Abstract

Type 1 von Willebrand disease (VWD) is a heterogeneous bleeding disorder in which genetic modifying factors, including ABO blood group, contribute towards the variability in von Willebrand factor (VWF) levels. Recent findings have reported an increased incidence of the Tyr1584Cys polymorphism in the VWF-A2 domain of patients with type 1 VWD. Presence of Cys1584 has been shown to cause increased intracellular retention of VWF, as well as lead to increased susceptibility of VWF to proteolysis by the metalloprotease ADAMTS13. An increased susceptibility to proteolysis by ADAMTS13 has also been demonstrated in the VWF of blood group O individuals. We have investigated the relationship between increased VWF antigen (VWF:Ag) clearance, ABO blood group and the presence of the Tyr1584Cys polymorphism in a group of patients with type 1 VWD. The VWF:Ag half-life (VWF:Ag t1/2) was prospectively evaluated in 45 patients with type 1 VWD, which included three families of two or more first-degree relatives. Median VWF:Ag level was 36.0iu/dl (range 4–50iu/dl); median VWF ristocetin cofactor activity (VWF:RCo) level was 35.0iu/dl (range 3–52iu/dl) and VWF:RCo/VWF:Ag ratio 0.97 (range 0.70–1.37). A normal multimeric pattern was demonstrated in all patients. 25 (55.5%) and 20 (44.5%) of the patients were of blood groups O and A respectively. The control group comprised eight patients with haemophilia A. VWF:Ag levels were measured over a 6 hour period following the administration of intravenous DDAVP. VWF:Ag t1/2 was calculated using the formula: C(t)=C0e−k.t, where C(t)=plasma [VWF:Ag] as a function of time; C0=[VWF:Ag] at time zero; e=base for natural logarithms; k=first order rate constant for the elimination phase (ß phase); t=time. The median value of the VWF:Ag t1/2 in the VWD group was 4.1 hours (95% C.I. 3.2–4.9h) and in the haemophilia A group 9.5 hours (95% C.I. 5.3–19h). This represents a significant difference in VWF:Ag t1/2 between the two groups (p<0.05). However, within the VWD patient group, there was no significant difference between the median VWF:Ag t1/2 values of patients of blood group O and those of blood group A (p>0.05). Within the three families, two affected family members of the same ABO blood group were studied and a concordant reduction in the VWF:Ag t1/2s was found in these subjects. To date, 24 of the VWD patients have been genotyped for the A/G polymorphism at nucleotide 24/1282 in the VWF gene, encoding a Tyr1584Cys polymorphism. The heterozygous presence of the G allele encoding Cys 1282 was demonstrated in one patient. The frequency of this polymorphism in normal and type 1 VWD individuals has been reported to be ~1% and 14% respectively. The median VWF:Ag t1/2 value of the 23 homozygous Tyr1584 patients was 3.4 hours (95% C.I. 3.2–4.8h), representative of the whole VWD group. The VWF:Ag t1/2 in the heterozygous patient was 4.8 hours. The finding of increased plasma VWF:Ag clearance as reflected by a reduction in VWF:Ag half-life in a significant number of patients with type 1 VWD, suggests that increased VWF:Ag clearance may be a contributory factor in the aetiology of type 1 VWD. However, this study suggests there is no relationship between increased VWF:Ag clearance and ABO blood group. Furthermore, the Tyr1584Cys polymorphism is not a major determinant of VWF:Ag clearance within this group of type 1 VWD patients.

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