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Extrinsic and Intrinsic Pathways of Hemostasis01:20

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The intricate allostery in factor VIIa: triggering the trigger.

Jesper J Madsen1, Egon Persson2, Ole H Olsen3

  • 1Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; Center for Global Health and Infectious Diseases Research, Global and Planetary Health, College of Public Health, University of South Florida, Tampa, FL 33612, USA.

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Tissue factor (TF) allosterically activates factor VIIa (FVIIa), initiating blood coagulation. New insights into FVIIa allostery and engineered variants offer advanced control over coagulation processes.

Keywords:
allosteric effectsfactor VIIaprocoagulant activitytenasetissue factor

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hemostasis

Background:

  • Factor VIIa (FVIIa) initiates blood coagulation, a process critically dependent on its cofactor, tissue factor (TF).
  • TF acts as a membrane-tethered allosteric activator of FVIIa, influencing substrate interactions and downstream coagulation.
  • Complex allosteric pathways within FVIIa are triggered by TF binding, involving intricate molecular interactions.

Purpose of the Study:

  • To elucidate the mechanisms of allosteric activation of FVIIa by TF.
  • To investigate the role of TF in modulating FVIIa activity and function.
  • To explore the potential of engineered FVIIa variants for therapeutic applications.

Main Methods:

  • Biochemical investigations of FVIIa and TF interactions.
  • Design and characterization of FVIIa variants.
  • In vivo validation of engineered FVIIa constructs.

Main Results:

  • TF binding induces complex allostery in FVIIa via at least two interconnected pathways.
  • Engineered FVIIa variants exhibit modulated properties and responses to TF-induced allosteric activation.
  • Antibodies can also modulate FVIIa activity, mimicking or diverging from TF-mediated effects.
  • Engineered FVIIa constructs show proof-of-concept beneficial effects in vivo.

Conclusions:

  • Significant advancements have been made in understanding and controlling FVIIa allostery.
  • Knowledge of FVIIa allosteric mechanisms enables precise modulation of coagulation.
  • Future research holds promise for developing advanced FVIIa-targeted therapies.