FXI and FXII in experimental stroke and FXI in clinical stroke trials.

Authors

Stine Mencl, Friederike Langhauser, Jordi Kühne Escolà, Benedikt Frank, Martin Köhrmann, Christoph Kleinschnitz

Published in

Neurological research and practice. Volume 8. Issue 1. Oct 16, 2026. Epub Oct 16, 2026.

Abstract

Targeting the contact activation system through Factor XI (FXI) or Factor XII (FXII) inhibition represents a major paradigm shift in antithrombotic therapy for ischemic stroke. Unlike traditional anticoagulants, contact pathway factors drive pathological thrombus propagation and thromboinflammation; crucially, while FXII plays a negligible role in physiological hemostasis, FXI contributes only secondarily, thereby substantially uncoupling antithrombotic efficacy from major bleeding risk. However, a notable disconnect exists between experimental models and clinical development. Preclinical stroke literature, primarily rodent middle cerebral artery occlusion (MCAO) models, is overwhelmingly concentrated on FXII targeting, where FXII deficiency or blockade consistently reduces cerebral infarct volumes, preserves microvascular perfusion, and attenuates thromboinflammation, whereas experimental studies of direct FXI treatment remain sparse. Conversely, human clinical translation has focused largely on oral FXIa inhibitors, maintaining a favorable bleeding profile across indications but yielding mixed efficacy, ranging from neutral Phase II studies and the early termination of OCEANIC-AF to positive secondary stroke prevention data. Following positive OCEANIC-STROKE findings, asundexian (under FDA priority review as of September 2026) emerges as a prospective add-on to antiplatelet therapy for the secondary prevention of noncardioembolic stroke or high-risk TIA, particularly in nonlacunar or atherosclerotic populations. Reconciling preclinical FXII data with clinical FXIa trial outcomes provides a timely rationale to systematically review evidence across MCAO models and human stroke trials to delineate the distinct therapeutic potentials of FXI and FXII inhibition.

PMID:
42888464
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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