Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition.
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 micrometer2. The hypercoagulable phenotype can be induced in younger chimeric mice by exposure to hypoxia, which causes a fivefold increase in beta-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.
Healy
A M
AM
The Pulmonary Center, Boston University School of Medicine; the Department of Pathology, Harvard Medical School, Boston, MA, USA. ahealy@bupula.bu.edu
Hancock
W W
WW
Christie
P D
PD
Rayburn
H B
HB
Rosenberg
R D
RD
D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D004903:Erythrocyte Aggregation / Q000473:pathology* / Q000503:physiopathology*; D005337:Fibrin / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018180:Thrombomodulin / Q000172:deficiency* / Q000235:genetics
D018180:Thrombomodulin; D005337:Fibrin