Abstract

The propeptide of von Willebrand factor (VWFpp) has been demonstrated to be critical for multimerization and intracellular storage of the mature von Willebrand factor (VWF) protein. Although VWFpp and VWF have been shown to circulate at a distinct ratio in plasma, they are stored in endothelial cells in equimolar amounts and stimulation of the endothelium results in acute simultaneous release of these polypeptides in equimolar concentrations. This includes following DDAVP administration to healthy individuals. An increased ratio of plasma VWFpp to VWF antigen (VWF:Ag) may reflect increased clearance of VWF:Ag or reduced clearance of VWFpp. We have quantitated plasma VWFpp levels and the VWFpp to VWF:Ag ratio in patients with type 1 VWD and examined their relationship with the plasma clearance of VWF:Ag and VWFpp. We have also examined the endothelial release of VWFpp and VWF:Ag following DDAVP stimulation in these patients. Plasma molar VWF:Ag and VWFpp concentrations were determined by immunosorbent assay1 in 27 patients with type 1 VWD and 21 normal controls. In the VWD patients VWF:Ag and VWFpp levels were quantitated over 6 hours following the administration of intravenous DDAVP. The half-lives of VWF:Ag (VWF:Ag t1/2) and VWFpp (VWFpp t1/2) were calculated by determining the first-order rate constant for the elimination phase of the respective proteins.2 To determine the molar ratio of VWFpp and VWF:Ag released following DDAVP, values at 30 mins were extrapolated from semi-log plots of VWFpp and VWF:Ag against time. Median concentrations of VWFpp and VWF:Ag were 2.9nmol/L (range, 1.4–10.9) and 24.5nmol/L (2.5–42) pre-DDAVP in VWD group and 9.7nmol/L (5.8–18.1) and 51.5nmol/L (32–98.5) at baseline in normal subjects. The median VWFpp/VWF:Ag ratio was 0.13 (0.06–1.5) in the VWD group as compared to 0.23 (0.08–0.34) in the normals. Median VWF:Ag t1/2 and VWFpp t1/2 values in the VWD patients were 4 hours (0.9–8.7) and 2.5 hours (1.7–8) respectively. VWF:Ag normally has a half-life of 8–12 hours in plasma,3 while that of VWFpp is 2–3 hours.1 In the patient group, inverse correlation was found between VWFpp/VWF:Ag ratio and VWF:Ag t1/2, r=−0.48, p=0.01. There was also significant inverse correlation between VWFpp and VWF:Ag t1/2, r=−0.53, p<0.005. In contrast, there was no correlation between VWFpp/VWF:Ag ratio and VWFpp t1/2, r=−0.29, p>0.1. The values for VWFpp and VWF:Ag extrapolated 30 mins post DDAVP were corrected for baseline values and plotted to give a slope of 0.48, representing release of two moles of VWF per mole VWFpp in the patient group. The range of the plasma VWFpp/VWF:Ag ratio is wide in type 1 VWD patients and this may reflect heterogeneity in the pathophysiological processes, including post secretion events such as increased clearance of VWF:Ag, that contribute towards disease phenotype. The finding of inverse correlation between VWF:Ag t1/2 and the ratio of VWFpp to VWF:Ag indicates that increased plasma clearance of VWF:Ag is not associated with an increased VWFpp clearance in some patients with type 1 VWD. In addition, we have not demonstrated equimolar release of VWFpp and mature VWF in patients with type 1 VWD.

1
Borchiellini A et al.
Blood
1996
;
88
:
2951
–2958
2
Brown SA et al.
J Thromb Haemost
2003
;
1
:
1714
–1717
3
Millar CM et al.
Blood
2004
;
104
:
76a
.

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