Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction

Authors:
  • AFA. Fernandes
    A. Fernandes
  • BKB. Kehrle
    B. Kehrle
  • BPB. Pedersen
    B. Pedersen
  • GPG. Parry
    G. Parry
  • JEJ. Erlich
    J. Erlich
  • RPR. Pyo
    R. Pyo
  • DGD. Gutstein
    D. Gutstein
  • JZJ. Zhang
    J. Zhang
  • FCF. Castellino
    F. Castellino
  • EME. Melis
    E. Melis
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Abstract
Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that mice expressing low levels of human TF (≈1% of wild-type levels) in an mTF−/− background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a selective heart defect that consisted of hemosiderin deposition and fibrosis. Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left ventricular function in 8-month-old low-TF mice compared with age-matched wild-type mice. Mice expressing low levels of murine FVII (≈1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, FIX−/− mice, a model of hemophilia B, had normal hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.

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