Physiological Implications for Murine Deficiencies of Key Proteins of the Coagulation Cascade

Master's Thesis


Deficiencies of key proteins of the coagulation cascade have a measurable impact in haemostasis when murine models are used. In our studies, these models allow us to study the implications of factor XI (FXI)-/-, factor XII (FXII)-/-, FXI-/-/ FXII-/-, very low-expressing factor VII (FVIItTA/tTA), fibrinogen (Fg)-/-, and protein C (PC)+/- mice in biological systems other than coagulation. These systems include inflammation and the resulting tissue modifications from such process. All of the murine models used in these studies exhibit extended life spans and do not develop the life threatening conditions seen in other murine deficiencies. Most of these deficient mice slowly develop pathologies and abnormalities caused by the partial or total lack of the coagulation protein. Occasionally a phenotype with no obvious compromises is seen under resting conditions, however, the deficiencies become very obvious after inflammatory or vascular challenge when compared to the responses observed in wild type (WT) mice. Evaluation of spontaneous and induced phenotypes of mice deficient in proteins from the contact system, reveal evidence implicating FXI and potentially FXII in the regulation of the normal inflammatory response. This response was evident in unchallenged FXI-/-mice and becomes more conspicuous after arterial oxidative challenge when a silicon-copper cuff is used (copper-based oxidative challenge). Potential implications of the contact system in the regulation of inflammation are observed by exacerbated counts of granulocytes in the blood of FXI and FXII double deficient mice. Similarly, a low expression of FVII in mice of the same genetic background produces an inflammatory response that results in spontaneous left ventricular fibrosis. This phenomenon seems to be caused by an angiogenesis-driven cardiomyocyte degeneration. This abnormality in endothelial cell behavior was only seen in mice with compromised tissue factor (TF)/FVIIa complex levels. The direct impact of the deficiency of Fg in haemostasis is frequently observed by clot instability if examined by transluminescent video microscopy and extension of coagulation times in Fg-specific, PT, and aPTT tests. However, cellular and structural differences are apparent when clots are studied at an ultrastructural level. Detailed differences that impact the size and stability of the clot, as well as the degree of platelet activation, become evident in electron micrographs of platelet clots in the absence of Fg. The impact of the anticoagulant PC on the regulation of thrombin-dependant angiogenesis and inflammation in mice exposed to copper-based oxidative arterial challenge was evaluated. A partial deficiency of normal PC levels (≈60% of WT) supports a normal development and viability in PC+/- mice. Nevertheless, these levels in PC+/- mice are enough to cause significant phenotypical differences upon copper-based oxidative challenge. Characterization of each one of these deficiencies under resting or challenging conditions reveal the extent of their effects on coagulation and, when also studied, in inflammation. Such effects often involve implications beyond the thrombin and/or fibrin-dependent induced cell behavior or inflammatory changes. These models for murine deficiencies disclose new or understudied potential interactions of each one of these proteins with other biological systems.


Attribute NameValues
  • etd-04142011-172142

Author Francisco A Noria
Advisor Dr. Thomas Nowak
Contributor Dr. Kristin Hager, Committee Member
Contributor Dr. Thomas Nowak, Committee Member
Degree Level Master's Thesis
Degree Discipline Chemistry and Biochemistry
Degree Name MS
Defense Date
  • 2011-04-14

Submission Date 2011-04-14
  • United States of America

  • factor VII

  • fibrinogen deficient mice

  • coagulation

  • FXI-/- mice

  • factor XI

  • University of Notre Dame

  • English

Record Visibility Public
Content License
  • All rights reserved

Departments and Units


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