Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis

Abstract

ABO blood group is an important determinant of plasma von Willebrand factor antigen (VWF:Ag) levels, with lower levels in group O. Previous reports have suggested that ABO(H) sugars affect the susceptibility of VWF to ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 repeats-13) cleavage. To further test this hypothesis, we collected plasma from individuals with the rare Bombay blood group. VWF:Ag levels were significantly lower in Bombay patients (median, 0.69 IU/mL) than in groups AB, A, or B (P < .05) and lower than in group O individuals (median, 0.82 IU/mL). Susceptibility of purified VWF fractions to recombinant ADAMTS13 cleavage, assessed using VWF collagen-binding assay (VWF:CB), was increased in Bombays compared with either group O or AB. Increasing urea concentration (0.5 to 2 M) increased the cleavage rate for each blood group but eliminated the differences between groups. We conclude that reduction in the number of terminal sugars on N-linked glycan increases susceptibility of globular VWF to ADAMTS13 proteolysis and is associated with reduced plasma VWF:Ag 4 Individuals with the very rare Bombay phenotype are non-Secretors and also fail to express H transferase (FUT 1). 5 Such people cannot synthesize A or B antigenic structures regardless of their ABO blood group genotype, and ABH antigens are absent from both their erythrocytes and secretions. 6 Para-Bombay individuals also fail to express H transferase, but do express the FUT2 (Secretor)-encoded ␣-1,2-fucosyltransferase, so that ABH antigens are present in their secretions but not on erythrocytes. 6,7 It is well established that ABO blood group exerts a major quantitative effect on plasma von Willebrand factor (VWF) levels, with significantly lower levels in group O individuals. 8,9 Moreover, ABH antigenic determinants have been identified on the N-linked glycans of circulating VWF according to the blood group of the individual. 10 However, the mechanism through which these glycans influence plasma-VWF antigen (VWF:Ag) levels remains unclear. Animal studies have shown that VWF glycans may influence rate of hepatic clearance, 11 and previous data suggested it may be mediated by the H antigen. 12 On the other hand, Bowen recently reported that VWF of different ABO blood groups exhibited different susceptibility to specific cleavage by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 repeats-13) (O Ն B Ͼ A Ն AB). 13 To further investigate how glycan expression on VWF influences plasma VWF:Ag levels, we have collected plasma samples from a series of Bombay and para-Bombay individuals. As these individuals lack the H antigen, they provide a critical test of current hypotheses. We report the novel observation that Bombay phenotype is associated with plasma-VWF levels similar or lower than group O. In addition, we demonstrate that Bombay VWF demonstrates significant increased susceptibility to cleavage by ADAMTS13, via a conformationdependent mechanism. Study design VWF glycans, VWF antigen, and VWF multim...

Plasma von Willebrand factor level and its associated parameters: Reference ranges in Nigeria

“…ADAMTS-13 activity was significantly higher in blood group O subjects when compared with non-O blood group. This agrees with earlier reports (O'Donnell et al, 2005;Bowen, 2003). The activity of ADAMTS-13 increased as follows B ˂ A ˂ O for this study.…”

Aberrant Expression of Histo-blood Group A Type 3 Antigens in Vascular Endothelial Cells in Inflammatory Sites

“…It is well established that the ABO blood group exerts a major quantitative effect on plasma vWF levels, with significantly lower levels in blood group O individuals (Gill et al 1987;Shima et al 1995;Jenkins and O'Donnell 2006). Furthermore, accumulating evidence suggest that reduction in the number of sugars on the oligosaccharide chains of vWF is clearly associated with an increased susceptibility to cleavage by ADAMTS13 (Bowen 2003;O'Donnell et al 2005). On the other hand, plasma vWF level is elevated in inflammation (Zezos et al 2005), which is controlled, at least in part, by cytokines and chemokines (Bernardo et al 2004).…”

Mechanism of von Willebrand factor scissile bond cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13)

“…Recombinant full-length WT VWF and these variants were expressed transiently in HEK293T cells (23). The concentration of VWF was determined by a specific ELISA (24), and VWF multimer analysis was assessed as previously described (24).…”