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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4188-4197
Intravascular Coagulation Activation in a Murine Model of
Thrombomodulin Deficiency: Effects of Lesion Size, Age, and Hypoxia on
Fibrin Deposition
Aileen M. Healy,
Wayne W. Hancock,
Patricia D. Christie,
Helen B. Rayburn, and
Robert D. Rosenberg
From The Pulmonary Center, Boston University School of Medicine; the
Department of Pathology, Harvard Medical School, Boston, MA; and the
Department of Biology, Massachusetts Institute of Technology,
Cambridge, MA.
We consecutively inactivated both alleles of the thrombomodulin (TM)
gene in murine embryonic stem (ES) cells and generated TM-deficient
(TM /) chimeric mice. Quantitation of an ES-cell
marker and protein C cofactor activity indicates that up to 50% of
pulmonary endothelial cells are ES-cell derived and therefore TM
deficient. Infusions of 125I-fibrinogen into mice show a
significant increase (fourfold, P < .005) in radiolabeled
cross-linked fibrin in TM/ chimeric mouse lung as
compared with wild-type mice. However, only chimeric mice that exhibit
at least a 30% reduction in protein C cofactor activity and are at
least 15 months old display this phenotype. Immunocytochemical
localization of TM in chimeras shows a mosaic pattern of expression in
both large and small blood vessels. Colocalization of cross-linked
fibrin and neo (used to replace TM) reveals that fibrin is deposited in
TM/ regions. However, the fibrin deposits were
largely restricted to pulmonary vessels with a lumenal area greater
than 100 µm2. The hypercoagulable phenotype can be
induced in younger chimeric mice by exposure to hypoxia, which causes a
fivefold increase in  -fibrin levels in lung. Our findings show that
TM chimerism results in spontaneous, intravascular fibrin deposition
that is dependent on age and the magnitude of the TM deficiency.
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