Vascular mechanisms and manifestations of COVID-19

Abstract

Severe COVID-19 is dominated by a multifaceted severe respiratory infection. The pathophysiology of acute disease is the focus of a Series of four papers in The Lancet Respiratory Medicine. Dennis McGonagle and colleagues1McGonagle D Bridgewood C Meaney J A tricompartmental model of lung oxygenation disruption to explain pulmonary and systemic pathology in severe COVID-19.Lancet Respir Med. 2021; (published online May 17.)https://doi.org/10.1016/S2213-2600(21)00213-7Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar propose that COVID-19 simultaneously affects three compartments of the lungs, thereby leading to disruption of oxygenation: inflammation of the alveolar space, immunothrombosis of the juxtaposed pulmonary vascular compartment, and thrombotic obstruction of the pulmonary and bronchial circulation. Apart from the respiratory features of COVID-19, many extrapulmonary manifestations can occur as well. Some of these disease characteristics might be expected in patients with severe acute lung injury and a systemic inflammatory response; however, COVID-19 includes some complications that seem to be specific to SARS-CoV-2 infection. Marcin Osuchowski and colleagues2Osuchowski MF Winkler MS Skirecki T et al.The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.Lancet Respir Med. 2021; (published online May 6.)https://doi.org/10.1016/S2213-2600(21)00218-6Summary Full Text Full Text PDF PubMed Scopus (202) Google Scholar describe the most common phenotypes of COVID-19 in their comprehensive review of disease pathophysiology. A remarkable finding in patients with severe Covid-19 are coagulation abnormalities, which have been associated with respiratory deterioration and death. COVID-19-associated coagulopathy mimics other systemic coagulopathies that are regularly seen in severe infections, most notably disseminated intravascular coagulation (DIC). However, COVID-19 has clinical and laboratory features that are distinctly different from the typical presentation of DIC.3Levi M Thachil J Iba T Levy JH Coagulation abnormalities and thrombosis in patients with COVID-19.Lancet Haematol. 2020; 7: e438-e440Summary Full Text Full Text PDF PubMed Scopus (870) Google Scholar Elevated D-dimer concentrations—sometimes many times higher than the levels (<0·5 mg/L) seen in healthy individuals —can be found in more than 50% of patients with Covid-19 and are related to a poor outcome.4Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Summary Full Text Full Text PDF PubMed Scopus (15774) Google Scholar A mild thrombocytopenia can also occur, with a platelet count between 100×109 and 150×109 per L, but more severe thrombocytopenia is seen in less than 5% of patients with COVID-19. A meta-analysis5Lippi G Plebani M Henry BM Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis.Clin Chim Acta. 2020; 506: 145-148Crossref PubMed Scopus (957) Google Scholar showed that the low platelet counts (about –30 × 109 per L, 95% CI –35 × 109 to –29 × 109) in critically ill patients with COVID-19 and thrombocytopenia—defined as counts below the lower limit of the reference range—were associated with a higher risk of severe disease. However, in contrast to low platelet counts seen in other severe infections, moderate thrombocytopenia in COVID-19 has not been associated with mortality. Coagulation abnormalities in severe COVID-19 are associated with a high risk of thrombotic vascular complications, in particular venous thromboembolism.6Di Minno A Ambrosino P Calcaterra I Di Minno MND COVID-19 and venous thromboembolism: a meta-analysis of literature studies.Semin Thromb Hemost. 2020; 46: 763-771Crossref PubMed Scopus (135) Google Scholar Pulmonary thrombosis or embolism can contribute to a sudden deterioration of pulmonary oxygen exchange, which is occasionally seen in patients with COVID-19. Local formation of platelet clots, as a manifestation of thrombotic microangiopathy, might contribute to organ dysfunction. Clinical observational studies in almost 2000 patients found venous thromboembolism in up to 35% of those with severe COVID-19.6Di Minno A Ambrosino P Calcaterra I Di Minno MND COVID-19 and venous thromboembolism: a meta-analysis of literature studies.Semin Thromb Hemost. 2020; 46: 763-771Crossref PubMed Scopus (135) Google Scholar Several retrospective studies point to a higher risk of venous thromboembolism in patients with more severe COVID-19 coagulopathy. The relevance of microvascular thrombosis for organ dysfunction has also been suggested by post-mortem pathological studies. Several reports highlight vascular wall thickening, stenosis of the vascular lumen, and microthrombus formation associated with COVID-19-related acute respiratory distress syndrome (ARDS).7Damiani S Fiorentino M De Palma A et al.Pathological post-mortem findings in lungs infected with SARS-CoV-2.J Pathol. 2021; 253: 31-40Crossref PubMed Scopus (39) Google Scholar Similar pathological observations have been made in the vasculature of other organs. In severe COVID-19, systemic levels of proinflammatory cytokines are markedly increased.2Osuchowski MF Winkler MS Skirecki T et al.The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.Lancet Respir Med. 2021; (published online May 6.)https://doi.org/10.1016/S2213-2600(21)00218-6Summary Full Text Full Text PDF PubMed Scopus (202) Google Scholar In a subset of the most severely affected patients, a so-called cytokine storm can be detected, characterised by high levels of proinflammatory cytokines and chemokines.8Angriman F Ferreyro BL Burry L et al.Interleukin-6 blockade in patients with COVID-19: placing clinical trials into context.Lancet Respir Med. 2021; (published online April 27.)https://doi.org/10.1016/S2213-2600(21)00139-9Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar In particular, interleukin-6 (IL-6) has gained attention as one of the central mediators of the inflammatory response to COVID-19, as extensively reviewed by Oliver McElvaney and colleagues9McElvaney O Curley G Rose-John S McElvaney NG Interleukin-6: obstacles to targeting a complex cytokine in critical illness.Lancet Respir Med. 2021; (published online April 16.)https://doi.org/10.1016/S2213-2600(21)00103-XSummary Full Text Full Text PDF PubMed Scopus (60) Google Scholar in this Series. IL-6 is also relevant for the vascular complications seen in Covid-19, because this pleiotropic cytokine induces tissue factor expression on monocytes and macrophages, which consequently leads to thrombin generation. Direct viral infection of endothelial cells, which abundantly express ACE2, can result in widespread endothelial dysfunction associated with recruitment of a vascular inflammatory response, which is presumably more exaggerated in patients with pre-existing vascular disease.10Varga Z Flammer AJ Steiger P et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Summary Full Text Full Text PDF PubMed Scopus (3669) Google Scholar The simultaneous presence of vascular inflammation and coagulopathy might explain the high incidence of thromboembolic complications in patients with COVID-19.6Di Minno A Ambrosino P Calcaterra I Di Minno MND COVID-19 and venous thromboembolism: a meta-analysis of literature studies.Semin Thromb Hemost. 2020; 46: 763-771Crossref PubMed Scopus (135) Google Scholar Direct endothelial infection by SARS-CoV-2 might also explain the remarkable fibrinolytic profile of COVID-19, as the endothelium is the principal storage site of plasminogen activators. Experiments in mice with a targeted deletion of the urokinase-type plasminogen gene pointed to a urokinase-driven pathway as an important factor in mortality.11Gralinski LE Bankhead A Jeng S et al.Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury.mBio. 2013; 4: e00271-e00313Crossref PubMed Scopus (200) Google Scholar It is likely that inflammation-driven endothelial cell perturbation results in substantial release of plasminogen activators, which might explain the high levels of D-dimer in the most severely affected patients with COVID-19. Also, plasmin effects on metalloproteinases can result in extracellular matrix modification, expediting capillary leakage and lung oedema. Of note, the effects on plasminogen activators do not translate into a hyperfibrinolytic state or an increased risk of systemic bleeding in patients with COVID-19. Endothelial infection and ensuing endothelial cell injury can provide an excellent scaffold for intravascular thrombus formation. It might also cause thrombotic microangiopathy in the microvasculature due to increased platelet–vessel wall interaction, as a consequence of the release of high-molecular-weight multimerS of von Willebrand factor that are insufficiently cleaved by deficient ADAMTS13. A marked relationship exists between bronchoalveolar coagulation and fibrinolysis, and the development of ARDS, in which intrapulmonary fibrin deposition as a result of deranged bronchoalveolar fibrin turnover is a crucial step. The clinical and laboratory picture of ARDS in ventilated patients with COVID-19 and important coagulation abnormalities suggests a potential role for bronchoalveolar fibrin turnover in the most severe disease. As local and systemic immunothrombosis seem to have a central role in pulmonary and extrapulmonary vascular complications in Covid-19, therapeutic intervention in this process seems rational.12Bonaventura A Vecchié A Dagna L et al.Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.Nat Rev Immunol. 2021; 21: 319-329Crossref PubMed Scopus (306) Google Scholar Besides general anti-inflammatory strategies (eg, dexamethasone), anti-IL-6 approaches have proved to be effective, as reviewed in this Series by Federico Angriman and colleagues.8Angriman F Ferreyro BL Burry L et al.Interleukin-6 blockade in patients with COVID-19: placing clinical trials into context.Lancet Respir Med. 2021; (published online April 27.)https://doi.org/10.1016/S2213-2600(21)00139-9Summary Full Text Full Text PDF PubMed Scopus (59) Google Scholar Antithrombotic prophylaxis is another approach that might be beneficial. In a retrospective study of 449 patients who were admitted to hospital with severe COVID-19, mortality was lower in those who received prophylactic heparin than in patients who did not receive anticoagulant treatment;13Tang N Bai H Chen X Gong J Li D Sun Z Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Crossref PubMed Scopus (2098) Google Scholar among participants with more extensive coagulopathy, mortality was lower in heparin-treated patients. In fact, ample evidence exists to support the use of prophylactic low-molecular-weight heparin for the prevention of venous thromboembolism in all critically ill patients. Although the hypercoagulable state and the increased risk of thrombosis in patients with severe COVID-19 suggest that higher doses of heparin might be beneficial, this was not shown in a large randomised controlled trial,14INSPIRATION InvestigatorsEffect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit.JAMA. 2021; 325: 1620-1630Crossref PubMed Scopus (346) Google Scholar and higher doses of heparin were associated with more haemorrhagic complications. Ongoing large, randomised studies—eg, REMAP-CAP (EudraCT 2015-002340-14) and RECOVERY (2020-001113-21)—are investigating the addition of antiplatelet agents to the antithrombotic regime. We declare no competing interests. The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entityThe zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. Full-Text PDF Interleukin-6: obstacles to targeting a complex cytokine in critical illnessCirculating concentrations of the pleiotropic cytokine interleukin-6 (IL-6) are known to be increased in pro-inflammatory critical care syndromes, such as sepsis and acute respiratory distress syndrome. Elevations in serum IL-6 concentrations in patients with severe COVID-19 have led to renewed interest in the cytokine as a therapeutic target. However, although the pro-inflammatory properties of IL-6 are widely known, the cytokine also has a series of important physiological and anti-inflammatory functions. Full-Text PDF Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into contextThe pleiotropic cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis of COVID-19, but uncertainty remains about the potential benefits and harms of targeting IL-6 signalling in patients with the disease. The efficacy and safety of tocilizumab and sarilumab, which block the binding of IL-6 to its receptor, have been tested in adults with COVID-19-related acute respiratory illness in randomised trials, with important differences in trial design, characteristics of included patients, use of co-interventions, and outcome measurement scales. Full-Text PDF A tricompartmental model of lung oxygenation disruption to explain pulmonary and systemic pathology in severe COVID-19The emergent 21st century betacoronaviruses, including SARS-CoV-2, lead to clinicopathological manifestations with unusual features, such as early-onset chest pain, pulmonary infarction, and pulmonary and systemic thromboembolism that is pathologically linked to extensive capillary, arteriolar, and venular thrombosis. Early ground glass opacities detected by CT, which are reminiscent of lung infarcts associated with pulmonary embolism, point to a novel vascular pathology in COVID-19. Under physiological conditions, normal parenchymal oxygenation is maintained by three sources: the alveolus itself and dual oxygen supply from the pulmonary and bronchial artery circulations. Full-Text PDF