Coagulopathy at intoxication with rodenticides – antagonists of vitamin K

The review is devoted to poisoning with rodenticides containing indirect anticoagulants – vitamin K antagonists (VKA). The work describes the main groups of anticoagulants that are used in such preparations, describes the mechanism of their action. The authors analyzed a significant number of foreign and local literary sources on the poisoning of the rodenticides of this group. It was concluded that VKA intoxication occurs much less frequently than other rodenticides; it is mainly the occasional intake of drugs, most of the victims are children. The use of rodenticides-VKA by psychiatric patients and criminal cases are not common. Analysis of the literature has shown that the overwhelming number of poisonings occurs when using VKA, which are contained in ready-made rodent-control baits available to the majority of the population. Intoxication with modern rodenticides-VKA – superwarfarins is possible with oral, dermal exposure and contact with the mucous membranes of the eye; they have a cumulative effect. The main clinical manifestation of superwarfarin poisoning is hemorrhagic syndrome. The clinical signs of coagulopathy are much more pronounced in case of deliberate poisoning than in case of accidental poisoning, since for the appearance of hemorrhagic syndrome, a large amount of the substance contained in the finished bait is required. The principles and features of diagnosis, differential diagnosis and treatment of coagulopathy of this genesis are described. All patients have changes in the coagulogram, characteristic of vitamin K-dependent coagulopathy: an increase in the international normalized ratio, prothrombin time and activated partial thromboplastin time, a decrease in the levels of II, VII, IX and X blood coagulation factors, physiological anticoagulants – proteins C and S. Determine the concentration of superwarfarin in the blood using high performance liquid chromatography is not possible in every medical institution. In the clinical diagnosis of coagulopathy and the identification in the coagulogram of changes characteristic of vitamin K deficiency, even if its etiological cause has not been established, it is immediately necessary to prescribe adequate therapy: the introduction of fresh frozen plasma and/or concentrates of prothrombin complex factors, prescription of vitamin K preparations, symptomatic therapy. Taking into consideration the long half-life of superwarfarins, coagulopathy can persist for several months, during which treatment should be continued. With timely diagnosis and the appointment of adequate therapy, the prognosis in most cases is favorable. The mortality rate among people with superwarfarin poisoning is not high. As an illustration, the authors cite two clinical cases from personal practice.

superwarfarins, poisoning, vitamin K-dependent coagulopathy, diagnosis, treatment

1. Henry J.A., Wiseman H.M. Management of poisoning. A handbook for health care workers. Moscow: Meditsina; 1998 (in Russian). ISBN 5225033083

2. Berny P., Velardo J., Pulce C., D'amico A., Kammerer M., Lasseur R. Prevalence of anticoagulant rodenticide poisoning in humans and animals in France and substances involved. Clin. Toxicol. 2010; 48(9):935−941. doi: 10.3109/15563650.2010.533678

3. Carvallo F.R., Poppenga R., Kinde H., Diab S.S., Nyaoke A.C., Hill A.E., Arthur R.M., Uzal F.A. Cluster of cases of massive hemorrhage associated with anticoagulant detection in race horses. J. Vet. Diagn. Invest. 2015; 27(1):P.112−116. doi: 10.1177/1040638714559970

4. Litovitz T.L., Klein-Schwartz W., White S., Cobaugh D.J., Youniss J., Omslaer J.C., Drab A., Benson B.E. 2000 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 2001; 19(5):337−395. doi: 10.1053/ajem.2001.25272

5. Litovitz T.L., Klein-Schwartz W., Rodgers G.C. Jr, Cobaugh D.J., Youniss J., Omslaer J.C., May M.E., Woolf A.D., Benson B.E. 2001 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 2002; 20(5):391‒452. doi: 10.1053/ajem.2002.34955

6. Watson W., Litovitz T.L., Rodgers G.C.Jr, Klein-Schwartz W., Youniss J., Rose S.R., Borys D., May M.E. 2002 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 2003; 21(5):353–421. doi: 10.1016/s0735-6757(03)00088-3

7. Spahr J.E., Maul J.S., Rodgers J.M. Superwarfarin poisoning: A report of two cases and review of the literature. Am. J. Hematol. 2007; 82(7):656−660. doi: 10.1002/ajh.20784

8. Zhang M., Fang X., Zhou L., Su L., Zheng J., Jin M., Zou H., Chen G. Pesticide poisoning in Zhejiang, China: a retrospective analysis of adult cases registration by occupational disease surveillance and reporting systems from 2006 to 2010. BMJ Open 2013; 3(11):e003510−e003510. doi: 10.1136/bmjopen-2013-003510

9. Peshin S.S., Srivastava A., Halder N., Gupta Y.K. Pesticide poisoning trend analysis of 13 years: a retrospective study based on telephone calls at the National Poisons Information Centre, All India Institute of Medical Sciences, New Delhi. J. Forensic Leg. Med. 2014; 22:57‒61. doi: 10.1016/j.jflm.2013.12.013

10. Zhou L., Liu L., Chang L., Li L. Poisoning deaths in Central China (Hubei): A 10-year retrospective study of forensic autopsy cases. J. Forensic Sci. 2010; 56(Suppl. 1):234−237. doi: 10.1111/j.1556-4029.2010.01625.x

11. Voĭtsekhovskiĭ V.V., Pivnik A.V., Bitiutskaia L.G., Protsko T.T. Acquired hemorrhagic coagulopathy due to contact with the rodenticide brodifacoum in the Nutcracker bait. Terapevticheskii arkhiv 2012; 84(7):66−71 (in Russian).

12. Galstyan G.M. Hemostasis disorders caused by deficiency of vitamin K-dependent coagulation factors: pathogenesis, correction methods and recommendations for treatment. Gematologiya i Transfuziologiya 2012; (2):7−21 (in Russian).

13. Kolosova I.V., Galstyan G.M., Orel E.B., Vasilyev S.A., Ryzhko V.V., Varlamova E.Yu., Gorodetsky V.M. Therapy for the hemorrhagic syndrome caused by deficiency of vitamin K-dependent coagulation factors (analysis of clinical cases). Gematologiya i Transfuziologiya 2012; (2):22−30 (in Russian).

14. Zobnin Yu.V., Kutateladze R.G., Malykh A.F., Pazyukov E.A., Provado I.P., Teterina I.P. Acute poisonings with anticoagulants according to the data of the Irkutsk Toxicological Center. Siberian Medical Journal (Irkutsk) 2013; 120(5):131−134 (in Russian).

15. Kruse J.A., Carlson R.W. Fatal poisoning with rodenticide brodifacoum. Ann. Emerg. Med. 1992; 21(3):331−336. doi: 10.1016/s0196-0644(05)80900-x

16. Huić M., Francetić I., Bakran I., Macolić-Sarinić V., Bilusić M. Acquired coagulopathy due to anticoagulant rodenticide poisoning. Croat. Med. J. 2002; 43(5):615−617.

17. Zhao S.L., Li P., Ji M., Zong Y., Zhang S.T. Upper gastrointestinal hemorrhage caused by superwarfarin poisoning. World J. Gastroenterol. 2010; 16(13):1680−1682. doi: 10.3748/wjg.v16.i13.168

18. Chua J.D., Friedenberg W.R. Superwarfarin poisoning. Arch. Intern. Med. 1998; 158(17):1929−1932. doi: 10.1001/archinte.158.17.1929

19. Watson W.A., Litovitz T.L., Rodgers G.C.Jr, Klein-Schwartz W., Reid N., Youniss J., Flanagan A., Wruk K.M. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 2005; 23(5):589−666. doi: 10.1016/j.ajem.2005.05.001

20. King N., Tran M.H. Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management. Transfus. Med. Rev. 2015; 29(4):250−258. doi: 10.1016/j.tmrv.2015.06.002

21. Gutiérrez W., Cerda P., Plaza-Plaza J.C., Mieres J.J., Paris E., Ríos J.C. Characterization of pesticide exposures reported between 2006 and 2013 to a poison information center in Chile. Rev. Med. Chil. 2015; 143(10):1269−1276 (in Spanish). doi: 10.4067/S0034-98872015001000009

22. Lee H.J., You M.R., Moon W.R., Sul H., Chung C.H., Park C.Y., Park S.G. Evaluation of risk factors in patients with vitamin K-dependent coagulopathy presumed to be caused by exposure to brodifacoum. Korean J. Intern. Med. 2014; 29(4):498−508. doi: 10.3904/kjim.2014.29.4.498

23. Belousov Yu.B., Кukes V.G., Lepakhin V.K., Pertrov V.I., editors. Clinical Pharmacology: National Guidelines. Moscow: GEOTAR-Media; 2014 (in Russian). ISBN 978-5-9704-2810-8

24. Wojciechowski V.V., Calina D., Tsarouhas K., Pivnik A.V., Sergievich A.A., Kodintsev V.V., Filatova E.A., Ozcagli E., Docea A.O., Gofita E., Arsene A.L., Tsitsimpikou C., Tsatsakis A.M., Golokhvast K.S. A guide to acquired vitamin K coagulophathy diagnosis and treatment: the Russian perspective. DARU 2017; 25(1):10. doi: 10.1186/s40199-017-0175-z

25. Carrying out emergency measures for disinsection and deratization in natural foci of plague on the territory of the Russian Federation. Methodological instructions MU 3.1.2565-09. Moscow; 2009 (in Russian). Available at: http://docs.cntd.ru/document/1200077783

26. GOST 12.1.007-76. Occupational safety standards system. Noxious substances. Classification and general safety requirements. Moscow; 2007 (in Russian). Available at: http://docs.cntd.ru/document/5200233

27. Assessment of toxicity and hazard of disinfectants. Methodical instructions MU 1.2.1105-02. Moscow; 2002 (in Russian). Available at: http://docs.cntd.ru/document/1200030376

28. Denisenko V.I. Hygienic rationale for the safe production and use of modern rodenticidal agents ‒ anticoagulants based on bromadiolone and brodifacum: abstract of PhD thesis. Moscow; 2008 (in Russian).

29. Mack R.B. Not all rats have four legs. Superwarfarin poisoning. N. C. Med. J. 1994; 55(11):554‒556.

30. Ling L.J., Clark R.F., Erickson T.B., Trestrail J.H.3rd Toxicology Secrets. St. Petersburg: Dialect; 2006 (in Russian). ISBN 1-56053-410-9

31. Corke PJ. Superwarfarin (brodifacoum) poisoning. Anaesth. Intensive Care 1997; 25(6):707−709. doi: 10.1177/0310057X9702500622

32. Abell T.L., Merigian K.S., Lee J.М., Holbert J.M., McCall J.W. 3rd. Cutaneous exposure to-like anticoagulant warfarin causing an intracerebral hemorrhage: a case report. J. Toxicol. Clin. Toxicol. 1994; 32(1):69−73. doi: 10.3109/15563659409000432

33. Zupancic-Salek S., Kovacevic-Metelko J., Radman I. Successful reversal of effect of anticoagulant superwarfarin poisoning with recombinant activated factor VII. Blood Coagul. Fibrinolysis 2005; 16(4):239−244. doi: 10.1097/01.mbc.0000169215.70184.56

34. Ginja N., Coggins A., Bidny S. Management of intentional superwarfarin poisoning with long-term vitamin K and brodifacoum levels. Clin. Toxicol. (Phila) 2011; 49(5):385−390. doi: 10.3109/15563650.2011.587126

35. Özdemir Z.N., Şahin U., Merter M., Gündüz M., Ateşağaoğlu B., Beksaç M. A case of superwarfarin poisoning due to repetitive occupational dermal rodenticide exposure in a worker. Turkish J. Haematol. 2016; 33(3):251−253. doi: 10.4274/tjh.2015.0433

36. Schneider W., Girmann G., Luthe R., Wagner H.J. Attempted murder with phenprocoumon (marcumar) (author's transl). Dtsch Med. Wochenschr. 1975; 100(37):1838−1841 (in German). doi: 10.1055/s-0028-1106469

37. McCurdy W. An attempted homicide using d-CON rat poison. J. Anal. Toxicol. 1988; 12(1):51−52. doi: 10.1093/jat/12.1.51

38. Altay S., Cakmak H.A., Boz G.C., Koca S., Velibey Y. Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning. Cardiovasc. J. Afr. 2012; 23(9):e9−e11. doi: 10.5830/CVJA-2012-051

39. Freixo A., Lopes L., Carvalho M., Araújo F. Superwarfarine Poisoning. Acta Méd. Port. 2015; 28(3):389−392. (in Portuguese).

40. Curcic M., Dadasovic J. Suicide and attempted suicide with rodenticides from 1968 to 2000. Med. Pregl. 2001; 54(5-6). P.256−260 (in Croatian).

41. Lubetsky A., Yonath H., Olchovsky D., Loebstein R., Halkin H., Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch. Intern. Med. 2003; 163(20):2469−2473. doi: 10.1001/archinte.163.20.2469

42. Bahouth M.N., Kraus P., Dane K., Plazas Montana M., Tsao W., Tabaac B., Jasem J., Schmidlin H., Einstein E., Streiff M.B., Shanbhag S. Synthetic cannabinoid-associated coagulopathy secondary to long-acting anticoagulant rodenticides: Observational case series and management recommendations. Medicine (Baltimore) 2019; 98(36):e17015. doi: 10.1097/MD.0000000000017015

43. Devgun J.M., Rasin A., Kim T., Mycyk M.B., Bryant S.M., Wahl M.S., DesLauriers C., Navon L., Moritz E.D., Thompson T.M., Swoboda H.D., Lu J., Aks S.E. An outbreak of severe coagulopathy from synthetic cannabinoids tainted with Long-Acting anticoagulant rodenticides. Clin. Toxicol. (Phila) 2019; 4:1−8. doi: 10.1080/15563650.2019.1690149

44. Feinstein D.L., Nosal D.G., Ramanathan S., Zhou J., Chen L., Hershow R.C., van Breemen R.B., Wright E., Hafner J.W., Rubinstein I. Effects of vitamin K1 treatment on plasma concentrations of long-acting anticoagulant rodenticide enantiomers following inhalation of contaminated synthetic cannabinoids. Clin. Toxicol. (Phila) 2020; 58(7):716−724. doi: 10.1080/15563650.2019.1687903

45. Dashti-Khavidaki S., Ghaffari S., Nassiri-Toossi M., Amini M., Edalatifard M. Possible unaware intoxication by anticoagulant rodenticide. J. Res. Pharm. Pract. 2014; 3(4):142−144. doi: 10.4103/2279-042X.145394

46. Card D.J., Francis S., Deuchande K., Harrington D.J. Superwarfarin poisoning and its management. BMJ Case Reports 2014; Oct 13:bcr2014206360. doi: 10.1136/bcr-2014-206360

47. Feldman M.D. Playing Sick? Untangling the Web of Munchausen Syndrome, Munchausen by Proxy, Malingering, and Factitious Disorder. New York: Brunner-Routledge; 2004.

48. Barkagan Z.S. Acquired hemorrhagic coagulopathy. In: Vorob’yov A.I., editor. Guide to Hematology. Third edition. Vol.3. Moscow: N'yudiamed; 2005:82–90 (in Russian).

49. Stanziale S.F., Christopher J.C., Fisher R.B. Brodifacoum rodenticide ingestion in a patient with shigellosis. South. Med. J. 1997; 90(8):833−835. doi: 10.1097/00007611-199708000-00013

50. Moery S., Pontious J.M. Coagulopathy associated with superwarfarin exposure. J. Okla. State Med. Assoc. 2009; 102(10):323−325.

51. Tsutaoka B., Miller M., Patel M. No adverse sequelae from an intentional overdose of superwarfarin and glass despite an INR of 38. In: North American Congress of Clinical Toxicology Annual Meeting, Montreal. 2001; Oct: 4−9. Clin. Toxicol. 2001; 39(5):476.

52. Galvin H., Newton A.W., Vandeven A.M. Update on Munchausen syndrome by proxy. Curr. Opin. Pediatr. 2005; 17(2):252−257. doi: 10.1097/01.mop.0000158729.18551.dd

53. Babcock J., Hartman K., Pedersen A., Murphy M., Alving B. Rodenticide-induced coagulopathy in a young child. A case of Munchausen syndrome by proxy. Am. J. Pediatr. Hematol. Oncol. 1993; 15(1):126−130. 10.1097/00043426-199302000-00021

54. Stanziale S.F., Christopher J.C., Fisher R.B. Brodifacoum rodenticide ingestion in a patient with shigellosis. South. Med. J. 1997; 90(8):833−835. doi: 10.1097/00007611-199708000-00013

55. Wu Y.F., Chang C.S., Chung C.Y., Lin H.Y., Wang C.C., Shen M.C. Superwarfarin intoxication: hematuria is a major clinical manifestation. Int. J. Hematol. 2009; 90(2):170−173. doi: 10.1007/s12185-009-0374-6

56. Ware K.M., Feinstein D.L., Rubinstein I., Weinberg G., Rovin B.H., Hebert L., Muni N., Cianciolo R.E., Satoskar A.A., Nadasdy T., Brodsky S.V. Brodifacoum induces early hemoglobinuria and late hematuria in rats: novel rapid biomarkers of poisoning. Am. J. Nephrol. 2015; 41(4-5):392−399. doi: 10.1159/000433568

57. Franco D., Everett G., Manoucheri M. I smell a rat: a case report and literature review of paradoxical thrombosis and hemorrhage in a patient with brodifacoum toxicity. Blood Coagul. Fibrinolysis 2013; 24(2):202−204. doi: 10.1097/MBC.0b013e328358e9

58. Saja M.F., Abdo A.A., Sanai F.M., Shaikh S.A., Gader A.G. The coagulopathy of liver disease: does vitamin K help? Blood Coagul. Fibrinolysis 2013; 24(1):10−17. doi: 10.1097/MBC.0b013e32835975ed

59. Cao X., Li L., Zheng Y. Clinical analysis of 12 patients caused by long-acting anticoagulant rodenticide occult poisoning. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2012; 37(8):849−853. doi: 10.3969/j.issn.1672-7347.2012.08.016

60. Olmos V., Lopez C.M. Brodifacoum poisoning with toxicokinetic data. Clin. Toxicol. (Phila) 2007; 45(5):487−489. doi: 10.1080/15563650701354093

61. Chua J.D., Friedenberg W.R. Superwarfarin poisoning. Arch. Intern. Med. 1998; 158(17):1929−1932. doi: 10.1001/archinte.158.17.1929

62. Boettcher S., Wacker A., Moerike K., Kopp H-G., Jaschonek K., Grobosch T., Kanz L., Salih H.R. Acquired coagulopathy caused by intoxication with the superwarfarin-type anticoagulant rodenticide flocoumafen. Eur. J. Haematolol. 2011; 86(2):173−175. https://doi.org/10.1111/j.1600-0609.2010.01550.x

63. Nelson A.T., Hartzell J.D., More K., Durning S.J. Ingestion of superwarfarin leading to coagulopathy: a case report and review of the literature. Medscape General Medicine 2006; 8(4):41.

64. Watson K.S., Mills G.M., Burton G.V. Superwarfarin intoxication: two case reports and review of pathophysiology and patient management. J. La State Med. Soc. 2012; 164(2):70−72.

65. Helmuth R.A., McCloskey D.W., Doedens D.J., Hawley D.A. Fatal ingestion of brodifacoum-containing rodenticide. Laboratory Medicine 1989; 20(1):25−27. https://doi.org/10.1093/labmed/20.1.25

66. Ingels M., Lai C., Tai W., Manning B.H., Rangan C., Williams S.R., Manoguerra A.S., Albertson T., Clark R.F. A prospective study of acute, unintentional, pediatric superwarfarin ingestions managed without decontamination. Ann. Emerg. Med. 2002; 40(1):73−78. doi: 10.1067/mem.2002.125449

67. Yiu K.H., Siu C.W., Jim M.H., Tse H.F., Fan K., Chau M.C., Chow W.H. Compration of the efficacy and safety profiles of intravenous vitamin K and fresh frozen plasma as treatment of warfarin –related over anticoagulation in patients with mechanical heart valves. Am. J. Cardiol. 2006; 97(3):409−411. doi: 10.1016/j.amjcard.2005.08.062

68. Luzhnikov E.A., editor. Medical toxicology: National guidelines. Moscow: GEOTAR-Media: 2014 (in Rusian). ISBN 978-5-9704-2971-6

69. Galstyan G.M. Label and off-label applications of prothrombin complex concentrates. new perspectives of old drugs. Russian journal of hematology and transfusiology 2018; 63(1):78–91 (in Russian). https://doi.org/10.25837/HAT.2018.30..1..008