Persistent Lung Injury and Prothrombotic State in Long COVID

Abstract

Lung injury may persist during the recovery period of COVID-19 as shown through imaging, six-minute walk, and lung function tests. The pathophysiological mechanisms leading to long COVID have not been adequately explained. Our aim is to investigate the basis of pulmonary susceptibility during sequelae and the possibility that prothrombotic states may influence long-term pulmonary symptoms of COVID-19. The patient's lungs remain vulnerable during the recovery stage due to persistent shedding of the virus, the inflammatory environment, the prothrombotic state, and injury and subsequent repair of the blood-air barrier. The transformation of inflammation to proliferation and fibrosis, hypoxia-involved vascular remodeling, vascular endothelial cell damage, phosphatidylserine-involved hypercoagulability, and continuous changes in serological markers all contribute to post-discharge lung injury. Considering the important role of microthrombus and arteriovenous thrombus in the process of pulmonary functional lesions to organic lesions, we further study the possibility that prothrombotic states, including pulmonary vascular endothelial cell activation and hypercoagulability, may affect long-term pulmonary symptoms in long COVID. Early use of combined anticoagulant and antiplatelet therapy is a promising approach to reduce the incidence of pulmonary sequelae. Essentially, early treatment can block the occurrence of thrombotic events. Because impeded pulmonary circulation causes large pressure imbalances over the alveolar membrane leading to the infiltration of plasma into the alveolar cavity, inhibition of thrombotic events can prevent pulmonary hypertension, formation of lung hyaline membranes, and lung consolidation.

Keywords: COVID-19; anticoagulation; long COVID; phosphatidylserine; therapy; thrombosis.

Figure 1

Common pathological changes in the lungs of patients with COVID-19. (A) SARS-COV-2 enters local alveolar type II cells along the airway, replicates, and damages the targeted cells. Various immune cells are mobilized and activated wherever the virus goes, inducing the release of inflammatory factors such as MCP-1, GM-CSF, IL-1β, TNF-α, IL-6, IFN-γ, etc. The inflammatory response produced in killing the virus also leads to the injury of alveolar type I and type II cells. When high viral load accompanies the inflammatory response, the air-blood barrier is destroyed on the alveolar side. The virus has the opportunity to invade vascular endothelial cells by crossing the local air-blood barrier, and strong cytokine responses can also spread to vascular endothelial cells. As the permeability of the blood-air barrier increases, blood components enter the alveolar cavity, forming pulmonary edema. (B) Significantly enhanced thrombin and elevated levels of endothelial cell biomarkers (vWF: Ag, vWFpp, FVIII, and sTM) were observed in the convalescence period. Impaired pulmonary vascular endothelium can cause uncontrolled activation of coagulation cascades, further leading to vascular thrombosis or fatal pulmonary fibrosis. (C) The initial response to the destruction of the alveolar epithelial-endothelial barrier is edematous infiltration in the alveoli and interstitial portion, followed by proliferation as the alveolar barrier is rebuilt by removing exudate. Extracellular matrix deposition occurs. Fibroblasts migrate and transform into muscle cells. (D) The damaged blood-air barrier, impaired pulmonary blood perfusion, reduced effective volume of alveolar cavities and the appearance of fibrosis all lead to the obstruction of the exchange of oxygen and carbon dioxide.

Figure 2

The function of PS. (A) PS acts as a signal to be engulfed by macrophages with two recognition modes. One is directly recognized by phagocytic receptors BAI1, TIM-4, and Stabilin 2. The other is indirect recognition. The bridging molecules MFG-E8 (also known as lactadherin) and GAS6 bind to PS, which is recognized by membrane proteins MER and α_Vβ₃. These two recognition patterns are not mutually exclusive and may co-occur. (B) PS provides a negatively charged surface to initiate and maintain coagulation. In normal conditions, PS is sequestered in the inner layer of cell membranes by the action of floppase and flippase. When intracellular Ca²⁺ increases, the ATP-dependent translocation enzyme is blocked, and the scramblase is activated, resulting in a random distribution of PS to both sides of the membrane. PS, initially located in the cell’s inner membrane, is exposed to the outer side. On the outer membrane, PS provides active clotting catalytic surfaces for forming TF-FVIIa complex, factor X-enzyme complex (FIXa-FVIIIa-Ca²⁺-PL), and prothrombinase complex (FXa-FVa-Ca²⁺-PL).