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Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy
Preprint
en Inglés
| medRxiv
| ID: ppmedrxiv-20159608
ABSTRACT
BackgroundEarly 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. MethodsWe 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. ResultsAcross 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 -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). ConclusionsWe 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?O_LIIn 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 -defensins. C_LIO_LIIncreased plasma FXIII alters fibrin structure and enhances incorporation of VWF into fibrin clusters. C_LIO_LIDefective fibrin structure, coupled with increased plasma PAI-1 and 2-antiplasmin, inhibits fibrinolysis by t-PA/plasmin. C_LI What are the clinical implications?O_LIProphylactic anticoagulation and management of thrombotic complications in COVID-19 patients are ongoing challenges requiring a better understanding of the coagulopathic mechanisms involved. C_LIO_LIWe have identified FXIII and VWF as potential therapeutic targets for treating fibrin formation defects in COVID-19 patients. C_LIO_LIWe 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. C_LI
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Texto completo:
Disponible
Colección:
Preprints
Base de datos:
medRxiv
Tipo de estudio:
Estudio observacional
/
Estudio pronóstico
Idioma:
Inglés
Año:
2020
Tipo del documento:
Preprint