inhibition under flow SHANNON BRIDE AND JAYDE THOMPSON February 2 nd - - PowerPoint PPT Presentation

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inhibition under flow SHANNON BRIDE AND JAYDE THOMPSON February 2 nd - - PowerPoint PPT Presentation

Jan 01, 2024 98 likes •295 views

A mathematical model of surface-mediated enzyme inhibition under flow SHANNON BRIDE AND JAYDE THOMPSON February 2 nd , 2020 Blood coagulation is a complex system System of chemical reactions required to form a clot, which prevents bleeding

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A mathematical model of surface-mediated enzyme inhibition under flow

SHANNON BRIDE AND JAYDE THOMPSON February 2nd, 2020

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Blood coagulation is a complex system

System of chemical reactions required to form a clot, which prevents bleeding Goal is to prevent bleeding but not

  • ver clot

System in balance

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System in balance

Procoagulant components enzymes, platelets Anticoagulant components inhibitors What is flow? Procoagulant or anticoagulant?

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One inhibitor under flow: TFPI

TFPI is an inhibitor of the initiation of clotting Most studies done under static conditions Math model of small injury under flow indicated TFPI is not effective What is the role of TFPI under flow?

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TF:VIIa TF:VIIa TF:VIIa TF TF TF VIIa

  • Injury exposes TF to the blood
  • Clotting factor VIIa binds to TF

Key: TF: Tissue Factor, VIIa: Activated factor VIIa

The initiation of coagulation: Step 1

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TF:VIIa TF:VIIa X X X:TF:VIIa TF:VIIa TF:VIIa Xa

The initiation of coagulation: Step 2

  • Clotting factor X binds TF:VIIa
  • TF:VIIa activates factor X
  • Activated factor Xa is a

necessary enzyme for clotting

Key: X: inactive factor X, Xa: active factor X

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TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TFPI Xa TFPI TFPI Xa:TFPI TFPI Xa

The inhibition of initiation: TFPI and Xa

Key: Xa: active factor X, TFPI: Tissue Factor Pathway Inhibitor

  • TFPI can directly inhibit Xa by binding in the bloodstream
  • This reaction is reversible
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TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TFPI Xa TFPI TFPI Xa:TFPI TF:VIIa:Xa:TFPI X

The inhibition of initiation: Xa:TFPI and TF:VIIa

Key: X: inactive factor X, Xa: active factor X, TFPI: Tissue Factor Pathway Inhibitor

  • The complex Xa:TFPI can rebind TF:VIIa and prevent further production of Xa
  • This is negative feedback
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TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa TF:VIIa Xa TFPI Xa:TFPI TF:VIIa:Xa:TFPI X X

Does TFPI effectiveness depend on injury size?

  • This is negative feedback takes time and space to occur
  • This could impact the effectiveness of TFPI
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X, Xa, TFPI, and Xa:TFPI are species within the fluid modeled with ADR TF:VIIa, X:TF:VIIa, and TF:VIIa:Xa:TFPI are species bound to the wall Fluid and wall bound species interact through binding reactions via boundary conditions

Advection Diffusion Reaction Model

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Examples of PDEs

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Testing TFPI effectiveness

We will use the Advection-Diffusion-Reaction model while varying Initial condition of TFPI Patch lengths of exposed TF:VIIa Flow rate We will monitor production of Xa by monitoring X:TF:VIIa

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Initial condition of TFPI

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Patch Length of Exposed TF:VIIa

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Flow Rates

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Conclusion and Future Work

TFPI effectiveness is dependent on: Initial condition of TFPI Patch length of TF:VIIa Flow rate Continuing the investigation: Add reactions to model

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Acknowledgements

  • Dr. Karin Leiderman for leading the project
  • Dr. Nicholas Danes for mentoring along the way

Colorado School of Mines Applied Mathematics Department

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Questions?