Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID‐19): evidence of acute and sustained endothelial cell activation

Abstract

Summary Endothelial cell (EC) activation plays a key role in the pathogenesis of pulmonary microvascular occlusion, which is a hallmark of severe coronavirus disease 2019 (COVID‐19). Consistent with EC activation, increased plasma von Willebrand factor antigen (VWF:Ag) levels have been reported in COVID‐19. Importantly however, studies in other microangiopathies have shown that plasma VWF propeptide (VWFpp) is a more sensitive and specific measure of acute EC activation. In the present study, we further investigated the nature of EC activation in severe COVID‐19. Markedly increased plasma VWF:Ag [median (interquatile range, IQR) 608·8 (531–830)iu/dl] and pro‐coagulant factor VIII (FVIII) levels [median (IQR) 261·9 (170–315) iu/dl] were seen in patients with severe severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. Sequential testing showed that these elevated VWF–FVIII complex levels remained high for up to 3 weeks. Similarly, plasma VWFpp levels were also markedly elevated [median (IQR) 324·6 (267–524) iu/dl]. Interestingly however, the VWFpp/VWF:Ag ratio was reduced, demonstrating that decreased VWF clearance contributes to the elevated plasma VWF:Ag levels in severe COVID‐19. Importantly, plasma VWFpp levels also correlated with clinical severity indices including the Sequential Organ Failure Assessment (SOFA) score, Sepsis‐Induced Coagulopathy (SIC) score and the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio). Collectively, these findings support the hypothesis that sustained fulminant EC activation is occurring in severe COVID‐19, and further suggest that VWFpp may have a role as a biomarker in this setting.

miR-24 Targets the Transmembrane Glycoprotein Neuropilin-1 in Human Brain Microvascular Endothelial Cells

“…Mounting evidence has shown that SARS-CoV-2 can directly target endothelial cells [48][49][50][51][52][53][54][55][56][57], an aspect initially reported by our group in March 2020 by simply observing the systemic manifestations in COVID-19 patients [48,49,58], and later corroborated by autoptic findings [59][60][61][62][63] and by the analysis of amputation specimens [64]. Intriguingly, brain endothelial cells show a distinct pro-inflammatory response when exposed to SARS-CoV-2 spike protein subunits [65] and infected vascular endothelial cells have been shown to spread SARS-CoV-2 to glial cells in the central nervous system [66].…”

Severe COVID-19 Infection Associated with Endothelial Dysfunction Induces Multiple Organ Dysfunction: A Review of Therapeutic Interventions

“…Additionally, the VWFpp/VWF:Ag ratio dropped as VWF clearance was reduced and this is thought to lead to the elevated plasma VWF:Ag levels seen in severe COVID-19. Thus, VWFpp levels constitute a more sensitive and specific measure of acute EC activation [20,21] encountered in these severe COVID-19 cases [19]. Furthermore, VWF:Ag, VWF ristocetin cofactor (RCo), and VWFpp levels elevated in accordance with disease severity while levels of A Disintegrin And Metalloprotease with ThromboSpondin 1 repeats, number 13 (ADAMTS13) concordantly decreased [22].…”

“…Słomka et al summarized the hematological manifestations in COVID-19 and several studies have shown hematological parameters are markers of disease severity [18]. Especially for blood coagulation, a recent study revealed that plasma von Willebrand factor antigen (VWF:Ag) and pro-coagulant factor VIII (FVIII) levels, as well as plasma VWF propeptide (VWFpp), markedly increased in COVID-19 patients [19]. Additionally, the VWFpp/VWF:Ag ratio dropped as VWF clearance was reduced and this is thought to lead to the elevated plasma VWF:Ag levels seen in severe COVID-19.…”

Longitudinal Analysis of COVID-19 Patients Shows Age-Associated T Cell Changes Independent of Ongoing Ill-Health

“…Age is strongly associated with disease severity, with older individuals suffering poorer outcomes (4,5). The immunological changes associated with severe disease are also known, with increased inflammatory proteins, coagulopathy and changes in myeloid cell populations reported (6)(7)(8). In particular, severe COVID-19 is characterised by expansion of immature myeloid populations, with loss of HLA-DR expression by monocytes and loss of CD10 expression on neutrophils (9,10).…”