Pulmonary intravascular coagulopathy in COVID-19 pneumonia
Authors: Brandon P Reines, Barry W Ninham
Journal: The Lancet Rheumatology (2020)

We read with interest the Viewpoint by Dennis McGonagle and colleagues.1McGonagle D O'Donnell JS Sharif K Emery P Bridgewood C Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia.Lancet Rheumatol. 2020; (published online May 7.)https://doi.org/10.1016/S2665-9913(20)30121-1Summary Full Text Full Text PDF Scopus (581) Google Scholar To account for unusual clinicopathological features of COVID-19 disease, particularly coagulopathy, the authors point to dysregulated immunity and systemic inflammation reminiscent of a cytokine storm or macrophage activation syndrome (MAS). Although the authors' contribution comes down firmly on the immunological side of the debate over whether COVID-19 coagulopathy is due principally to immune or endothelial dysfunction,2Reines BP Ninham BW Structure and function of the endothelial surface layer: unraveling the nanoarchitecture of biological surfaces.Q Rev Biophys. 2019; 52: e13Crossref PubMed Scopus (26) Google Scholar the common background assumption to both sides is that modelling COVID-19 using previously described clinical syndromes and traditional pharmacological and physiological mechanisms will lead to deeper insights into the disease. We question this assumption on both clinical and physical-chemical grounds. McGonagle and colleagues themselves detail the many important ways in which MAS differs from COVID-19. Indeed, many key features of MAS, including hyperferritinaemia, only occur in the most severe COVID-19 cases. But the deeper problem in analysing COVID-19 pathogenesis, as reflected in the authors' usage of the term diffuse to describe virtually every aspect of the pathology of COVID-19, is that few truly discrete lesions exist in the bodies of patients with COVID-19. It is true that, late in the disease, alveolar damage occurs, as it is found at autopsy. But, in contrast to severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) does not injure pneumocytes and other cells in the alveolar lining sufficiently to induce either early respiratory distress or radiographic evidence of alveolar inflammation and oedema. Indeed, the unexpected preservation of lung compliance in the face of hypoxaemia suggests that SARS-CoV-2 has fairly modest effects on pneumocytes and other pulmonary cells. Otherwise, one would expect early and intense alveolar cellular inflammation and oedema. However, what is actually seen on CT is bilateral interstitial oedema and often virtually normal gas volume in the lungs on presentation. The absence of apparent alveolar damage on CT has led many authors to presume that hypoxaemia is not due to a failure of gas exchange at the alveolar-capillary interface, but instead to a more general vascular abnormality leading to ventilation-perfusion mismatch. The presence of viral inclusion structures in endothelial cells of pulmonary blood vessels has been taken as evidence that the primary target of viral damage is not the alveoli but the endothelium. However, we believe SARS-CoV-2 does not directly damage the cells of the alveolus or endothelium but instead injures their loosely adherent extracellular surface layers.2Reines BP Ninham BW Structure and function of the endothelial surface layer: unraveling the nanoarchitecture of biological surfaces.Q Rev Biophys. 2019; 52: e13Crossref PubMed Scopus (26) Google Scholar As such layers are only understandable through physicochemical analysis, we suggest that COVID-19 presents such an unusual clinicopathological course that we need an entirely new conceptual framework to explain the disease. The most notable anomaly in COVID-19 presentation is profound hypoxaemia in the face of preserved lung compliance. Although abnormal hypoxic vasoconstriction could explain the hypoxaemia to some degree, little evidence exists for such aberrant vascular mechanisms until quite late in the disease course. But could the virus somehow short-circuit gas exchange at the alveolar surface in a more direct way? In fact, although still little known, pulmonary surfactant has a gas exchange function,3Larsson M Larsson K Andersson S et al.The alveolar surface structure: transformation from a liposome-like dispersion into a tetragonal CLP bilayer phase.J Dispers Sci Technol. 1999; 20: 1-12Crossref Scopus (27) Google Scholar which is more important than its better known surface-tension-lowering function. Although, according to older physical-chemical knowledge, damage to surfactant should lead to drastically impaired lung compliance, new knowledge strongly suggests that surfactant damage would mainly hinder gas exchange and have little, if any, effect on compliance.4Ninham BW Larsson K Lo Nostro P Two sides of the coin. Part 2. Colloid and surface science meets real biointerfaces.Colloids Surf B Biointerfaces. 2017; 159: 394-404Crossref PubMed Scopus (19) Google Scholar Paradoxically, SARS-CoV-2 appears to create less systemic inflammation and general cell damage than previous viruses that cause acute respiratory distress and might have evolved a way of undergoing replication cycles while sparing host cells. Therefore, we postulate that SARS-CoV-2 mainly injures the alveolar and endothelial surface layers. Such subtle damage would coherently explain the unusual combination of pulmonary and endothelial effects of SARS-CoV-2 infection, including alterations in blood viscosity and clotting tendency.5Copley AL The endoendothelial fibrin (ogenin) lining and its physiological significance.Biorheology. 1988; 25: 377-399Crossref PubMed Scopus (10) Google Scholar In the appendix, we outline the main anomalies in COVID-19 and compare current explanations with our surface-layer damage hypothesis. We declare no competing interests. Download .pdf (.29 MB) Help with pdf files Supplementary appendix Pulmonary intravascular coagulopathy in COVID-19 pneumoniaWe read with pleasure the thoughtful Viewpoint by Dennis McGonagle and colleagues1 on lung immunothrombosis during infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, some of the key pathogenetic events were not highlighted by the authors. Full-Text PDF Pulmonary intravascular coagulopathy in COVID-19 pneumonia – Authors' replyWe thank Gianfranco Ferraccioli and colleagues, Brandon Reines and colleagues, and Hisyovi Cárdenas Suri for their comments on our Viewpoint1 discussing the diffuse, alveolar-centred inflammation that triggers immunothrombosis in the lung microvasculature of patients with COVID-19 pneumonia. Full-Text PDF Pulmonary intravascular coagulopathy in COVID-19 pneumoniaI read with interest the Viewpoint by Dennis McGonagle and colleagues,1 in which they associate the changes that occur in the lungs of patients with COVID-19 with macrophage activation syndrome (MAS) and emphasise the possible occurrence of pre-terminal disseminated intravascular coagulation. Full-Text PDF Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumoniaThe lung pathology seen in patients with coronavirus disease 2019 (COVID-19) shows marked microvascular thrombosis and haemorrhage linked to extensive alveolar and interstitial inflammation that shares features with macrophage activation syndrome (MAS). We have termed the lung-restricted vascular immunopathology associated with COVID-19 as diffuse pulmonary intravascular coagulopathy, which in its early stages is distinct from disseminated intravascular coagulation. Increased circulating D-dimer concentrations (reflecting pulmonary vascular bed thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations (reflecting emergent ventricular stress induced by pulmonary hypertension) in the face of normal fibrinogen and platelet levels are key early features of severe pulmonary intravascular coagulopathy related to COVID-19. Full-Text PDF