Contact Activation of Human Plasma Coagulation
Open Access
- Author:
- Zhuo, Rui
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 02, 2006
- Committee Members:
- Erwin A Vogler, Committee Chair/Co-Chair
William O Hancock, Committee Member
Christopher Alan Siedlecki, Committee Member
James Patrick Runt, Committee Member - Keywords:
- coagulation
FXII
Thrombin
Blood - Abstract:
- Development of fully hemocompatible materials remains a substantially unrealized objective of applied biomaterials. Unfavorable cell-and-protein interactions with biomaterial surfaces that lead to thrombus formation are major obstacles that modern surface engineering seeks to overcome. Future advances in the surface-engineering of blood-contacting biomaterials are critically dependent on a detailed understanding of how blood interacts with artificial materials at a molecular level. Research summarized in this thesis is aimed at such a molecular understanding and seeks to establish structure-property relationships linking material characteristics such as surface chemistry/energy with the propensity to activate blood coagulation. Blood-plasma coagulation occurs through a series of linked zymogen-enzyme conversions collectively known as the plasma coagulation cascade. The so-called intrinsic pathway of this cascade becomes activated when plasma contacts artificial material surfaces. As a consequence, all known cardiovascular biomaterials activate blood coagulation to a measurable extent. Previous research (corroborated by this thesis work) demonstrated that the propensity to activate plasma coagulation scales as an exponential-like function of surface energy, with low catalytic potential observed for hydrophobic (poorly water wettable, low surface energy) materials and much higher activation for hydrophilic (fully water wettable, high surface energy) materials. This thesis work further shows that the relationship between surface energy and contact activation holds only in the presence of plasma proteins, providing an important insight into the biochemical mechanism of plasma coagulation. Blood factor XII (FXII, Hageman factor) is central to contact activation. The intrinsic pathway of coagulation is potentiated by conversion of the zymogen FXII into the enzyme form, FXIIa, through a surface-mediated reaction termed autoactivation. It is shown herein that autoactivation occurs with equal efficiency at hydrophilic and hydrophobic surfaces in neat-buffer solution but that autoactivation rate and yield is substantially attenuated at hydrophobic surfaces in the presence of plasma proteins. Thus it is concluded that FXII activation in the presence of plasma proteins leads to an apparent specificity for hydrophilic surfaces that is actually due to a relative diminution of the FXIIFXIIa reaction at hydrophobic surfaces. It is further concluded that contact activation of blood FXII in neat-buffer solution is not specific for anionic hydrophilic procoagulants as proposed by the accepted biochemistry of surface activation. These findings may lead to a new paradigm for the interpretation of hemocompatibility that can guide development of advanced hemocompatible biomaterials.