Vascular regulation of endogenous fibrinolysis in man

• Main Author: Newby, David Ernest
• Published: University of Edinburgh 2009
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.739027

The initiation, modulation and resolution of thrombus associated with eroded or unstable coronary plaques are critical determinants of acute coronary events. This itself is dependent on the cellular function of the surrounding endothelium and vascular wall. In particular, the regulation of vascular tone and the acute release of tissue plasminogen activator by the endothelium make important contributions to the defence against intravascular thrombosis. These aspects of endothelial function will provide major new insights into the pathophysiology of cardiovascular disease, and to shape future therapeutic interventions. The experimental medicine models presented here originate from an early interest in exploring these novel aspects of endothelial function, and in particular, the acute release of the endothelium-derived fibrinolytic factor, tissue plasminogen activator. This model was initiated, developed and applied to a diverse range of physiological and pathophysiological circumstances that have informed health and disease. Publications are grouped into 5 main sections. Section 1 describes the early validation and exploration of the model to stimulate acute tissue plasminogen activator release using a variety of physiological and pathophysiological mediators. This describes the early identification of potent stimulators of acute tissue plasminogen activator release including substance P, bradykinin, desmopressin and thrombin receptor agonists. This work was extended to demonstrate the important role of nitric oxide and vascular inflammation in this process. Subsequent sections cover the application of these techniques in patient populations with a predisposition to cardiovascular disease (Section 2) as well as with established (Section 3) and end-stage disease (Section 4). These sections also explore the potentially important modulation of the renin-angiotensin system with particular reference to angiotensin-converting enzyme inhibition and the role of bradykinin. Section 5 contains some miscellaneous work and reviews of the subject area bring together the key aspects of the field as well as an important study to address the vascular endothelial function in patients with a rare haematological deficiency, type 3 von Willebrand disease.