Abstract

The decreased survival of von Willebrand factor (VWF) in plasma has recently been identified as a novel mechanism causing type 1 VWD. Patients with this phenotype are characterized by a substantially reduced plasma VWF:Ag (< 30 IU/dL), a robust response to DDAVP, and a reduced half-life of VWF:Ag after DDAVP administration. Although a normal distribution of plasma VWF multimers appears to be present, the multimer satellite bands are decreased in intensity. A few mutations have been identified in type 1C VWD patients including C1130F/G/R, W1144G, R1205H, and S2179F. Identification of type 1 VWD patients with this phenotype is clinically important because DDAVP may not be the treatment of choice in this subset of patients due to the reduced half-life of the VWF released into plasma. Although previous studies have facilitated the characterization of this phenotype, the prevalence of the reduced survival, type 1C VWD has not yet been determined. We have previously reported that assay of plasma VWF:Ag and VWF propeptide (VWFpp) can be used to identify type 1C VWD patients having reduced VWF survival. These individuals have a substantially increased ratio of steady-state plasma VWFpp/VWF:Ag in contrast to normal individuals where the ratio is equal to one. We subsequently established blood group-specific normal ranges for VWFpp/VWF:Ag by assay of 279 healthy blood donors. Here we report the assay of VWF:Ag and VWFpp in 192 normal controls and 61 type 1 VWD index cases recruited from eight US centers within the TS Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCB - VWD) study. VWD type 1C individuals previously reported from our center were excluded from the current study. Using VWF:Ag and VWFpp levels determined for the 192 normal controls, we established a 2-standard deviation normal range for VWFpp/VWF:Ag ratio of 0.5 to 1.6, consistent with our previous studies. Of the 61 type 1 VWD index cases, three individuals were identified with a substantially increased VWFpp/VWF:Ag ratio (mean = 5.0). One individual was found to have the well-characterized R1205H VWF gene mutation that has been associated with reduced VWF survival. These individuals demonstrated laboratory parameters consistent with a reduced VWF survival phenotype including moderate to severely decreased plasma VWF:Ag (mean = 16.6 IU/dL), a diminished intensity of multimer satellite bands amongst an essentially normal distribution of plasma multimers, and an elevated bleeding score (mean = 4.7). Together these data indicate a reduced survival phenotype (type 1C) in 4.9% of type 1 VWD index cases in the ZPMCB - VWD study. Identification of type 1 VWD individuals with a reduced plasma VWF survival phenotype is clinically essential as these individuals may require alternative treatment strategies.

Author notes

Disclosure: No relevant conflicts of interest to declare.