Pitviper Envenomation Guidelines Should Address Choice Between FDA-approved Treatments for Cases at Risk of Late Coagulopathy

To the Editor:

We salute Dr. Kanaan and colleagues for their recent contribution, “The Wilderness Medical Society Practice Guidelines for the Treatment of Pitviper Envenomations in the United States and Canada,” an excellent paper encompassing many aspects of a complex disease. ¹ Given the otherwise thorough treatment of the subject, it was a surprise to find that these guidelines contained such a minimal treatment of late coagulopathy, which we feel is among the most significant and challenging aspects of North American rattlesnake envenomation management today. This topic has been the source of ongoing debate since the approval of Fab ovine antivenom (CroFab; BTG International Inc, Conshohocken, PA), and it has gained special importance in 2015 with the Food and Drug Administration’s marketing approval of a competing F(ab’)₂ equine antivenom (Anavip, Instituto Bioclon SA de CV, Mexico City, Mexico).

Late coagulopathy is a common event in patients treated for North American rattlesnake envenomation and may place the patient at risk for bleeding and death after they have left the health care setting. CroFab clinical trials showed a 53% rate of recurrent, late, or persistent coagulopathy 2 to 14 days after envenomation, including outpatient platelet counts as low as 12,000/mm³ and 1 case of clinically significant postsurgical bleeding associated with afibrinogenemia. ²

After CroFab received market approval, an Arizona case series confirmed that recurrent or delayed hematotoxicity was common after routine use and recommended that all patients receive close outpatient monitoring of coagulation studies after completion of inpatient treatment. ³ An in-depth case report, including prospectively collected serum, demonstrated the relationship of recurrent thrombocytopenia to the rapid clearance of Fab and secondary rise of venom in serum. ⁴ Sporadic reports (including some mentioned by Kanaan and colleagues) have since explored the phenomenon and its possible treatment with alternative dosing regimens.^5,6 Finally, a randomized Phase 2 trial specifically addressed the relationship of antivenom to venom levels and recurrent coagulopathy after treatment with Fab ovine antivenom in comparison with F(ab’)₂ equine antivenom. In this trial, 2 of 6 recipients of Fab ovine antivenom required extended hospital treatment. ⁷

In this context, the recent Food and Drug Administration approval of the first F(ab’)₂ snake antivenom should be of great interest to clinicians, despite legal difficulties ⁸ that have delayed its US use. Particularly in those parts of the United States and Canada where coagulopathy is common after snakebite, such as the Crotalus atrox–endemic southwest, vigilant management of very low platelet and fibrinogen levels remains essential after hospital discharge. It may be true that “medically significant late sequelae” are uncommon in US reports, but this is at least in part because of careful post discharge treatment reflected in published series. F(ab’)₂ antivenoms for pit viper envenomation have been used in Canada and the United States for years through public health and zoo importation mechanisms as well as two clinical trials. These antivenoms are the standard of care in much of Latin America, and evidence-based guidelines should address their use regardless of legal settlements between manufacturers.