Acquired von Willebrand Syndrome and Desmopressin Resistance During Venovenous Extracorporeal Membrane Oxygenation in Patients With COVID-19: A Prospective Observational Study

Abstract

Objectives: Although COVID-19 is associated with high von Willebrand factor (vWF) parameters promoting thrombosis, venovenous extracorporeal membrane oxygenation (vvECMO) is associated with the development of acquired von Willebrand syndrome (AVWS) promoting bleeding. This study was designed to assess both the incidence and severity of AVWS in COVID-19 patients undergoing vvECMO, and the benefit of comprehensive vWF analyses.

Design: Prospective observational study.

Setting: ICU at a tertiary-care center.

Patients: Twenty-seven consecutive COVID-19 patients with acute respiratory distress syndrome (ARDS) requiring vvECMO.

Measurements and main results: Comprehensive vWF analyses (including sodium dodecyl-sulfate polyacrylamide gel electrophoresis) were performed before, during, and after vvECMO. In a subgroup of 12 patients with AVWS, effectiveness of treatment with desmopressin was assessed. The patients' mean age was 53 years (range, 23-73), 70% were male, and all had various comorbidities. Following markedly elevated vwf antigen (vWF: Ag; mean, 546% ( sd , 282]), vWF collagen binding capacity (mean, 469% [ sd , 271]), vWF activity (vWF:A; mean, 383% [ sd , 132]), and factor VIII activity (mean, 302% [ sd , 106]), and only borderline decreases in high-molecular-weight (HMW) vWF multimers before vvECMO, all of these variables decreased and HMW vWF multimers became undetectable within hours following initiation of vvECMO. All variables fully recovered within 3-38 hours after discontinuation of vvECMO. During vvECMO, decreases in the vWF:A/vWF:Ag ratio correlated with absent HMW vWF multimers. Desmopressin did not affect vWF parameters.

Conclusions: In patients with COVID-19-associated ARDS, AVWS developed soon after initiation of vvECMO. The vWF:A/vWF:Ag ratio was a suitable screening test for AVWS. As desmopressin was ineffective, bleeding during vvECMO-associated AVWS should preferably be treated with concentrates containing vWF.

Figure 1.

Violin plots of high-molecular-weight von Willebrand factor multimers. t1: before cannulation of venovenous extracorporeal membrane oxygenation (vvECMO), t2: 30 min, t3: 3 hr, t4: 6 hr after cannulation of vvECMO; t5 during vvECMO therapy, t6: shortly before, t7, t8, t9, and t10: 30 min, and 3, 6, and 24 hr after decannulation of vvECMO. ---- = median, .... = 25–75 quartiles.

Figure 2.

von Willebrand factor analysis using collagen binding capacity. Upper and lower whiskers, box, and the inside horizontal line represent range of values, interquartile range, and median, respectively. VWF:Ag = von Willebrand factor antigen, VWF:CB = von Willebrand factor collagen binding capacity.

Figure 3.

von Willebrand factor parameters and factor VIII activity before, during, and after extracorporeal membrane oxygenation using commercially available assays. T1, within 24 h before cannulation of venovenous extracorporeal membrane oxygenation (vvECMO); T2, within 48 hr after cannulation of vvECMO; T3, during vvECMO; T4, within 48 hr before decannulation of vvECMO; T5, within 24 hr after decannulation of vvECMO; and T6, at least 3 d after decannulation of vvECMO circuit. VWF:A = von Willebrand factor activity, VWF:Ag = von Willebrand factor antigen.

Figure 4.

von Willebrand factor parameters before and after treatment with desmopressin (n = 12). VWF:Ag = von Willebrand factor antigen; VWF:A = von Willebrand factor activity.