Mechanisms, diagnostics and therapies for thromboinflammation

Abstract

Thrombosis, the disruption of blood flow in the circulation by a blood clot (thrombus), can cause serious and life-threatening disease and still forms an important healthcare challenge. Thrombosis resulting from cardiovascular disease, such as myocardial Infarction (MI), stroke, and pulmonary embolism (PE) resulting from deep vein thrombosis (DVT) for instance is a major cause of death. Our extensive knowledge on haemostasis (the process of stopping bleeding at sites of vascular injury), has culminated in the development of numerous antithrombotic therapies that target the coagulation cascade (anticoagulant agents) or platelets (antiplatelet agents) to treat and prevent thrombosis. However, due to the overlap in processes involved in haemostasis and thrombosis many antithrombotic agents unfortunately increase the risk of bleeding. Some forms of thrombotic disease are also driven by immunity (inflammation). Haemostasis, thrombosis, and inflammation are highly interwoven processes. This intertwinement is illustrated by the fact that inflammation can promote thrombosis, and thrombosis can trigger inflammation. This has led to the introduction of terms such as immunohaemostasis, immunothrombosis and thromboinflammation to better describe different forms and mechanisms of inflammation associated with thrombosis. It is intriguing to speculate about the identification of processes involved solely in immunothrombosis or thromboinflammation might provide targets for new therapeutical intervention, preferably without affecting haemostasis. This thesis aims to expand our understanding of the molecular and cellular pathophysiology of thromboinflammation, to explore the diagnostic potential of in house developed assays, and to pinpoint targets for novel therapeutical intervention whilst focussing on several different forms of thrombotic and cardiovascular disease. Although thromboinflammation occurs in many different types of disease, the exploration of thromboinflammation in this thesis is limited to thrombotic and cardiovascular disease. This thesis consists of three parts, the first part focusses on the potential amplification carried out by platelets in thromboinflammation. The second part focusses on the contact system and its inflammatory product: bradykinin. The final part focusses on the fibrinolytic enzyme plasmin, and its potential therapeutic use for thrombotic microangiopathy. This thesis has led to the following insight: Prevention of intra-thrombus contact activation on platelet polyphosphate might inhibit thromboinflammation. The FXII fibronectin type II domain is responsible for correct shielding of the FXII activation loop. While the EGF-1 domain is critical for surface binding of FXII. With this knowledge FXII variants could be designed that lack surface binding properties, for example. Localising and amplifying plasminogen activation towards VWF by the thrombolytic fusion protein microlyse could be used as a therapy for treating (VWF-driven, microvascular) thrombosis and might also inhibit thromboinflammation.