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COVID19 Severe Lung Injury

The most common pattern of coagulopathy in patients hospitalized with COVID-19 is an elevation in D-Dimer and fibrinogen in association with a rise in inflammatory markers such as CRP. Unlike classic DIC, prolongation of PT and aPTT is minimal and thrombocytopenia is mild. Lupus anticoagulants have been reported in some patients who have a prolonged aPTT.

Elevated D-Dimer at admission and markedly increasing D-Dimer levels over time are associated with increased likelihood of mortality. Increased D-Dimer is most likely due to activation of the fibrinolytic pathway following thrombosis.

The risk of hospitalization, morbidity, and mortality from COVID19 is highest for older patients with preexisting conditions such as hypertension, diabetes, cardiovascular disease and obesity. A common theme of all these comorbidities is their association with vascular inflammation and endothelial dysfunction.

A recent autopsy report compared the histologic patterns of lungs from patients who died from influenza with patients who died from COVID19. Both groups had diffuse alveolar damage with hyaline membranes and perivascular T-lymphocyte infiltrates. The lungs from patients with COVID19 had distinctive vascular features due to invasion of endothelial cells with SARS-CoV-2, resulting in disruption of cell membranes and severe endothelial injury. This caused microangiopathy and widespread thrombosis in the small vessels and capillaries of the lungs. Alveolar capillary microthrombi were nine times more prevalent in patients who died from COVID19 compared to patients with influenza. Tissue ischemia secondary to thrombosis led to angiogenesis and new vessel growth.

Endothelial cells possess ACE2 receptors like cells lining the respiratory tract. SARS-CoV-2 may directly infect endothelial cells by binding to their ACE2 receptors. Infection of endothelial cells, endothelial cell disruption and subsequent perivascular inflammation has been termed endothelialitis. Endothelial cell injury exposes capillary basement membranes and activates the coagulation cascade. Activated endothelial cells express P-selectin, von Willebrand factor (VWF) and fibrinogen, which enhances platelet adhesion. Activated platelets release VEGF which triggers endothelial cells to upregulate expression of tissue factor. Together, these events can lead to thrombosis and tissue ischemia.

An imbalance of VWF and ADAMTS13 may also play a role in COVID19 associated coagulopathy. Activated platelets secrete VWF, which facilitates binding of platelets to sub-endothelium through its interactions with collagen. ADAMTS13 regulates hemostasis by cleaving prothrombotic ultra-large VWF multimers that are secreted from endothelial cells into hemostatically active high molecular weight multimers.

VWF is an acute-phase response protein released by activated endothelial cells in response to inflammatory stimuli. In the event of vascular injury, VWF facilitates binding of platelets to sub-endothelium through its interactions with collagen, thereby inducing thrombus formation. VWF also binds to neutrophil extracellular traps (NETs) released from activated neutrophils and recruits additional platelets and leukocytes which further promote thrombosis.

In contrast, ADAMTS13 is a negative acute response protein. Its activity decreases in response to inflammation. Release of proinflammatory mediators during the severe phase of COVID-19 may increase secretion of ultra-large VWF multimers and decrease secretion of ADAMTS13 leading to thrombosis and thrombocytopenia.

SARS-CoV-2 induced microangiopathy and thrombosis may be responsible for the very low oxygen saturation levels observed in patients with COVID19. SARS-CoV-2 causes severe lung injury and reduces tissue oxygenation not only by causing pneumonia and adult respiratory distress syndrome (ARDS), but also by promoting thrombosis.


Lee AYY et al. COVID-19 and coagulopathy: Frequently asked questions. Version 3, may 18, 2020,

Ackermann M, et al. Pulmonary vascular endothelialitis, thrombosis and angiogenesis in Covid-19. N Engl J Med, May 21, 2020, DOI: 10.1056/NEJMoa2015432

Fox SE, et al. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. The Lancet, Published online May 27, 2020.

Katneni UK et al. Consumptive coagulopathy and thrombosis during severe COVID-19 infection: Potential involvement of VWF/ADAMTS13, doi:10.20944/preprints202005.0385.v1

Teuwen LA et al. COVID-19: the vasculature unleashed. Nature Reviews s41577-020-0343-0

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