Functional thrombomodulin deficiency causes enhanced thrombus growth in a murine model of carotid artery thrombosis

Thrombomodulin (TM) bound thrombin initiates the protein C anticoagulant pathway and defects in TM result in enhanced coagulation. Recent studies suggest a role for TM in arterial vascular disease. In order to corroborate this association we studied arterial thrombus formation in mice with a functional TM defect. We used mice homozygous for a ⁴⁰⁴Glu-to-Pro mutation in the TM gene (TM^pro/pro) and compared these with wildtype littermates in a model of FeCl₃ induced carotid artery thrombosis. Time-to-occlusion (TTO) was assessed by arterial blood flow measurement, using a Doppler flow probe. Complete occlusion occurred in 8/10 (80%) TM^pro/pro mice and in 3/11 (27%) littermate controls. Mean time to occlusion (TTO) [± SE] was 767 ± 196 s in the F2-TM^pro/pro mice, versus 1507 ± 159 s in controls (p = 0.007, Mann Whitney U test). Histology and immunostaining for tissue factor did not reveal any differences in thrombus morphology or thrombogenicity between the two groups. These data confirm and extend the finding that a functional deficiency in TM results in enhanced thrombus formation in a muriae model of carotid artery thrombosis and support a role for TM defects in arterial thrombotic disease.