Role of Hemostatic Biomarkers for the Identification of Patients with LONG-COVID19 Syndrome: Results from the 'Accordi' Study

Introduction: Hemostatic alterations of patients with acute Covid-19 are well described, while post-Covid-19 clinical and laboratory consequences are less clear. Survivors of Covid-19 exhibit a complex array of symptoms, whose underlying pathology is still to be elucidated. The term 'long-Covid' is used to describe this condition developing after acute Covid-19.

Materials and Methods: After the first wave of the pandemic, we started an ad hoc multidisciplinary follow-up project for Covid-19 patients discharged from our Institution (ACCORDI STUDY). The program was run from July to November 2020. Patients were reassessed one time for clinical, instrumental, and laboratory parameters. Blood samples were collected from each participant for the measurement of hemostatic biomarkers. Here we present the first interim analysis of the biomarkers study.

The laboratory study included complete blood cell count, liver and renal functional tests, LDH, C-reactive protein, fibrinogen, D-dimer (DD), von Willebrand factor antigen (vWF:Ag), thrombomodulin (TM), tissue plasminogen activator (tPA) and plasminogen activator inhibitor PAI-1, prothrombin fragment 1+2 (F1+2).

Results: A cohort of 1471 (554F/917M) patients was recruited in the ACCORDI program with a median age of 60 (19-93). The median time from Covid-19 onset was 107 days (range 65-142). At the onset of disease, patients had the following symptoms: cardiopulmonary (94%), flu-like (91%), respiratory (82%), and neurological (57%). At the follow-up visit, cardiopulmonary symptoms persisted in 88%, flu-like in 64%, respiratory in 42%, and neurological in 13%. No differences in symptoms' distribution were present in relation to age and gender at either disease onset or follow-up visit. Based on the time of symptom persistence, 771 (53%) patients were classified as long-Covid, while the remaining 700 (47%) were symptoms-free. The median age of long-Covid patients was 59 (range 38-80) years, 55% male, with cardiopulmonary as the prevalent symptoms.

In a subgroup of 468 patients [322M/146F, age range 65 (38-83) years], 231 long-Covid and 237 symptoms-free, an interim analysis of hemostatic biomarker test results was performed. The analysis (Table 1) showed that, compared to symptoms-free subjects, long-Covid patients had significantly (p<0.05) higher levels of vWF:Ag and PAI-1. In addition, among subjects evaluated within 12 weeks from disease onset, the symptomatic subjects (n=48) had significantly higher levels of PAI-1 and TM (p<0.05) than the symptoms-free ones (n=78), whereas, among subjects evaluated after 12 weeks of disease onset (n=184), i.e. the post-Covid syndrome patients, had significantly (p<0.05) higher levels of vWF:Ag as compared to symptoms-free subjects (n=159). No significant differences were observed in the levels of tPA, DD, fibrinogen, F1+2 of symptomatic vs asymptomatic individuals. In a model of logistic regression analysis corrected for age and gender, having at least one among TM and PAI-1 biomarkers above the 75^th percentile within 12 weeks from the disease onset, was significantly associated with a diagnosis of long-Covid (OR 2.425; 95% CI:1.037-5.671; p=0.041).

Conclusions: In conclusion, in this study cohort, patients with long-Covid syndrome are characterized by the persistence of cardiopulmonary symptoms. Preliminary results on hemostatic biomarkers analysis show that endothelial (TM and vWF:Ag) and fibrinolytic (PAI) biomarkers are associated with long-Covid symptoms and may be useful for the identification of affected subjects.

No relevant conflicts of interest to declare.