Vascular mechanisms and manifestations of COVID-19

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 colleagues¹ 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 colleagues² 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.³ 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.⁴ 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-analysis⁵ 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.⁶ 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-19.⁶ 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).⁷ Similar pathological observations have been made in the vasculature of other organs.

In severe COVID-19, systemic levels of proinflammatory cytokines are markedly increased.² 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.⁸ 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 colleagues⁹ 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.¹⁰ The simultaneous presence of vascular inflammation and coagulopathy might explain the high incidence of thromboembolic complications in patients with COVID-19.⁶ 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.¹¹ 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.¹² 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.⁸ 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;¹³ 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,¹⁴ 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.

© 2021 Springer Medizin/SPL

We declare no competing interests.