Diagnostic Value of Measuring Platelet Von Willebrand Factor in Von Willebrand Disease

Abstract

Von Willebrand disease (VWD) may be caused by an impaired von Willebrand factor (VWF) synthesis, its increased clearance or abnormal function, or combinations of these factors. It may be difficult to recognize the different contributions of these anomalies. Here we demonstrate that VWD diagnostics gains from measuring platelet VWF, which can reveal a defective VWF synthesis. Measuring platelet VWF revealed that: severe type 1 VWD always coincided with significantly lower platelet and plasma VWF levels, whereas mild forms revealed low plasma VWF levels associated with low or normal platelet VWF levels, and the latter were associated with a slightly shorter VWF survival; type Vicenza (the archetype VWD caused by a reduced VWF survival) featured normal platelet VWF levels despite significantly reduced plasma VWF levels; type 2B patients could have either normal platelet VWF levels associated with abnormal multimer patterns, or reduced platelet VWF levels associated with normal multimer patterns; type 2A patients could have reduced or normal platelet VWF levels, the former associated mainly with type 2A-I, the latter with type 2A-II; plasma and platelet VWF levels were normal in type 2N, except when the defect was associated with a quantitative VWF mutation. Our findings show that measuring platelet VWF helps to characterize VWD, especially the ambiguous phenotypes, shedding light on the mechanisms underlying the disorder.

Fig 1. Mean plasma and platelet VWF in patients with quantitative (upper panel) and functional (lower panel) VWF defects.

Type 1 VWD patients were divided into severe and mild cases, based on their circulating VWF levels (< 10U/dL and < 50 U/dL, respectively). Mild type 1 patients were further grouped according to their normal or low platelet VWF content. Functional VWF defects in type 2A were separated into a defective VWF synthesis (2A-I) and an increased susceptibility to ADAMTS13 (2A-II). Type 2B cases were divided according to their multimer pattern, and type 2N according to whether VWF synthesis was normal or reduced, the latter depending on the nature of the type 2N mutation, or the presence of a combined quantitative VWF mutation.

Fig 2. Mean post-DDAVP pharmacokinetic parameters of VWF:Ag, VWF:CB and FVIII in patients with normal-platelet-VWF and low-platelet-VWF mild type 1 VWD.

The VWF T_1/2elimination (T_1/2el) was statistically shorter, and VWF clearance (Cl) was significantly faster in the former patients than in the latter.