Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro

Karla P Mercado-Shekhar; Robert T Kleven; Hermes Aponte Rivera; Ryden Lewis; Kunal B Karani; Hendrik J Vos; Todd A Abruzzo; Kevin J Haworth; Christy K Holland

doi:10.1016/j.ultrasmedbio.2018.08.005

Effect of Clot Stiffness on Recombinant Tissue Plasminogen Activator Lytic Susceptibility in Vitro

Ultrasound Med Biol. 2018 Dec;44(12):2710-2727. doi: 10.1016/j.ultrasmedbio.2018.08.005. Epub 2018 Sep 26.

Authors

Karla P Mercado-Shekhar¹, Robert T Kleven², Hermes Aponte Rivera³, Ryden Lewis³, Kunal B Karani³, Hendrik J Vos⁴, Todd A Abruzzo⁵, Kevin J Haworth⁶, Christy K Holland⁶

Affiliations

¹ Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA. Electronic address: mercadka@ucmail.uc.edu.
² Department of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, USA.
³ Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
⁴ Department of Biomedical Engineering, Erasmus Medical Center, Rotterdam, The Netherlands.
⁵ Department of Radiology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
⁶ Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, Ohio, USA.

Abstract

The lytic recombinant tissue plasminogen activator (rt-PA) is the only drug approved by the Food and Drug Administration for treating ischemic stroke. Less than 40% of patients with large vessel occlusions who are treated with rt-PA have improved blood flow. However, up to 6% of all patients receiving rt-PA develop intracerebral hemorrhage. Predicting the efficacy of rt-PA treatment a priori could help guide therapeutic decision making, such that rt-PA is administered only to those individuals who would benefit from this treatment. Clot composition and structure affect the lytic efficacy of rt-PA and have an impact on elasticity. However, the relationship between clot elasticity and rt-PA lytic susceptibility has not been adequately investigated. The goal of this study was to quantify the relationship between clot elasticity and rt-PA susceptibility in vitro. Human and porcine highly retracted and mildly retracted clots were fabricated in glass pipettes. The rt-PA lytic susceptibility was evaluated in vitro using the percent clot mass loss. The Young's moduli of the clots were estimated using ultrasound-based single-track-location shear wave elasticity imaging. The percent mass loss in mildly retracted porcine and human clots (28.9 ± 6.1% and 45.2 ± 7.1%, respectively) was significantly higher (p < 0.05) than in highly retracted porcine and human clots (10.9 ± 2.1% and 25.5 ± 10.0%, respectively). Furthermore, the Young's moduli of highly retracted porcine and human clots (5.33 ± 0.92 and 3.21 ± 1.97 kPa, respectively) were significantly higher (p < 0.05) than those of mildly retracted porcine and human clots (2.66 ± 0.55 and 0.79 ± 0.21 kPa, respectively). The results revealed an inverse relationship between the percent clot mass loss and Young's modulus. These findings motivate continued investigation of ultrasound-based methods to assess clot stiffness in order to predict rt-PA thrombolytic efficacy.

Keywords: Clot composition; Clot stiffness; Lytic efficacy; Recombinant tissue plasminogen activator; Shear wave imaging; Ultrasound elastography.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Elasticity Imaging Techniques / methods*
Humans
In Vitro Techniques
Models, Animal
Phantoms, Imaging
Reference Values
Swine
Thrombosis / drug therapy*
Tissue Plasminogen Activator / pharmacology*

Substances

Tissue Plasminogen Activator

Grants and funding

R01 NS047603/NS/NINDS NIH HHS/United States