Mechanisms of COVID-19 Associated Pulmonary Thrombosis: A Narrative Review

Abstract

COVID-19, the infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is frequently associated with pulmonary thrombotic events, especially in hospitalized patients. Severe SARS-CoV-2 infection is characterized by a proinflammatory state and an associated disbalance in hemostasis. Immune pathology analysis supports the inflammatory nature of pulmonary arterial thrombi composed of white blood cells, especially neutrophils, CD₃⁺ and CD₂₀⁺ lymphocytes, fibrin, red blood cells, and platelets. Immune cells, cytokines, chemokines, and the complement system are key drivers of immunothrombosis, as they induce the damage of endothelial cells and initiate proinflammatory and procoagulant positive feedback loops. Neutrophil extracellular traps induced by COVID-19-associated "cytokine storm", platelets, red blood cells, and coagulation pathways close the inflammation-endotheliopathy-thrombosis axis, contributing to SARS-CoV-2-associated pulmonary thrombotic events. The hypothesis of immunothrombosis is also supported by the minor role of venous thromboembolism with chest CT imaging data showing peripheral blood clots associated with inflammatory lesions and the high incidence of thrombotic events despite routine thromboprophylaxis. Understanding the complex mechanisms behind COVID-19-induced pulmonary thrombosis will lead to future combination therapies for hospitalized patients with severe disease that would target the crossroads of inflammatory and coagulation pathways.

Keywords: COVID-19; SARS-CoV-2 infection; coagulopathy; embolism; immunothrombosis; inflammation; pulmonary in situ thrombosis.

Figure 1

Normal host alveolar capillary associated immune defense system. The alveolar space is lined with alveolar epithelium, consisting of two kinds of cells: type I and type II pneumocyte; type II cells are involved in surfactant secretion (light yellow in the figure) and in local innate immune defense. They are also a target for SARS-CoV-2, which replicates inside these cells and can be further transferred into adjacent endothelial cells (ECs). The alveolar macrophages (AMφs) are placed into alveolar space, adjacent to the alveolar epithelium. AMφs are largely involved in immune defense, mainly by two processes: phagocytosis and chemoattraction of neutrophils. The alveolar-capillary layer is very thin over a large area, consisting of the adjacent membranes of both respiratory epithelium and vascular endothelium, and it is thicker where the body of these cells and other cells (fibroblasts in interstitium, mast cells (MCs) in subendothelial place) or other interstitial elements are placed. MCs are involved in COVID-19 pathogenicity. They contain granules with histamine and specific proteases. The capillary, lined with flat ECs, contains red blood cells (RBCs), platelets, and white blood cells. Neutrophils could pass into alveolar space if they are chemoattracted by activated AMφs. They are involved in the phagocytosis process. They contain granules with oxidants, that could be released outside the cell. They also can release extracellular traps (NETs) consisting of web-like structures containing DNA filaments coated with histones and granule proteins that can entrap and eliminate various pathogens.

Figure 2

The in situ immunothrombosis in COVID-19. SARS-CoV-2 replicates into the type II pneumocytes. Furthermore, SARS-CoV-2 could be transferred to adjacent ECs that have ACE-2 receptors and passed into the blood. AMφs interact with SARS-CoV-2 and activate themselves (1a). After activation, the major process in COVID-19 is the chemoattraction of neutrophils (1b). AMφs could also act like antigen presenters to T lymphocytes (1c). Neutrophils, attracted by AMφs, come into the area of the immune conflict, crawling, and squeezing (3a), and they activate and release neutrophil extracellular traps (NETosis) (3b); aberrant NETosis and oxidants released (3c) into the environment contribute to “cytokine storm” (4), tissue and vascular injuries and initiate immune-activated coagulation (6). SARS-CoV-2 activates MCs (2a) and they release histamine, other specific proteases, prostaglandins and leukotrienes, cytokines and chemokines (2b), contributing to capillary permeabilization and to the “cytokine storm” (4), ending with in situ immunothrombosis (6). Monocytes are excessively recruited in the area (5) and contribute to the “cytokine storm” (4) and to the activation of coagulation pathways (6). The blood clot (6) contains RBCs, activated platelets, fibrin, NETs, and lymphocytes supporting the immune mechanism for thrombosis.