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The Use of Synthetic Platelets to Augment Hemostasis

Shoffstall, Andrew J
http://rave.ohiolink.edu/etdc/view?acc_num=case1363775111

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Uncontrolled hemorrhage comprises 60-70% of trauma-associated mortality in the absence of other lethal conditions (e.g. damage to central nervous or cardiac system). Immediate intervention is critical to improving chances of survival. While there are several products to control bleeding for external wounds including pressure dressings, tourniquets or topical hemostatic agents there are few, if any, effective treatments that can be administered in the field to help staunch internal bleeding. Intravenous hemostatic nanoparticles that augment blood clotting when administered after trauma have been previously shown to half bleeding times in a femoral artery injury model in rats. The aims of the present study were to: 1) Determine their efficacy in a lethal hemorrhagic liver injury model, 2) determine the impact of targeting ligand concentration on hemostasis, and 3) test them in a clinically relevant porcine model of hemorrhage. Nanoparticle administration (GRGDS-NP1, 40 mg/kg) after lethal liver resection in the rat increased 1-hour survival to 80% compared to 40-47% in controls. Targeting ligand conjugation was then increased 100-fold (GRGDS-NP100), and a dosing study performed. GRGDS-NP100 hemostatic nanoparticles (2.5 mg/kg) were efficacious at doses 8-fold lower than GRGDS-NP1, and increased 1-hour survival to 92%. In vitro analysis using rotational thromboelastometry (ROTEM) confirmed the increased dose-sensitivity of GRGDS-NP100 and laid the foundation for methods to determine optimal ligand concentration parameters. Hemostatic nanoparticles were then tested in a clinically relevant porcine liver injury model, which elucidated an unexpected adverse reaction, comprised of a massive hemorrhagic response. A naive (uninjured) porcine model was then employed. These experiments revealed an adverse reaction consistent with complement activation related pseudoallergy (CARPA), which could be mediated by tuning nanoparticles’ zeta potential. Neutralizing the nanoparticle charge mitigated the onset of CARPA, while negative (-30 mV) or positive (+20 mV) zeta potential led to adverse CARPA symptoms (e.g., cardiopulmonary dysfunction with spontaneous recovery within minutes). While the sensitivity to CARPA is exaggerated in the pig model compared to humans, its consequences when triggered during hemorrhagic injury could be catastrophic in a subset of the population. Therefore, minimizing its risk will be paramount to the clinical translation of this technology.
Erin Lavik, Sc.D. (Committee Chair)
Jeffrey Ustin, M.D. (Committee Member)
Horst von Recum, Ph.D. (Committee Member)
Robert Miller, Ph.D. (Committee Member)
199 p.
Biomedical Engineering; Biomedical Research; Medicine
synthetic platelets; rgd; nanoparticles; nanomedicine; carpa; pseudoallergy; trauma; bleeding; hemostasis; hemostat; intravenous; nanospheres; plga; peg; liver injury; liver trauma; blunt trauma; porcine; swine; pig; survival; lethality; blood

Recommended Citations

Citations

  • Shoffstall, A. J. (2013). The Use of Synthetic Platelets to Augment Hemostasis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1363775111

    APA Style (7th edition)

  • Shoffstall, Andrew. The Use of Synthetic Platelets to Augment Hemostasis. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1363775111.

    MLA Style (8th edition)

  • Shoffstall, Andrew. "The Use of Synthetic Platelets to Augment Hemostasis." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1363775111

    Chicago Manual of Style (17th edition)

case1363775111
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© 2013, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.