Thrombosis and COVID-19 pneumonia: the clot thickens!

Abstract

Pulmonary thrombosis appears to be common in COVID-19 pneumonia and takes two forms, proximal pulmonary emboli and/or distal thrombosis. The possible mechanisms and clinical implications are discussed. https://bit.ly/372Xdhw

FIGURE 1

Hypothesis of the origin of coronavirus disease 2019 (COVID-19)-associated pulmonary emboli and lung microcirculatory thrombotic disease: interaction of inflammation and coagulation. When severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells expressing the surface receptors angiotensin-converting enzyme 2 (ACE-2), active replication and release of the virus may cause the host cell to undergo pyroptosis (pro-inflammatory apoptosis) and release damage-associated molecular patterns (DAMPs), activating oxidant stress, and generating pro-inflammatory cytokine and chemokine release from nearby epithelial cells, endothelial cells and alveolar macrophages. These proteins in turn attract inflammatory cells to the site of infection, promoting a pro-inflammatory feedback loop. Tissue factor, usually hidden on the subendothelium, is upregulated on platelets, leukocytes and endothelial cells (ECs) during inflammation, leading to activation of both the extrinsic and intrinsic coagulation pathways to make thrombin. Complement activation is also relevant. Thrombin binds to protease-activated receptors (e.g. PAR-1) to promote the formation of fibrin from fibrinogen, the activation of platelets and subsequent clot stabilisation, also propagating further inflammation. Natural anticoagulants and fibrinolytics may also be reduced in COVID-19/SARS-CoV-2 infection. Occluded small pulmonary blood vessels are likely to contain fibrin, platelets and coagulation factors, as well as neutrophils that become trapped in neutrophil extracellular traps (NETs) as they pass through the lung. Ongoing inflammation provides a positive feedback loop. Additional procoagulant stimuli include lung hypoxia, for example via upregulation of plasminogen activator inhibitor-1 (PAI-1) through suppression of fibrinolysis. In this prothrombotic pneumonitis or acute respiratory distress syndrome, whether similar mechanisms promote both microthrombosis as well as larger vessel pulmonary embolic disease is not known.