On platelet biology and cardiovascular disease

Abstract

Cardiovascular disease is one of the major causes of death, being responsible for 30% of the deaths worldwide in 2010. Cardiovascular disease is mainly caused by atherosclerosis. Clinical complications occur when a plaque suddenly ruptures and platelets form a thrombus on the plaque and the coronary artery becomes occluded. Atherosclerotic plaque rupture is the cause of approximately 70% of myocardial infarctions. Blood platelets play a pivotal role in cardiovascular disease, because aggregate formation of blood platelets in response to an unstable atherosclerotic plaque causes acute blockade of blood flow, and subsequent ischemia and infarction. In addition to the role of platelets in arterial thrombosis, it is becoming clearer that platelets also play an important role in the progression of atherosclerosis. Platelet a-granules contain numerous cytokines, chemokines and growth factors, and through interaction with leukocytes and endothelial cells platelets can promote inflammation and atherosclerosis. The central goal of this thesis was to investigate the responsiveness of platelets by means of a-granule release in relation to severity of cardiovascular disease symptoms, and to future cardiovascular disease events. In addition to platelet response in relation to cardiovascular disease, we have identified novel conditions and aspects that regulate platelet function. Chapter 1 addresses a systematic review to the current state of art of cardiovascular disease risk prediction with circulating markers. Chapter 2 describes a study investigating the relation between platelet responsiveness and cardiovascular disease symptoms and future cardiovascular disease events, which are assessed in the CTMM Circulating Cells cohort. We find that ADP platelet responsiveness is reduced in patients with unstable cardiovascular disease. The effect of ischemic coronary artery narrowing on platelet responsiveness is investigated in Chapter 3. We find that although the platelet response of patients with flow limiting stenoses is not different compared to patients without flow-limiting coronary stenoses, the formation of platelet-leukocyte complexes is associated with flow-limiting conditions. The influence of selective serotonin re-uptake inhibitors on platelet granule release is addressed in chapter 4. We find that citalopram is a stronger platelet function inhibitor than paroxetine. In chapter 5 we describe that platelets can release their granules independently of an aggregatory response, which is the result of selective aIIbb3 inhibition. We argue that this has implications for platelet physiologic functions. In Chapter 6, we describe the discovery and characterisation of a novel intracellular signalling molecule that belongs to the class of regulators of the RhoGTPase family. We conclude that this novel intracellular signalling molecule has influence on platelet filopodia formation in response to collagen like surfaces. Lastly, in Chapter 7 the composition of the platelet releasate in response to stimulation of either the thrombin receptor PAR-1, or PAR-4 is described with the use of novel quantitative mass spectrometry techniques. We find that stimulation of either receptor induces similar releasates and intra-cellular phosphorylation patterns