von Willebrand disease R1374C: Type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia)

Abstract

Patients initially diagnosed with type 1 von Willebrand disease (VWD) have been reclassified as type 2 after a more exhaustive analysis in several studies. Our study's objectives were (1) to reanalyze patients that were previously diagnosed as type 1 to achieve a more accurate diagnosis and (2) to compare the von Willebrand factor (VWF) ristocetin cofactor assay (VWF:RCo) and the VWF collagen binding assay (VWF:CB) in order to evaluate the possibility of replacing the former assay with the latter in the diagnosis of VWD. Twenty-one patients from two large unrelated families and 104 normal controls were studied. VWF:Ag, VWF:RCo, FVIII coagulant activity (FVIII:C), bleeding time (BT), PFA 100 , and multimeric analysis of VWF were tested. Genetic analysis by sequencing exon 28 on the VWF gene was also carried out. Patients presented lower levels of VWF:Ag and VWF:RCo, a dissociation between VWF:RCo/VWF:Ag, and the presence of all sizes of multimers in plasma VWF. The results for VWF:CB varied depending on the type of collagen used. The genetic analysis showed that the mutation R1374C is responsible for type 2M VWD. A high frequency of the R1374C mutation is observed in northwestern Spain (Galicia). Some types of 2M VWD are misdiagnosed as type 1 VWD. The VWF:CB (with type I collagen) assay was unable to discriminate defective platelet binding of the R1374C VWF. This confirms that VWF:CB cannot substitute for VWF:RCo, and both should be tested when diagnosing VWD. Am. J. Hematol. 80:188-196, 2005Hematol. 80:188-196, . ª 2005 Wiley-Liss, Inc.

Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD)

“…Patients analyzed by others with mutations such as R1205H, R1315C, and R1374C have previously been described as having Vicenza subtype or type 2M VWD. [26][27][28] The 95% mutation detection sensitivity in group 1 (at least 1 mutation identified in 54 of 57 ICs) indicated that the combination For personal use only. on May 10, 2018. by guest www.bloodjournal.org From of mutation detection techniques used in the study detected most exonic and closely flanking intronic mutations.…”

Autosomal Dominant von Willebrand Disease Type 2M

“…Other investigators preferred to classify it as type 2A due to the lower relative proportion of HMWM [7]. It has also been categorized as severe type 1 VWD [8], as well as type 1B [9], and 1B variant of 2A [10]. Finally, in the ISTH registry of VWD [11], it has been included as unclassified VWD.…”

“…However, the VWF:CB assay is unable to discriminate defective platelet-binding VWD variants with normal multimeric patterns such as VWD type 2M [19]. Moreover, it has been observed that the results for VWF:CB are dependent on the type of collagen used [10]. The VWF:CB/VWF:Ag ratio was indeed found to be higher (0.7) for type I collagen, while the results for type III collagen were variable [10].…”

“…Moreover, it has been observed that the results for VWF:CB are dependent on the type of collagen used [10]. The VWF:CB/VWF:Ag ratio was indeed found to be higher (0.7) for type I collagen, while the results for type III collagen were variable [10]. This is important, given that, if only the values for the type I collagen VWF:CB results are taken into account, they would confirm a diagnosis of type I VWD.…”

“…In low-resolution SDS-agarose gels ( a ), the patients with the R1374C mutation show a quantitative distribution between N and 2A. In high-resolution agarose gels ( b ), a decreased but almost normal satellite banding pattern is observed in the patient with the R1374C mutation compared to the increased triplet satellite banding pattern in type 2A (IIA) of VWD (Penas et al [10]). …”