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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3442-3450
Structure-Function Analyses of Thrombomodulin by Gene-Targeting in
Mice: The Cytoplasmic Domain Is Not Required for Normal Fetal
Development
Edward M. Conway,
Saskia Pollefeyt,
Jan Cornelissen,
Inky DeBaere,
Marta Steiner-Mosonyi,
Jeffrey I. Weitz,
Hartmut Weiler-Guettler,
Peter Carmeliet, and
Désiré Collen
From the Center for Transgene Technology and Gene Therapy, Flanders
Interuniversity Institute for Biotechnology, University of Leuven,
Leuven, Belgium; The Blood Center for Southeastern Wisconsin,
Milwaukee, WI; the Hamilton Civic Hospital Research Center, Hamilton,
Ontario, Canada; and The Toronto Hospital and Department of Medicine,
University of Toronto, Toronto, Ontario, Canada.
Thrombomodulin (TM) is a widely expressed glycoprotein receptor that
plays a physiologically important role in maintaining normal hemostatic
balance postnatally. Inactivation of the TM gene in mice
results in embryonic lethality without thrombosis, suggesting that
structures of TM not recognized to be involved in coagulation might be
critical for normal fetal development. Therefore, the in vivo role of
the cytoplasmic domain of TM was studied by using homologous
recombination in ES cells to create mice that lack this region of TM
(TMcyt/cyt). Cross-breeding of F1 TMwt/cyt mice
(1 wild-type and 1 mutant allele) resulted in more than 300 healthy
offspring with a normal Mendelian inheritance pattern of 25.7%
TMwt/wt, 46.6% TMwt/cyt, and 27.7%
TMcyt/cyt mice, indicating that the tail of TM is not
necessary for normal fetal development. Phenotypic analyses showed that
the TMcyt/cyt mice responded identically to their wild-type
littermates after procoagulant, proinflammatory, and skin wound
challenges. Plasma levels of plasminogen, plasminogen activator
inhibitor 1 (PAI-1), and  2-antiplasmin were
unaltered, but plasmin:2-antiplasmin (PAP) levels were
significantly lower in TMcyt/cyt mice than in
TMwt/wt mice (0.46 ± 0.2 and 1.99 ± 0.1 ng/mL,
respectively; P < .001). Tissue levels of TM antigen were
also unaffected. However, functional levels of plasma TM in the
TMcyt/cyt mice, as measured by thrombin-dependent
activation of protein C, were significantly increased (P < .001). This supported the hypothesis that suppression in PAP levels may
be due to augmented activation of thrombin-activatable fibrinolysis
inhibitor (TAFI), with resultant inhibition of plasmin generation. In
conclusion, these studies exclude the cytoplasmic domain of TM from
playing a role in the early embryonic lethality of TM-null mice
and support its function in regulating plasmin generation in plasma.
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