IntroductionPlatelet plug formation at the site of vascular injury is initiated by von Willebrand factor (VWF) interacting with the subendothelial matrix, followed by its binding to platelet glycoprotein (GP) Ib 1,2 and subsequent platelet activation and aggregation. VWF is synthesized by endothelial cells and megakaryocytes, 3,4 and one of its main particular features is a polymer structure ranging in size from 500 000 to more than 20 million Dalton, 5 the largest forms being hemostatically the most efficient. 6 A broad range of values characterizes plasma VWF levels, which average around 10 g/mL. Acquired and inherited factors both modulate plasma VWF levels, and twin studies have demonstrated that 66% of all variations in plasma VWF are genetically determined, while 30% of them depend on ABO blood group, 7 O blood group individuals having plasma VWF levels 25% lower than non-O subjects. 8 ABO group genotyping shows that O 1 O 1 subjects have the lowest VWF levels, and non-O group individuals heterozygous for the O 1 allele have significantly lower VWF levels than AA, AB, or BB subjects. 9,10 Glycosylation accounts for 19% of VWF by weight, and ABO determinants identified on the N-linked oligosaccharide chains are part of this glycosylation process. 11,12 ABO groups are added to the N-linked glycan chains of VWF in the post-Golgi compartment of endothelial cells before VWF secretion, albeit with the variable contribution of the endothelial cells from different vascular beds. 13 The carbohydrate moiety plays an important part in VWF polymerization and function, 14 and also affects the liver-mediated clearance of VWF. In animal models, the removal of sialic acid has been shown to induce an increase in VWF clearance, 15 and the half-life of VWF is halved in mice characterized by an aberrantly glycosylated VWF (due to the absence of the enzyme ST3Gal-IV). 16 Moreover, recombinant VWF, lacking in carbohydrate, is cleared from the circulation faster than its glycosylated counterpart, 16 and posttranslational changes in VWF induced by Galgt2, aberrantly expressed in endothelial cells, lead to a 20-fold increase in VWF clearance. 17 ABO group determinants may also regulate the susceptibility of VWF to the proteolytic action of ADAMTS13, proteolysis being faster in the case of the O blood group. 18 A different susceptibility to cleavage by ADAMTS13 may thus be one of the ways in which ABO group affects VWF removal from the circulation and consequent VWF levels.Although the mechanisms behind ABO blood group and VWF levels have yet to be fully clarified, it has been clearly demonstrated that the effects are mediated by the ABO antigen structures on the N-linked oligosaccharide chains of circulating VWF, and particularly by H antigen expression. 19 Understanding these mechanisms is of clinical relevance: non-O individuals have been shown to carry a significantly greater risk of venous thromboembolism, ischemic heart disease, and peripheral vascular disease, 21-23 while the O blood group is much more common in von Willebra...
