Novel coronavirus (COVID-19) pneumonia is associated with significant mortality predominantly attributable to a progressive bilateral pneumonia, that ultimately progresses to acute respiratory distress syndrome (ARDS) which is refractory to standard therapies. Previous multivariate regression analysis studies performed in Wuhan have shown that elevated plasma levels of fibrin degradation D-dimers constitute a key independent biomarker of poor prognosis in COVID-19. Interestingly however, despite this prognostic increase in D-dimers, COVID-19 patients do not typically develop systemic disseminated intravascular coagulation (DIC). Nonetheless, post-mortem studies in COVID-19 infected patients have highlighted marked pathological changes restricted to within the lung microvasculature. These include disseminated micro-thrombi and haemorraghic necrosis. Cumulatively, these findings suggest that the refractory ARDS phenotype observed in COVID-19 is due in part to a novel pulmonary-specific vasculopathy. Critically however, pathobiological mechanisms underpinning this unique vasculopathy remain completely undefined.
Although D-dimer levels are being used globally as prognostic marker in patients with COVID-19, no studies have sought to investigate why coagulation D-dimers are elevated, nor why D-dimer levels and coagulation activation correlate so strongly with clinical outcomes. In this cross-disciplinary Irish COVID-19 Vasculopathy Study (iCVS), we will systematically investigate the biological pathways that ultimately lead to elevated plasma D-dimer levels. These include (i) EC activation (ii) procoagulant cascade activation (iii) down-regulation of normal anticoagulant pathways (iv) fibrinolytic pathways (v) platelet activation respectively. The plan of investigation will define novel vascular biomarkers beyond crude D-dimers that can be used to better define prognosis for COVID-19 patients and thereby prioritise ICU resources. In addition, elucidating the biology underlying the unique pulmonary vasculopathy involved in severe COVID-19 sepsis will identify subsets of patients likely to benefit from specific anti-inflammatory, anticoagulant and/or antiplatelet therapies respectively. Consequently, the proposed studies are not only of scientific interest, but directly address an important clinical unmet need.
