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• W1566807166 abstract "von Willebrand disease (VWD) is believed to be the most common bleeding disorder [1], and is diagnosed on clinical grounds (primarily a mucocutaneous bleeding history) followed by laboratory testing to confirm a defect or deficiency in von Willebrand factor (VWF) [2]. von Willebrand disease is characterized into one of six types, with type 2B defining patients showing enhanced responsiveness in a ristocetin-induced platelet agglutination assay (RIPA) [2]. By light transmittance aggregometry (LTA), low-dose RIPA responsiveness characteristic of 2B VWD is typically identified using 0.5 mg ristocetin mL−1, this being the value most laboratories report using in surveys of practise [3, 4], and also reflecting the current approved CLSI guideline [5]. However, it is recognized that some forms of 2B VWD, evidenced by mutational studies, may not show evidence of enhanced RIPA [2], or may only show RIPA at higher concentrations, as recently reported in a large study by Federici and colleagues [6], and as discussed in an accompanying commentary [7]. Notably, several 2B VWD patients failed to show a positive RIPA finding at 0.5 mg mL−1, with many instead showing thresholds of 0.7 mg mL−1. The normal reference range for RIPA in this study was 0.8–1.2 mg mL−1. Our laboratory has also occasionally observed (unpublished observations) that some of our well-characterized 2B VWD patients [8] sometimes fail to show a RIPA response at 0.5 mg mL−1. Indeed, RIPA is known to be poorly reproducible and not consistently reflective of VWD severity in other types of VWD [2]. Nevertheless, ‘low-dose’ RIPA responsiveness remains a diagnostic feature of 2B VWD (as well as its close cousin, platelet type VWD [9]), and the study by Federici and colleagues has led our laboratory (and presumably others) to re-evaluate ‘low-dose’ RIPA testing in this setting, essentially by extending the range of ristocetin concentrations used during the RIPA evaluation during our routine platelet function testing procedure. For these investigations, we initially assess responsiveness using 1.0 mg mL−1 and, for patients showing a response, sequentially test using lower concentrations, now including both 0.5 and 0.7mg mL−1, reflecting our classical 2B VWD cut-off and that identified by the Federici study [6]. It should be noted that our laboratory is very selective in terms of undertaking comprehensive platelet function studies, considering the highly time-consuming and technical nature of testing [10]. Accordingly this service is only offered to internal (hematology) newly referred patients with a significant history of bleeding or those with a previously diagnosed bleeding disorder for confirmation or exclusion, or for differential diagnosis of type 2 VWD and/or PT-VWD. Platelet function screening using the platelet function analyser-100 (PFA-100®) [11] is otherwise offered for clinicians requesting ‘platelet function testing’ for other indications. Of relevance to the current report is our recent observation of ‘enhanced’ RIPA responsiveness in three out of 18 of our most recent platelet function evaluations using a RIPA cut-off value above 0.5 mg ristocetin mL−1. Thus, although these 18 patients reflected a variety of clinical histories and indications, two showed a significant aggregation response to ristocetin at 0.7 mg ristocetin mL−1, and one at 0.6 mg mL−1, but none at 0.5 mg mL−1 (Table 1). However, clinical histories and other laboratory studies were generally not suggestive of either 2B or PT VWD, most likely indicating these to be ‘false positives’ within the context of 2B or PT VWD investigation. Subsequent testing in all cases suggested that the perceived ‘elevated’ RIPA responsiveness appeared to be ‘plasma based’ (using RIPA mixing [9]) and possibly in part due to relatively high levels of VWF (Table 1). Also interesting was that all three patients yielded a relatively short PFA-100 closure time (CT) using the PFA-100® (Table 1), which is sometimes identified as a risk factor for thrombosis [11], and which was consistent with the high plasma VWF levels. Finally, genetic testing comprising Exon 28 of the VWF gene was undertaken, and no mutation was detected in any of these cases. In summary, we have observed three cases (out of the last 18 sequential platelet function investigations performed = 16.7%) showing ‘elevated’ RIPA responses using 0.6 or 0.7 mg ristocetin mL−1 (but not 0.5 mg mL−1), and thus potentially falsely identifying cases of 2B VWD, should our laboratory adopt the 0.8–1.2 mg mL−1 reference range and 0.7 mg mL−1 cut-off identified by the large 2B VWD study of Federici and colleagues [6]. We do not wish to make too much of this finding, other than cautioning laboratories against an expectation that a RIPA response below a well-established normal reference range inevitably defines 2B VWD, which it does not. Ideally, each laboratory should define its normal reference range for test parameters, including platelet function [12]. Establishing a normal reference range for RIPA, however, is nearly impossible for most laboratories, given the discontinuous variable that RIPA testing represents, and the need for very large numbers of control samples. Moreover, in an ideal setting, given the inherent RIPA variability, and likely frequent changes in ristocetin batches, ongoing validation of any established reference range would be similarly challenging. Indeed, it is more likely that laboratories will decide on a low-dose level of ristocetin (be it 0.5 mg mL−1 as classically applied, or even 0.7 mg mL−1 as evidenced by the Federici study), and then assess this value for suitability against established patients with 2B VWD and normal individuals, for example as performed by Hayward’s group [12]. This would in general also reflect our practise. In conclusion, RIPA testing remains problematic. The classically applied cut-off value of 0.5 mg ristocetin mL−1 will miss some individuals with 2B VWD (e.g. our unpublished experience on occasion using well-characterized patients [Table 1], and the Federici study [6]). In contrast, using a higher applied cut-off value of 0.6 or 0.7 mg ristocetin mL−1 will miss fewer individuals with 2B VWD [6], but will also identify some ‘false’ cases of 2B VWD, as evidenced by this report. It is unclear whether this finding reflects subtle variations in actual ristocetin concentrations in different batches or supplies of ristocetin, or simply a normal range effect (analogous to the overlap observed in VWF levels between the normal ‘clinically asymptomatic/non-bleeding’ population and those symptomatic patients identified to have ‘mild type 1 VWD’ or ‘low VWF’ [13]). We would be interested to hear from other laboratories of their experience in this area. We also reflect that there are occasionally patients identified as putative 2B VWD (or PT-VWD) based on RIPA that do not have an identifiable VWF or platelet glycoprotein Ib mutation identified [14, 15], thus raising additional questions about either possible false identification of 2B VWD/PT-VWD or false-negative genetic analysis. The authors state that they have no conflict of interest." @default.
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• W1566807166 title "2B or not 2B? Masquerading as von Willebrand disease?" @default.
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