Is COVID-19 Coagulopathy a Thrombotic Microangiopathy? A Prospective, Observational Study

Abstract

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.

Keywords: ADAMTS13; COVID-19-associated coagulopathy; complement activation; inflammatory cytokines; von Willebrand factor.

Figure 1

Difference in serum levels of C2 (A) and C5a (B) in mild vs. severe group.

Figure 2

Difference in C3b/iC3b serum levels in mild vs. severe group.

Figure 3

Cross interaction between the complement system and coagulation cascade. Complement pathways in SARS-CoV-2 infection. Activation of the lectin pathway by the virus via the MBL/MASP-1/MASP-2 complex runs out after binding of MBL/MASP complexes to the surface of pathogens. MASP-1 autoactivates and transactivates MASP-2, and C2 and C4 components are cleaved generating the C3 convertase. The alternative pathway is initiated by the spontaneous hydrolysis of component C3, generating C3a and C3b. C3b binds to factor B and is cleaved by factor D, forming the C3 convertase of the alternative pathway. After this step, the three pathways converge into a single pathway. The C3 convertase enzyme cleaves component C3 into C3a and C3b. C3a and C4a are anaphylatoxins that contribute to an increase in inflammatory processes and to the chemotaxis of neutrophils and macrophages. MASP-3 also participates in the cleavage of pro-factor D into factor D of the alternative pathway. The elements of the figure are not shown in their actual proportions. MASP activation participates in coagulation cascade activation. MASP-2 determines pro-thrombin cleavage in thrombin that promotes coagulation activation.