Long-COVID- 19 syndrome: From the clinical evidences to a pathophysiological mechanism

ABSTRACT

Background: Long-COVID- 19 syndrome (LCS) is defined as symptoms persisting beyond initial phase of infection. Among them, pulmonary fibrotic damage remains in 25-30% of COVID-19 patients at 3-6 month-follow- up. We documented that acute COVID-19 patients have massive platelet activation characterized by the formation of platelet-leukocyte aggregates (PLA), that may be involved in the pulmonary microthrombi found in autoptic specimens, and by a prothrombotic phenotype. No data are currently available on contribution of platelet activation to residual pulmonary impairment and procoagulant potential in LCS patients. Aim(s) To characterize platelet activation, microvesicle (MV) profile, platelet thrombin generation capacity (pTGC) in LCS patients at 6-month- follow- up (6mo-FU) compared to acute COVID-19 infection patients. Method(s) Twentyfour 6mo-FU COVID-19 patients with established LCS defined according to their residual pulmonary impairment assessed by Cardiopulmonary Exercise Testing (CPET) and 64-rows- CT scan evaluation were enrolled. Platelet activation (P-selectin, Tissue Factor [TF] and PLA) and MV profile were evaluated by flow cytometry;pTGC by calibrated automated thrombogram. Fortysix patients enrolled during acute COVID-19 infection and 46 healthy subjects (HS) were used for comparison. Result(s) Dispnea in LCS patients was confirmed by CPET showing compromised alveolus-capillary membrane diffusion and residual pulmonary impairment. TF+-platelet and -MV levels were 3-and 2-fold lower at 6mo-FU compared to acute phase, being comparable to HS, as well as pTGC. At 6mo-FU, the MV profile (total number and derived from different cells) returned to physiological levels. Conversely, although lower than that measured in acute phase, a 2.5-fold higher platelet P-selectin expression and PLA formation was observed at 6mo-FU compared to HS. Interestingly, a significant correlation between PLA formation and residual pulmonary impairment was observed. Conclusion(s) These data strengthen the hypothesis that the presence of PLA in the bloodstream, and thus also in the pulmonary microcirculation, may contribute to support pulmonary dysfunction still observed in LCS patients.