{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:09:27Z","timestamp":1768291767957,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001109","name":"Flinn Foundation","doi-asserted-by":"publisher","award":["#22-06454"],"award-info":[{"award-number":["#22-06454"]}],"id":[{"id":"10.13039\/100001109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Eastern Diamondback Rattlesnake (Crotalus adamanteus) envenomation is a medical emergency encountered in the Southeastern United States. The venom contains a snake venom thrombin-like enzyme (SVTLE) that is defibrinogenating, causing coagulopathy without effects on platelets in humans. This investigation utilized thrombelastographic methods to document this coagulopathy kinetically on the molecular level in a rabbit model of envenomation via the analyses of whole blood samples without and with platelet inhibition. Subsequently, the administration of a novel ruthenium compound containing site-directed antivenom abrogated the coagulopathic effects of envenomation in whole blood without platelet inhibition and significantly diminished loss of coagulation in platelet-inhibited samples. This investigation provides coagulation kinetic insights into the molecular interactions and results of SVTLE on fibrinogen-dependent coagulation and confirmation of the efficacy of a ruthenium antivenom. These results serve as a rationale to investigate the coagulopathic effects of other venoms with this model and assess the efficacy of this site-directed antivenom.<\/jats:p>","DOI":"10.3390\/ijms25126334","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T11:56:48Z","timestamp":1717761408000},"page":"6334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ruthenium Antivenom Inhibits the Defibrinogenating Activity of Crotalus adamanteus Venom in Rabbits"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8072-9883","authenticated-orcid":false,"given":"Vance G.","family":"Nielsen","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/0002-9343(69)90192-2","article-title":"Afibrinogenemia in man following the bite of a rattlesnake (Crotalus adamanteus)","volume":"47","author":"Weiss","year":"1969","journal-title":"Am. J. Med."},{"key":"ref_2","first-page":"906","article-title":"A purified procoagulant enzyme from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus): In vivo and in vitro studies","volume":"79","author":"Damus","year":"1972","journal-title":"J. Lab. Clin. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/ajh.2830140405","article-title":"Mechanism of defibrination in humans after envenomation by the Eastern diamondback rattlesnake","volume":"14","author":"Kitchens","year":"1983","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jprot.2013.11.001","article-title":"Linking the transcriptome and proteome to characterize the venom of the eastern diamondback rattlesnake (Crotalus adamanteus)","volume":"96","author":"Margres","year":"2014","journal-title":"J. Proteom."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1080\/15563650.2020.1788053","article-title":"Utilization of thromboelastograms in management of Crotalus adamanteus envenomation","volume":"59","author":"Rushton","year":"2021","journal-title":"Clin. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1080\/15563650701753849","article-title":"Recurrent hemorrhage after western diamondback rattlesnake envenomation treated with crotalidae polyvalent immune fab (ovine)","volume":"46","author":"Fazelat","year":"2008","journal-title":"Clin. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1182\/blood.V63.1.1.1","article-title":"Fibrinogenolytic afibrinogenemia after envenomation by western diamondback rattlesnake (Crotalus atrox)","volume":"63","author":"Budzynski","year":"1984","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"107029","DOI":"10.1016\/j.toxicon.2023.107029","article-title":"Severe, persistent thrombocytopenia in Crotalus horridus envenomation despite antivenom: A retrospective review","volume":"224","author":"Trautman","year":"2023","journal-title":"Toxicon"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0196-0644(97)70108-2","article-title":"Thrombocytopenia following timber rattlesnake envenomation","volume":"30","author":"Bond","year":"1997","journal-title":"Ann. Emerg. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1080\/15563650.2017.1284334","article-title":"Use of polyvalent equine anti-viper serum to treat delayed coagulopathy due to suspected Sistrurus miliarius streckeri envenomation in two children","volume":"55","author":"Williams","year":"2017","journal-title":"Clin. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/0041-0101(82)90012-5","article-title":"Envenomation by the northern blacktail rattlesnake (Crotalus molossus molossus): Report of two cases and the in vitro effects of the venom on fibrinolysis and platelet aggregation","volume":"20","author":"Hardy","year":"1982","journal-title":"Toxicon"},{"key":"ref_12","first-page":"393","article-title":"Failure of electric shock treatment for rattlesnake envenomation","volume":"230","author":"Schaeffer","year":"1984","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1177\/0960327115621366","article-title":"Iron and carbon monoxide prevent degradation of plasmatic coagulation by thrombin-like activity in rattlesnake venom","volume":"35","author":"Nielsen","year":"2016","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_14","first-page":"39","article-title":"Boomslang bite--diagnosis and management. A report of 2 cases","volume":"78","author":"Aitchison","year":"1990","journal-title":"S. Afr. Med. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3968","DOI":"10.1177\/00031348221086815","article-title":"Thromboelastography Use to Guide Resuscitation and Antivenom Administration after Gaboon Viper Bite","volume":"89","author":"Faulkner","year":"2023","journal-title":"Am. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.toxicon.2022.05.042","article-title":"Coagulopathy induced by viperid snake venoms in a murine model: Comparison of standard coagulation tests and rotational thromboelastimetry","volume":"214","author":"Rucavado","year":"2022","journal-title":"Toxicon"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3000605211067321","DOI":"10.1177\/03000605211067321","article-title":"Correlations between rotational thromboelastometry (ROTEM) and standard coagulation tests following viper snakebites","volume":"50","author":"Dang","year":"2022","journal-title":"J. Int. Med. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"746","DOI":"10.4269\/ajtmh.21-0875","article-title":"Case Report: Rotational Thromboelastometry in Taipan Envenomation","volume":"106","author":"Tacon","year":"2021","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.4102\/safp.v63i1.5299","article-title":"A case report of detecting subclinical coagulopathy in a patient with boomslang (Dipholidus typus) bite","volume":"63","author":"Tambwe","year":"2021","journal-title":"S. Afr. Fam. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/trstmh\/trab052","article-title":"Comparison of rotational thromboelastometry parameters with 20-minute whole blood clotting test as a predictor of envenoming in Russell\u2019s viper bite patients","volume":"115","author":"Gooneratne","year":"2021","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1080\/15563650.2020.1839663","article-title":"Echis coloratus envenomation in a dog: Clinical, hemostatic and thromboelastometric findings and treatment","volume":"59","author":"Atamna","year":"2021","journal-title":"Clin. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1111\/vec.13008","article-title":"Thromboelastographic evaluation of 2 dogs with boomslang (Dispholidus typus) envenomation","volume":"30","author":"Kopke","year":"2020","journal-title":"J. Vet. Emerg. Crit. Care"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Park, E.J., Choi, S., Kim, H.H., and Jung, Y.S. (2020). Novel Treatment Strategy for Patients with Venom-Induced Consumptive Coagulopathy from a Pit Viper Bite. Toxins, 12.","DOI":"10.3390\/toxins12050295"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1080\/15563650.2020.1713332","article-title":"Thromboelastometry (ROTEM) and thromboelastography (TEG) in copperhead snakebites: A case series","volume":"58","author":"Mullins","year":"2020","journal-title":"Clin. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1111\/1742-6723.13367","article-title":"Thromboelastography for the detection of acute anticoagulant coagulopathy associated with Black Snake envenomation","volume":"31","author":"Coggins","year":"2019","journal-title":"Emerg. Med. Australas."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s13181-019-00729-8","article-title":"Thromboelastography with Platelet Studies (TEG\u00ae with PlateletMapping\u00ae) after Rattlesnake Envenomation in the Southwestern United States Demonstrates Inhibition of ADP-Induced Platelet Activation as Well as Clot Lysis","volume":"16","author":"Kang","year":"2020","journal-title":"J. Med. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1097\/MBC.0000000000000771","article-title":"Thromboelastography in the management of snakebite-induced coagulopathy: A case series and literature review","volume":"29","author":"Leffers","year":"2018","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1097\/MBC.0000000000000702","article-title":"Thromboelastographic study of the snakebite-related coagulopathy in Djibouti","volume":"29","author":"Jean","year":"2018","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1177\/000313481708300417","article-title":"Thromboelastography Utilization in Delayed Recurrent Coagulopathy after Severe Eastern Diamondback Rattlesnake Envenomation","volume":"83","author":"McBride","year":"2017","journal-title":"Am. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1080\/15563650.2016.1263857","article-title":"Rotational thromboelastometry (ROTEM) guided treatment of an Afghanistan viper envenomation at a NATO military hospital","volume":"55","author":"Roszko","year":"2017","journal-title":"Clin. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0035-9203(99)90300-0","article-title":"The role of thromboelastography in the management of children with snake-bite in southern Africa","volume":"93","author":"Hadley","year":"1999","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1097\/MBC.0000000000001294","article-title":"Ruthenium-based antivenom attenuates Crotalus atrox venom mediated coagulopathy in rabbits","volume":"35","author":"Nielsen","year":"2024","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Nielsen, V.G. (2023). Novel Toxicodynamic Model of Subcutaneous Envenomation to Characterize Snake Venom Coagulopathies and Assess the Efficacy of Site-Directed Inorganic Antivenoms. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241813939"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/bcpt.12846","article-title":"Crotalus atrox Venom Exposed to Carbon Monoxide Has Decreased Fibrinogenolytic Activity In Vivo in Rabbits","volume":"122","author":"Nielsen","year":"2018","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.bjae.2022.07.003","article-title":"Point-of-care viscoelastic testing","volume":"22","author":"Wells","year":"2022","journal-title":"BJA Educ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1213\/00000539-200007000-00007","article-title":"Evaluation of the contribution of platelets to clot strength by thromboelastography in rabbits: The role of tissue factor and cytochalasin D","volume":"91","author":"Nielsen","year":"2000","journal-title":"Anesth. Analg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"358","DOI":"10.3109\/09537104.2014.916793","article-title":"Platelet factor XIIIa release during platelet aggregation and plasma clot strength measured by thrombelastography in patients with coronary artery disease treated with clopidogrel","volume":"26","author":"Kreutz","year":"2015","journal-title":"Platelets"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/j.1399-6576.2005.00602.x","article-title":"Effects of coagulation factor deficiency on plasma coagulation kinetics determined via thrombelastography: Critical roles of fibrinogen and factors II, VII, X and XII","volume":"49","author":"Nielsen","year":"2005","journal-title":"Acta Anaesthesiol. Scand"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1055\/s-2006-939552","article-title":"A cell-based model of thrombin generation","volume":"32","author":"Roberts","year":"2006","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_40","first-page":"69","article-title":"Fibrinogen\/fibrin degradation products (FDP\/fdp). Characterization, anticoagulant activity, and influence on laboratory assays","volume":"27","author":"Arnesen","year":"1977","journal-title":"J. Oslo. City Hosp."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Nielsen, V.G. (2020). Ruthenium, Not Carbon Monoxide, Inhibits the Procoagulant Activity of Atheris, Echis, and Pseudonaja Venoms. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082970"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6334\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:55:38Z","timestamp":1760108138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/12\/6334"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,7]]},"references-count":41,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25126334"],"URL":"https:\/\/doi.org\/10.3390\/ijms25126334","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,7]]}}}