Bothrops jararaca venom metalloproteinases are essential for coagulopathy and increase plasma tissue factor levels during envenomation
| Autor: | André F. Alves, Katia C. Barbaro, Marcelo L. Santoro, Karine M. Yamashita |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
Pharmacology Biochemistry chemistry.chemical_compound Medicine and Health Sciences Platelet Bothrops Sulfones Lung Blood coagulation test Skin Disseminated intravascular coagulation Factor VII lcsh:Public aspects of medicine Hematology Blood Coagulation Disorders Body Fluids Infectious Diseases Blood Snake venom Prothrombin Blood Coagulation Tests Anatomy Coagulation Factors Research Article Blood Platelets Platelets lcsh:Arctic medicine. Tropical medicine Serine Proteinase Inhibitors lcsh:RC955-962 Platelet disorder Hemorrhage Biology Thromboplastin Crotalid Venoms medicine Coagulopathy Animals Rats Wistar Envenomation Blood Coagulation Edetic Acid Plasma Proteins Coagulation Disorders Public Health Environmental and Occupational Health Fibrinogen Biology and Life Sciences Proteins lcsh:RA1-1270 Disseminated Intravascular Coagulation medicine.disease Thrombocytopenia Rats chemistry Immunology Metalloproteases Serine Proteases |
| Zdroj: | PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 8, Iss 5, p e2814 (2014) |
| ISSN: | 1935-2735 |
| Popis: | Background/Aims Bleeding tendency, coagulopathy and platelet disorders are recurrent manifestations in snakebites occurring worldwide. We reasoned that by damaging tissues and/or activating cells at the site of the bite and systemically, snake venom toxins might release or decrypt tissue factor (TF), resulting in activation of blood coagulation and aggravation of the bleeding tendency. Thus, we addressed (a) whether TF and protein disulfide isomerase (PDI), an oxireductase involved in TF encryption/decryption, were altered in experimental snake envenomation; (b) the involvement and significance of snake venom metalloproteinases (SVMP) and serine proteinases (SVSP) to hemostatic disturbances. Methods/Principal Findings Crude Bothrops jararaca venom (BjV) was preincubated with Na2-EDTA or AEBSF, which are inhibitors of SVMP and SVSP, respectively, and injected subcutaneously or intravenously into rats to analyze the contribution of local lesion to the development of hemostatic disturbances. Samples of blood, lung and skin were collected and analyzed at 3 and 6 h. Platelet counts were markedly diminished in rats, and neither Na2-EDTA nor AEBSF could effectively abrogate this fall. However, Na2-EDTA markedly reduced plasma fibrinogen consumption and hemorrhage at the site of BjV inoculation. Na2-EDTA also abolished the marked elevation in TF levels in plasma at 3 and 6 h, by both administration routes. Moreover, increased TF activity was also noticed in lung and skin tissue samples at 6 h. However, factor VII levels did not decrease over time. PDI expression in skin was normal at 3 h, and downregulated at 6 h in all groups treated with BjV. Conclusions SVMP induce coagulopathy, hemorrhage and increased TF levels in plasma, but neither SVMP nor SVSP are directly involved in thrombocytopenia. High levels of TF in plasma and TF decryption occur during snake envenomation, like true disseminated intravascular coagulation syndrome, and might be implicated in engendering bleeding manifestations in severely-envenomed patients. Author Summary Although the abundance of reports about hemostatic disturbances in snakebites, few studies have addressed how crude snake venoms evoke blood coagulation disturbances in vivo. Snake venoms contain several components that disturb hemostasis, and the prevailing model claims that coagulation disturbances observed in patients are triggered directly by those toxins. However, taking into account the physiological mechanisms that activate the coagulation cascade, tissue factor might also be generated and decrypted during snake envenomation. We investigated herein if tissue factor and protein disulfide isomerase, an enzyme that controls the encryption/decryption of tissue factor, were altered during experimental envenomation in rats. We observed increased activity/expression of tissue factor at the site of venom injection, as well as in lungs, and decreased expression of protein disulfide isomerase at the site of venom injection. Moreover, tissue factor levels were raised in plasma, demonstrating thereby that this via may be crucial to activate blood coagulation in patients, especially in those more severely envenomed. We also noticed that snake venom metalloproteinases accounted for most fibrinogen consumption. Our results clarify the mechanisms that activate blood coagulation during envenomation, evidencing that true intravascular coagulation syndrome, due to increased tissue factor expression, might occur during snake envenomation in human beings. |
| Databáze: | OpenAIRE |
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