Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy
Authors: South Kieron , Roberts Lucy , Morris Lucy , Mann Elizabeth R. , Menon Madhvi , Knight Sean Blandin , Konkel Joanne E. , Ustianowski Andrew , Bakerly Nawar Diar , Dark Paul , Simpson Angela , Felton Timothy , Horsley Alexander ,   CIRCO, Hussell Tracy , Grainger John R. , Smith Craig J. , Allan Stuart M. 
Published: August 2020

Background

Early clinical reports have suggested that the prevalence of thrombotic complications in the pathogenesis of COVID-19 may be as high as 30% in intensive care unit (ICU)-admitted patients and could be a major factor contributing to mortality. However, mechanisms underlying COVID-19-associated thrombo-coagulopathy, and its impact on patient morbidity and mortality, are still poorly understood.

Methods

We performed a comprehensive analysis of coagulation and thromboinflammatory factors in plasma from COVID-19 patients with varying degrees of disease severity. Furthermore, we assessed the functional impact of these factors on clot formation and clot lysis.

Results

Across all COVID-19 disease severities (mild, moderate and severe) we observed a significant increase (6-fold) in the concentration of ultra-large von Willebrand factor (UL-VWF) multimers compared to healthy controls. This is likely the result of an interleukin (IL)-6 driven imbalance of VWF and the regulatory protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Upregulation of this key pro-coagulant pathway may also be influenced by the observed increase (~6-fold) in plasma α-defensins, a consequence of increased numbers of neutrophils and neutrophil activation. Markers of endothelial, platelet and leukocyte activation were accompanied by increased plasma concentrations of Factor XIII (FXIII) and plasminogen activator inhibitor (PAI)-1. In patients with high FXIII we observed alteration of the fibrin network structure in in vitro assays of clot formation, which coupled with increased PAI-1, prolonged the time to clot lysis by the t-PA/plasmin fibrinolytic pathway by 52% across all COVID-19 patients (n=23).

Conclusions

We show that an imbalance in the VWF/ADAMTS13 axis causing increased VWF reactivity may contribute to the formation of platelet-rich thrombi in the pulmonary vasculature of COVID-19 patients. Through immune and inflammatory responses, COVID-19 also alters the balance of factors involved in fibrin generation and fibrinolysis which accounts for the persistent fibrin deposition previously observed in post-mortem lung tissue.

What is new?

In all COVID-19 patients, even mild cases, UL-VWF is present in plasma due to the alteration of VWF and ADAMTS13 concentrations, likely driven by increased IL-6 and α-defensins.

Increased plasma FXIII alters fibrin structure and enhances incorporation of VWF into fibrin clusters.

Defective fibrin structure, coupled with increased plasma PAI-1 and α2-antiplasmin, inhibits fibrinolysis by t-PA/plasmin.

What are the clinical implications?

Prophylactic anticoagulation and management of thrombotic complications in COVID-19 patients are ongoing challenges requiring a better understanding of the coagulopathic mechanisms involved.

We have identified FXIII and VWF as potential therapeutic targets for treating fibrin formation defects in COVID-19 patients.

We have identified a multifaceted fibrinolytic resistance in COVID-19 patient plasma with potential implications in the treatment of secondary thrombotic events such as acute ischaemic stroke or massive pulmonary embolism.