Laboratory diagnosis of von Willebrand disorder (vWD) and monitoring of DDAVP therapy: efficacy of the PFA‐100^® and vWF:CBA as combined diagnostic strategies

Abstract

We have coevaluated a combination of test processes for diagnosing von Willebrand disease (vWD) and monitoring deamino-delta-D-arginine vasopressin (DDAVP) therapy. Using normal controls (n = 23), closure time (CT) ranges measured by PFA-100(R) were (mean +/- 2SD): (i) collagen/ADP cartridge (C/ADP): 67-127 s (ii) collagen/epinephrine (C/Epi): 94-162 s. From a panel of 125 patients undergoing evaluation for clinical haemostatic defects, 29/30 samples from patients with vWD [17/18 type 1, 1/1 type 3, 3/3 type 2A, 7/7 type 2B and 1/1 pseudo-vWD] gave prolonged CTs using C/Epi. The C/ADP was less sensitive, being normal in 7/18 of the type 1 vWD individuals, with higher sensitivity to more severe vWD. Individuals with haemophilia (six factor VIII-deficient, one factor XI-deficient) gave normal CTs, while those with clinical thrombocytopenia (n=13) gave normal or prolonged CTs, somewhat dependent on platelet count. The PFA-100 was also evaluated as a part of the laboratory monitoring procedure in patients with either vWD or haemophilia undergoing a DDAVP trial as a therapeutic management process. For vWD, correction of an initially prolonged CT by DDAVP, accompanied by normalization of von Willebrand factor (vWF) measurable by von Willebrand factor antigen, vWF collagen binding activity and vWF ristocetin cofactor assays (vWF:Ag, vWF:CBA and vWF:RCof), was achieved in type 1 vWD (n=5). In an individual with type 2A vWD, DDAVP normalized vWF:Ag and vWF:RCof, but had no apparent effect on the baseline maximally prolonged CT. In an individual with type 2B vWD, factor VIII/vWF concentrate also normalized vWF:Ag and vWF:RCof, but similarly had no apparent effect on the baseline maximally prolonged CT. vWF:CBA did not normalize for either of these individuals, potentially suggesting that normalization of vWF:CBA might be required for normalization of CT. This concept is supported by correlation analysis undertaken between CT and various vWF parameters. Among these, vWF:CBA held the strongest relationship in our data set, which showed an inverse progressive rise in CT for falling vWF:CBA. Based on these results, we would conclude that the PFA-100 is highly sensitive to the presence of vWD, and may thus provide a valuable screening test for vWD. Furthermore, the combined utility of the PFA-100 and vWF:CBA as markers of DDAVP responsiveness may prove to be simple, quick but powerful, predictors for its clinical efficacy.

Laboratory diagnosis and monitoring of desmopressin treatment of von Willebrand's disease by flow cytometry

“…PFA-100 ® , which is a simple and rapid test, has a good sensitivity but a low specificity for diagnosing VWD. 6 Flow cytometry is emerging as a useful methodology in the study of platelets and for the diagnosis of thrombocytopenia and platelet disorders. 17 Indeed many hematology or hemostasis laboratories now possess a flow cytometer and dedicated technicians.…”

“…VWF:CB is a quantitative and qualitative assay which measures, typically by enzyme-linked immunosorbent assay (ELISA), the ability of VWF to bind collagen and is highly sensitive to the presence of high molecular weight VWF multimers. 6 Recently many reports have focused on the development of new tests for the diagnosis of VWD [6][7][8][9][10][11] and for monitoring the effects of treatments. 6,12 Indeed, patients with VWD are often treated with desmopressin (1-deamino-8-arginine vasopressin, DDAVP), a synthetic analog of the antidiuretic hormone vasopressin, which increases the plasma levels of factor VIII (FVIII) and VWF by 3 to 5-fold.…”

“…6 Recently many reports have focused on the development of new tests for the diagnosis of VWD [6][7][8][9][10][11] and for monitoring the effects of treatments. 6,12 Indeed, patients with VWD are often treated with desmopressin (1-deamino-8-arginine vasopressin, DDAVP), a synthetic analog of the antidiuretic hormone vasopressin, which increases the plasma levels of factor VIII (FVIII) and VWF by 3 to 5-fold. 13,14 The variability in the individual response to DDAVP does, however, mean that this treatment needs to be tested before therapeutic use, and its efficacy is monitored by measuring the above mentioned parameters before and after DDAVP infusion.…”

Response to Letter by Creutzfeldt et al

“…6,7 Although none of the patients in our cohort were known to have an inherited disorder of platelet function, platelet function assay results are helpful for the diagnosis of von Willebrand disease and may guide the response to therapy. 8,9 We agree that there is no consensus that known antiplatelet medication use impacts outcome after ICH; however, we feel this is the wrong question. The correlation between medication history and platelet activity in patients with ICH is suboptimal for a number of potential reasons.…”

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

“…Thus, error rates approaching 30% aredue to misidentification of VWDorVWD subtype.Our own laboratory'sviewonthis subjecthas been widelydisseminated (2,3,8,9) butperhaps largelyoverlookedbyotherexperts, as it is somewhat at odds with the prevailing classicalview. Indeed, we first reported on the utility of the VWF:CB in diagnostics over 15 years ago (12),and proposedoveradecade ago (13) that use of the VWF:CB would provide additional utility within the context of DDAV Ptherapymonitoring, and then later,in2001 (14),r eported on the combined utility of the VWF:CB and PFA-100 in this setting. The situation wasreviewedand updated recently (2)(3)(4)15).…”