The elusive and heterogeneous pattern of type 2M von Willebrand disease: A diagnostic challenge.

Unlabelled: Type 2M is a very heterogeneous form of von Willebrand disease (VWD) associated with impaired platelet and von Willebrand factor (VWF) interactions not due to a lack of large VWF multimers.

Objectives: To investigate type 2M heterogeneity and to establish the most appropriate diagnostic flowchart.

Methods: Hemostatic and genetic VWF analyses were performed in 14 type 2M VWD patients carrying the p.G1324S, p.R1374H, p.R1374C, p.A1344_A1350del, or p.F1293L mutations.

Results: PFA-100 was always significantly prolonged, and ristocetin-induced platelet aggregation (RIPA) and VWF ristocetin cofactor (VWF:RCo) greatly reduced or absent. Plasma VWF antigen (VWF:Ag) was reduced except in the p.G1324S patient, while platelet VWF:Ag was normal or near normal except in the p.R1374C patients. The ratio of collagen binding (VWF:CB) to VWF:Ag was normal or near normal except in patients carrying the p.R1374H and p.A1344_A1350del mutations, whose large VWF multimers were slightly reduced. Multimer patterns were normal or lacking in large oligomers, or with larger than normal VWF components.

Conclusions: Only PFA100, RIPA and VWF:RCo were always abnormal. We thus propose a minimal diagnostic test battery: RIPA (demonstrating the defective VWF-platelet interaction), VWF:Ag (exploring VWF synthesis), and VWF:CB and its ratio (to explore multimer patterns). Other tests would only serve for confirmation, if necessary.