Pulmonary vascular disease in Ireland and the burden of haematological abnormalities: from molecular mechanisms to clinical outcomes

The pulmonary circulation is a high flow, low pressure system, that receives the entirety of the cardiac output from the right heart. It serves numerous essential functions including blood oxygenation and filtration, and therefore, pathologies of the pulmonary circulation such as pulmonary hypertension (PH) and COVID-19 can have meaningful clinical consequences. PH is a prevalent disease of the pulmonary vasculature that includes group 1 pulmonary arterial hypertension (PAH) and group 4 chronic thromboembolic pulmonary hypertension (CTEPH). There is a paucity of data regarding the characteristics of PAH and CTEPH in Ireland and the pathobiology of these conditions are incompletely defined. A number of haematological derangements have been described in PAH and CTEPH, which may provide valuable insights into the pathobiology of these conditions and opportunities to explore new therapeutic pathways. These include quantitative and qualitative changes in platelet characteristics, coagulation parameters and extracellular vesicle (EV) autocrine and paracrine signalling. This thesis describes the characteristics of PH in Ireland and explores the role of platelets, coagulation and EVs in the pulmonary vasculature, with a specific focus on PAH and CTEPH. Exploration of the characteristics of PH in Ireland revealed a calculated annual incidence of PAH and CTEPH of 3.11 and 1.39 cases per million population between 2010 and 2020. While the true global incidence of PAH and CTEPH are unknown, these estimates appear low relative to other European countries. Choropleth mapping of the origin of referrals exposed marked geographic heterogeneity regarding the source of referrals. These findings suggest that a national strategy to improve disease awareness, case recognition and specialist referral would be valuable. This work describes the haematological profiles and thrombin generation characteristics of a cohort of incident and prevalent subjects with PAH. Significantly lower platelet counts and higher mean platelet volume (MPV) were noted in subjects with PAH relative to healthy controls, which is consistent with existing published data. Furthermore, thrombin generation using calibrated automated thrombography uncovered significantly reduced peak thrombin generation, endogenous thrombin potential and thrombin generation velocity index in subjects with PAH relative to healthy controls. This suggests a hypocoagulable profile in PAH and may reflect impaired coagulant activity due to sustained activation of procoagulant pathways. It is plausible that injured pulmonary vascular endothelium and high shear stress in the pulmonary circulation may result in chronic platelet and coagulation cascade activation and subsequent diminished activity. The observation of increased tissue factor antigen expression in plexiform lesions in subjects with PAH and evidence of increased fibrinopeptide A in subjects with primary pulmonary hypertension (IPAH) supports this hypothesis. The clinical implications of these findings will require additional exploration. Nanoparticle tracking analysis (NTA) was used to define EV characterises in PAH and CTEPH. Results indicated that circulating EV size and concentration were not significantly different between subjects with PAH, CTEPH and healthy controls, and further experiments are required to define qualitative EV characteristics in different PH groups. Finally, the COVID-19 pandemic has had a dramatic impact on global health and the disease is associated with substantial morbidity and mortality, which includes pulmonary vascular complications. The final chapter of this thesis describes the platelet profiles of hospitalised patients with COVID-19. This is characterised by increased platelet aggregation in response to low-dose agonist stimulation and increased circulating levels of platelet activation markers such as platelet factor 4, suggesting a hyperactive platelet phenotype.