Effects of milvexian alone or with heparin on catheter-induced clotting and thrombin generation

BACKGROUND: Milvexian, an oral factor (F)XIa inhibitor, is undergoing phase 3 evaluation for acute coronary syndrome. Such patients often require percutaneous coronary intervention (PCI). The PCI catheters trigger clotting by inducing activation of FXII and FXI. It is unknown whether milvexian blocks this or if adjunctive heparin is needed. OBJECTIVES: To (a) compare the effect of FXII depletion or FXI depletion on catheter clotting, (b) investigate catheter-induced FXI activation, and (c) determine the effect of milvexian alone or with heparin on catheter-induced clotting and thrombin generation. METHODS: In a 96-well plate assay, catheter-induced clotting and thrombin generation were assessed in recalcified control or depleted plasmas supplemented with control plasma by monitoring absorbance and thrombin substrate hydrolysis, respectively. FXI activation by catheters, FXIIa, or thrombin was evaluated by chromogenic assay. Milvexian, dabigatran, heparin, or milvexian plus heparin were added to control plasma to assess effects. RESULTS: Catheters promoted autoactivation of FXI and augmented FXIIa- and thrombin-mediated FXI activation. Clotting was attenuated in FXII-depleted plasma and abolished in FXI-depleted plasma. Even small amounts of FXI triggered clotting. Milvexian and dabigatran at clinically relevant concentrations did not prevent catheter-induced clotting or thrombin generation. Heparin potentiated milvexian's inhibitory effect on catheter-induced clotting. CONCLUSION: Catheters promote FXI autoactivation, bypassing FXII, and highlighting the critical role of FXI. The limited capacity of milvexian supports the need for adjunctive heparin in patients treated with milvexian undergoing PCI.