Animal, Cellular & Molecular Models
July 18, 2002
13:00 to 17:00
Stanbro Room
Boston Park Plaza Hotel
Chairman: P. Carmeliet, Belgium
Co-chairs: L. Drouet, France; P. Jagadeeswaran, USA; G. Johnson,
USA; N. Maeda, USA
Business: The meeting was chaired by Subcommittee CoChairs, G. Johnson
and P. Jagadeeswaran. It was attended by approximately 100 persons.
Dr. G. Johnson proposed that the Subcommittee authorize a Working Party
to develop a comprehensive data base on murine hemostatic parameters and models
of thrombosis. The Working Party will tabulate published and volunteered
unpublished data and prepare a manuscript for approval as an official SSC
publication at the 2003 meeting. This proposal was approved by the Subcommittee.
Dr. Johnson will Chair the Working Party.
Scientific Program:
Justin Hamilton, University of California at San Francisco, described
studies of PAR 4 and PAR 3 knockout mice. Both knockouts manifested
prolonged bleeding times, impaired thrombin-induced platelet aggregation
and protection from experimental thrombosis. These studies demonstrate
the important cofactor function of PAR 3 in vivo.
Mieke Dewerchin, Center for Transgenic Technology and Gene Therapy, Leuven,
presented results of studies of antithrombin R47C mutant mice. This
mutation resulted in a high rate of neonatal mortality. Survivors
developed spontaneous thrombi in multiple organs. Thromboses were
not prevented by the administration of pentasaccharide. These studies
emphasize the critical functional role of the heparin binding site
of antithrombin.
Brian Peterson, Scripps Research Institute, San Diego, spoke about the
consequences of low tissue factor (~1% in brain) in mice. These animals
had increased post-partum uterine hemorrhage, fatal hemorrhage in 20% and
tissue fibrosis resulting in impaired cardiac function. These
mice were resistant to experimental arterial thrombosis that was not corrected
by transplantation of wild type bone marrow. Thus deficiency of vascular
tissue factor appeared to be more responsible for hemorrhage and resistance
to thrombosis than blood cell tissue factor.
Pudur Jagadeeswaran, University of Texas, San Antonio, presented an overview
of his laboratory's extensive characterization of hemostatic parameters
and thrombosis in zebrafish. The similarity of blood coagulation factors,
platelets and thrombosis in zebrafish to those of mammals, combined with
their utility as genetic models, make zebrafish a valuable model for the
study of mechanisms of hemostasis and thrombosis.
Laveena Sharma, Monash University, Australia, presented evidence from studies
of mice with a targeted deletion of the cytoplasmic domain of tissue factor
that the carboxyl terminus plays an important role in inflammation.
Animals with the deletion challenged with LPS demonstrated improved survival,
decreased pulmonary neutrophil accumulation and cytokine production, and
they manifested impaired delayed hypersensitivity.
Ed Conway, Center for Transgenic Technology and Gene Therapy, Leuven, described
studies that demonstrated the importance of the lectin domain of thrombomodulin
in inflammation. Deletion of the lectin domain resulted in normal
development and fertility, and normal interaction with protein C, but mice
with this deletion had exaggerated responses to LPS and experimental arthritis,
increased experimental myocardial infarction size and increased neutrophil
adhesion to endothelial cells.
Anne Angellilo, University Medical Center, Geneva, spoke of studies of
the role of Gas 6 in mouse platelet function. Gas 6 knockout mice
had normal plasmatic coagulation, bleeding time and fibrinolysis, but they
demonstrated impaired platelet aggregation and secretion. These mice
were protected against experimental thromboembolic death. The impaired
platelet aggregation was restored by addition of exogenous Gas 6.
These mice also demonstrated impaired inflammarory responses.