Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group

Blood group 0 and the cysteine allele of the Y/C1584 change in von Willebrand factor (VWF) are enriched in type I VWD, but neither causes disease. We investigated the effect of C1584, alone and in combination with the ABO blood group, on the level and properties of plasma VWF. A cohort of 5052 blood donors was recruited: 50 donors were heterozygous for Y/C1584 and 5002 were homozygous for Y/Y1584. Mean VWF antigen (VWF:Ag) for heterozygotes (82 +/- 35 IUdL(-1)) was significantly lower than for homozygotes (111 +/- 37 IUdL(-1)) (P < .001). For each ABO blood group, VWF:Ag was decreased among Y/C1584 heterozygotes compared with Y/Y1584 homozygotes; a larger decrease was observed for group O. Among donors with VWF:Ag levels of 50 IUdL-1 or lower, Y/C1584 heterozygosity was markedly enriched (18%) compared with the entire cohort (1.5%). Blood group 0 was enriched to a lesser extent (2.4%), but Y/C1584 in conjunction with group 0 was strikingly enriched (34.8%). VWF collagen binding activity (VWF:CB) and ristocetin cofactor activity (VWF:RCo) were significantly lower for Y/C1584 heterozygotes than for Y/Y1584 homozygotes, and a qualitative difference in Y/C1584 plasma VWF multimer profile was observed compared with that for Y/Y1584 VWF The data support a multifactorial basis for low VWF levels in some individuals.