Subacute coagulopathy in a randomized, comparative trial of Fab and F(ab')₂ antivenoms

Background: Envenomation by pit vipers is associated with coagulation disorders including hypofibrinogenemia and thrombocytopenia. These abnormalities correct following antivenom treatment during the acute phase of the disease. Delayed or recurrent coagulation abnormalities have been reported following use of Fab antivenom, resulting in risk of hemorrhage or death. Methods: We hypothesized that the longer plasma persistence of F(ab')₂ antivenom, relative to Fab, in patients at risk of coagulopathy would result in decreased venonemia and coagulopathy one week after treatment. We conducted a Phase 2, randomized comparative clinical trial of rattlesnake bitten adults presenting for care in Tucson, Arizona, USA. Patients were randomly assigned to receive either Fab or F(ab')₂ antivenom using a predefined treatment schedule. Endpoints included platelet counts, fibrinogen levels, and venom and antivenom ELISAs. Measurements were conducted at baseline and at various times over the following two weeks. Results: Twelve patients were studied, with 6 randomly assigned to each treatment group. Early response of platelet counts, fibrinogen, and venom levels to acute treatment was similar in the two groups. One week following treatment, platelet counts and fibrinogen levels were lower in the Fab group than in the F(ab')₂ group, following a characteristic pattern that reached its lowest point approximately one week after initial treatment. Venom levels dropped below detection limits in all patients following initial treatment but subsequently rebounded into the measurable range in 4 of 6 Fab cases. F(ab')₂ antivenom levels demonstrated a longer plasma persistence than Fab levels, with a less rapid drop during the two days following treatment. Two patients in the Fab group had significant adverse events involving coagulation abnormalities, for which additional antivenom was administered following the initial treatment period. Conclusions: Following the acute phase of presentation and treatment for pit viper envenomation, there appears to be a roughly 2-week subacute phase of the disease during which ongoing presence of venom may result in serious delayed or recurrent coagulation defects. Late hypofibrinogenemia and thrombocytopenia are associated with recurrent venonemia and drop in antivenom levels. This pattern was apparent in patients treated with Fab antivenom but was not seen among F(ab')₂ recipients in this Phase 2 study, consistent with pharmacokinetic differences between the two products. Improved understanding of Fab pharmacokinetics is important for the management of coagulopathy-prone pit viper envenomation. Use of F(ab')₂ antivenom may prevent recurrent venom effects, but larger studies are necessary for statistical confirmation of this observation.