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Review
. 2020 Jul;2(7):e437-e445.
doi: 10.1016/S2665-9913(20)30121-1. Epub 2020 May 7.

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia

Dennis McGonagle  1   2 , James S O'Donnell  3 , Kassem Sharif  4 , Paul Emery  1   2 , Charles Bridgewood  1   2
Affiliations
Review

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia

Dennis McGonagle et al. Lancet Rheumatol. 2020 Jul.

Abstract

The 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. Extensive immunothrombosis over a wide pulmonary vascular territory without confirmation of COVID-19 viraemia in early disease best explains the adverse impact of male sex, hypertension, obesity, and diabetes on the prognosis of patients with COVID-19. The immune mechanism underlying diffuse alveolar and pulmonary interstitial inflammation in COVID-19 involves a MAS-like state that triggers extensive immunothrombosis, which might unmask subclinical cardiovascular disease and is distinct from the MAS and disseminated intravascular coagulation that is more familiar to rheumatologists.

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Figures

Figure 1
Figure 1
Early macrophage activation syndrome versus early COVID-19 (A) Secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome is associated with organomegaly, thrombocytopenia, haemophagocytosis, and disseminated intravascular coagulation with pulmonary involvement in half of cases. Activation of bone marrow, lymphoid organ, hepatic Kupffer cells, and circulating mononuclear cells lead to a severe consumptive coagulopathy with low fibrinongen levels and increased fibrinogen degradation. Additionally, liver dysfunction exacerbates the consumptive coagulopathy. A rapid onset disseminated intravascular coagulation pattern with hyperferritinaemia reflects generalised haemophagocytosis with erythrocyte degradation, sequestration, and export with diffuse clotting and bleeding. (B) Pulmonary involvement without generalised lymphoid organ hyperplasia is typical of COVID-19 pneumonia. Haemophagocytosis, albeit intrapulmonary, has also been reported in coronavirus family infection. However, in the early stages systemic coagulopathy is not a feature. Such intrapulmonary haemophagocytosis, which then drains to regional nodes, indicates removal of extravascular red blood cells mediated by activated macrophages, secondary to vascular injury. A disseminated intravascular coagulation picture might also develop late in the course of COVID-19 pneumonia in patients who develop acute respiratory distress syndrome. COVID-19=coronavirus disease 2019.
Figure 2
Figure 2
Extent of alveolar lung surface involved in COVID-19 and bronchopneumonia (A) Some coronavirus family members gain access to the lungs via the ACE2 receptor that is expressed most abundantly on a subpopulation of type II pneumocytes. Shaded boxes indicate the much greater capability for immunothrombosis given the alveolar tropism of SARS-CoV-2. (B) Segmental bronchopneumonia (eg, bacterial and influenza) typically has a different lung distribution, with prominent bronchial tree involvement, including haemorrhagic destruction of trachea and large airways, and generally patchy alveolar network disease. There might be large areas with normal perfusion. The slow evolution of COVID-19 with alveolar hypoxia and microthrombosis might result in pulmonary arterial hypertension and the cardiac picture that mostly occurs with hypoxaemia and raised D-dimers. The scale of alveolar and microvascular inflammation, rather than systemic viral infection per se, determines the cardiovascular pattern of disease. Nonetheless, segmental bronchopneumonia could result in a degree of immunothrombosis sufficient to cause a cardiac event, especially in older patients with known or silent cardiac disease. ACE2=angiotensin-converting enzyme 2. COVID-19=coronavirus disease 2019. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
Figure 3
Figure 3
Pulmonary intravascular coagulopathy in COVID-19 pneumonia Scheme showing how extensive COVID-19 lung involvement with large anatomical interface between infected type II pneumocytes, extensive interstitial immunocyte activation similar to macrophage activation syndrome, and the extensive pulmonary microvascular network, triggers diffuse pulmonary bed extrinsic inflammation with immunothrombosis. This inflammation causes microthrombotic immunopathology that leads to right ventricular stress and contributes to mortality. Diffuse type II pneumocyte centric pathology with extension into the interstitium leads to extensive pulmonary macrophage recruitment and activation, resulting in a clinical picture similar to local macrophage activation syndrome. Proinflammatory and procoagulants gain access to the capillary network (lower circle). The low pressure nature of the vascular system and thin vessel walls in and proximal to the alveolar network triggers immunothrombosis by various mechanisms (eg, local elevations in proinflammatory cytokines), vessel wall tissue damage with tissue factor production, and direct injury to small vessels. Vigorous fibrinolytic activity (detected early by D-dimer elevation) might not keep in check the extensive microthrombi formation, leading to the evolution of pulmonary infarction, haemorrhaging, and pulmonary hypertension induced by pulmonary intravascular coagulopathy, all of which are driven by COVID-19 inflammation. Thus, risk factors for cardiovascular disease might increase the likelihood of death in severe COVID-19 inflammation. COVID-19=coronavirus disease 2019.
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