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COVID-19 is associated with relative ADAMTS13 deficiency and VWF multimer formation resembling TTP
medRxiv - Infectious Diseases Pub Date : 2020-08-25 , DOI: 10.1101/2020.08.23.20177824
Adrian A. N. Doevelaar , Martin Bachmann , Bodo Hoelzer , Felix S Seibert , Benjamin S Rohn , Frederic Bauer , Oliver Witzke , Ulf Dittmer , Michael Bachmann , Serap Yilmaz , Rita Dittmer , Sonja Schneppenheim , Nina Babel , Ulrich Budde , Timm H. Westhoff

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:

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。
更新日期:2020-08-25
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