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CC BY 4.0 · TH Open 2023; 07(03): e195-e205
DOI: 10.1055/s-0043-1770782
Original Article

A Combination of Ex Vivo and In Vivo Strategies for Evaluating How Much New Oral Anticoagulants Exacerbate Experimental Intracerebral Bleeding

Juliana R. P. Ferreira
1   Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
,
Isabela D. Sucupira
1   Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
,
Gabriella M. C. Carvalho
2   Laboratório de Coagulação e Trombose, Hospital Universitário Clementino Fraga Filho, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
,
Fernando F. Paiva
3   Centro de Imagens e Espectroscopia por Ressonância Magnética (CIERMag). Departamento de Física e Ciência Interdisciplinar. Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, Brazil
,
Pedro M. Pimentel-Coelho
4   Laboratório Intermediário de Neuropatologia Experimental. Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
5   Laboratório Intermediário de Neuropatologia Experimental. Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Rio de Janeiro, Brazil
,
Paulo H. Rosado-de-Castro
2   Laboratório de Coagulação e Trombose, Hospital Universitário Clementino Fraga Filho, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
5   Laboratório Intermediário de Neuropatologia Experimental. Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Rio de Janeiro, Brazil
,
Paulo A. S. Mourão‡   *
1   Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
,
Roberto J. C. Fonseca‡   *
2   Laboratório de Coagulação e Trombose, Hospital Universitário Clementino Fraga Filho, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
› Author Affiliations Funding This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
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Abstract

Background Intracerebral hemorrhage is the most serious complication of anticoagulant therapy but the effects of different types of oral anticoagulants on the expansion of these hemorrhages are still unclear. Clinical studies have revealed controversial results; more robust and long-term clinical evaluations are necessary to define their outcomes. An alternative is to test the effect of these drugs in experimental models of intracerebral bleeding induced in animals.

Aims To test new oral anticoagulants (dabigatran etexilate, rivaroxaban, and apixaban) in an experimental model of intracerebral hemorrhage induced by collagenase injection into the brain striatum of rats. Warfarin was used for comparison.

Methods Ex vivo anticoagulant assays and an experimental model of venous thrombosis were employed to determine the doses and periods of time required for the anticoagulants to achieve their maximum effects. Subsequently, volumes of brain hematoma were evaluated after administration of the anticoagulants, using these same parameters. Volumes of brain hematoma were evaluated by magnetic resonance imaging, H&E (hematoxylin and eosin) staining, and Evans blue extravasation. Neuromotor function was assessed by the elevated body swing test.

Results and Conclusions The new oral anticoagulants did not increase intracranial bleeding compared with control animals, while warfarin markedly favored expansion of the hematomas, as revealed by magnetic resonance imaging and H&E staining. Dabigatran etexilate caused a modest but statistically significant increase in Evans blue extravasation. We did not observe significant differences in elevated body swing tests among the experimental groups. The new oral anticoagulants may provide a better control over a brain hemorrhage than warfarin.

Keywords

intracerebral hemorrhage - apixaban - rivaroxaban - dabigatran - warfarin

Author Contributions

J.R.P.F., I.D.S., and G.M.C.C. performed experiments, F.F.P. and P.H.R.C. performed MRI analysis, P.M.P.C. helped with the ICH model and histological analyses, P.A.S.M. and R.J.C.F. analyzed results and wrote the manuscript.


* These authors contributed equally to this work.




Publication History

Received: 02 March 2023

Accepted: 22 May 2023

Article published online:
10 July 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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