Is COVID-19 Coagulopathy a Thrombotic Microangiopathy? A Prospective, Observational Study
Silingardi, Mauro; Zappulo, Fulvia; Dormi, Ada; Pizzini, Attilia Maria; Donadei, Chiara; Cappuccilli, Maria; Fantoni, Chiara; Zaccaroni, Stefania; Pizzuti, Valeria; Cilloni, Nicola; Tantillo, Simona; Guidi, Antonella; Mancini, Rita; La Manna, Gaetano; Comai, Giorgia
Severe COVID-19 is often associated with coagulopathy and thrombotic complications. The underlying mechanisms are complex and multifactorial, involving platelet activation, dysregulation of the complement cascade, fibrinolytic imbalance, release of pro-inflammatory cytokines, immunothrombosis, antiphospholipid antibodies, and alterations in the von Willebrand factor (vWF)/ADAMTS13 axis. These pathways are also implicated in thrombotic microangiopathies (TMAs), characterized by endothelial injury and widespread microvascular thrombosis.
In this prospective monocentric observational study, we investigated whether COVID-19-associated coagulopathy meets the criteria for TMA and evaluated the roles of complement activation and vWF/ADAMTS13 imbalance in disease severity. Forty-three hospitalized COVID-19 patients were enrolled and stratified by disease severity. Blood samples collected at admission were analyzed for hematologic, coagulation, inflammatory, and complement parameters. A 30-day follow-up recorded survival and thrombotic events.
All patients showed elevated vWF and factor VIII levels; however, only vWF collagen-binding activity (vWF-CBA) significantly correlated with disease severity. ADAMTS13 activity remained above 60% in all cases, and no schistocytes were detected, arguing against a diagnosis of classical TMA. Nevertheless, the vWF-CBA/ADAMTS13 ratio was significantly higher in severe cases, particularly in unvaccinated individuals, suggesting endothelial dysregulation. Complement analysis revealed increased C5a levels and decreased C3b/iC3b ratios in severe disease, consistent with complement activation and consumption. C2 levels were also lower in these patients. Although complement activation and vWF/ADAMTS13 imbalance did not directly correlate, both pathways showed a similar trend according to disease severity.
Overall, our findings indicate that COVID-19-related coagulopathy does not fulfill the criteria for classical TMA but shows features of complement-mediated endothelial injury and vWF dysregulation. The vWF-CBA may serve as a rapid, standardized tool for assessing endothelial dysfunction. Activation of the complement system, particularly via the lectin and alternative pathways, appears central to the prothrombotic state in severe COVID-19.
Link | PDF (International Journal of Molecular Sciences) [Open Access]
Silingardi, Mauro; Zappulo, Fulvia; Dormi, Ada; Pizzini, Attilia Maria; Donadei, Chiara; Cappuccilli, Maria; Fantoni, Chiara; Zaccaroni, Stefania; Pizzuti, Valeria; Cilloni, Nicola; Tantillo, Simona; Guidi, Antonella; Mancini, Rita; La Manna, Gaetano; Comai, Giorgia
Severe COVID-19 is often associated with coagulopathy and thrombotic complications. The underlying mechanisms are complex and multifactorial, involving platelet activation, dysregulation of the complement cascade, fibrinolytic imbalance, release of pro-inflammatory cytokines, immunothrombosis, antiphospholipid antibodies, and alterations in the von Willebrand factor (vWF)/ADAMTS13 axis. These pathways are also implicated in thrombotic microangiopathies (TMAs), characterized by endothelial injury and widespread microvascular thrombosis.
In this prospective monocentric observational study, we investigated whether COVID-19-associated coagulopathy meets the criteria for TMA and evaluated the roles of complement activation and vWF/ADAMTS13 imbalance in disease severity. Forty-three hospitalized COVID-19 patients were enrolled and stratified by disease severity. Blood samples collected at admission were analyzed for hematologic, coagulation, inflammatory, and complement parameters. A 30-day follow-up recorded survival and thrombotic events.
All patients showed elevated vWF and factor VIII levels; however, only vWF collagen-binding activity (vWF-CBA) significantly correlated with disease severity. ADAMTS13 activity remained above 60% in all cases, and no schistocytes were detected, arguing against a diagnosis of classical TMA. Nevertheless, the vWF-CBA/ADAMTS13 ratio was significantly higher in severe cases, particularly in unvaccinated individuals, suggesting endothelial dysregulation. Complement analysis revealed increased C5a levels and decreased C3b/iC3b ratios in severe disease, consistent with complement activation and consumption. C2 levels were also lower in these patients. Although complement activation and vWF/ADAMTS13 imbalance did not directly correlate, both pathways showed a similar trend according to disease severity.
Overall, our findings indicate that COVID-19-related coagulopathy does not fulfill the criteria for classical TMA but shows features of complement-mediated endothelial injury and vWF dysregulation. The vWF-CBA may serve as a rapid, standardized tool for assessing endothelial dysfunction. Activation of the complement system, particularly via the lectin and alternative pathways, appears central to the prothrombotic state in severe COVID-19.
Link | PDF (International Journal of Molecular Sciences) [Open Access]