Correlating Fibrinogen Consumption and Profiles of Inflammatory Molecules in Human Envenomation's by Bothrops atrox in the Brazilian Amazon

Abstract

Snakebites are considered a major public health problem worldwide. In the Amazon region of Brazil, the snake Bothrops atrox ( B. atrox ) is responsible for 90% of the bites. These bites may cause local and systemic signs from acute inflammatory reaction and hemostatic changes, and present common hemorrhagic disorders. These alterations occur due the action of hemostatically active and immunogenic toxins which are capable of triggering a wide range of hemostatic and inflammatory events. However, the crosstalk between coagulation disorders and inflammatory reaction still has gaps in snakebites. Thus, the goal of this study was to describe the relationship between the consumption of fibrinogen and the profile of inflammatory molecules (chemokines and cytokines) in evenomations by B. atrox snakebites. A prospective study was carried out with individuals who had suffered B. atrox snakebites and presented different levels of fibrinogen consumption (normal fibrinogen [NF] and hypofibrinogenemia [HF]). Seventeen patients with NF and 55 patients with HF were eligible for the study, in addition to 50 healthy controls (CG). The molecules CXCL-8, CCL-5, CXCL-9, CCL-2, CXCL-10, IL-6, TNF, IL-2, IL-10, IFN-γ, IL-4, and IL-17A were quantified in plasma using the CBA technique at three different times (pre-antivenom therapy [T0], 24 h [T1], and 48 h [T2] after antivenom therapy). The profile of the circulating inflammatory response is different between the groups studied, with HF patients having higher concentrations of CCL-5 and lower IFN-γ. In addition, antivenom therapy seems to have a positive effect, leading to a profile of circulating inflammatory response similar in quantification of T1 and T2 on both groups. Furthermore, these results suggest that a number of interactions of CXCL-8, CXCL-9, CCL-2, IL-6, and IFN-γ in HF patients are directly affected by fibrinogen levels, which may be related to the inflammatory response and coagulation mutual relationship induced by B. atrox venom. The present study is the first report on inflammation-coagulation crosstalk involving snakebite patients and supports the better understanding of envenomation's pathophysiology mechanisms and guides in the search for novel biomarkers and prospective therapies.

Involvement of von Willebrand factor and botrocetin in the thrombocytopenia induced by Bothrops jararaca snake venom

“…Thus, botrocetin exerted a feeble role in evoking thrombocytopenia during envenomation, and other proteins and mechanisms may be attributed to it. Moreover, the present findings (Fig 2 ) confirmed that SVMP had no involvement in venom-induced thrombocytopenia [7,57].…”

“…At the laboratory level, patients present hemostatic alterations-e.g. consumption of blood coagulation factors, particularly of fibrinogen, factor V and VIII, thrombocytopenia, and increased levels of fibrinogen/fibrin degradation products-and inflammatory changes, as increased levels of C-reactive protein and interleukin 6 [4][5][6][7][8][9]. In vitro, BjV induces platelet aggregation in washed platelets, activates blood coagulation and promotes fibrin(ogen)olysis [10][11][12][13].…”

Clinical and Evolutionary Implications of Dynamic Coagulotoxicity Divergences in Bothrops (Lancehead Pit Viper) Venoms

“…This, indeed, lends supports to the hypothesis that this trait is an ancestral relic and, assuming no ecological difference among the Bothrops species examined, not subjected to purifying selection pressure. However, as has been noted in clinical cases [ 24 , 52 ], human bite victims survive long enough for the additional depletion of fibrinogen to contribute to the consumptive coagulopathy; therefore, the documentation of the species with the greatest relative potency in this regard will contribute to the body of knowledge, which is useful for designing evidence-based clinical management strategies. The species with the most relatively potent action (small R and small A values) in this regard were the terrestrial species B. jararacussu (all tested), B. asper (Costa Rica and Ecuador only amongst those tested in this study), B. atrox (all tested), B. leucurus , B. moojeni (all tested) , B. neuwiedi (Curitiba, Brazil only amongst those tested in this study), B. pauloensis , and B. jararaca (all tested except Rio Negrino).…”

“…As this action is slower than the procoagulant toxicity, it has been proposed as being an evolutionary relic left over from the anticoagulant snakes from which Bothrops diverged prior to uniquely evolving procoagulant toxicity [ 36 , 43 ]. However, while the prey capture role is unresolved, the direct action upon fibrinogen is of relevance to human envenomations, as bite victims survive long enough for fibrinogen depletion to become a significant variable, and thereby contribute to consumptive coagulopathy [ 24 , 52 ]. Other activities of clinical significance have been documented in Bothrops venoms, including direct actions upon platelets, and vessel damage [ 53 ].…”

Association of a Network of Immunologic Response and Clinical Features With the Functional Recovery From Crotalinae Snakebite Envenoming

“…Interestingly, this study did not find a significant elevation of tumor necrosis factor alpha (TNF-alpha). Previous work has shown a relationship between increasing TNF and SBE ( 72 – 74 ). Our unanticipated finding may be due to the predominant species enrolled in this study, Agkistrodon contortrix , is known to typically have a less severe clinical course.…”