemoglobin of 1.8 g/dL. The patient received 32 vials of antivenom along with numerous blood product transfusions. He developed acute respiratory distress syndrome, acute renal failure, and Gram-negative sepsis and died on hospital day 5 after care was withdrawn. This case has been previously published.[4]

All patients had their antiplatelet/anticoagulant medications discontinued at admission, and all patients except for the single patient who had been on clopidogrel for recent cardiac stent placement were told not to resume their antiplatelet/anticoagulant medications after discharge until it was felt they were no longer in danger of developing late coagulopathy or thrombocytopenia.

Discussion

Rattlesnake envenomation produces coagulopathy and thrombocytopenia in a significant percentage of victims, depending on the geographic range of the species.[1, 8] Even when patients present with combined venom-induced coagulopathy and thrombocytopenia after rattlesnake bite, early bleeding, in the initial hours to days following the envenomation, is very uncommon. Published studies of patients with rattlesnake bite rarely describe early bleeding,[1, 9-11] and case reports of early bleeding are rare.[3, 4] Consistent with the paucity of cases reported in the literature, only 2% of patients in our study presented with or developed bleeding during their initial treatment phase; however, in the subgroup of patients on antiplatelet/anticoagulant medications, early bleeding was relatively common, occurring in nearly 10% of patients.

Late bleeding was not described in the medical literature prior to introduction of FabAV for treatment of crotaline envenomation in 2000. Since FabAV replaced antivenom crotalidae polyvalent for treatment of North American crotaline envenomation, many reports of late bleeding have been published, one of which resulted in death.[5-7, 12] Reports of late bleeding in the published medical literature were recently examined in a systematic review of cohort studies and case series which included more than 1,000 patients with crotaline envenomation.[13] The authors found that only nine patients experienced late bleeding, with only five bleeding events considered medically significant, and none resulting in death or permanent sequelae. While this review of late bleeding in the setting of treated crotaline envenomation suggests the risk of late bleeding to be low in the general population of patients bitten by crotaline snakes, the risk in populations with comorbidities or use of medications that predispose to bleeding is unknown.

Antiplatelet and anticoagulant medications are used by millions of people in the United States annually.[14] The risk of hemorrhage in patients with nonvalvular atrial fibrillation treated with warfarin versus aspirin is 2.2 versus 1.3 events per 100 patient-years.[15] We hypothesized that patients using antiplatelet/anticoagulant medications who then experience a rattlesnake envenomation, which itself may create both hematologic toxicity and tissue injury, would be at increased risk for bleeding compared to patients not taking these medications. Our results demonstrate this hypothesis to be true.

There are no published guidelines available to assist clinicians who are presented with rattlesnake envenomation patients who use antiplatelet/anticoagulant medications. In our institution the standard practice is to discontinue all antiplatelet and anticoagulant medications when a patient presents with an envenomation, regardless of presence of coagulopathy or thrombocytopenia, since a significant percentage of our patients develop hematologic toxicity.[1, 8] If a patient never develops hematologic toxicity during the initial treatment phase and hospitalization, we weigh the risks versus benefits of restarting the medications, considering that he or she may go on to develop late hematologic toxicity and experience life-threatening bleeding. In this study, all but one patient on antiplatelet/anticoagulant medications was instructed to discontinue the medications until the time frame for development of hematologic toxicity had passed. The single patient who was instructed to continue his clopidogrel was scheduled for routine follow-up 4 days after his last antivenom dose, and 3 days after his laboratory values were documented as normal (PT 14.6 seconds, fibrinogen 228 mg/dL, platelets 175 × 10[9]/L). By the time of follow-up he had experienced a retroperitoneal hemorrhage.

Antiplatelet effects of aspirin are expected to last 7 to 10 days, so discontinuation of aspirin for 1 to 2 weeks until the risk of venom-induced late hematologic toxicity has passed is unlikely to produce harm in most patients. The risk of stopping other antiplatelet/anticoagulant medications depends on the patient and the indication for the medication. Whenever possible, we believe that it is safest to discontinue all anticoagulant medications until the patient has completed follow-up, and late coagulopathy or thrombocytopenia have recovered or been proven to not occur. If the benefit of continuation of the medication has been determined to be greater than the risk of discontinuation, it is imperative that the patient be followed closely with repeat platelet and coagulation studies at least every 2 days in the first week following the last dose of antivenom to ensure there are no abnormal trends in laboratory parameters. Development of thrombocytopenia or coagulopathy can be rapid and can occur despite a positive trend in platelets and coagulation studies in the initial days after treatment. Patients should be notified of the risk for bleeding and warned to go to an emergency department (ED) for any signs of bleeding.

If late hematologic toxicity occurs, patients may require retreatment with antivenom. The practice at this institution is to re-treat only those patients with late thrombocytopenia (platelets <30 × 10[9]/L) or combined late thrombocytopenia and coagulopathy (platelets <50 × 10[9]/L AND fibrinogen <80 mg/dL) or those who have additional risk factors for bleeding. Patients with isolated late coagulopathy are observed as outpatients.[16] A patient with isolated coagulopathy but also a history of recent use of antiplatelet/anticoagulant medications would meet criteria for re-treatment, because we would consider them to be functionally thrombocytopenic. The results of this study support a conservative approach to retreatment of patients with use of antiplatelet/anticoagulant medications and late venom-induced hematologic toxicity.

A strength of this study is that it was performed at a tertiary care referral center for snake envenomation in a geographic area where hematologic toxicity is common and where the clinicians emphasize the potential for late bleeding and importance of follow-up to patients. Patients receive written discharge instructions regarding potential late hematologic toxicity, prescriptions for repeat laboratory studies are provided at discharge, and patients are encouraged to return to the admitting toxicologist's office for follow-up. If patients cannot return for follow-up, the admitting physicians have the laboratory results faxed to them and review them with the patients. The goal of these precautions is to identify patients with late hematologic toxicity who meet criteria for retreatment with antivenom prior to onset of bleeding. However, this careful monitoring may have led to a lower incidence of late bleeding in our study than would have occurred were these precautions not taken.

Limitations

The limitation of the study to a single geographical region may alternatively have overestimated late bleeding events, as recurrent coagulopathy and thrombocytopenia may be more common in the southwestern United States than in other regions. An additional limitation is the retrospective study design, with conclusions limited by the quality and completeness of the data recorded in the medical record. To minimize these effects, continuous variables (e.g., fibrinogen or platelet counts) and categorical variables (e.g., transfusion or not) were collected. Choosing these specific variables likely reduced (if not eliminated) abstractor bias and thus minimized some of the limitations seen in retrospective studies.[16] Another limitation is that no patients in this study were on factor Xa inhibitors, direct thrombin inhibitors, or thienopyridines other than clopidogrel. It is not known if risk of bleeding with these agents would be similar to that observed in this study, but until additional information is available, it is prudent to exercise similar caution with patients taking any antiplatelet or anticoagulant medication.

It is possible that unmeasured confounding variables could have contributed to the differences in the results. Logistic regression was not attempted, as the small number of subjects with the outcome of bleeding did not allow adjustment for confounders without introducing the problem of overfitting the data. In this study, we opted to create a composite endpoint of major bleeding at any time, shock, death, or readmission. While these variables are not equal, we opted to use these, as all are clinically relevant endpoints and would change practice.

Conclusions

Bleeding is uncommon following rattlesnake envenomation. However, risk of bleeding appears to be increased in patients taking anticoagulant or antiplatelet medication at the time of the envenomation compared with those patients not taking anticoagulant or antiplatelet medications.

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