Novel Endothelial Protective and Anti-Thrombotic Effects of Therapeutic Agents in Malignant and Inflammatory Diseases: Molecular Mechanisms and Translational Relevance

While the primary physiological function of the blood coagulation system is to prevent bleeding following vascular injury, a complex interplay is known to exist between components of the blood coagulation cascade and the activity of various other biological processes and systemic diseases including inflammation, tumour metastasis and pulmonary vascular disease. Moreover, the potential of this interplay to provide novel therapeutic opportunities is increasingly representing a source of scientific and translational interest, particularly in the setting of clinical scenarios where therapeutic options are limited, such as in the treatment and prevention of cancer metastasis and in the management of thrombotic risk among individuals at high risk of bleeding.The work described within this thesis was conducted with the aim of exploring the nature of this interplay in the context of two disease states, cancer metastasis and Eisenmenger syndrome, and to explore potential novel therapeutic strategies which target the interaction between coagulation activation and the underlying systemic disease in both cases. LMWH, an anticoagulant drug, appears to mediate an anti-metastatic effect in vivo but the underlying mechanisms remain to be elucidated and the associated risk of bleeding precludes its use in cancer solely for the prevention of tumour dissemination. Eisenmenger syndrome is associated with a significant risk of both haemorrhage and thrombosis, the underlying mechanisms remain poorly understood and the nature of the competing thrombotic and haemorrhagic risks presents significant clinical dilemmas.LMWH was found to support endothelial barrier function in vitro (a key barrier to tumour metastasis) and to inhibit tumour cell trans-endothelial migration. This activity does not appear to be linked to its anticoagulant function and both a non-anticoagulant LMWH fraction and a combination of low dose LMWH with a statin were found to represent a novel means of delivering the cytoprotective effects of LMWH in vitro in the absence of a significant anticoagulant effect.Abnormal platelet procoagulant activity was found to represent a key determinant of the prothrombotic phenotype in Eisenmenger syndrome but, interestingly, platelets were also found to modulate the activity of endogenous anticoagulant pathways in a manner which would be predicted to increase the bleeding risk (reflecting the clinical phenotype). Remarkably, following a course of treatment with macitentan, a dual endothelin-1 receptor antagonist which does not directly affect haemostasis, the derangements in both procoagulant and anticoagulant pathways were found to be attenuated.In summary, the cross-talk between coagulation and systemic disease represents a potential source of novel therapeutic opportunities. The in vitro results described in this thesis may, if replicated in vivo, represent a means of addressing significant clinical dilemmas in two high risk patient groups.