Background: Thrombotic microangiopathy (TMA) has been repeatedly described in COVID-19 and may contribute to SARS-CoV-2 associated hypercoagulability. The underlying mechanisms remain elusive. We hypothesized that endothelial damage may lead to substantially increased concentrations of Von Willebrand Factor (VWF) with subsequent relative deficiency of ADAMTS13. Methods: A prospective controlled trial was performed on 75 patients with COVID-19 of mild to critical severity and 10 healthy controls. VWF antigen (VWF:Ag), ADAMTS13 and VWF multimer formation were analyzed in a German hemostaseologic laboratory. Results: VWF:Ag was 4.8 times higher in COVID-19 patients compared to healthy controls (p<0.0001), whereas ADAMTS13 activities were not significantly different (p=0.24). The ADAMTS13/VWF:Ag ratio was significantly lower in COVID-19 than in the control group (24.4±20.5 vs. 79.7±33.2, p<0.0001). Fourteen patients (18.7%) undercut a critical ratio of 10 as described in thrombotic thrombocytopenic purpura (TTP). Gel analysis of multimers resembled the TTP constellation with loss of the largest multimers in 75% and a smeary triplet pattern in 39% of the patients. The ADAMTS13/VWF:Ag ratio decreased continuously from mild to critical disease (ANOVA p=0.026). Moreover, it differed significantly between surviving patients and those who died from COVID-19 (p=0.001) yielding an AUC of 0.232 in ROC curve analysis. Conclusion: COVID-19 is associated with a substantial increase in VWF levels, which can exceed the ADAMTS13 processing capacity resulting in the formation of large VWF multimers identical to TTP. The ADAMTS13/VWF:Ag ratio is an independent predictor of severity of disease and mortality. These findings render further support to perform studies on the use of plasma exchange in COVID-19 and to include VWF and ADAMTS13 in the diagnostic workup.

中文翻译：

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COVID-19与ADAMTS13相对缺乏和类似TTP的VWF多聚体形成有关

背景：血栓性微血管病（TMA）已在COVID-19中重复描述，可能与SARS-CoV-2相关的高凝性有关。潜在的机制仍然难以捉摸。我们假设内皮损伤可能导致血管性假血友病因子（VWF）的浓度显着升高，随后ADAMTS13相对缺乏。方法：一项前瞻性对照试验在75例轻至重度的COVID-19患者和10例健康对照者中进行。在德国血液酶实验室对VWF抗原（VWF：Ag），ADAMTS13和VWF多聚体形成进行了分析。结果：与健康对照组相比，COVID-19患者的VWF：Ag高4.8倍（p <0.0001），而ADAMTS13活性无显着差异（p = 0.24）。ADAMTS13 / VWF：在COVID-19中，Ag比率显着低于对照组（24.4±20.5对79.7±33.2，p <0.0001）。如血栓性血小板减少性紫癜（TTP）中所述，有14名患者（18.7％）的临界比率降低了10。多聚体的凝胶分析与TTP星座相似，最大的多聚体损失了75％，而油污三联体模式则损失了39％。ADAMTS13 / VWF：Ag比率从轻度到重度持续下降（ANOVA p = 0.026）。此外，在幸存的患者和死于COVID-19的患者之间差异显着（p = 0.001），ROC曲线分析得出的AUC为0.232。结论：COVID-19与VWF水平的大幅增加有关，可以超过ADAMTS13的处理能力，导致形成与TTP相同的大型VWF多聚体。ADAMTS13 / VWF：银比是疾病严重程度和死亡率的独立预测因子。这些发现为在COVID-19中使用血浆交换进行研究以及在诊断检查中包括VWF和ADAMTS13提供了进一步的支持。