The ADAMTS13-von Willebrand factor axis in COVID-19 patients

Abstract

Background: Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients.

Objectives: To investigate the mechanism of microthrombosis in COVID-19 progression.

Patients/methods: We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin-cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross-sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high-flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19).

Results: Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID-19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high-to-low molecular-weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care.

Conclusions: We found a significant alteration of the VWF-ADAMTS13 axis in COVID-19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID-19 patients and their risk of microthrombosis.

Keywords: ADAMTS13 Protein; COVID-19; Microvasculature; Severe acute respiratory syndrome coronavirus 2; Thrombosis; von Willebrand factor.

Figure 1

Box plots of (A) VWF antigen, (B) ADAMTS13 activity, and (C) VWF antigen to ADAMTS13 activity ratio stratified by disease severity. Bonferroni‐adjusted P values of the post hoc Dunn's test for pairwise comparisons are reported. Black dots represent single values. Black dots above or below the range‐depicting horizontal lines represent outliers

Figure 2

Representative multimeric structures of plasma VWF and densitometric analysis in COVID‐19 patients. Samples from TTP patients are included as pathologic reference. Lane 1: TTP patient at the first acute episode with loss of HMW VWF multimers; lane 2: TTP patient with undetectable ADAMTS13 activity during disease remission with ultra‐large VWF multimers (UL‐VWF); lanes 3 to 6: COVID‐19 patients with different degrees of HMW VWF multimers depletion; lane 7: pooled normal plasma. Low molecular weight multimers (LMWM, peaks 1 to 3), intermediate molecular weight multimers (IMWM, peaks 4 to 7) and high molecular weight multimers (HMWM, peaks 8 and above) are indicated on the right side of the blot image. The solid gray line and the pink line depict densitograms of pooled normal plasma and patient plasmas, respectively