Mechanisms of Pulmonary Vasculopathy in Acute and Long-Term COVID-19: A Review

Abstract

Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulation, and many cases of severe acute pulmonary embolism have been reported. The demonstrated presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the endothelial cells suggests that direct viral effects, in addition to indirect effects of perivascular inflammation and coagulopathy, may contribute to pulmonary vasculopathy in COVID-19. In this review, we discuss the pathological mechanisms leading to pulmonary vascular damage during acute infection, which appear to be mainly related to thromboembolic events, an impaired coagulation cascade, micro- and macrovascular thrombosis, endotheliitis and hypoxic pulmonary vasoconstriction. As many patients develop post-COVID symptoms, including dyspnea, we also discuss the hypothesis of pulmonary vascular damage and pulmonary hypertension as a sequela of the infection, which may be involved in the pathophysiology of long COVID.

Keywords: COVID-19; endothelial dysfunction; endotheliitis; post-/long COVID; pulmonary hypertension; pulmonary vasculopathy; thrombosis.

Figure 1

Selected pathophysiological mechanisms involved in COVID-19-associated pulmonary vasculopathy. The SARS-CoV-2 cycle begins with the interaction with the ACE2 (angiotensin-converting enzyme 2) receptor on epithelial cells, macrophages, perivascular pericytes, arterial and venous endothelial cells, and arterial smooth muscle cells.

Figure 2

Schematic representation of the mechanisms through which SARS-CoV-2 induces hypercoagulability and endotheliitis.

Figure 3

Possible mechanisms of pulmonary vascular disease after COVID-19. * Pulmonary vascular disease is defined as precapillary pulmonary hypertension (PH), in turn defined by right heart catheterization as mean pulmonary artery pressure > 20 mmHg, pulmonary capillary wedge pressure ≤ 15 mmHg and pulmonary vascular resistance > 2 Wood units. COPD: chronic obstructive pulmonary disease, FGF: fibroblast growth factor; group 3 PH: pulmonary disease associated with respiratory disease; group 4 PH: chronic thromboembolic pulmonary hypertension; PDGF: platelet-derived growth factor; PH: pulmonary hypertension; and VEGF: vascular endothelial growth factor.