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Bleeding is a common hemostatic disorder that occurs in Bothrops envenomations. We evaluated the changes in coagulation, fibrinolysis components, and platelets in Bothrops atrox envenomations with bleeding. This is an observational study with B. atrox snakebite patients (n = 100) treated in Manaus, Brazilian Amazon. Bleeding was recorded on admission and during hospitalization. We found that the platelet count in our patients presented a weak correlation to tissue factor, factor II, and plasminogen. Tissue factor presented weak correlation to factor V, II, D-dimer, plasminogen, alpha 2-antiplasmin, and moderate correlation to fibrinogen and fibrin/fibrinogen degradation product (FDP). Patients with systemic bleeding (n = 20) presented low levels of factor V, II, fibrinogen, plasminogen, and alpha 2-antiplasmin, and high levels of tissue factor and FDP compared to those without bleeding. Patients with only local bleeding (n = 41) and without bleeding showed similar levels of hemostatic factors. Thrombocytopenia was observed mainly in patients with systemic bleeding and increased levels of serum venom. No association was found between venom levels and systemic bleeding, or between venom levels and clinical severity of envenomation. This is the first report that shows the participation of the extrinsic coagulation pathway in the consumption coagulopathy of B. atrox envenomations with systemic bleeding due to tissue factor release.

Snakebite envenoming is a neglected tropical disease with significant morbidity and mortality, particularly in areas with limited resources. Bothrops atrox is the most important snake involved in human envenomings in the Amazon. Its venom induces complex vascular damage that contributes to hemorrhage and systemic complications. This study employs the chicken chorioallantoic membrane (CAM) model to illustrate and quantify the acute vascular toxicity of B. atrox venom. Fertilized chicken eggs at embryonic day 9 were exposed to escalating doses of B. atrox venom (1, 50, and 100 µg/egg) for up to 300 seconds. Vascular alterations were assessed using macroscopic imaging, quantitative analysis with ImageJ and AngioTool, and histological examination. Venom exposure resulted in dose- and time-dependent vascular disruption, mainly vascular rupture and hemorrhage. At low doses, we observed minimal hemorrhage without any significant changes in vascular network architecture. At high doses, histopathology revealed endothelial disorganization, vessel dilation, leukocyte infiltration, and microthrombi formation, consistent with direct cytotoxic and inflammatory effects. B. atrox venom rapidly compromises vascular integrity and triggers an inflammatory response in the CAM model, reflecting key pathophysiological features of envenomation. The severity of these effects was proportional to the duration of exposure and the venom dose used. These findings support the use of CAM assay as a translational tool for screening venom-induced vascular toxicity and underscore the imperative of early antivenom administration.

Background: Consumption coagulopathy and hemorrhagic syndrome are the typical features of Bothrops sp. snake envenoming. In contrast, B. lanceolatus envenoming can induce thrombotic complications. Our aim was to test whether crude B. lanceolatus and B. atrox venoms would display procoagulant activity and induce thrombus formation under flow conditions. Methods and Principal Findings: Fibrin formation in human plasma was observed for B. lanceolatus venom at 250–1000 ng/mL concentrations, which also induced clot formation in purified human fibrinogen, indicating thrombin-like activity. The degradation of fibrinogen confirmed the fibrinogenolytic activity of B. lanceolatus venom. B. lanceolatus venom displayed consistent thrombin-like and kallikrein-like activity increases in plasma conditions. The well-known procoagulant B. atrox venom activated plasmatic coagulation factors in vitro and induced firm thrombus formation under high shear rate conditions. In contrast, B. lanceolatus venom induced the formation of fragile thrombi that could not resist shear stress. Conclusions: Our results suggest that crude B. lanceolatus venom displays amidolytic activity and can activate the coagulation cascade, leading to prothrombin activation. B. lanceolatus venom induces the formation of an unstable thrombus under flow conditions, which can be prevented by the specific monovalent antivenom Bothrofav®.

Abstract The objective of this study was to document the infection by cestodes Crepidobothrium sp. in Bothrops atrox, which are from the Tapajós National Forest, located in the western part of Pará state, Brazil. Thirty-six specimens of B. atrox were examined, of which 13 individuals (36%) were infected by Crepidobothrium sp. and a total of 147 parasites were collected from these hosts. The mean abundance of these endoparasites was 4.1 and the mean infection intensity was 11.3. In relation to parasitic infection sites, 88.4% of these cestodes were found in the small intestine, 9.52% in the large intestine and 2% in the stomach of the hosts. This was the first report of Crepidobothrium sp. in B. atrox in the Brazilian Amazon. Resumo O objetivo deste estudo foi registrar infecção por cestoides Crepidobothrium sp. em Bothrops atrox, as quais são provenientes da floresta Nacional do Tapajós, localizada no oeste do estado do Pará, Brasil. Foram examinados 36 espécimes de B. atrox, dos quais 13 indivíduos (36%) estavam infectados por Crepidobothrium sp. e um total de 147 parasitos foram coletados desses hospedeiros. A abundância média desses endoparasitos foi de 4,1 e intensidade média de infecção de 11,3. Em relação aos sítios de infecção parasitária, 88,4% destes cestoides foram encontrados no intestino delgado, 9,52% no intestino grosso e 2% no estômago dos hospedeiros. Este foi o primeiro relato de Crepidobothrium sp. em B. atrox na Amazônia brasileira.

The Amazon region reports the highest incidence of snakebite envenomings in Brazil. We aimed to describe the epidemiology of snakebites in the state of Amazonas and to investigate factors associated with disease severity and lethality. We used a nested case-control study, in order to identify factors associated with snakebite severity and mortality using official Brazilian reporting systems, from 2007 to 2012. Patients evolving to severity or death were considered cases and those with non-severe bites were included in the control group. During the study period, 9,191 snakebites were recorded, resulting in an incidence rate of 52.8 cases per 100,000 person/years. Snakebites mostly occurred in males (79.0%) and in rural areas (70.2%). The most affected age group was between 16 and 45 years old (54.6%). Fifty five percent of the snakebites were related to work activities. Age ≤15 years [OR=1.26 (95% CI=1.03-1.52); (p=0.018)], age ≥65 years [OR=1.53 (95% CI=1.09-2.13); (p=0.012)], work related bites [OR=1.39 (95% CI=1.17-1.63); (p<0.001)] and time to medical assistance >6 hours [OR=1.73 (95% CI=1.45-2.07); (p<0.001)] were independently associated with the risk of severity. Age ≥65 years [OR=3.19 (95% CI=1.40-7.25); (p=0.006)] and time to medical assistance >6 hours [OR=2.01 (95% CI=1.15-3.50); (p=0.013)] were independently associated with the risk of death. Snakebites represent an occupational health problem for rural populations in the Brazilian Amazon with a wide distribution. These results highlight the need for public health strategies aiming to reduce occupational injuries. Most cases of severe disease occurred in the extremes of age, in those with delays in medical attention and those caused by Micrurus bites. These features of victims of snakebite demand adequate management according to well-defined protocols, including prompt referral to tertiary centres when necessary, as well as an effective response from surveillance systems and policy makers for these vulnerable groups.

Bothrops atrox envenomation can cause significant local and systemic effects. Adjunctive therapies, such as cold and heat applications, are proposed to enhance antivenom efficacy, but their clinical value remains unclear. This randomized, three-arm clinical trial included 94 patients allocated in a 1:1:1 ratio to Cold Therapy Group (CTG, n = 30), Heat Therapy Group (HTG, n = 31), or Control Group (CG, n = 33). All participants received standard antivenom therapy, with CTG and HTG receiving additional interventions applied for 24 hours post-admission. Primary outcomes included changes in creatine kinase (CK) levels. Secondary outcomes assessed pain intensity, edema, local temperature, and functional recovery using the World Health Organization Disability Assessment Schedule (WHODAS 2.0) assessed four to six months after hospital discharge. Kaplan-Meier survival analysis evaluated time-to-event outcomes. Baseline characteristics were comparable across groups. CK levels decreased similarly in all groups at 48 hours (p = 0.89). No significant differences were observed in the reduction of limb circumference, edema extent and bite site temperature, either the ITT or PP analysis. CTG showed a significant reduction in pain within 24 hours in the per-protocol analysis (Log-rank p = 0.04). Disability assessed by WHODAS 2.0 revealed no significant differences between groups after 6 months of follow-up. No adverse events were associated with the interventions. Adjunctive HTG had no efficacy in treating local effects of B. atrox envenomation. Adjunctive CTG demonstrated benefits observed in pain reduction.

Snakebites are a serious public health problem and, in the Amazon, the snake is the most frequent cause of envenomation. venom (BaV) causes pathophysiological changes with intense, local inflammatory processes, such as severe tissue complication (STC). However, mechanisms associated with the inflammatory process in humans are still poorly understood. Thus, in this study, we sought to describe the profile of local and systemic immunological soluble molecules in envenomation patients treated at a specialist tertiary healthcare unit in the Brazilian Amazon. An analytical and prospective study was performed with patients who had snakebites with different clinical outcomes (STC and Mild Tissue Complication-MTC) using venous blood and blister exudate in order to measure immunological soluble molecules present in the response process. Twenty STC patients and 20 MTC patients were eligible for the study. In addition, 20 healthy donors (HD) who had never been bitten by a snake were used as controls. The biomarkers CXCL-8, CCL-5, CXCL-9, CCL-2 and CXCL-10; C3a, C4a, and C5a; IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, TNF, IFN-γ and IL-17A were quantified using flow cytometry and ELISA. The circulating response profile differs between the studied groups, with MTC patients presenting a mixed profile and STC patients presenting a more polarized profile for Th1 response. In addition, individuals who develop STC have a more intense local immune response, because the tissue response differs from the circulating immunological soluble molecules and presents Th1/Th2/Th17 response polarization. Furthermore, these results suggest that CCL-2 and CXCL-10 are biomarkers for STC and the response profile they assume against snakebite should reflect in the clinical practice for the patient.

Lance-headed snakes are found in Central and South America, and they account for most snakebites in Brazil. The phylogeny of South American pitvipers has been reviewed, and the presence of natural and non-natural hybrids between different species of Bothrops snakes demonstrates that reproductive isolation of several species is still incomplete. The present study aimed to analyze the biological features, particularly the thrombin-like activity, of venoms from hybrids born in captivity, from the mating of a female Bothrops erythromelas and a male Bothrops neuwiedi, two species whose venoms are known to display ontogenetic variation. Proteolytic activity on azocoll and amidolytic activity on N-benzoyl-DL-arginine-p-nitroanilide hydrochloride (BAPNA) were lowest when hybrids were 3 months old, and increased over body growth, reaching values similar to those of the father when hybrids were 12 months old. The clotting activity on plasma diminished as hybrids grew; venoms from 3- and 6-months old hybrids showed low clotting activity on fibrinogen (i.e., thrombin-like activity), like the mother venom, and such activity was detected only when hybrids were older than 1 year of age. Altogether, these results point out that venom features in hybrid snakes are genetically controlled during the ontogenetic development. Despite the presence of the thrombin-like enzyme gene(s) in hybrid snakes, they are silenced during the first six months of life.

Bothrops venom consists primarily of metalloproteinase and phospholipase A2 toxins, which are responsible for the acute inflammatory, coagulant and hemorrhagic action following snakebite. The local effects of snakebite envenomation by Bothrops species are particularly prevalent yet poorly studied, but include pain, edema, erythema, blistering, bleeding, and ecchymosis. In this study, we describe the dermatopathological findings observed in a series of 22 patients diagnosed with Bothrops envenomation treated in a tertiary hospital of Manaus, in the Brazilian Amazon. Clinically, pain and edema were observed in all patients, followed by fang marks (63.6%), secondary infection (36.3%), ecchymosis (31.8%), erythema (22.7%), blister (13.6%), and necrosis (4.5%). Regarding histopathological findings, epidermal alterations such as spongiosis, acanthosis and hyperkeratosis were the most observed characteristics in our cases series, with isolated cases of hyperplasia, hemorrhagic intraepidermal blister and severe necrosis. Changes in dermis and hypodermis consisted mainly of hemorrhage, inflammatory infiltrate, edema, congestion, and vascular damage, whereas cases of collagen damage, necrosis, abscess, and signs of tissue repair, indicated by the presence of granulation tissue, were also observed, with a persistence of inflammatory and hemostatic alterations even days after antivenom administration. Therefore, the tissue damage resulting from Bothrops envenomation could be related to both direct venom activity as well as inflammatory response or presence of infectious process. The histopathological analysis of human skin injury can enlighten the pathological and endogenous effects of local envenomation and could underpin new strategies, including novel treatments, adjuvants or changes in clinical management, that lead to better outcomes in snakebite patients.

Snakebite envenomation is a relevant medical hazard in French Guiana and Martinique, two French territories in the Americas. All snakebite envenomations in Martinique are inflicted by the endemic viperid species Bothrops lanceolatus , whereas Bothrops atrox is responsible for the majority of snakebites in French Guiana, although other venomous snake species also occur in this South American territory. This review summarizes some of the key aspects of the natural history of these species, as well as of their venom composition, the main clinical manifestations of envenomations, and their treatment by antivenoms. B . atrox venom induces the typical set of clinical manifestations characteristic of Bothrops sp. venoms, i.e., local tissue damage and systemic alterations associated with coagulopathies, hemorrhage, hemodynamic alterations, and acute kidney injury. In the case of B . lanceolatus venom, in addition to some typical features of bothropic envenomation, a unique and severe thrombotic effect occurs in some patients. The pathogenesis of this effect remains unknown but may be related to the action of venom components and inflammatory mediators on endothelial cells in the vasculature. A monospecific antivenom has been successfully used in Martinique to treat envenomations by B . lanceolatus . In the case of French Guiana, a polyvalent antivenom has been used for some years, but it is necessary to assess the preclinical and clinical efficacy against viperid venoms in this country of other antivenoms manufactured in the Americas.