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Updated: Jun 23, 2025

Measurement of Factor V Activity in Human Plasma Using a Microplate Coagulation Assay
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Dual Inhibition of Factor XIIa and Factor XIa Produces a Synergistic Anticoagulant Effect

Shuai Jiang1, Yitong Li1, Jiali Zhang1

  • 1School of Life Science and Technology, China Pharmaceutical University, Nanjing, China ; and.

Journal of Cardiovascular Pharmacology
|June 26, 2024
PubMed

Insights

Combining FXIa and FXIIa inhibitors offers a novel anticoagulant strategy. This dual inhibition shows synergistic effects in preventing thrombosis without increasing bleeding risk, addressing a critical unmet need.

Area of Science:

  • Thrombosis and Hemostasis
  • Pharmacology

Background:

  • A significant unmet need in thrombosis prevention is anticoagulant therapy with minimal bleeding risk.
  • Factor XIa (FXIa) and Factor XIIa (FXIIa) inhibitors are being investigated for their potential low bleeding risk.
  • The synergistic anticoagulant effects of combined FXIa and FXIIa inhibition have not been previously explored.

Purpose of the Study:

  • To investigate the synergistic anticoagulant effects of combining a FXIa inhibitor (PN2KPI) and a FXIIa inhibitor (Infestin4).
  • To evaluate the efficacy and bleeding risk of this dual inhibition in preclinical thrombosis models.

Main Methods:

  • Activated partial thromboplastin time (aPTT) assays were used to assess anticoagulation.
  • The SynergyFinder tool was employed to analyze synergistic effects of PN2KPI and Infestin4.
  • Mouse models of FeCl3-induced carotid artery thrombosis and transient middle cerebral artery occlusion were utilized.

Main Results:

  • Synergistic anticoagulation effects were identified between the FXIa inhibitor PN2KPI and the FXIIa inhibitor Infestin4.
  • The combination of PN2KPI (28.57% effective dose) and Infestin4 (6.25% effective dose) significantly prevented coagulation in vivo.
  • Dual inhibition with PN2KPI and Infestin4 did not result in any observed bleeding risk.

Conclusions:

  • Combined inhibition of FXIa and FXIIa demonstrates synergistic anticoagulation.
  • This dual inhibition strategy represents a promising approach for thrombosis prevention with a potentially improved safety profile regarding bleeding risk.

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