The Management of Bleeding Risk in Von Willebrand Disease: Should Blood Group O Make a Difference?

Type 1 von Willebrand disease (VWD) is a common inherited bleeding disorder characterized by a quantitative deficiency of von Willebrand factor (VWF) and excessive mucocutaneous bleeding. It is well known that von Willebrand factor (VWF) levels are significantly lower in persons with ABO blood group O and that there is a significantly higher prevalence of blood group O in patients with a diagnosis of type 1 VWD. This raises a question important to the clinical care of patients with low VWF; is there a difference in bleeding risk in patients with a deficiency of VWF on the basis of blood group O versus those with a deficiency of VWF due to a sequence variation in the VWF gene. To explore this question, we examined index cases enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD with a quantitative deficiency of VWF including those with a phenotypic diagnosis of low VWF [von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor activity (VWF:RCo)≤ 50 U/dL and >40 U/dL], type 1 VWD (VWF:Ag or VWF:RCo≤40 U/dL) and type 1C VWD (VWF:Ag ≤30 U/dL and VWF propeptide/Ag ratio >3 indicating increased clearance of VWF). VWF:Ag, VWF:RCo, VWF propeptide and multimer distribution were analyzed in the clinical hemostasis laboratory at the BloodCenter of Wisconsin. Full length VWF gene sequencing including intron-exon boundaries was performed for all index cases. Bleeding symptoms were scored utilizing the ISTH, MCMDM1 and PBQ bleeding assessment tools. Since there was a high correlation among bleeding scores with these three methods, the ISTH score was utilized for this analysis.

Complete data were available for 91 subjects with low VWF, 161 subjects with type 1 VWD, 53 subjects with type 1C VWD and 74 normal control subjects. Median ages were not different among the diagnostic groups. As expected based on previous reports, the groups of VWD patients with lower VWF:Ag values (Mean±1SD) had an increased percentage of subjects with an identified sequence variation; low VWF group, VWF:Ag 50.4±8.4, 38% with sequence variation; Type 1 VWD, VWF:Ag 30.8±11.6, 70% with sequence variation; and Type 1C VWD, VWF:Ag 9.8±5.9, 83% with sequence variation. The low VWF group and the type 1 VWD groups both had a significantly increased frequency of subjects with blood group O (70 – 80%) vs. nonO (19-30%) in comparison to those with type 1C in whom the frequency of blood group O (57% ) vs. nonO (43%) was not different than that in the normal control population (43% O vs. 57% nonO). This suggests that the type 1 and low VWF groups have a significant proportion of subjects with low VWF on the basis of blood group O alone. Since those subjects with a diagnosis of low VWF or Type 1 VWD who have no identifiable sequence variation are more likely to be affected by blood group O alone, we examined the ISTH bleeding scores in subjects with similar VWF levels and blood group O with and without an identifiable VWF gene sequence variation. We found that there was no difference in the ISTH bleeding scores in blood group O subjects regardless of the presence of a VWF gene sequence variation; low VWF, no sequence change (N=45), median bleeding score 6.0 vs. 5.0 with sequence change (N=27); type 1 VWD, no sequence change (N=39), median bleeding score 5.0 vs. 5.0 with sequence change (N=73); type 1C VWD, no sequence change (N=6), median bleeding score 7.0 vs. 7.0 with sequence change (N=24). There were no differences in median bleeding scores in blood group O vs. nonO groups, and none in the nonO groups with or without sequence variation in any of the VWD phenotypic diagnostic categories. There were no significant differences in bleeding scores by gender in any of the diagnostic categories.

In conclusion, we found no differences in ISTH bleeding scores in the groups of subjects most likely to have low VWF on the basis of blood group O alone, i.e., those with blood group O and no identifiable VWF gene sequence variation compared to those with VWF gene sequence variations. Thus, management of persons with VWF deficiency should be based on baseline VWF levels and not modified in those with blood group O.