SURFACE ENGINEERING IN CONTACT ACTIVATION OF COAGULATION

Project: Research project

Description

Activation of the blood plasma (a cellular) coagulation cascade by contact with materials is thought to be initiated by molecular assembly of the proteins of the activation complex directly onto procoagulant surfaces, leading to conversion of the zymogen Factor XII to the protease form FXIIa that desorbs into the solution phase. This mechanism is at odds with the experimental observation that the efficiency of contact activation is critically dependant on procoagulant surface energy in reverse order of protein adsorbent capacity, with very efficient activation for high-surface energy (water wettable) surfaces that are inefficient protein adsorbents and inefficient activation for intermediate- and low-energy (poorly water wettable) surfaces that are efficient adsorbents. Furthermore, it is difficult to rationalize from a surface energetic perspective how procoagulant surfaces can simultaneously serve as efficient FXII adsorbents (leading to molecular assembly on a surface) and inefficient FXIIa adsorbents (leading to release from a surface), especially in view of the relatively minor molecular difference between zymogen and protease forms. These and other discrepancies between proposed mechanism and experiment can be rationalized by an alternative hypothesis proposing that: Proteins of the contact activation complex assemble near procoagulant surfaces within a vicinal water region having special solvent properties that result from the hydration of high-energy surfaces. Self-amplifying zymogen-enzyme conversion occurs within this vicinal water zone, but not directly on surfaces, and propagates into the bulk plasma phase therefrom. Solvent properties of water near intermediate-to-low surface energy materials does not induce activation of FXII and adsorption directly onto these relatively hydrophobic surfaces does not potentiate the intrinsic pathway of the plasma coagulation cascade. The overarching objective of the work outlined within this application is to test the veracity of this proposition and underlying lemma with an eye to elucidating surface-engineering routes to materials with improved hemocompatibility for blood- contact applications. The proposed work is a balanced mix of biophysical and hematological approaches to a long-standing bioengineering problem that will relate surface thermodynamics of protein adsorption, surface-protein binding directly measured by AFM, and the procoagulant efficiency of surfaces variably bearing immobilized factors.
StatusFinished
Effective start/end date4/1/024/30/16

Funding

  • National Institutes of Health: $337,826.00
  • National Institutes of Health: $412,803.00
  • National Institutes of Health: $351,164.00
  • National Institutes of Health: $333,266.00
  • National Institutes of Health: $352,477.00
  • National Institutes of Health: $376,903.00
  • National Institutes of Health: $320,554.00
  • National Institutes of Health: $307,800.00
  • National Institutes of Health: $307,800.00
  • National Institutes of Health: $15,252.00
  • National Institutes of Health: $345,867.00
  • National Institutes of Health: $347,851.00
  • National Institutes of Health: $307,800.00

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Coagulation
Chemical activation
Blood
Plasmas
Enzyme Precursors
Adsorption
Adsorbents
Proteins
Interfacial energy
Biocompatible Materials
Membrane Proteins
Water
Biochemistry
Peptide Hydrolases
Bearings (structural)
Enzymes