COVID-19 is associated with relative ADAMTS13 deficiency and VWF multimer formation resembling TTP

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.