Secretion of von Willebrand Factor and Suppression of ADAMTS-13 Activity by Markedly High Concentration of Ferritin

Abstract

Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity.

Associations between the von Willebrand Factor—ADAMTS13 Axis, Complement Activation, and COVID-19 Severity and Mortality

“…The hypoxic and inflammatory state characteristic for severe COVID-19 can increase the secretion and interfere with the cleavage of VWF by multiple mechanisms. 40 41 In particular, there is emerging evidence supporting the role of neutrophil granulocyte activation and the release of neutrophil extracellular traps (NETosis) in the pathogenesis of COVID-19 42 43 ; these processes may also affect the VWF-ADAMTS13 axis through the oxidative modification, sialylation or citrullination of its components, or by otherwise interfering with their interaction. 44 45 46 47 48 If their cleavage is hindered by the above mechanisms, persisting ultra-large VWF multimers form large strings that are capable of binding platelets firmly.…”

Reduced ADAMTS13 Activity in Correlation with Pathophysiology, Severity, and Outcome of COVID-19: A Retrospective Observational Study

“…cases included in their study, however, there was a significant decrease in ADAMTS13/von Willebrand factor antigen ratio; this was explained by the production of excess VMF that exceeded the proteolytic capacity of ADAMTS13, resulting in its deficiency (Doevelaar et al, 2021). Meanwhile, Bashir and her colleagues proposed that increased secretion of VWF and decreased ADAMT13 activity could be mediated by hyperferritinemia and consequently inducing pathologic immune activation, thrombosis, and organ damage (Bashir et al, 2021).…”

Age-Associated Increase in Thrombogenicity and Its Correlation with von Willebrand Factor

“…In a cohort of 150 elderly COVID-19 patients with a medical history of cardiovascular, respiratory, and multiple organ abnormalities, median VWF levels were reported at 455% of normal [ 128 ]. In some cases, VWF elevation is augmented by a deficiency of the VWF cleavage enzyme ADAMTS-13 or reduced ADAMTS13 activity in the blood [ 126 , 139 , 140 ]. Considering the age-associated increase in VWF, it is plausible to hypothesize that elevated basal levels of VWF in elderly may increase their susceptibility towards development of CAC complications as a result of CoV-2 infection.…”