Experimental assessment of the risk of hemorrhagic complications following parenteral administration of direct anticoagulants: dabigatran etexilate and rivaroxaban
Abstract
We investigated the efficacy and safety of dabigatran etexilate and rivaroxaban after subcutaneous administration to rats. Heparin sodium was used as a reference drug. It was revealed that 2 hours following heparin sodium administration (250; 500; 1000 U/kg), dabigatran etexilate (4,0; 5,0; 7,5; 10,0; 15,0 mg/kg) and rivaroxaban (2,5; 5,0; 7,5; 10,0 mg/kg) have pronounced anticoagulant effect. Heparin sodium (1000 U/kg) and rivaroxaban (10,0 mg/kg) caused a significant prolongation of rat tail bleeding time and a critical increase in parameters of blood coagulation. Dabigatran etexilate was shown to be of higher therapeutical possibility than heparin sodium and rivaroxaban. Our results can justify the development of injectable dosage form of dabigatran etexilate. It may be important to improve the treatment of critical states with high risk of disseminated intravascular coagulation in emergency and military conflicts.
About the Authors
V. A. Pugach
ФГБУ «Государственный научно-исследовательский испытательный институт военной медицины» Министерства обороны России
Russian Federation
Russian Federation
M. A. Tyunin
ФГБУ «Государственный научно-исследовательский испытательный институт военной медицины» Министерства обороны России
Russian Federation
Russian Federation
E. A. Tarasov
ФГБУ «Государственный научно-исследовательский испытательный институт военной медицины» Министерства обороны России
Russian Federation
Russian Federation
A. S. Gogolevskiy
ФГБУ «Государственный научно-исследовательский испытательный институт военной медицины» Министерства обороны России
Russian Federation
Russian Federation
E. I. Strokina
ФГБУ «Государственный научно-исследовательский испытательный институт военной медицины» Министерства обороны России
Russian Federation
Russian Federation
References
1. Кубышкин А.В., Пылаева Н.Ю., Фомочкина И.И., Писарев А.А. Травма, гемостаз и синдром диссеминированного внутрисосудистого свертывания: патогенетические механизмы нарушений гемокоагуляции // Клиническая патофизиология. - 2016. - Т. 22. - № 4. - С. 104-117.
2. Руководство по проведению доклинических исследований лекарственных средств. Ч. 1. / Под общ. ред. А.Н. Миронова. - М.: Гриф и К. - 2012. - 944 с.
3. Саввин Ю.Н., Кудрявцев Б.П. Клинические рекомендации по оказанию медицинской помощи пострадавшим с политравмой в чрезвычайных ситуациях. - М., 2015. - 66 c.
4. Шабанов В.Э., Саввин Ю.Н., Алексеев А.А. и др. Клинические рекомендации по оказанию медицинской помощи пострадавшим с термической травмой в чрезвычайных ситуациях. - М., 2015. - 37 c.
5. Adcock D.M., Gosselin R. Direct Oral Anticoagulants (DOACs) in the Laboratory: 2015 Review // Thromb Res. - 2015. - V. 136, No. 1. - Pp. 7-12.
6. Baglin T., Keeling D., Kitchen S. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: Guidance from the British Committee for Standards in Haematology // British J. of Haematology. - 2012. - V. 159, No. 4. - Pp. 427-429.
7. East J.M., Cserti-Gazdewich C.M., Granton J.T. Heparin-induced thrombocytopenia in the critically ill patient // Chest. - 2017. - S. 0012-3692(17). - Pp. 33223-3.
8. Kadohira Y., Yamada S., Matsuura E., et al. Aortic aneurysm-associated disseminated intravascular coagulation that responded well to a switch from warfarin to rivaroxaban // Intern Med. - 2017. - V. 56, No. 21. - Pp. 2913-17.
9. Kawano H., Hata T., Uda A., Maemura K. Use of rivaroxaban for the effective management of disseminated intravascular coagulation associated with abdominal aortic aneurysm // Intern Med. - 2015. - V. 54. - Pp. 2625-28.
10. Linkins L.A., Dans A.L., Moores L.K., et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines // Chest. - 2012. - V. 141. - Pp. 495-530.
11. Maegele M., Schochl H., Cohen M.J. An update on the coagulopathy of trauma // Shock. - 2014. - V. 41. - Pp. 21-25.
12. Perzborn E., Hirth-Dietrich C., Fischer E., et al. Rivaroxaban has protective effects in a model of disseminated intravascular coagulation (DIC) in rats // Blood. - 2007. - V. 110. - P. 935.
13. Randrianarisoa E., Kopp H.G., Balletshofer B.M., et al. Management of disseminated intravascular coagulopathy with direct factor Xa inhibitor rivaroxaban in Klippel-Trenaunay syndrome // Blood Coagul Fibrinolysis. - 2013. - V. 24, No. 7. - Pp. 766-770.
14. Yasumoto A., Ishiura R., Narushima M., Yatomi Y. Successful treatment with dabigatran for consumptive coagulopathy associated with extensive vascular malformations // Blood Coagul Fibrinolysis. - 2017. - V. 28, No. 8. - Pp. 670-674.
15. Kubyshkin A.V., Pylayeva N.Yu., Fomochkina I.I., Pisarev A.A. Travma, gemostaz i sindrom disseminirovannogo vnutrisosudistogo svertyvaniya: patogeneticheskie mekhanizmy narushenij gemokoagulyacii [Trauma, hemostasis and disseminated intravascular coagulation syndrome: pathogenic mechanisms of coagulation disorders]. Klinicheskaya patofiziologiya [Clinical pathophysiology]. 2016. V. 22. No. 4. Pp. 104-117. (In Russian).
16. Rukovodstvo po provedeniyu doklinicheskih issledovanij lekarstvennyh sredstv. Ch. 1 [Guidelines for preclinical research of drugs. Part I]. Ed. by Mironov A.N. Moscow: Grif i K. 2012. 944 p. (In Russian).
17. Savvin Yu.N., Kudryavcev B.P. Klinicheskie rekomendacii po okazaniyu medicinskoj pomoshchi postradavshim s politravmoj v chrezvychajnyh situaciyah [The clinical guidelines for medical care delivery in polytrauma in emergency]. Moscow. 2015. 66 p. (In Russian).
18. Shabanov V.Eh., Savvin Yu.N., Alekseev A.A., et al. Klinicheskie rekomendacii po okazaniyu medicinskoj pomoshchi postradavshim s termicheskoj travmoj v chrezvychajnyh situaciyah [The clinical guidelines for medical care delivery in thermal trauma in emergency]. Moscow. 2015. 37 p. (In Russian).
19. Adcock D.M., Gosselin R. Direct Oral Anticoagulants (DOACs) in the Laboratory: 2015 Review. Thromb Res. 2015. V. 136, No. 1. Pp. 7-12.
20. Baglin T., Keeling D., Kitchen S. Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: Guidance from the British Committee for Standards in Haematology. British J. of Haematology. 2012. V. 159, No. 4. Pp. 427-429.
21. East J.M., Cserti-Gazdewich C.M., Granton J.T. Heparin-induced thrombocytopenia in the critically ill patient. Chest. 2017. S. 0012-3692(17). Pp. 33223-3.
22. Kadohira Y., Yamada S., Matsuura E., et al. Aortic aneurysm-associated disseminated intravascular coagulation that responded well to a switch from warfarin to rivaroxaban. Intern Med. 2017. V. 56, No. 21. Pp. 2913-17.
23. Kawano H., Hata T., Uda A., Maemura K. Use of rivaroxaban for the effective management of disseminated intravascular coagulation associated with abdominal aortic aneurysm. Intern Med. 2015. V. 54. Pp. 2625-28.
24. Linkins L.A., Dans A.L., Moores L.K., et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012. V. 141. Pp. 495-530.
25. Maegele M., Schochl H., Cohen M.J. An update on the coagulopathy of trauma. Shock. 2014. V. 41. Pp. 21-25.
26. Perzborn E., Hirth-Dietrich C., Fischer E., et al. Rivaroxaban has protective effects in a model of disseminated intravascular coagulation (DIC) in rats. Blood. 2007. V. 110. P. 935.
27. Randrianarisoa E., Kopp H.G., Balletshofer B.M., et al. Management of disseminated intravascular coagulopathy with direct factor Xa inhibitor rivaroxaban in Klippel-Trenaunay syndrome. Blood Coagul Fibrinolysis. 2013. V. 24, No. 7. Pp. 766-770.
28. Yasumoto A., Ishiura R., Narushima M., Yatomi Y. Successful treatment with dabigatran for consumptive coagulopathy associated with extensive vascular malformations. Blood Coagul Fibrinolysis. 2017. V. 28, No. 8. Pp. 670-674.
Review
For citations:
Pugach V.A., Tyunin M.A., Tarasov E.A., Gogolevskiy A.S., Strokina E.I. Experimental assessment of the risk of hemorrhagic complications following parenteral administration of direct anticoagulants: dabigatran etexilate and rivaroxaban. Journal Biomed. 2018;(4):79-87. (In Russ.)
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