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However, mounting evidence suggests these venoms can additionally cause coagulopathic symptoms, as demonstrated by some Asian elapids and African spitting cobras. This study sought to investigate the coagulopathic potential of venoms from medically important elapids of the genera Naja (true cobras), Hemachatus (rinkhals), and Dendroaspis (mambas). Crude venoms were bioassayed for coagulant effects using a plasma coagulation assay before RPLC\/MS was used to separate and identify venom toxins in parallel with a nanofractionation module. Subsequently, coagulation bioassays were performed on the nanofractionated toxins, along with in-solution tryptic digestion and proteomics analysis. These experiments were then repeated on both crude venoms and on the nanofractionated venom toxins with the addition of either the phospholipase A2 (PLA2) inhibitor varespladib or the snake venom metalloproteinase (SVMP) inhibitor marimastat. Our results demonstrate that various African elapid venoms have an anticoagulant effect, and that this activity is significantly reduced for cobra venoms by the addition of varespladib, though this inhibitor had no effect against anticoagulation caused by mamba venoms. Marimastat showed limited capacity to reduce anticoagulation in elapids, affecting only N. haje and H. haemachatus venom at higher doses. Proteomic analysis of nanofractionated toxins revealed that the anticoagulant toxins in cobra venoms were both acidic and basic PLA2s, while the causative toxins in mamba venoms remain uncertain. This implies that while PLA2 inhibitors such as varespladib and metalloproteinase inhibitors such as marimastat are viable candidates for novel snakebite treatments, they are not likely to be effective against mamba envenomings.<\/jats:p>","DOI":"10.3390\/toxins14110736","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T22:36:17Z","timestamp":1666910177000},"page":"736","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A Combined Bioassay and Nanofractionation Approach to Investigate the Anticoagulant Toxins of Mamba and Cobra Venoms and Their Inhibition by Varespladib"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6596-2847","authenticated-orcid":false,"given":"Arif","family":"Arrahman","sequence":"first","affiliation":[{"name":"Division of Bioanalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"},{"name":"Centre for Analytical Sciences Amsterdam (CASA), 1012 WX Amsterdam, The Netherlands"},{"name":"Faculty of Pharmacy, Universitas Indonesia, Kampus Baru UI, Depok 16424, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5383-0505","authenticated-orcid":false,"given":"Taline D.","family":"Kazandjian","sequence":"additional","affiliation":[{"name":"Centre for Snakebite Research and Interventions. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina B. M.","family":"Still","sequence":"additional","affiliation":[{"name":"Division of Bioanalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"},{"name":"Centre for Analytical Sciences Amsterdam (CASA), 1012 WX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Slagboom","sequence":"additional","affiliation":[{"name":"Division of Bioanalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"},{"name":"Centre for Analytical Sciences Amsterdam (CASA), 1012 WX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4200-2015","authenticated-orcid":false,"given":"Govert W.","family":"Somsen","sequence":"additional","affiliation":[{"name":"Division of Bioanalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"},{"name":"Centre for Analytical Sciences Amsterdam (CASA), 1012 WX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freek J.","family":"Vonk","sequence":"additional","affiliation":[{"name":"Division of Bioanalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"},{"name":"Naturalis Biodiversity Centre, Darwinweg 2, 2333 CR Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-4719","authenticated-orcid":false,"given":"Nicholas R.","family":"Casewell","sequence":"additional","affiliation":[{"name":"Centre for Snakebite Research and Interventions. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0011-5612","authenticated-orcid":false,"given":"Jeroen","family":"Kool","sequence":"additional","affiliation":[{"name":"Division of Bioanalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands"},{"name":"Centre for Analytical Sciences Amsterdam (CASA), 1012 WX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1371\/journal.pmed.0050218","article-title":"The Global Burden of Snakebite: A Literature Analysis and Modelling Based on Regional Estimates of Envenoming and Deaths","volume":"5","author":"Kasturiratne","year":"2008","journal-title":"PLoS Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17063","DOI":"10.1038\/nrdp.2017.63","article-title":"Snakebite Envenoming","volume":"3","author":"Calvete","year":"2017","journal-title":"Nat. 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