The meeting was chaired by G. Johnson at the request of Chairman, P. Carmeliet

Attendance: ~100 persons

Scientific Presentations:

P. Jagadeeswaran, San Antonio, reported on innovative studies of hemostatic parameters and thrombosis in zebrafish. Using techniques developed in his laboratory, Dr. Jagadeeswaran has been able to perform clotting assays on extremely small volumes of blood, evaluate platelet aggregation and induce thrombosis. Anticoagulant effects on hemostasis and thrombosis and platelet inhibitory drugs have been evaluated. Genes for all the human coagulation factors, except Factors VIII and IX, have been identified in the Zebrafish. An additional Factor VII-like gene has also been identified. Combination of the functional assays with the enormous potential of the zebrafish for rapid genetic analysis make this model a very promising one for analysis of the complex interactions of multiple proteins in hemostasis and thrombosis.

G. Johnson, Minneapolis, presented an overview of the signaling defect that exists in thromboxane-insensitive dog platelets. This defect in activation of PLC-beta results in impaired secretion stimulated by thromboxane A₂ or thromboxane analogs. The cause of this signaling defect apprears to be an elevated level of basal thromboxane receptor phosphorylation that is reversible by epinephrine. Thromboxane-insensitive dog platelets are a useful model for the study of the control of G protein-coupled receptors by phosphorylation.

L. Drouet, Paris, reported progress on the development of a pig model of unstable atherosclerotic plaque. Homozygous, LDL mutant, hypercholesterolemic pigs with spontaneously developing atherosclerosis had carotid stenosis lesions induced by application of an externally constricting collar combined with a ligature. These lesions develop flow reduction and down-stream thrombosis. The effects of angioplasty and antithrombotic agents on these lesions has been evaluated. Some spontaneous plaque rupture develops in this model when these animals are fed an atherogenic diet. Additional studies are in progress to further refine this very promising model.

Berend Isermann, Milwaukee, reported on a series of studies performed in mice with targeted disruption of genes for components of the thrombomodulin\protein C pathway. These studies have highlighted the contributions of components of this pathway to normal in-utero development. Thrombomodulin expression is required in the placenta during mid gestation, before development of a functional cardiovascular system. During the second half of pregnancy and at birth, embryos with disrupted hemostatic systems often succumb to hemorrhage or thrombosis. Several successful strategies have been developed to circumvent the intrauterine lethality of mice with defects in the thrombomodulin\protein C pathway. Animal models with defects in the thrombomodulin\protein C pathway will be very useful in the identification of modifer genes for thrombosis, the study of vascular bed-specific hemostasis and the evaluation of thrombophilia-associated pregnancy complications.

Old Business: The manuscript, The Utility and Limitations of Animal Venous Thrombosis Models, approved for publication by the SSC at the 2000 meeting in Maastricht, has been revised to meet the editorial criteria of Thrombosis and Haemostasis. It has been reviewed and approved by the co-authors and the Chairman. It will be resubmitted to Thrombosis and Haemostasis as an official SSC publication.

New Business: Discussion of future activities included critical evaluation of the important characteristics of animal models that must be considered in the selection of appropriate models for the study of research topics, such as arterial thrombosis in large and small animals. Characteristics, such as levels of hemostatic parameters, availability of antisera, functional characteristics of platelets and endothelium, and other important parameters would be compiled and made available via a registry. A particular need exists for this type of information for mouse models. Subcommittee members will submit proposals for this type of analysis to G. Johnson who will coordinate this activity for the Subcommittee. A goal will be to have a draft developed for submission to the Subcommittee at the 2002 meeting.