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Primate models for studying fibrinolysis , thrombosis and tissue remodelling

Objective

To develop a complete methodology to study thrombosis, fibrinolysis, thrombolysis, and the plasminogen activator system, in primates (Macaca mulatta);
To define base-line data regarding the normal physiology and regulation of these systems and their components in M.mulatta;
To describe the effects of interventions on the functioning of the systems, to understand the pathophysiological changes that occur, in order to be able to improve the functioning of the systems in these circumstances;
To develop non-human primate model systems for thrombosis, thrombolysis, and restenosis, in which models pathogenetic mechanisms can be studied, as well as the effects of therapeutic procedures and of drugs.

Cardiovascular disease and consequent thrombosis is one of the main causes of death and morbidity in the Western world. Thrombosis is a main factor in vascular diseases such as angina, claudicatio, pulmonary embolism, thrombotic stroke, and endocarditis. Apart from these acute effects, thrombosis is also believed to play a major role in the slow progression of arteriosclerotic and atherosclerotic vascular lesions over time. Moreover, the fibrinolytic (plasminogen activator) system is intimately involved in tissue remodelling such as occurs during restenosis and wound healing.
The occurrence of thrombosis is due to a imbalance between prothrombotic factors on the one hand, and antithrombotic factors on the other. Among the latter factors, the fibrinolytic system plays a major role. An insufficiently active fibrinolytic system will not succeed in removing forming fibrin fast enough to prevent the growth of a thrombus, and will also, once a thrombus has been formed, not be able to remove the thrombus rapidly enough to prevent ischemia and tissue damage.
We still know little about the in vivo functioning of the fibrinolytic system, nor about its physiological and pathophysiological regulation. This is largely due to the impossibility, for ethical reasons, to study the system in detail in vivo in man, and also to the lack of relevant animal models. Over the past years it has become clear that animal (rodent and other) models of fibrinolysis/thrombolysis differ too much from the human situation to allow a profitable extrapolation to man.
Therefore nine main European centres have initiated this proposal for a Reinforced Concerted Action to develop and study model systems for thrombosis, fibrinolysis and thrombolysis in non-human primates.
The outcome of this program will, for the first time, allow the study of all aspects of the thrombosis/fibrinolysis system in a non-human primate model that is relevant to the situation in man.

Coordinator

NETHERLANDS ORGANISATION FOR APPLIED SCIENTIFIC RESEARCH - TNO
Address
9,Zernikedreef 9
2333 CK Leiden
Netherlands