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
Department of Internal Medicine, Ospedale Maggiore "Carlo Alberto Pizzardi", 40133 Bologna, Italy.
Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
Int J Mol Sci. 2025 Jun 4;26(11):5395. doi: 10.3390/ijms26115395.
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.
重症新型冠状病毒肺炎（COVID-19）常伴有凝血病和血栓形成并发症。其潜在机制复杂且多因素，涉及血小板活化、补体级联反应失调、纤维蛋白溶解失衡、促炎细胞因子释放、免疫血栓形成、抗磷脂抗体以及血管性血友病因子（vWF）/ADAMTS13轴的改变。这些途径也与血栓性微血管病（TMA）有关，其特征为内皮损伤和广泛的微血管血栓形成。在这项前瞻性单中心观察性研究中，我们调查了COVID-19相关凝血病是否符合TMA标准，并评估补体激活和vWF/ADAMTS13失衡在疾病严重程度中的作用。43例住院的COVID-19患者入组并按疾病严重程度分层。对入院时采集的血样进行血液学、凝血、炎症和补体参数分析。进行为期30天的随访，记录生存情况和血栓形成事件。所有患者的vWF和因子VIII水平均升高；然而，只有vWF胶原结合活性（vWF-CBA）与疾病严重程度显著相关。所有病例中ADAMTS13活性均保持在60%以上，且未检测到裂体细胞，不支持经典TMA的诊断。尽管如此，严重病例中vWF-CBA/ADAMTS13比值显著更高，尤其是未接种疫苗的个体，提示内皮功能失调。补体分析显示重症疾病中C5a水平升高，C3b/iC3b比值降低，与补体激活和消耗一致。这些患者的C2水平也较低。虽然补体激活和vWF/ADAMTS13失衡没有直接相关性，但这两条途径根据疾病严重程度显示出相似的趋势。总体而言，我们的研究结果表明，COVID-19相关凝血病不符合经典TMA标准，但显示出补体介导的内皮损伤和vWF失调的特征。vWF-CBA可作为评估内皮功能障碍的快速、标准化工具。补体系统的激活，尤其是通过凝集素和替代途径的激活，似乎是重症COVID-19血栓前状态的核心。
