Summary
Identifying and evaluating new therapeutic targets in platelets requires advanced
animal models in which platelet responses can be measured directly and in situ.This is important because platelet function is strongly influenced by external factors
such as those originating from the vascular endothelium. Our objectives were to record
graded, non-lethal thromboembolic platelet responses to platelet agonists in situ in the mouse and to demonstrate an inhibitory effect of aspirin in our model. Radiolabelled
platelets were infused into anaesthetized mice and responses to ADP, collagen and
thrombin measured as changes in platelet associated counts in miniaturized detection
probes placed over the thoracic region. All agonists induced dose-dependent changes
in platelet counts due to accumulation of thrombi in the pulmonary vasculature. We
confirmed a specific platelet effect by comparing platelet and erythrocyte responses
and showing platelet aggregates in the lung vasculature histologically. Simultaneous
injection of collagen and adrenaline induced increased and protracted synergistic
platelet responses compared with individual injection of these agents and aspirin
inhibited collagen-induced responses. We confirmed the clinical relevance of our model
by showing that platelet thromboembolism in the mouse, like pulmonary embolism in
humans, impaired cardiovascular performance. We present a refined method for measuring
platelet agonist dose-responses and thromboembolism in real-time without inducing
mortality in the mouse. Our technique will be useful in investigating the molecular
determinants of physiological and pathophysiological platelet function in an in-vivo
context and will enable investigations of both platelet and non-platelets mediators
of thrombus formation.
Keywords
Animal model - platelet - mouse - thrombosis
