Resistance to fibrinolysis in critically ill patients with COVID-19 can be overcome by n-acetylcysteine in vitro

Background : Coronavirus disease 2019 (COVID-19) is associated with a significant risk of thrombosis. A resistance to fibrinolysis has been highlighted in COVID-19 patients but its clinical relevance has not been established yet. In experimental stroke models, Nacetylcysteine (NAC) promoted lysis of tPA-resistant thrombi by reducing large von Willebrand factor (vWF) multimers. Aims : To better characterize the clinical relevance of fibrinolysis resistance in COVID-19 patients and to evaluate the capacity of NAC to restore fibrinolysis in vitro . Methods : 28 critically ill patients with COVID-19 and 28 healthy controls were included in this single-center observational study. A modified thromboelastography assay (ROTEM ® Delta) using EXTEM ® reagent and 150 ng mL -1 t-PA (Actilyse ® ) was performed in the presence of 10 mM NAC or buffer. Residual percentage of clot firmness 30 min after coagulation (LI30) and time required to complete lysis (LT) assessed the efficiency of t-PA-triggered fibrinolysis. Results : Blood clots from COVID-19 patients were resistant to fibrinolysis as indicated by increased LI30 (median 94% [35-100] versus 1% [0-45], P = 0.0007) and prolonged LT (2609 s [1855-3043] versus 1560 s [1376-1994], P = 0.0003) compared to healthy controls. LI30 and LT were positively correlated with vWF levels ( r = 0.6, P = 0.009 and r = 0.5, P = 0.04, respectively), suggesting a role for vWF in fibrinolysis resistance. Resistance to tPA-induced fibrinolysis was delayed in patients with thrombosis ( n = 10) compared to patients without thrombosis, as indicated by higher LI30 (100% [97-100] versus 82.5% [0.5-97];P = 0.002) and prolonged LT (3189 s [2706-3772] versus 2217 s [1583 2840];P = 0.008). Both LI30 and LT were correlated with SOFA ( r = 0.7, P = 0.0003 and r = 0.5, P = 0.01, respectively) and Simplified Acute Physiology Score (SAPS) II scores ( r = 0.7, P = 0.0004 and r = 0.7, P = 0.0009, respectively). In vitro, NAC efficiently restored fibrinolysis in COVID-19 patient blood. Conclusions : Resistance to fibrinolysis in critically ill COVID-19 patients is associated with thrombosis and clinical severity. NAC could represent a new adjunct therapy to promote endogenous fibrinolysis in severe COVID-19 patients.