key: cord-0734870-obrjpij3
authors: Keragala, Charithani B.; Medcalf, Robert L.; Myles, Paul S.
title: Fibrinolysis and COVID‐19: a tale of two sites?
date: 2020-07-21
journal: J Thromb Haemost
DOI: 10.1111/jth.15017
sha: fb76f1e38291947f2786814915d92fc3f165f1f7
doc_id: 734870
cord_uid: obrjpij3

We thank Tang et al. for their perspective on the possible limitation of D‐dimer levels guiding anticoagulant treatment in patients with COVID‐19 [1]. Although there is a clear association with elevated D‐dimer and severity of COVID‐19 disease, it is important to highlight the fact that D‐dimer has always been utilised in conjunction with clinical pre‐test probability, as a predictive tool to help exclude a possible diagnosis of venous thromboembolism. It has never been validated to guide clinical treatment or anticoagulation. It has recently been noted that a significant proportion of the recent literature concerning D‐dimer in COVID‐19 is fraught with variable, poor or incomplete reporting which further muddies its role in the management of COVID‐19 related coagulopathy[2].

We thank Tang et al. for their perspective on the possible limitation of D-dimer levels guiding anticoagulant treatment in patients with COVID-19 [1] . Although there is a clear association with elevated D-dimer and severity of COVID-19 disease, it is important to highlight the fact that Ddimer has always been utilised in conjunction with clinical pre-test probability, as a predictive tool to help exclude a possible diagnosis of venous thromboembolism. It has never been validated to guide clinical treatment or anticoagulation. It has recently been noted that a significant proportion of the recent literature concerning D-dimer in COVID-19 is fraught with variable, poor or incomplete reporting which further muddies its role in the management of COVID-19 related coagulopathy [2] . 

This article is protected by copyright. All rights reserved reported a plasma half-life of 12 h [5] while a study in 2000 reported a plasma half-life of PAP complexes to be ~4.5 h [6] .

Another point about PAP levels is the degree to which changes in PAP levels reflect changes in fibrinolysis. Fibrin formation was aptly described by Gaffney et al. to "orchestrate its own destruction" [7] by initiating plasminogen activation. While this will also result in an increase in PAP levels, it is important to highlight the fact that increases or decreases in PAP levels may not necessarily reflect changes in fibrinolysis, since misfolded and aggregated proteins can also promote plasminogen activation [8, 9] and generate PAP complexes. Hence the reduction in PAP levels shown in the non-surviving group, while consistent with a reduction in fibrinolysis actually indicates that plasminogen activation has been reduced overall.

Taken together, these data are consistent with our view that the fibrinolytic system is initially activated and then suppressed in patients developing the more severe grades of COVID-19. We proposed that this could be a consequence of consumption due to the overwhelming production of fibrin [10] , however active suppression or shutdown may also be occurring due to an elevation of PAI-1, although this has yet to be confirmed.

The use of plasma as a source for monitoring changes in fibrinolysis is perfectly reasonable when evaluating systemic fibrinolysis. But in the case of COVID-19, the integrity and responsiveness of the fibrinolytic system within the lung parenchyma is also critical and this may indeed be different to the circulation. So are there actually two fibrinolytic systems that we need to consider in patients with COVID-19? It is well-known that the main plasminogen activator that initiates plasmin formation in the lung is in fact urokinase (u-PA) [11] [12] [13] [14] rather than t-PA, and it would therefore seem important to also evaluate uPA, together with other parameters of the fibrinolytic 

Sun, Z, Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant

Reporting of D-dimer data in COVID-19: some confusion and potential for misinformation

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Plasma D-dimers in the diagnosis of venous thromboembolism

Formation, inhibition and clearance of plasmin in vivo

The haemostatic balance --Astrup revisited

A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury

Nucleocytoplasmic Coagulation: An Injury-Induced Aggregation Event that

Disulfide Crosslinks Proteins and Facilitates Their Removal by Plasmin

Fibrinolysis and COVID-19: a plasmin paradox

Alveolar epithelial cells express both plasminogen activator and tissue factor. Potential role in repair of lung injury

Disorders of lung matrix remodeling

Plasminogen-plasmin system in the pathogenesis and treatment of lung and pleural injury

Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio

Plasminogen improves lung lesions and hypoxemia in patients with COVID-19

Accepted Article