A better approach to monitoring of therapy in von Willebrand disease?

Thromb Haemost 2008; 100: 371–373 Von Willebrand disease (VWD) is the most common inherited bleeding disorder, diagnosed following a clinical and physical review, with personal and familial evidence of (primarily mucocutaneous) bleeding, and characterised by low levels of, or abnormal function in, the plasma protein von Willebrand factor (VWF) (1, 2). Laboratory investigation typically entails initial plasma testing of factor VIII coagulant (FVIII:C), VWF protein (‘antigen’; VWF:Ag) and VWF function, with this classically assessed using the ristocetin cofactor (VWF:RCo) assay, although more recent international attention is starting to focus on newer tests of VWF function such as the collagen binding assay (VWF:CB) (3). Supplementary laboratory testing may also be performed and include VWF multimers, ristocetin induced platelet agglutination (RIPA), VWF-factor VIII binding (VWF:FVIIIB), and in some cases genetic analysis (1, 2). The PFA-100® (platelet function analyzer) may also have a role in the identification of VWD (4). Nevertheless, for most laboratories, the core battery of tests remains FVIII:C, VWF:Ag and VWF:RCo. Broadly, six types of VWD can be defined, comprising type 1, type 2 (with breakdown into 2A, 2B, 2M and 2N), and type 3 (1, 2). Types 1 and 3 are quantitative defects. Type 1 individuals produce low levels of otherwise functionally normal VWF, and VWF is absent in type 3 VWD. In contrast, type 2 VWD represents qualitative defects characterised by the presence of dysfunctional VWF, with the particular defect or dysfunction characterised within the subtype. Desmopressin (DDAVP) is now considered a standard treatment for some cases ofVWD, in particular type 1 (1, 5), although there are some varied viewpoints on the utility of DDAVP for other patients with VWD subtypes, in particular type 2 VWD. The alternative option for therapy inVWD patients unresponsive to DDAVP, or for which DDAVP is contraindicated, or for extended needs, remains VWF concentrate, although the commercially available options vary greatly in relative content (6, 7). Of upmost importance here is the variability in the relative molecular weight species of VWF contained within the concentrate as well as the relative content of factor VIII to VWF. Nevertheless, the significance of this varied content and its effect on therapeutic efficacy remains controversial, with some proponents giving preferential weight to the presence of high-molecularweight (HMW) VWF and others proposing that in-vivo correction of FVIII is more important. Moreover, there continues to be some contention regarding the best panel of tests with which to identify VWD and to monitor therapy for VWD. The classical approach, using the core test set previously mentioned (FVIII:C, VWF:Ag and VWF:RCo), supplemented where available with multimer analysis, continues to predominate. The main problem with this classical approach in diagnostics, however, are the high diagnostic error rates, identified both within external quality assurance settings (8–11), as well as by expert VWD studies involving genetic/phenotype correlations (reviewed in [3]). Thus, error rates approaching 30% are due to misidentification of VWD or VWD subtype. Our own laboratory’s view on this subject has been widely disseminated (2, 3, 8, 9) but perhaps largely overlooked by other experts, as it is somewhat at odds with the prevailing classical view. Indeed, we first reported on the utility of the VWF:CB in diagnostics over 15 years ago (12), and proposed over a decade ago (13) that use of the VWF:CB would provide additional utility within the context of DDAVP therapy monitoring, and then later, in 2001 (14), reported on the combined utility of the VWF:CB and PFA-100 in this setting. The situation was reviewed and updated recently (2–4, 15). In brief, we could identify striking differential patterns in test results using the panel of FVIII:C, VWF:Ag, VWF:RCo, VWF:CB and PFA-100 closure times (CT), both for the identification of VWD as well as when monitoring DDAVP therapy in VWD. Thus, type 1 VWD was characterised by good absolute and relative rises in all FVIII:C and VWF test parameters, although highest absolute and relative rises were consistently observed for FVIII:C and VWF:CB, and CB/Ag ratio increases in these patients overshadowed increases in RCo/Ag ratios. This is consistent with the view that increases in VWF:CB reflect the initial release of (ultra-) HMW VWF post-DDAVP, together with the higher comparative sensitivity of VWF:CB (ie compared to other VWF assays including VWF:Ag and VWF:RCo) for detection of these forms of VWF (3), but this concurrently challenges © 2008 Schattauer GmbH, Stuttgart