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Review
. 2023 Jul 15;24(14):11508.
doi: 10.3390/ijms241411508.

Crosstalk of Inflammation and Coagulation in Bothrops Snakebite Envenoming: Endogenous Signaling Pathways and Pathophysiology

Joeliton S Cavalcante  1 , Denis Emanuel Garcia de Almeida  2 , Norival A Santos-Filho  3 , Marco Aurélio Sartim  4   5   6 , Amanda de Almeida Baldo  7 , Lisele Brasileiro  6 , Polianna L Albuquerque  8   9 , Sâmella S Oliveira  10 , Jacqueline Almeida Gonçalves Sachett  5   6 , Wuelton Marcelo Monteiro  5   6 , Rui Seabra Ferreira Jr  1   11   12
Affiliations
Review

Crosstalk of Inflammation and Coagulation in Bothrops Snakebite Envenoming: Endogenous Signaling Pathways and Pathophysiology

Joeliton S Cavalcante et al. Int J Mol Sci. .

Abstract

Snakebite envenoming represents a major health problem in tropical and subtropical countries. Considering the elevated number of accidents and high morbidity and mortality rates, the World Health Organization reclassified this disease to category A of neglected diseases. In Latin America, Bothrops genus snakes are mainly responsible for snakebites in humans, whose pathophysiology is characterized by local and systemic inflammatory and degradative processes, triggering prothrombotic and hemorrhagic events, which lead to various complications, organ damage, tissue loss, amputations, and death. The activation of the multicellular blood system, hemostatic alterations, and activation of the inflammatory response are all well-documented in Bothrops envenomings. However, the interface between inflammation and coagulation is still a neglected issue in the toxinology field. Thromboinflammatory pathways can play a significant role in some of the major complications of snakebite envenoming, such as stroke, venous thromboembolism, and acute kidney injury. In addition to exacerbating inflammation and cell interactions that trigger vaso-occlusion, ischemia-reperfusion processes, and, eventually, organic damage and necrosis. In this review, we discuss the role of inflammatory pathways in modulating coagulation and inducing platelet and leukocyte activation, as well as the inflammatory production mediators and induction of innate immune responses, among other mechanisms that are altered by Bothrops venoms.

Keywords: complement; hemostasis; inflammation; neutrophil; platelet; snake venom; thromboinflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Local clinical manifestations of Bothrops atrox snakebite envenoming. (A) Edema on the right hand; (B) blisters on the right hand; (C) blisters on the right foot; (D) edema on the right leg; (E) right wrist bleeding (bite site in the joint of the hand with the arm); (F) necrosis in the right hallux; (G): ecchymosis on the entire left thigh, distant from the bite site; (H): right limb swelling. Photos were taken by Lisele Brasileiro.
Figure 2
Figure 2
Clinical systemic manifestations of Bothrops atrox snakebite envenoming. (A) Patient after hematemesis; (B) hemoptysis in a male patient; (C) macroscopic hematuria; (D) gum bleeding. Photos were taken by Lisele Brasileiro.
Figure 3
Figure 3
Components of the hemostatic system targeted by toxins and several consequences of general changes in hemostasis during Bothrops snakebite envenoming. * Components of the hemostatic system that are affected by Bothrops toxins. Created with BioRender.com, accessed on 30 September 2022 by Joeliton S. Cavalcante.
Figure 4
Figure 4
Mechanisms of activation of the complement system by Bothrops venoms. Bothrops venoms activate the complement system via classical pathways, some also via lectins or the alternative pathway. All Bothrops venoms cleave C3 and C4, resulting in the synthesis of anaphylotoxins C3a, C4a, and C5a, and the terminal complement complex causing activation of chemotaxis. * Components of the complement system that are affected by Bothrops venoms. Created with BioRender.com, accessed on 30 September 2022 by Joeliton S. Cavalcante.
Figure 5
Figure 5
Thromboinflammatory pathways in Bothrops envenomation. The direct action of toxins on components of the hemostatic and complement system leads to hemostatic and inflammatory changes in Bothrops envenomation, which can result in clinical complications responsible for cases of tissue loss and death. Bothrops venoms act directly on clotting factors, causing the activation of the cascade that culminates in the formation of fibrin. During fibrin formation, clotting factors are consumed, resulting in disseminated intravascular coagulation. The generated fibrin induces the formation of intravascular thrombin, and plays a critical role in thrombotic microangiopathy through the lysis of erythrocytes that collide with it, which can lead to acute renal failure. The activation of the complement system modulated by the cleavage of key factors by the action of venoms amplifies the toxicity of the venom through chemotaxis and the activation of leukocytes, especially neutrophils. Neutrophils can form NETs that damage local tissue which has already been affected by the venom entering the body. In addition, the activation of the complement system culminates in the formation of the membrane attack complex that potentiates local tissue damage. Endothelial activation by platelets, leukocytes, and ischemia–reperfusion events result in the expression of adhesion molecules, including P-selectin, which recruits leukocytes and, in turn, red blood cells to blood vessel walls. The recruitment of leukocytes, platelets, and red blood cells to the vascular wall, together with the clotting processes, extracellular neutrophil trap components, and the formation of heterocellular aggregates between platelets, leukocytes, and red blood cells, with the subsequent entrapment of red blood cells; this results in the cerebral vaso-occlusive processes. In other cases, due to thrombocytopenia, cerebral hemorrhage occurs. Exclamation points represent targets of toxins. Skulls represent clinical complications associated with the effects of venom. Loupes indicate the need to study the consequences of clinical complications that are poorly understood. Created with BioRender.com, accessed on 4 June 2023 by Joeliton S. Cavalcante.
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