Identification and prevalence of von Willebrand disease type 2N (Normandy) in Australia

Abstract

We report an investigation of type 2N von Willebrand disease (VWD), covering the past 7 years and evaluating 1031 plasma samples from over 500 patients. Samples included specific requests for investigation of possible type 2N VWD (including family studies) and samples from 'hemophilia' or nonspecified VWD investigations that could unknowingly be type 2N VWD. In total, 13 new patients with type 2N VWD were identified, four of whom initially presented with normal levels of factor VIII and only three of whom (i.e. 23%) derived from specific clinical requests for investigation of type 2N VWD. Furthermore, type 2N VWD was excluded in 91% of specific clinical requests for type 2N VWD investigations. Poststudy evaluation indicates that type 2N VWD in this geographic region has an incidence rate similar to that in other westernized regions, accounting for around 1-2% of all identified VWD cases and about 13% of all type 2 VWD cases. In conclusion, this study highlights that clinicians requesting laboratory investigations related to a bleeding tendency often fail to appropriately recognize the possibility of type 2N VWD, that a normal plasma factor VIII will not exclude type 2N VWD, and although a relatively uncommon form of VWD overall, type 2N VWD represents a significant qualitative disorder.

Type 2N von Willebrand disease: Characterization and diagnostic difficulties

“…For the time being, subjects heterozygous for type 2N VWD were considered as carriers of the defect and were not included in the type 2N VWD group. 30 An even higher prevalence of type 2N VWD has been reported in other countries, such as India (3.6%), and especially Mexico (10%). 31,32 Such marked differences may be due to different geographical areas having homogeneous genetic patterns, especially in more remote regions where the type 2N defect is present (due to inbreeding).…”

Diagnosis and classification of von Willebrand disease

“…von Willebrand factor VIII-binding assay This assay is typically performed as an ELISA assay, with either an ELISA-based or chromogenic detection step at completion [16]. A commercial method has recently become available [72].…”

“…FVIII, VWF:Ag, VWF:RCo, VWF:CB, VWF:Act and VWF:multimers). As haemophilia A is more common that 2N VWD, some cases of the latter will simply be assumed to be haemophilia A after initial testing [16], and if not further pursued for clarification by VWF:FVIIIB testing. However, discrimination of 2N VWD and haemophilia A is considered important because of differential management, with FVIII concentrates used in haemophilia A, but VWF concentrates used in 2N VWD (note, desmopressin may be used as supportive therapy in some cases of both haemophilia A and 2N VWD, notably mild cases or for minor procedures; however, desmopressin leads to release of dysfunctional VWF in 2N VWD and, thus, often defines a nonoptimal treatment choice).…”

“…Phenotypically, 2N VWD tends to mimic haemophilia A or haemophilia A carriers and, thus, may be misdiagnosed as such. However, 2N VWD can be theoretically distinguished from these and, thus, appropriately identified using the VWF:FVIIIB assay, with low FVIIIB/VWF ratios in 2N VWD, but normal ratios in haemophilia A (/carriers) [16].…”

Quality in coagulation and haemostasis testing

“…No net he le ss, as the VWF:CB re ec ts a di e re nt fun ctio nal pro per ty of VWF than the VWF:R Co, both tes ts are requi red to iden ti fy all pos sib le for ms of VWD (32,33). Se ve ral ot her hig hly spe cia li zed pro ce du res are avai lable to he lp fun ctio nal ly charac te ri ze or clas si fy VWD (32,(36)(37)(38), in clu di ng the ris to ce tin indu ced pla te let aggre ga tion (RIPA) pro ce du re (typi cal ly per for med as a pa rt of pla telet fun ction tes ti ng), VWF:mul ti mer ana lysis (to help as se ss for struc tu ral de fects ari si ng from al te red VWF as sem bly or pro teo lysis) and VWF:FVIII bindi ng (VWF:FVIIIB).…”