Re The source of elevated plasma D-dimer levels in COVID-19 infection.

Dear Sir,

Markedly elevated D‐dimer levels are seen in severe Covid‐19 infection and have been related to a poor prognosis. , D‐dimers are elevated alongside other acute inflammatory plasma markers such as fibrinogen, C‐reactive protein (CRP) and serum ferritin. The elevation of plasma D‐dimers has been taken to indicate there is a coagulopathy, and the assumption has been made that the increased fibrinolysis is secondary (due to thrombin generation), indeed an indication of disseminated intravascular coagulation (DIC). However frank DIC seems unlikely as these patients do not fulfil the International Society on Thrombosis and Haemostasis (ISTH) criteria for DIC and there is hardly consumption of coagulation factors and physiological anticoagulants; indeed fibrinogen levels are very elevated. , , ,

We propose an alternative hypothesis: we suggest that the origin of D‐dimers is a direct consequence of the acute lung injury seen in Covid‐19 pneumonia. For one, the hallmark of acute lung injury is intra‐alveolar fibrin deposition. The levels of fibrin are controlled by alveolar epithelial cells which produce urokinase and regulate extravascular proteolysis by regulating expression of urokinase‐type plasminogen activator (uPA), its receptor uPAR, and plasminogen activator inhibitor‐1 (PAI‐1) at post‐transcriptional levels. Urokinase then converts plasminogen to plasmin, which cleaves local fibrin.

Covid‐19 infection has many clinical and histological similarities to Severe Acute Respiratory Syndrome Coronoavirus (SARS‐CoV). Gralinski et al. have shown in a mouse model of SARS‐CoV a critical role for the urokinase pathway in regulating severe end‐stage lung disease outcomes following SARS‐CoV infection. They showed that the larger the dose of SARS the more severe was the clinical manifestation and greater the rise in lung urokinase expression. Lastly, another marker of Covid‐19 pneumonia is the presence of many macrophages within the lung tissue. Macrophages are well known to generate plasmin and metalloproteinases (MMPs), but they have also been described to produce fibrinolysis by an alternative pathway — fibrin and fibrinogen bind to CD11b/CD16 (also known as Mac‐1) and are internalised into lysosomes where cathepsin D can degrade fibrin and fibrinogen independently of plasmin.

Based on the above evidence we suggest it is logical to consider that D‐dimer levels, like those of other acute‐phase proteins such as CRP, ferritin and fibrinogen, which are similarly very high in severe Covid‐19 infections, represent the degree of lung inflammation present within the lungs in Covid‐19 infection. Being related to the extent of lung inflammation would therefore explain why their plasma levels relate to clinical outcome .

Conflicts of interest

The authors declare to have no potential conflicts of interest regarding the present work.