key: cord-0992988-zbr3kfv2
authors: von Meijenfeldt, Fien A.; Havervall, Sebastian; Adelmeijer, Jelle; Thalin, Charlotte; Lisman, Ton
title: Persistent endotheliopathy in the pathogenesis of long COVID syndrome: Comment from von Meijenfeldt et al.
date: 2021-11-22
journal: J Thromb Haemost
DOI: 10.1111/jth.15580
sha: 6619f5594142ec1c98ae42dade65ef51db921d75
doc_id: 992988
cord_uid: zbr3kfv2

To the Editor: With great interest we read the recent brief report by dr. Fogarty and colleagues providing evidence for persistent endothelial cell activation in convalescent COVID-19 patients [1]. The authors showed that plasma levels of von Willebrand factor (VWF), factor VIII, and soluble thrombomodulin were elevated at a median of 68 days after initial COVID-19 symptom resolution or discharge from the hospital. Interestingly, not all these patients experienced severe disease. Levels of endothelial injury markers were associated with long-term symptoms, including dyspnoea, fatigue and concentration impairment, often referred to as long COVID.

displays the hemostatic status of COVID-19 patients on admission and 4, 8, and 12 months after hospital discharge. D-dimer levels that are known to be markedly elevated during COVID-19 infection declined to comparably low levels at 4-, 8-, and 12-month follow-up, although levels remained numerically higher than in healthy controls. VWF and FVIII also decreased over time and were comparable to levels in healthy controls 12 months after hospital discharge. Plasminogen activator inhibitor type 1 (PAI-1) levels were substantially elevated on admission and at 4 months after discharge, 3 and, despite a gradual decline, remained significantly elevated both 8 and 12 months after hospital discharge compared to levels found in healthy controls, which may be related to obesity, which is known to be associated with elevated PAI-1 levels. 4 In addition, clot lysis time, which is determined in part by PAI-1 plasma levels, remained significantly prolonged at 8-and 12-month follow-ups compared to healthy controls. Thrombin generation potential was still elevated at 8 months post-hospital discharge, but was comparable to healthy controls at 12 months. Interestingly, a recent study using rotational thromboelastometry to assess clot formation and fibrinolysis showed normalization of these parameters at 6 months after discharge of the intensive care for COVID-19. 5 Next, we assessed functional impairment of convalescent COVID-19 patients 8 and 12 months after hospital discharge.

Notably, approximately 15% of patients reported marked impair- (Table S1 in supporting information).

In conclusion, our results suggest that endothelial cell activation and plasma hypercoagulability assessed with thrombin generation assays persist up to 8 months after hospital discharge, and normalize after 1 year. A hyperfibrinolytic state persists at 12 months, but this may be related to obesity. In this study, hemostatic markers were not associated with functional impairment scored by patients, 

which contrasts with the data from Fogarty and colleagues, which were scored at a median of 68 days after symptom resolution or hospital discharge. We determined functional impairment scores at 8 and 12 months after initial disease. Functional impairment scores at 4 months were not available in our cohort, nor did we perform a 6-min walking test as described by Fogarty et al. We concur that ongoing endothelial cell activation and hypercoagulability may contribute to long COVID, although our data indicate that larger and more detailed investigations into factors that contribute to long COVID are warranted.

The authors have no conflicts of interest to disclose. 

Persistent endotheliopathy in the pathogenesis of long COVID syndrome

Sustained prothrombotic changes in COVID-19 patients 4 months after hospital discharge

Prothrombotic changes in patients with COVID-19 are associated with disease severity and mortality

Increased plasminogen activator inhibitor results in a hypofibrinolytic state in adolescents with obesity: in vivo and ex vivo evidence

Hemostasis and fibrinolysis in COVID-19 survivors 6 months after intensive care unit discharge