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

Abstract

Background Endothelial and complement activation were both associated with immunothrombosis, a key determinant of COVID-19 severity, but their interrelation has not yet been investigated. Objectives We aimed to determine von Willebrand factor (VWF) antigen (VWF:Ag) concentration, VWF collagen binding activity (VWF:CBA), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (ADAMTS13:Ac), and their ratios in hospitalized COVID-19 patients, and to investigate how these parameters and their constellation with complement activation relate to disease severity and in-hospital mortality in COVID-19. Methods Samples of 102 hospitalized patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 positivity were included in our observational cohort study. Patients were stratified according to the peak severity of COVID-19 disease in agreement with the World Health Organization ordinal scale. Twenty-six convalescent plasma donors with previous COVID-19 disease formed the control group. VWF:Ag concentration and VWF:CBA were determined by enzyme-linked immunosorbent assay (ELISA); ADAMTS13:Ac was determined by fluorescence resonance energy transfer. Complement C3 and C3a were measured by turbidimetry and ELISA, respectively. Clinical covariates and markers of inflammation were extracted from hospital records. Results VWF:Ag and VWF:CBA were elevated in all groups of hospitalized COVID-19 patients and increased in parallel with disease severity. ADAMTS13:Ac was decreased in patients with severe COVID-19, with the lowest values in nonsurvivors. High (> 300%) VWF:Ag concentrations or decreased (< 67%) ADAMTS13:Ac were associated with higher risk of severe COVID-19 disease or in-hospital mortality. The concomitant presence of decreased ADAMTS13:Ac and increased C3a/C3 ratio—indicating complement overactivation and consumption—was a strong independent predictor of in-hospital mortality. Conclusion Our results suggest that an interaction between the VWF-ADAMTS13 axis and complement overactivation and consumption plays an important role in the pathogenesis of COVID-19.

Prognostic value of von Willebrand factor and ADAMTS13 in patients with COVID-19: A systematic review and meta-analysis

“…The final full-text review included 163 reports, from which 123 studies did not meet the inclusion criteria and were excluded. A total of 40 studies comprising of 3764 patients met the including criteria and were included in this systematic review and meta-analysis [24] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] . Fig.…”

“…The exact dynamic changes of VWF multimeric pattern after COVID-19 still need further study. The majority of studies reported normal or mildly to moderately decreased ADAMTS13:Ac levels [51] , [62] , [70] , [72] , [80] , [87] , and a strongly elevated VWF:Ag/ADAMTS13:Ac ratio in patients with COVID-19 when compared to healthy controls, especially in those with worse illness or in non-survivors [55] , [70] , [80] . We confirmed that lower levels of ADAMTS13:Ac and higher VWF:Ag/ADAMTS13:Ac ratio and VWF:Rco were related to poor clinical outcomes.…”

“…Although several case reports showed SARS-CoV-2 infection trigger acute TTP [153] , [154] , [155] , and therapeutic plasma exchange, a mainstay treatment for TTP, has shown to reduce immunothrombosis while improve respiratory parameters and clinical outcomes in critically ill patients with COVID-19 [156] , [157] , [158] . CAC do not resemble a classic TTP since there is lack of severe ADAMTS13 deficiency (activity levels <10 %), major thrombocytopenia, or hemolytic anemia [22] , [54] , [64] , [68] , [70] , [80] , [81] . However, the imbalanced VWF-ADAMTS13 axis combined with clinical and pathologic findings of widespread microvascular thrombi in multi-organs may suggest a secondary TMA-like phenomenon [62] , which can also be seen in other forms of TMA (drug, cancer, or hematopoietic stem cell transplant induced TMA [159] ) and thrombotic disorders (e.g., severe sepsis, malaria, trauma, and preeclampsia) [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] .…”

“…Journal Pre-proof levels less than 10%), major thrombocytopenia, or hemolytic anemia [22,54,64,68,70,80,81]. However, the imbalanced VWF-ADAMTS13 axis combined with clinical and pathologic findings of widespread microvascular thrombi in multi-organs may suggest a secondary TMA-like phenomenon [62], which can also be seen in other forms of TMA (drug, cancer, or hematopoietic stem cell transplant induced TMA [159]) and thrombotic disorders (e.g., severe sepsis, malaria, trauma, and preeclampsia) [29][30][31][32][33][34][35][36][37][38][39].…”

Evaluation of Covid-19-Associated Hypercoagulability with Functional Coagulation Assays and Extracellular Vesicles

“…The overactivation of the complement system releases C3 and C5 proteins, thus maintaining the inflammation and enhancing a hypercoagulable state. The point of convergence between the complement system and the coagulation cascade may lie in the presence of circulating ultra-large VWF molecules stemming from the reduced activity of the metalloproteinase ADAMTS13 caused by the SARS-CoV-2 infection 20 . It is hypothesized that these ultra-large VWF molecules may provide an additional surface for platelet adhesion and complement activation.…”