Honickel Markus, Akman Necib, Grottke Oliver
*Department of Anesthesiology, RWTH Aachen University Hospital, Aachen, Germany †Department of Anesthesiology and Intensive Care, Istanbul Faculty of Medicine, University of Istanbul, Istanbul, Turkey.
Shock. 2017 Aug;48(2):144-158. doi: 10.1097/SHK.0000000000000848.
Several direct oral anticoagulants (DOACs), including direct thrombin and factor Xa inhibitors, have been approved as alternatives to vitamin K antagonist anticoagulants. As with any anticoagulant, DOAC use carries a risk of bleeding. In patients with major bleeding or needing urgent surgery, reversal of DOAC anticoagulation may be required, presenting a clinical challenge. The optimal strategy for DOAC reversal is being refined, and may include use of hemostatic agents such as prothrombin complex concentrates (PCCs; a source of concentrated clotting factors), or DOAC-specific antidotes (which bind their target DOAC to abrogate its activity). Though promising, most specific antidotes are still in development.Preclinical animal research is the key to establishing the efficacy and safety of potential reversal agents. Here, we summarize published preclinical animal studies on reversal of DOAC anticoagulation. These studies (n = 26) were identified via a PubMed search, and used rodent, rabbit, pig, and non-human primate models. The larger of these animals have the advantages of similar blood volume/hemodynamics to humans, and can be used to model polytrauma. We find that in addition to varied species being used, there is variability in the models and assays used between studies; we suggest that blood loss (bleeding volume) is the most clinically relevant measure of DOAC anticoagulation-related bleeding and its reversal.The studies covered indicate that both PCCs and specific reversal agents have the potential to be used as part of a clinical strategy for DOAC reversal. For the future, we advocate the development and use of standardized, clinically, and pharmacologically relevant animal models to study novel DOAC reversal strategies.
几种直接口服抗凝剂（DOACs），包括直接凝血酶抑制剂和Xa因子抑制剂，已被批准作为维生素K拮抗剂类抗凝剂的替代药物。与任何抗凝剂一样，使用DOACs有出血风险。对于发生大出血或需要紧急手术的患者，可能需要逆转DOAC抗凝作用，这带来了一项临床挑战。DOAC逆转的最佳策略正在完善中，可能包括使用止血剂，如凝血酶原复合物浓缩剂（PCCs；一种浓缩凝血因子的来源），或DOAC特异性解毒剂（其与目标DOAC结合以消除其活性）。尽管前景广阔，但大多数特异性解毒剂仍在研发中。临床前动物研究是确定潜在逆转剂有效性和安全性的关键。在此，我们总结已发表的关于逆转DOAC抗凝作用的临床前动物研究。这些研究（n = 26）通过PubMed检索确定，使用了啮齿动物、兔子、猪和非人类灵长类动物模型。这些较大的动物具有与人类相似的血容量/血流动力学优势，可用于模拟多发伤。我们发现，除了使用的物种各异外，不同研究之间使用的模型和检测方法也存在差异；我们认为失血量（出血量）是DOAC抗凝相关出血及其逆转在临床上最相关的衡量指标。所涵盖的研究表明，PCCs和特异性逆转剂都有潜力作为DOAC逆转临床策略的一部分。展望未来，我们提倡开发和使用标准化的、具有临床和药理学相关性的动物模型来研究新型DOAC逆转策略。
