Thrombosis remains a significant barrier to the use of blood contacting medical devices for treatment of disease. Contact activation of blood plasma coagulation occurs via interactions between material surfaces and proteins of the contact activation complex. Recent results show that the prevailing mechanistic model of contact activation is inconsistent with measured adsorption properties of blood proteins and fails to account for relationships among activator surface properties, production of enzyme intermediates, and time to plasma coagulation in vitro. This work has identified key problems to be solved in order to propose a revised scheme for surface activation of plasma coagulation, with work proposed guided by this central hypothesis. Blood plasma coagulation is initiated by contact with material surfaces through a complex surface-catalyzed activation reaction that rapidly converts the zymogen FXII into a distribution of activated fragments exhibiting procoagulant and/or ordinary amidolytic activity. The distribution of fragments depends on activator surface chemistry and nanoscopic distribution of that chemistry. Procoagulant fragments stimulate proportional activation of subsequent steps of the intrinsic pathway, ultimately leading to proportional production of thrombin in the penultimate step of the coagulation cascade. This hypothesis differs from the conventional paradigm of material-induced blood coagulation in that it envisions contact activation as a non-specific, surface-induced event producing a variety of FXII activation products, some of which are capable of inducing coagulation. Furthermore, the hypothesis states that propagation of the cascade occurs through a series of self-limiting reactions. The hypothesis will be tested through four specific aims that utilize biochemical and surface analysis methods to quantify the amount and activity of FXII fragments formed by blood-surface contact. Results will be used to develop new materials with sub-micron spatially distributed chemistries and for which there is evidence improved hemocompatibility compared to materials having chemistries distributed at the macro scale. Prospectively designed biomaterials have been a long-sought objective of the biomaterials community and represent a new-generation of synthetic, hemocompatible materials for medical devices.

Public Health Relevance

The formation of blood clots on biomaterials used in medical devices is a significant problem in diagnosis and treatment of disease. The reasons behind clot formation are unclear, and the current description of blood clot formation seemingly contradicts what is already known about how blood interacts with materials. This proposal seeks to understand the reasons for clot formation on materials by identifying how blood components change after contact with materials, and then to use that information to design new materials intended to interact with blood.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Link, Rebecca P
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Pennsylvania State University
Schools of Medicine
United States
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Xu, Li-Chong; Wo, Yaqi; Meyerhoff, Mark E et al. (2017) Inhibition of bacterial adhesion and biofilm formation by dual functional textured and nitric oxide releasing surfaces. Acta Biomater 51:53-65
Bauer, James W; Xu, Li-Chong; Vogler, Erwin A et al. (2017) Surface dependent contact activation of factor XII and blood plasma coagulation induced by mixed thiol surfaces. Biointerphases 12:02D410
Golas, Avantika; Pitakjakpipop, Harit; Rahn, Matthew S et al. (2015) Enzymes produced by autoactivation of blood factor XII in buffer: A contribution from the Hematology at Biomaterial Interfaces Research Group. Biomaterials 37:1-12
Xu, Li-Chong; Bauer, James W; Siedlecki, Christopher A (2014) Proteins, platelets, and blood coagulation at biomaterial interfaces. Colloids Surf B Biointerfaces 124:49-68
Golas, Avantika; Yeh, Chyi-Huey Josh; Pitakjakpipop, Harit et al. (2013) A comparison of blood factor XII autoactivation in buffer, protein cocktail, serum, and plasma solutions. Biomaterials 34:607-20
Krishnan, Anandi; Vogler, Erwin A; Sullenger, Bruce A et al. (2013) The effect of surface contact activation and temperature on plasma coagulation with an RNA aptamer directed against factor IXa. J Thromb Thrombolysis 35:48-56
Noh, Hyeran; Barnthip, Naris; Parhi, Purnendu et al. (2013) Electrophoretic implementation of the solution-depletion method for measuring protein adsorption, adsorption kinetics, and adsorption competition among multiple proteins in solution. Methods Mol Biol 1025:157-66
Josh Yeh, Chyi-Huey; Dimachkie, Ziad O; Golas, Avantika et al. (2012) Contact activation of blood plasma and factor XII by ion-exchange resins. Biomaterials 33:9-19
Vogler, Erwin A (2012) Protein adsorption in three dimensions. Biomaterials 33:1201-37
Golas, Avantika; Yeh, Chyi-Huey Joshua; Siedlecki, Christopher A et al. (2011) Amidolytic, procoagulant, and activation-suppressing proteins produced by contact activation of blood factor XII in buffer solution. Biomaterials 32:9747-57

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