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Quel avenir pour les médicaments de l’hémostase dans le traitement du sepsis sévère après le Xigris® ?

After Xigris®, what is the future for drugs targeting haemostasis in sepsis treatment?

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Réanimation

Résumé

Le traitement du sepsis sévère par la protéine C activée (Xigris®) a suscité beaucoup d’espoir mais aussi fait couler beaucoup d’encre. Le rationnel de son évaluation dans cette indication était basé sur une connaissance de plus en plus approfondie de la physiopathologie du sepsis sévère qui a clairement mis en exergue un emballement réciproque des processus d’inflammation et de coagulation chez ces patients. La protéine C activée, comme d’autres inhibiteurs de la coagulation, possède des propriétés anti-inflammatoires en plus de leur activité anticoagulante, faisant de ces protéines des candidats intéressants dans cette indication. Cependant, après le retrait du marché de la protéine C activée et les résultats négatifs des essais de phase III évaluant deux autres inhibiteurs, l’inhibiteur de la voie du facteur tissulaire (TFPI) et l’antithrombine, reste-t-il une place pour ces médicaments ciblant l’hémostase ? D’autres pistes comme l’utilisation de thrombomoduline soluble, le développement de variants optimisés de la protéine C activée ou le développement d’inhibiteurs des axes facteur tissulaire-FVIIa ou FXIa-FXIIa restent des pistes intéressantes et sont, pour certaines d’entre elles, en cours d’évaluation.

Abstract

Treatment of severe sepsis with activated protein C (Xigris®) has generated great hopes but has also been a subject of controversy. The rational for its evaluation in this indication was based on the increasing knowledge regarding severe sepsis pathophysiology, which has clearly highlighted a reciprocal runaway between inflammation and coagulation processes in these patients. Activated protein C, like other coagulation inhibitors, possesses anti-inflammatory properties in addition to their anticoagulant activity, making them attractive candidates in this indication. However, after Xigris® withdrawal and the negative results of phase III trials evaluating two other inhibitors, tissue factor pathway inhibitor (TFPI) and antithrombin, is there still a place for new drugs targeting haemostasis? The use of soluble thrombomodulin, development of optimized variants of activated protein C as well as inhibitors of both tissue factor-FVIIa and FXIIa-FXIa axes are currently under evaluation.

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  1. Service d’hématologie et d’immunologie, hôpital Ambroise-Paré, 9, avenue Charles-de-Gaulle, F-92100, Boulogne-Billancourt, France

    D. Borgel

  2. EA4531, faculté de pharmacie, université Paris-Sud, 5, rue Jean-Baptiste-Clément, F-92296, Chatenay-Malabry, France

    D. Borgel

  3. Département de réanimation médicale et médecine hyperbare, CHU d’Angers, F-49933, Angers, France

    N. Lerolle

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Borgel, D., Lerolle, N. Quel avenir pour les médicaments de l’hémostase dans le traitement du sepsis sévère après le Xigris® ?. Réanimation 22, 181–190 (2013). https://doi.org/10.1007/s13546-013-0665-z

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