The development of an in-vivo method for assessing the antithrombotic properties of pharmaceutical compounds
The formation of a thrombus stems from the malfunction of a normal physiological function referred to as haemostasis and the activity of blood platelets; such thrombi give rise to debilitating and often fatal strokes. Consequently much effort is associated with the search for pharmacological compounds capable of their prevention or dispersion. · Most of the primary screens associated with such work rely on in-vitro tests and in separating the blood from it's vasculature, the influence and results associated with several naturally occuring moderators may be lost. There therefore exists the incentive to develop more representative in-vivo screening methods. Following an introduction to the underlying physiology and pharmacology and a review of established screening methods, this thesis proceeds to describe the development of a novel technique suitable for such in-vivo studies. It's inception is shown to be a consequence of an amalgamation of ultrasonic methods associated with the clinical detection of occlusions and laser Doppler velocimetry. Both topics are individually surveyed and then brought together through a concept whereby the efficacy of compounds might be evaluated in animal models by measuring the velocity of blood in the fluid jet formed distal to an induced thrombus.The main underlying assumption is that the jet velocity will reflect the degree of encroachment of the thrombus into the vasculature. In accord with the evolved measurement rationale there then follows a description of a specific laser Doppler velocimeter and some associated experiments, designed to qualitatively appraise the validity of the underlying assumptions. The ensuing results in turn give rise to the design of a laser Doppler microscope, an analyser for extracting the required velocity information from the Doppler shift spectrum and an additional series of experiments. Central to this latter stage of validation is the use of a thrombus analogue in a narrow bored glass flow tube. Finally, some preliminary in-vivo experiments and results are presented.