Diagnostic challenges of von Willebrand disease

S. Schneppenheim, R. Dittmer, H. El-Abd Müller, U. Budde (Hamburg, Germany)

Laboratory tests
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: Von Willebrand disease is caused by mutations of von Willebrand factor, a complex protein, which harbours different structural and functional domains. A normal high molecular weight multimer (HMWM) structure of VWF is essential for its proper function under high shear conditions in the microcirculation and arteries. Due to its complexity, the function of VWF in primary haemostasis and in coagulation cannot be assessed by a single test. Besides quantification of VWF:Ag by ELISA methods, a number of assays have been developed, which measure particular functions of VWF like VWF:GPIb binding, VWF:collagen binding and VWF:FVIII binding. VWF:clearance from the circulation can be estimated by the ratio of VWF:Ag to the VWF:propeptide. However, none of these parameters describes the essential VWF shear-dependent functions, which are definitely dependent on VWF HMWMs under high shear conditions. We assessed the diagnostic power of VWF multimer analysis on the correct diagnosis of VWD.

Methods: From 2002 until 2015, a cohort of 3,669 patients were diagnosed with VWD type 2 by assessing the ratio of VWF:CB/VWF:Ag, and by multimer analysis.

Results: By multimer analysis, patients were diagnosed with either VWD type 2A/2B and enhanced ADAMTS13 proteolysis, patients with VWD type 2A/IIE with reduced proteolysis, patients with VWD type 2M and patients with type 2A/IB (s. Table). Among them, we identified patients with normal functional parameters and normal VWF:Ag, displaying an abnormal electrophoretic migration due to cysteine mutations in the carboxy-terminal region of VWF, implicated in VWF lateral self-association in a high shear environment. The percentages of the correct diagnosis by using the VWF:CB/VWFAg ratio compared to VWF multimers are given in Table 1.

Conclusion: Dependent on the type, a significant number of patients with VWD would remain undiagnosed by conventional quantitative and functional assays but without multimer analysis. A normal structure of VWF HMWM in plasma is the result of proper synthesis, secretion, clearance, responsiveness to shear and normal size regulation by ADAMTS13. Since all these parameters influence the structure of VWF multimers, their analysis is further on an indispensable tool for a valid diagnosis or exclusion of VWD. In addition, the multimer pattern hints to the site of particular mutations causing VWD.