COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.

Fig. 1

Pathophysiology for microthrombosis in patients with COVID-19. The figure summarizes hypothetical steps of the thrombotic sequence from direct or indirect of SARS-CoV-2 effects on endothelial cells inducing an endotheliopathy and a coagulopathy leading to lung obstruction and potential consequences on the right heart ventricle

Fig. 2

Autopsy studies of patients dying of COVID-19. a Hematoxylin and eosin histology demonstrated perivascular lymphocytic infiltration (10X, bar = 100um). b Higher resolution (60X) imaging of the alveolar septa demonstrating microthrombus in alveolar capillaries (black arrows). c Scanning electron microscopy of the COVID-19 lung demonstrating preserved architecture with perivascular and interstitial lymphocytes. Intravascular thrombus was visualized in many vessels (white arrows; bar = 200um). d Corrosion casting demonstrating luminal irregularities associated with endothelial injury and endothelialitis. In the affected microcirculation, innumerable intraluminal pillars (circles), seen as small holes in the cast, reflect the process of intussusceptive angiogenesis (bar = 100um)

Fig. 3

Intussusceptive angiogenesis: hypothesis for lung vessels modification in COVID-19

Fig. 4

Emergency myelopoiesis. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) released by damaged tissues after the pathogen insult are sensed by tissue-resident macrophages, hematopoietic stem and progenitor cells (HSPC), mesenchymal stroma cells (MSC) and endothelial cells (EC) via the pattern recognition receptors ie Toll-like receptors. These cells release inflammatory cytokines forcing the proliferation and differentiation of HSPC into granulocyte-monocyte progenitors (GMP), which produce neutrophils and monocytes with immunosuppressive phenotype. In severe COVID-19, immature neutrophils and dysfunctional monocytes that resemble myeloid-derived suppressive cells produce high amounts of calprotectin, which in turn amplifies the emergency myelopoiesis. IL-1: interleukin 1, IL-6: interleukin 6, IFN-γ: interferon γ, GM-CSF: granulo-monocyte colony-stimulating factor, G-CSF: granulocyte colony-stimulating factor, M-CSF: monocyte colony-stimulating factor