Reversal of the Anticoagulant Effect of Milvexian by 4-Factor PCC and rFVIIa in Healthy Participants: a Two-Part, Randomized, Crossover Study

作者：Victor Dishy, Sue Sha, Anastasiya Koshkina, Fisseha Tesfaye, Alexei N. Plotnikov, Hideo Makimura, Madhu Chintala · 发表于：Journal of Cardiovascular Pharmacology · 年份：2026 · DOI：10.1097/fjc.0000000000001859 · 研究领域：Coagulation, Bradykinin, Polyphosphates, and Angioedema、Blood Coagulation and Thrombosis Mechanisms、Atrial Fibrillation Management and Outcomes

Milvexian is a selective, oral factor XIa inhibitor. Individuals receiving anticoagulation may require prompt reversal of anticoagulative effects. This study assessed reversal of milvexian's anticoagulant effects by recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants. This was a 2-part, randomized, crossover study. In Part A, milvexian (100 or 500mg single doses) was followed by rFVIIa (30μg/kg) or placebo 4 hours later. In Part B, milvexian 200mg was administered q12h for 3 consecutive days, with 4F-PCC (50IU/kg) or placebo given 4 hours after last dose in the morning of Day 4. Anticoagulation was assessed through activated partial thromboplastin time (aPTT) and thrombin generation (endogenous thrombin potential [ETP], peak thrombin) utilizing 2 activators: kaolin (intrinsic pathway [IP] effects) and tissue factor (TF; extrinsic pathway [EP] effects). rFVIIa partially reversed milvexian's effects on aPTT (milvexian 100mg: ∼18%; 500mg: ∼15%), IP-induced ETP (milvexian-induced ETP reversal; 100mg: ∼50%; 500mg: ∼80%) and peak thrombin, and EP-induced peak thrombin but not ETP. Milvexian 200mg prolonged aPTT, strongly inhibited IP-induced ETP/peak thrombin, and mildly inhibited EP-induced ETP. 4F-PCC partially reversed milvexian's effect on aPTT (∼17%) and IP-induced ETP/peak thrombin; it reversed milvexian's effect on EP-initiated ETP (∼68% increase). Reversal was rapid (15 minutes) and long-lasting (≥8 hours). Mi...