The Crotalinae subfamily of snakes (family Viperidae), commonly known as pit viper snakes, include rattlesnakes (
Snakebite envenomation causes not only localized tissue damage, but also systemic derangements. One of the well-known sequelae after snakebites is the systemic coagulopathy due to enzymes within the venom, which result in laboratory abnormalities, including elevated d-dimer, hypofibrinogenemia, prolonged prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), and thrombocytopenia. The use of antivenom can correct these laboratory abnormalities; however variable response has also been observed; the coagulopathy may recur, persist, or result in death after a latency period [
The manufacturer and the local poison center recommend initial boluses of CroFab with subsequent maintenance boluses as needed until initial control is achieved. In this case report, we describe a patient with recurrent coagulopathy after a snakebite that ultimately required 51 vials of Crofab. Furthermore, the coagulopathy resolved only after a continuous intravenous infusion of CroFab was administered.
A previously healthy 50-year-old intoxicated man was driving on a road on a May afternoon when he attempted to move a snake off the road with a stick to prevent it from being run over. He was bitten on the dorsum of his right hand by a positively identified 6-foot long diamondback rattlesnake (Figure
Photograph of the eastern diamondback rattlesnake (
Upon arrival in the emergency department (ED) less than one hour after the initial injury, the patient was noted to be tachycardic (HR 131), hypotensive (92/79), and stridorous. On physical examination, he had decreased mental status, voice change, and significant perioral, pharyngeal, and marked glossal edema. Rapid sequence intubation (RSI) was initiated due to impending complete upper airway obstruction. The patient was pretreated with 100 mcg of phenylephrine IV to prevent hemodynamic decompensation during RSI. During video-assisted laryngoscopy, pronounced epiglottal and cord edema was noticed, and multiple attempts of passing a styletted endotracheal tube and gum elastic bougie failed. Bag valve mask ventilation was difficult despite use of an oral airway with a decline in his oxygen saturation to 78%. Thus the decision was made to proceed with emergency cricothyrotomy using a bougie-assisted landmark-guided technique, which was successful on its first attempt. A cuffed 6-0 endotracheal tube was passed over the bougie, with good chest rise and end-tidal capnography. At the time of securing the airway, the patient’s oxygen saturation had returned to 100% secondary to continued uninterrupted two-person oral airway assisted bag valve mask ventilation.
Initial arterial blood gas analysis showed a pH of 7.03, pCO2 of 56.1 mmHg, and pO2 of 174.0 mmHg on 60% FiO2. He received 125 mg IV methylprednisolone and 1 L Plasma-Lyte A with improvement of his blood pressure to 119/76.
His right upper extremity was noted to have fang marks 2.5 cm apart in the first dorsal webspace (Figure
Fang marks located on the patient’s right upper extremity with local tissue damage, edema, ecchymoses, and mottling.
The state’s poison center was simultaneously consulted in the ED; an initial bolus of 6 vials of FabAV (CroFab) was administered. Initial pre-FabAV laboratory findings from the emergency department demonstrated consumptive coagulopathy: thrombocytopenia (platelets 20 × 103 mm−3), d-dimer > 20
The state’s poison control recommended boluses of CroFab per their protocol, which initially corrected his coagulopathy. His coagulation panel at the time of administration of FabAV throughout his hospitalization is shown in Table
Serial coagulation panel.
Day | 1 | 2 | 3 | 4 | 5 | 6 | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Time | 1600 | 2259 | 0557 | 1415 | 2037 | 0411 | 1620 | 0004 | 0800 | 1535 | 2150 | 0353 | 1300 | 2359 | 0607 | 1210 |
Platelets × 103 mm−3 | 20 | 493 | 528 | 416 | 352 | 293 | 200 | 263 | 335 | 341 | 219 | 141 | 115 | 116 | ||
PT, sec | 150 | 29.8 | 16.9 | 15.5 | 15.6 | 15 | 14.6 | 15 | 15.5 | 15.1 | 15 | 14.6 | 14.3 | 15.7 | 15 | 14.5 |
INR | 8 | 2.9 | 1.4 | 1.5 | 1.2 | 1.5 | 1.1 | 1.2 | 1.2 | 1.2 | 1.2 | 1.1 | 1.1 | 1.2 | 1.2 | 1.1 |
Fibrinogen, mg dL−1 | 35 | 35 | 104 | 167 | 176 | 166 | 158 | 164 | 151 | 129 | 156 | 150 | 189 | 232 | 291 | 319 |
D-dimer, |
20 | 20 | 20 | 16.93 | 12.58 | 17.27 | 20 | 20 | 17.05 | 12.38 | 8.8 | 10.16 | 10.9 | |||
CroFab, time, and vials | 1700 12 | 0715 2 | 1845 2 | 1342 4 | 1939 4 | 0152 2 | 0658 2 | 1048 1 | 1628 1 | |||||||
2036 6 | 1220 2 | 2229 1 | ||||||||||||||
2246 6 | ||||||||||||||||
|
||||||||||||||||
Day | 7 | 8 | 9 | 10 | 11 | 12 | 19 | |||||||||
|
||||||||||||||||
Time | 0005 | 1215 | 0000 | 1145 | 2005 | 0410 | 1246 | 0405 | 1810 | 0535 | 1315 | 1715 | 0640 | 0907 | ||
Platelets × 103 mm−3 | 97 | 97 | 91 | 77 | 67 | 43 | 48 | 60 | 109 | 128 | 150 | 245 | 612 | |||
PT, sec | 15.4 | 15 | 15.4 | 15.2 | 17.1 | 17.4 | 15.9 | 15.9 | 15.5 | 15.4 | 15.3 | 14.6 | 14.4 | 13 | ||
INR | 1.2 | 1.2 | 1.2 | 1.2 | 1.4 | 1.4 | 1.3 | 1.3 | 1.2 | 1.2 | 1.2 | 1.1 | 1.1 | 1 | ||
Fibrinogen, mg dL−1 | 394 | 452 | 495 | 305 | 110 | 111 | 183 | 195 | 314 | 243 | 261 | 267 | 282 | 464 | ||
D-dimer, |
8.17 | 4.53 | ||||||||||||||
CroFab, time, and vials | 2241 1† | 0520 1† | 2331 1† | 1100 1† | 2235 1† | |||||||||||
1048 1† |
On day 8 of his hospitalization, his fibrinogen and platelet count trended downwards, and his PT and INR trended upwards. He remained hemodynamically stable with no drop in his blood pressure, hemoglobin, or hematocrit and did not exhibit signs or symptoms of bleeding from his coagulopathy. There was no recurrence of swelling. Hematology was consulted, and decision was made to start him on FabAV infusions each over 6 hours instead of 1 hour. After six vials of FabAV were infused over 6 hours each, his coagulopathy resolved. The resolution of his coagulopathy is demonstrated in Table
Snakebite envenomation is not an uncommon occurrence in the United States. In the United States, 8,000 poisonous snakebites occur annually, which result in 9 to 15 fatalities [
The toxic effects of venom assist in its function to obtain food for the snake. The enzymes it contains help to decrease digestive time and to immobilize the snake’s prey. These enzymes alter the endothelial lining, break down plasma membranes, and promote edema and hemorrhage. Therefore, when humans are subjected to snake venom, hypovolemic shock, pulmonary edema, tissue necrosis, and renal failure ensue [
For many years, the coagulopathy after snakebites has been observed in vivo and in vitro, resulting in hemorrhagic and thrombotic events, with or without laboratory perturbations, due to activation of specific anticoagulant and/or procoagulant pathways [
In the past, the duration of coagulopathy after snakebite has traditionally been considered short-lived and patients were routinely discharged after initial correction of coagulopathy [
The mechanism of recurrence is unclear. The half-life of FabAV is less than 12 hours. It has been hypothesized that depots of unneutralized venom may continue to be released into the circulation after antivenom levels fall causing recurrent coagulopathy. Another hypothesized mechanism is the dissociation of antivenom-venom complexes, similar to digoxin-specific Fab dissociation, causing a recrudescence of coagulopathy [
Again, the clinical significance of recurrent late coagulopathy is unclear. Some experts believe that because the coagulopathy is a result of defibrination syndrome, patients are not at increased risk of bleeding [
In this case, our patient initially received boluses of FabAV per current prescribing guidelines. His local injury was well-controlled with no progression of swelling or extension after the first 24 hours. Despite initial correction of his coagulopathy, our patient developed recurrence of his coagulopathy on day 8. He did not demonstrate any local or systemic signs or symptoms of venom toxicity, nor did he have any clinically significant hemorrhage or hemodynamic instability secondary to coagulopathy; he remained hemodynamically stable with an intact airway and no worsening of his extremity edema despite his coagulopathy. Lavonas et al. and White hypothesized that antivenom redosing and maintenance dosing may be required in order to (1) provide sufficient antivenom to neutralize initial acute venom levels and to (2) neutralize latent venom release from soft tissue depots that can last for two weeks [
Bush et al. reported a retrospective case series of five patients envenomated by rattlesnakes with similar success. Despite initial bolus dosing of FabAV, the patients experienced either transient or inadequate response with profound delayed hematologic abnormalities. After initiating a continuous FabAV infusion at 2 to 4 vials per 24 hours, the hematologic derangements improved within six to fourteen days after initial injury [
In summary, snakebites cause in vivo and in vitro coagulopathy, which, at this point, has uncertain clinical significance with respect to hemorrhage. This coagulopathy can persist or recur up to two weeks after injury. Therefore, despite the unknown incidence of clinically significant bleeding, patients appear to be one step away from a catastrophic hemorrhage. At this time, there are many unknowns: the bleeding risk of delayed or recurrent snakebite coagulopathy, the consequences of prolonged antivenom administration, and the optimal rate of infusion to correct coagulopathy and prevent hypothetical thromboembolic events. It is uncertain whether any downsides exist for administering FabAV using maintenance dosing; we feel it would be prudent to monitor for thromboembolic events in the setting of coagulopathy. More importantly, we demonstrate in this case that maintenance dosing in the form of an infusion is a plausible modality of administration that may be considered in the management of serious Crotalinae envenomation complicated by coagulopathy.
The authors alone are responsible for the content and writing of the paper.
The authors report no conflict of interests.