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Crit Care Med
. 2021 Feb 15.
doi: 10.1097/CCM.0000000000004918. Online ahead of print.
von Willebrand Factor Multimer Formation Contributes to Immunothrombosis in Coronavirus Disease 2019
Adrian A N Doevelaar 1 , Martin Bachmann, Bodo H?lzer, Felix S Seibert, Benjamin J Rohn, Frederic Bauer, Oliver Witzke, Ulf Dittmer, Michael Bachmann, Serap Yilmaz, Rita Dittmer, Sonja Schneppenheim, Nina Babel, Ulrich Budde, Timm H Westhoff
Affiliations
- PMID: 33591004
- DOI: 10.1097/CCM.0000000000004918
Abstract
Objectives: Prevention and therapy of immunothrombosis remain crucial challenges in the management of coronavirus disease 2019, since the underlying mechanisms are incompletely understood. We hypothesized that endothelial damage may lead to substantially increased concentrations of von Willebrand factor with subsequent relative deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13).
Design: Prospective controlled cross-over trial.
Setting: Blood samples of patients with confirmed coronavirus disease 2019 and healthy controls were obtained in three German hospitals and analyzed in a German hemostaseologic laboratory.
Patients: Seventy-five patients with confirmed coronavirus disease 2019 of mild to critical severity and 30 healthy controls.
Measurements and main results: von Willebrand factor antigen, ADAMTS13, and von Willebrand factor multimer formation were analyzed. von Willebrand factor antigen was 4.1 times higher in COVID-19 patients compared with healthy controls (p < 0.0001), whereas ADAMTS13 activities were not significantly different (p = 0.18). The ADAMTS13/von Willebrand factor antigen ratio was significantly lower in COVID-19 than in the control group (24.4 ? 20.5 vs 82.0 ? 30.7; p < 0.0001). Fourteen patients (18.7%) undercut a critical ratio of 10 as described in thrombotic thrombocytopenic purpura. Gel analysis of multimers resembled a thrombotic thrombocytopenic purpura pattern with loss of the largest multimers in 75% and a smeary triplet pattern in 39% of the patients. The ADAMTS13/von Willebrand factor antigen ratio decreased continuously from mild to critical disease (analysis of variance p = 0.026). Furthermore, it differed significantly between surviving patients and those who died from COVID-19 (p = 0.001) yielding an area under the curve of 0.232 in receiver operating characteristic curve curve analysis.
Conclusion: COVID-19 is associated with a substantial increase in von Willebrand factor levels, which can exceed the ADAMTS13 processing capacity resulting in the formation of large von Willebrand factor multimers indistinguishable from thrombotic thrombocytopenic purpura. The ADAMTS13/von Willebrand factor antigen ratio is an independent predictor of severity of disease and mortality. These findings provide a rationale to consider plasma exchange as a therapeutic option in COVID-19 and to include von Willebrand factor and ADAMTS13 in the diagnostic workup.