SURFACE ENGINEERING IN CONTACT ACTIVATION OF COAGULATION

Summary

Principal Investigator: Christopher A Siedlecki
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2002-04-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Plasma coagulation response to surfaces with nanoscale chemical heterogeneity
    Rachel Miller
    Department of Surgery, Biomedical Engineering Institute, Pennsylvania State University College of Medicine, The Milton S Hershey Medical Center, H151, 500 University Drive, Hershey, PA 17033, USA
    Biomaterials 27:208-15. 2006
  2. pmc Contact activation of blood-plasma coagulation
    Erwin A Vogler
    Department of Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 30:1857-69. 2009
  3. pmc Atomic force microscopy studies of the initial interactions between fibrinogen and surfaces
    Li Chong Xu
    Hematology at Biomaterial Interfaces Research Group, Department of Surgery, The Pennsylvania State University, College of Medicine, Biomedical Engineering Institute, Hershey, Pennsylvania 17033, USA
    Langmuir 25:3675-81. 2009
  4. pmc Moderation of prekallkrein-factor XII interactions in surface activation of coagulation by protein-adsorption competition
    Kaushik Chatterjee
    Department of Bioengineering, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Biomaterials 30:4915-20. 2009
  5. pmc Volumetric interpretation of protein adsorption: kinetics of protein-adsorption competition from binary solution
    Naris Barnthip
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 30:6495-513. 2009
  6. pmc Volumetric interpretation of protein adsorption: capacity scaling with adsorbate molecular weight and adsorbent surface energy
    Purnendu Parhi
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 30:6814-24. 2009
  7. pmc Surface-energy dependent contact activation of blood factor XII
    Avantika Golas
    Department of Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 31:1068-79. 2010
  8. pmc Stability of aqueous films between bubbles. Part 2. Effects of trace impurities and evaporation
    Vassili V Yaminsky
    Ian Wark Research Institute, University of South Australia, Mawson Lakes, SA 5095, Australia
    Langmuir 26:8075-80. 2010
  9. pmc Stability of aqueous films between bubbles. Part 1. The effect of speed on bubble coalescence in purified water and simple electrolyte solutions
    Vassili V Yaminsky
    Ian Wark Research Institute, University of South Australia, Mawson Lakes, SA 5095, Australia
    Langmuir 26:8061-74. 2010
  10. pmc Volumetric interpretation of protein adsorption: interfacial packing of protein adsorbed to hydrophobic surfaces from surface-saturating solution concentrations
    Ping Kao
    Department of Electrical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 32:969-78. 2011

Detail Information

Publications32

  1. ncbi Plasma coagulation response to surfaces with nanoscale chemical heterogeneity
    Rachel Miller
    Department of Surgery, Biomedical Engineering Institute, Pennsylvania State University College of Medicine, The Milton S Hershey Medical Center, H151, 500 University Drive, Hershey, PA 17033, USA
    Biomaterials 27:208-15. 2006
    ....
  2. pmc Contact activation of blood-plasma coagulation
    Erwin A Vogler
    Department of Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 30:1857-69. 2009
    ....
  3. pmc Atomic force microscopy studies of the initial interactions between fibrinogen and surfaces
    Li Chong Xu
    Hematology at Biomaterial Interfaces Research Group, Department of Surgery, The Pennsylvania State University, College of Medicine, Biomedical Engineering Institute, Hershey, Pennsylvania 17033, USA
    Langmuir 25:3675-81. 2009
    ..The activation energies of protein unfolding derived from the data offer insight into the role of surface wettability in affecting adhesion, conformational changes, and ultimately, the activity of proteins at biomaterial surfaces...
  4. pmc Moderation of prekallkrein-factor XII interactions in surface activation of coagulation by protein-adsorption competition
    Kaushik Chatterjee
    Department of Bioengineering, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Biomaterials 30:4915-20. 2009
    ....
  5. pmc Volumetric interpretation of protein adsorption: kinetics of protein-adsorption competition from binary solution
    Naris Barnthip
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 30:6495-513. 2009
    ..Implications for understanding biocompatibility are discussed using a computational example relevant to the problem of blood-plasma coagulation...
  6. pmc Volumetric interpretation of protein adsorption: capacity scaling with adsorbate molecular weight and adsorbent surface energy
    Purnendu Parhi
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 30:6814-24. 2009
    ..Overall, results are consistent with the idea that protein adsorption is primarily controlled by water/surface interactions...
  7. pmc Surface-energy dependent contact activation of blood factor XII
    Avantika Golas
    Department of Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 31:1068-79. 2010
    ..Results are interpreted within the context of blood plasma coagulation and the role of water and proteins at procoagulant surfaces...
  8. pmc Stability of aqueous films between bubbles. Part 2. Effects of trace impurities and evaporation
    Vassili V Yaminsky
    Ian Wark Research Institute, University of South Australia, Mawson Lakes, SA 5095, Australia
    Langmuir 26:8075-80. 2010
    ..We discuss surface tension gradients in transient films created by temperature differences, impurity concentration, and expansion of the films...
  9. pmc Stability of aqueous films between bubbles. Part 1. The effect of speed on bubble coalescence in purified water and simple electrolyte solutions
    Vassili V Yaminsky
    Ian Wark Research Institute, University of South Australia, Mawson Lakes, SA 5095, Australia
    Langmuir 26:8061-74. 2010
    ..This work highlights the significance of bubble approach speed as well as electrolyte concentration in affecting bubble coalescence...
  10. pmc Volumetric interpretation of protein adsorption: interfacial packing of protein adsorbed to hydrophobic surfaces from surface-saturating solution concentrations
    Ping Kao
    Department of Electrical Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 32:969-78. 2011
    ....
  11. pmc The Goldilocks surface
    Erwin A Vogler
    Departments of Materials Science and Engineering and Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 32:6670-5. 2011
    ..3 kJ/mole-of-surface-sites is expended in wetting hydrophobic surfaces; hydrophilic surfaces wet with >1 hydrogen bond per water molecule whereas hydrophobic surfaces wet with <1 hydrogen bond per water molecule...
  12. pmc Amidolytic, procoagulant, and activation-suppressing proteins produced by contact activation of blood factor XII in buffer solution
    Avantika Golas
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 32:9747-57. 2011
    ..Suppression proteins may be responsible for the experimentally-observed autoinhibition of the autoactivation reaction...
  13. pmc Contact activation of blood plasma and factor XII by ion-exchange resins
    Chyi Huey Josh Yeh
    Departments of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 33:9-19. 2012
    ..The principal role is impeding FXII contact with activating surfaces, but this same effect can displace FXIIa from an activating surface into solution where the protease can potentiate subsequent steps of the plasma coagulation cascade...
  14. pmc Protein adsorption in three dimensions
    Erwin A Vogler
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 33:1201-37. 2012
    ....
  15. pmc A comparison of blood factor XII autoactivation in buffer, protein cocktail, serum, and plasma solutions
    Avantika Golas
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 34:607-20. 2013
    ..Results of this study strongly suggest that activator surface-area dependence observed in contact activation of plasma coagulation does not solely arise at the FXII activation step of the intrinsic pathway...
  16. pmc Superhydrophobic effect on the adsorption of human serum albumin
    Evan S Leibner
    Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
    Acta Biomater 5:1389-98. 2009
    ..This observation implies that measurement of protein bound after surface rinsing significantly underestimates the actual amount of protein concentrated by adsorption into the surface region of a protein-contacting material...
  17. pmc Contributions of contact activation pathways of coagulation factor XII in plasma
    Kaushik Chatterjee
    Department of Bioengineering, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biomed Mater Res A 90:27-34. 2009
    ..Results further suggest that reciprocal-activation occurs in proportion to the amount of FXIIa produced by the initiating autoactivation step...
  18. ncbi Mathematical modeling of material-induced blood plasma coagulation
    Zhe Guo
    Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Biomaterials 27:796-806. 2006
    ..FXIIa-induced self-amplification of FXII is insignificant...
  19. ncbi Interfacial energetics of blood plasma and serum adsorption to a hydrophobic self-assembled monolayer surface
    Anandi Krishnan
    Department of Bioengineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 27:3187-94. 2006
    ..Any single blood protein or mixture of proteins consequently displaces nearly an equivalent amount of interfacial water and hence adsorption is observed to scale similarly with solution concentration expressed in w/v units...
  20. ncbi Interfacial rheology of blood proteins adsorbed to the aqueous-buffer/air interface
    Florly S Ariola
    Integrative Biosciences Graduate Program, Huck Institutes for Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 27:3404-12. 2006
    ..By contrast to purified-protein solutions, serially diluted human blood serum shows no resolvable concentration-dependent G(')and G('')...
  21. ncbi Autoactivation of blood factor XII at hydrophilic and hydrophobic surfaces
    Rui Zhuo
    Department of Bioengineering, Pennsylvania State University College of Medicine, University Park, PA 16802, USA
    Biomaterials 27:4325-32. 2006
    ....
  22. ncbi Practical application of a chromogenic FXIIa assay
    Rui Zhuo
    Department of Bioengineering, University Park, PA 16802, USA
    Biomaterials 27:4840-5. 2006
    ..Autohydrolysis can be used as a means of amplifying FXIIa produced by contacting neat-buffer solutions of FXII with biomaterials, suggesting a route to highly sensitive measurement of biomaterial hemocompatibility...
  23. ncbi Procoagulant activity of surface-immobilized Hageman factor
    Kaushik Chatterjee
    Department of Bioengineering, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Biomaterials 27:5643-50. 2006
    ..The uninfluential role of the surface on FXIIa suggests that the solid surface activates FXII in biomaterial-induced blood coagulation but is not otherwise involved in FXIIa activity as described by the classical mechanism...
  24. ncbi Volumetric interpretation of protein adsorption: Partition coefficients, interphase volumes, and free energies of adsorption to hydrophobic surfaces
    Hyeran Noh
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 27:5780-93. 2006
    ..Proteins with molecular weight MW<100kDa occupy a single layer at surface saturation whereas the larger proteins IgG and fibrinogen required two layers...
  25. ncbi Volumetric interpretation of protein adsorption: mass and energy balance for albumin adsorption to particulate adsorbents with incrementally increasing hydrophilicity
    Hyeran Noh
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 27:5801-12. 2006
    ....
  26. pmc Volumetric interpretation of protein adsorption: competition from mixtures and the Vroman effect
    Hyeran Noh
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 28:405-22. 2007
    ..Theory is extended to hypothetical ternary mixtures using a computational experiment that illustrates the profound impact size-discrimination has on adsorption from complex mixtures such as blood...
  27. pmc Effects of surface wettability and contact time on protein adhesion to biomaterial surfaces
    Li Chong Xu
    Department of Surgery, Biomedical Engineering Institute, The Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA
    Biomaterials 28:3273-83. 2007
    ..Time-dependent changes in adhesion force were used to calculate unfolding energies relating to protein-surface interactions. This analysis provides justification for a 2-step model of protein denaturation on surfaces...
  28. pmc Competitive-protein adsorption in contact activation of blood factor XII
    Rui Zhuo
    Department of Bioengineering, University Park, PA 16802, USA
    Biomaterials 28:4355-69. 2007
    ..FXII adsorption competition with other proteins in the fluid phase is proposed to affect the balance of activation and autoinhibition, leading to the observed moderation of FXIIa yield...
  29. ncbi Interfacial energetics of protein adsorption from aqueous buffer to surfaces with varying hydrophilicity
    Paul Cha
    Department of Materials Science, Materials Research Institute, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Langmuir 24:2553-63. 2008
    ....
  30. pmc Volumetric interpretation of protein adsorption: ion-exchange adsorbent capacity, protein pI, and interaction energetics
    Hyeran Noh
    Department of Materials Science and Engineering, Huck Institute of Life Sciences and Materials Research Institute, The Pennsylvania State University, University Park, PA 16802, USA
    Biomaterials 29:2033-48. 2008
    ....
  31. pmc Volumetric interpretation of protein adsorption: kinetic consequences of a slowly-concentrating interphase
    Naris Barnthip
    Department of Materials Science and Engineering, The Pennsylvania State University, University Park, PA 16802, United States
    Biomaterials 29:3062-74. 2008
    ..Implications of the alternative interpretation of adsorption kinetics on biomaterials and biocompatibility are discussed...
  32. ncbi Electrophoretic implementation of the solution-depletion method for measuring protein adsorption, adsorption kinetics, and adsorption competition among multiple proteins in solution
    Hyeran Noh
    Department of Optometry and Vision Science, Seoul National University and Technology, Seoul, South Korea
    Methods Mol Biol 1025:157-66. 2013
    ..Electrophoretic separation enables quantification of adsorption competition among multiple proteins in solution for the same adsorbent surface, demonstrated herein by adsorption--competition kinetics from binary solution. ..

Research Grants31

  1. Dopamine and Angiotensin Receptor Interactions in Genetic Hypertension
    Robin A Felder; Fiscal Year: 2013
    ..abstract_text> ..
  2. Chemistry and Biology of Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013
    ..This program seeks to develop new information by which key reactions of blood clotting are regulated. This information will lead to new concepts and strategies for the treatment of blood clotting-related human disease. ..
  3. MULTI-SCALE MODEL OF THORMBOSIS IN ARTIFICIAL CIRCULATION
    James F Antaki; Fiscal Year: 2013
    ..The purpose of this project is to create a computer simulation program that will predict when this might occur, and thereby guide developers of these devices to produce more safe and effective devices. ..
  4. Mechanism of Thrombosis in Heparin Induced Thrombocytopenia
    RAJ SUNDAR KASTHURI; Fiscal Year: 2013
    ..The goal of this application is to understand the reason for this complication so that it can be prevented. This could result in significant benefit to both patients and the healthcare system. ..
  5. Molecular Basis for Nonadhesive Properties of Fibrinogen Matrices
    Tatiana P Ugarova; Fiscal Year: 2013
    ..This knowledge should be translatable into the design of better vascular grafts. ..
  6. Novel Surfaces for Enriching Epithelial Cells: A Breastmilk Model
    Maria M Santore; Fiscal Year: 2013
    ....
  7. Mechanisms Underlying Chronic Lung Pathology
    Wayne Mitzner; Fiscal Year: 2013
    ..This tightly integrated, synergistic program will thereby provide new insights into the mechanisms that underlie the pathogenic progression of chronic lung diseases. ..
  8. Structure and Function of Protein-Membrane Interactions in Blood Clotting
    Chad M Rienstra; Fiscal Year: 2013
    ..These studies will shed new light on the regulation of the blood clotting system, with a particular focus on achieving a detailed understanding of how and why blood clotting reactions occur on membrane surfaces. ..
  9. Simultaneous Time-Resolved X-ray Spectroscopy and Crystallography: A Mechanistic
    Rosalie Tran; Fiscal Year: 2013
    ..abstract_text> ..
  10. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  11. Protein Dynamics in Enzymatic Catalysis
    Robert Callender; Fiscal Year: 2013
    ..The Equipment Core (Core A) supports the specialized comprehensive suite of instrumentation for the Program. The Administrative Core (Core B) administers the Program Project. ..
  12. Proteinase Allostery and the Regulation of Blood Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013
    ..Our findings have the potential to reveal new strategies for therapeutic targeting of this enzyme in thrombotic and vascular disease. ..