Laboratory assays of VWF activity and use of desmopressin trials in the diagnosis of VWD: a systematic review and meta-analysis

Abstract

Von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment is important to prevent and treat these symptoms. We systematically reviewed the accuracy of any VWF activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. Risk of bias was assessed using QUADAS-2 and certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR , VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appears to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with VWD suspected of type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

Guideline for laboratory diagnosis and monitoring of von Willebrand disease: A joint guideline from the United Kingdom Haemophilia Centre Doctors' Organisation and the British Society for Haematology

“…However, a recent meta-analysis of published data showed comparable accuracy between VWF:RCo, VWF:GPIbR and VWF:GPIbM. 59 VWF activity assays based on flow cytometric techniques have not yet been proven to be as sensitive as automated VWF:GPIbR assays. 49 Pending further data, they cannot be recommended for use in the diagnosis of VWD.…”

“…65 VWF:GPIbR VWF:GPIbR assays are based on the ability of VWF to bind recombinant wild-type GPIb-fragment in the presence of ristocetin, and are highly sensitive and moderately specific. 59 Some VWF:GPIbR activity assays are falsely reduced in individuals with p.(Arg1472His) and p.(Pro1467Ser), 58 but others are not. 57,58 Both the Werfen HemosIL VWF:RCo LIA and the Werfen AcuStar VWF:RCo CLIA measure VWF:GPIbR (not VWF:RCo); these assays have limitations associated with LIA and CLIA assays as previously described.…”

“…VWF:GPIbM assays are based on the ability of VWF to bind a recombinant GPIb-fragment modified with two gain-offunction mutations, and are highly sensitive and moderately specific. 59 The assay does not utilise ristocetin so is insensitive to the p.(Arg1472His) and p.(Pro1467Ser) variants. 63 The automated Siemens INNOVANCE VWF:Ac LIA measures VWF:GPIbM and has limitations associated with LIA assays as previously described.…”

“…1 There are little data regarding the monitoring of response to DDAVP using VWF:GPIbR or VWF:GPIbM assays. However, the assays have been well described in measuring VWF activity, 59 and the ability to measure VWF activity rapidly and accurately supports their use as functional measurement in monitoring response to DDAVP.…”

“…148,149 Field studies should be performed and published on VWF concentrates, but until more conclusive data are available, laboratories should consider performing local verification using either VWF:GPIbR or VWF:GPIbM if these assays are to be used. However, the assays have been well described in measuring VWF activity, 59 and the ability to measure VWF activity rapidly and accurately supports their use as functional measurement in monitoring VWF concentrate infusions.…”