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Pathologic Shear and Elongation Rates Do Not Cause Cleavage of Von Willebrand Factor by ADAMTS13 in a Purified System

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Abstract

Introduction

Pathological flows in patients with severe aortic stenosis are associated with acquired von Willebrand syndrome. This syndrome is characterized by excessive cleavage of von Willebrand factor by its main protease, A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13 (ADAMTS13) leading to decreased VWF function and mucocutaneous bleeding. Aortic valve replacement and correction of the flow behavior to physiological levels reverses the syndrome, supporting the association between pathological flow and acquired von Willebrand syndrome. We investigated the effects of shear and elongational rates on von Willebrand factor cleavage in the presence of ADAMTS13.

Methods

We identified acquired von Willebrand syndrome in five patients with severe aortic stenosis. Doppler echography values from these patients were used to develop three computational fluid dynamic (CFD) aortic valve models (normal, mild and severe stenosis). Shear, elongational rates and exposure times identified in the CFD simulations were used as parameters for the design of microfluidic devices to test the effects of pathologic shear and elongational rates on the structure and function of von Willebrand factor.

Results

The shear rates (0–10,000s−1), elongational rates (0–1000 s−1) and exposure times (1–180 ms) tested in our microfluidic designs mimicked the flow features identified in patients with aortic stenosis. The shear and elongational rates tested in vitro did not lead to excessive cleavage or decreased function of von Willebrand factor in the presence of the protease.

Conclusions

High shear and elongational rates in the presence of ADAMTS13 are not sufficient for excessive cleavage of von Willebrand Factor.

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Funding

This work was supported in part by American Heart Association Pre-Doctoral Fellowship (18PRE33990253), the National Institutes of Health (R01 HL120728 and R01 HL141794) the National Science Foundation (1762705) and by an award from the American Heart Association (18CDA34110134).

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Author notes

  1. Maria Bortot and Alireza Sharifi have contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Maria Bortot, Katrina Ashworth, Faye Walker, Allaura Cox, Keith B. Neeves & David Bark Jr.

  2. Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Maria Bortot & Keith B. Neeves

  3. Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, 80523, USA

    Alireza Sharifi & David Bark Jr.

  4. Hemophilia Center, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Katherine Ruegg

  5. Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA

    Nathan Clendenen

  6. School of Biomedical Engineering, Colorado State University, Fort Collins, CO, 80523, USA

    David Bark Jr.

  7. Department of Pediatrics, Washington University in St. Louis, 660 S. Euclid Avenue, Campus Box 8208, 5th floor MPRB, St. Louis, MO, 63110, USA

    Jorge Di Paola

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  1. Maria Bortot
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  2. Alireza Sharifi
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Correspondence to Jorge Di Paola.

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Bortot, M., Sharifi, A., Ashworth, K. et al. Pathologic Shear and Elongation Rates Do Not Cause Cleavage of Von Willebrand Factor by ADAMTS13 in a Purified System. Cel. Mol. Bioeng. 13, 379–390 (2020). https://doi.org/10.1007/s12195-020-00631-2

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