E. Jousselme 1 Y. Jourdy 1,2 L. Rugeri 3 C. Négrier 1,2,3 C. Nougier 1. Abstract 1 INTRODUCTION ORIGINAL ARTICLE
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1 Received: 6 June 2017 Accepted: 18 August 2017 DOI: /ijlh ORIGINAL ARTICLE Comparison of an automated chemiluminescent assay to a manual ELISA assay for determination of von Willebrand Factor collagen binding activity on VWD plasma patients previously diagnosed through molecular analysis of VWF E. Jousselme 1 Y. Jourdy 1,2 L. Rugeri 3 C. Négrier 1,2,3 C. Nougier 1 1 Service d hématologie biologique, Hospices Civils de Lyon, Groupement hospitalier Est, Bron, France 2 EA 4609 Hémostase et cancer, University of Lyon, Université Claude Bernard Lyon 1, Lyon, France 3 Centre Régional de traitement des hémophiles, Hospices Civils de Lyon, Groupement hospitalier Est, Bron, France Correspondence Emilie Jousselme, Hemostasis Laboratory, Groupement Hospitalier Est, Centre de Biologie et Pathologie Est, Bron Cedex France. emilie.jousselme@chu-lyon.fr Funding information Instrumentation Laboratory Abstract Introduction: The correct diagnosis and classification of VWD (von Willebrand disease) is crucial and must be optimized by including the collagen binding assay (VWF:CB). VWF:CB remains an under- recognized tool, not fully automated. The objective of this study was to evaluate and to compare the previously evaluated automated chemiluminescent assay (HemosIL AcuStar VWF:CB) to the ELISA ASSERACHROM assay used routinely in our laboratory in patients with molecular diagnosis of VWD. Methods: A plasma sample from 49 patients previously diagnosed with VWD (type 1; type 2A, type 2M, type 2B) through phenotype and VWF (von Willebrand factor) analysis and 15 healthy controls was analysed. The VWF ristocetin cofactor activity (VWF:Rco) and VWF antigen (VWF:Ag) were performed simultaneously on the VWD plasma samples, and VWF:CB/VWF:Ag ratios were calculated. Results: The AcuStar VWF:CB assay was quickly performed with Pearson s correlation coefficient (r²) of.9571 between assays and a bias of +5.1U/dL (AcuStar > ELISA). Discrepancies of VWF:CB/VWF:Ag ratio were observed in type 2M- 2A- like VWD (ratio <0.6 with AcuStar assay in 4/5 samples). Conclusion: The AcuStar VWF:CB assay has demonstrated good performance to detect VWF mutational changes with capacity to discriminate quickly principal types of VWD. KEYWORDS chemiluminescence, ELISA, laboratory automation, von Willebrand disease, Willebrand collagen binding assay 1 INTRODUCTION von Willebrand disease (VWD) is the most common inherited bleeding disorder; the prevalence is estimated to be 1% worldwide. 1 VWD is caused by quantitative and/or qualitative deficiency in plasma von Willebrand factor (VWF), a high molecular weight (HMW) glycoprotein that plays a crucial role in primary haemostasis. VWD is classified into 6 types. Types 1 and 3 correspond to partial or total quantitative VWF deficiencies, respectively. Types 2A, 2B, 2M and 2N define qualitative VWF deficiencies. 2 Type 2A is characterized by a decrease in VWFdependent platelet adhesion due to deficiency of HMW multimers, type 2B by increased affinity of VWF for platelet GPIb, often also associated with loss of HMW, type 2M by decrease in VWF- dependent platelet adhesion without loss of HMW and type 2N by loss of VWF- FVIII binding. 2 Variants of VWD are also described. 2 Some variants are difficult to classify such as type 2M- 2A- like which is different from Int J Lab Hem. 2018;40: wileyonlinelibrary.com/journal/ijlh 2017 John Wiley & Sons Ltd 77
2 78 JOUSSELME et al. classical type 2M by some loss of large VWF multimers but not as much as classical type 2A. 3 The correct diagnosis and classification of VWD is crucial because the biological activity of VWF determines both the haemorrhagic risk and the patient s clinical management. In laboratories, a dynamic algorithm is usually used to diagnose patients with VWD, including the assessment of plasma FVIII coagulant activity (FVIII:C), of VWF antigen (VWF:Ag) and of VWF activity, notably the ristocetin cofactor activity (VWF:RCo) which evaluates the ability of VWF to bind platelet GPIb. To interpret the VWF assay results, the VWF:RCo/VWF:Ag ratio is considered; 4 a ratio >0.6 is predictive of quantitative VWF deficiencies, whereas a ratio <0.6 is predictive of qualitative VWF deficiencies. 5 Another activity assay is available, collagen binding assay (VWF:CB) which evaluates HMW VWF multimers adhesion to collagen. 6 This assay which is interpreted in a similar fashion, 7 but remains under- recognized, 8 is not frequently used in routine practice as the ELISA (enzyme- linked immunosorbent assay) method has not been fully automated. However, Favaloro et al identified that the 3 standard test panels (FVIII, VWF:Ag, VWF:RCo) must be optimized by VWF:CB assay to reduce misdiagnosis of VWD In particular, diagnosis of type 2M VWD was missed by 75-90% of laboratories using only 1 of the 2 VWF activity assays (VWF:RCo or VWF:CB), whereas the error rate was 3 times lower in the laboratories performing the 2 activity assays. 8 Recently, a chemiluminescent method (HemosIL AcuStar VWF:CB; Instrumentation Laboratory, Bedford, MA, USA) has been commercialized. The assay has been previously compared to an ELISA method; 11 however, the patients included in this study did not have molecular confirmation of diagnosis, which limits the conclusions as to the capacity of this method to correctly classify patients with VWD. The objective of this study was therefore to evaluate and to compare the chemiluminescent assay to ELISA ASSERACHROM assay used routinely in our laboratory in patients with molecular diagnosis of VWD. 2 MATERIALS AND METHODS 2.1 Population A plasma sample from 49 patients previously diagnosed with VWD (and classified) through phenotype and VWF analysis by the French reference centre and 15 healthy controls was analysed in this study. All patients with VWD had been referred to the Haemophilia Care Centre of Lyon, France. Criteria for diagnosis and classification of VWD conformed to recommendations of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. 2 Complete phenotype characterization was performed including FVIII:C, VWF:RCo, VWF:Ag, VWF:CB, Ristocetin- induced platelet agglutination (VWF:RIPA) and multimer analysis. Type 1 VWD was defined as VWF:Ag <30 U/dL, normal VWF:RCo/VWF:Ag ratio (>0.6) confirmed by molecular analysis. Samples from patients with type 2 VWD were defined by VWF mutational changes. Genetic classifications were performed according to the Sheffield VWF database in January 2017 ( For the study, all plasma samples were studied in parallel using both VWF:CB assays to compare phenotype characterization of plasma samples using AcuStar VWF:CB and ELISA VWF:CB. For the 49 plasma samples from patients with VWD only, the VWF:Ag and VWF:RCo were simultaneously performed to calculate the VWF:RCo/VWF:Ag and the VWF:CB/VWF:Ag ratios. 2.2 Blood samples Peripheral venous blood was drawn into 3.2% (0.109 mol/l) sodium citrate tubes. Platelet- poor plasma was prepared by double centrifugation at 2500 g for 15 minutes at room temperature. Plasma samples were stored at 80 C and thawed for 5 minutes in a water bath at 37 C before analysis. 2.3 von Willebrand factor collagen binding assays (VWF:CB) VWF:CB was performed on all samples using both VWF:CB assays. The HemosIL AcuStar VWF:CB (Instrumentation laboratory) was executed on the ACL AcuStar System (Instrumentation laboratory) according to manufacturer s instructions. This assay is a fully automated chemiluminescent assay. Plasma samples are mixed with buffer and paramagnetic particles coated with type III collagen- triple- helical peptide as source of collagen (full sequence, GPC- (GPP)5- GPRGQOGVMGFO- (GPP)5- GPCNH2). These particles represent the solid phase and capture VWF present in the sample. After magnetic separation and a wash step, an anti- VWF polyclonal antibody labelled with isoluminol is added. The next incubation is followed by the chemiluminescent reaction produced by 2 triggers. The emitted light is measured as relative light units (RLUs) by the optical system. The RLU value is proportional to the VWF:CB activity and reported as a percentage with a calibration curve. The ELISA ASSERACHROM VWF:CB (Diagnostic Stago, Asnières, France) assay is manually performed according supplier recommendations and contained a type III human placental collagen. For the assessment of analytical performance of VWF:CB assays, the within- run precision and the betweenrun precision were performed by repeating controls for each assay. For the automated assay, the 2 controls used were provided by the manufacturer: HemosIL AcuStar VWF normal and abnormal controls; for the manual assay, the control was on the kit and was used pure and diluted. 2.4 von Willebrand factor ristocetin cofactor activity (VWF:RCo) and antigen (VWF:Ag) The HemosIL AcuStar VWF:RCo and VWF:Ag (Instrumentation laboratory) kits were used on the ACL AcuStar System (Instrumentation laboratory) according to manufacturer s instructions at the same time as VWF:CB determinations. 2.5 Statistical analysis The statistical analysis was performed using GraphPad Prism software (La Jolla, CA, USA). Results are presented as median and interquartile
3 JOUSSELME et al. 79 range or mean and standard deviation (SD). Pearson s correlation coefficient between the AcuStar VWF:CB and the ELISA VWF:CB was calculated; agreement was calculated using the 95% limit- of- agreement method developed by Bland and Altman 12 in which the difference between 2 continuous variables is plotted against their means, with the 95% confidence intervals (CIs). Comparison was performed by the Wilcoxon matched paired test. A P- value <.05 was considered statistically significant. 3 RESULTS 3.1 Population Among the 49 patients with VWD, there were 21 type 1 and 28 type 2; 10 type 2A (including 8 type 2A(IIA), 1 type 2A(IID) and 1 type 2A(IIC)), 7 type 2M VWD (including 2 type 2M and 5 type 2M- 2A- like) and 11 type 2B (Table 1). 3.2 Characteristics of VWF:CB assays The AcuStar VWF:CB was performed on the automated system simultaneously with VWF:RCo and VWF:Ag. Calibration curves were performed once for all series, and results were obtained from 30 minutes and then 1 minute more for each value. The coefficient of variations (CV) of AcuStar VWF:CB was for the within- run precision (n = 20), 6.3% for normal control and 3.8% for abnormal control and for the between- run precision (n = 20), 9.6% for normal control and 7.0% for abnormal control. For the VWF:CB ELISA assay, the calibration curve was performed for each measurement series, and results were obtained after at least TABLE 1 Phenotypes and molecular analysis of patients with type 2 VWD of the study Plasma sample VWD n AcuStar RCo/Ag AcuStar CB/Ag ELISA CB/Ag Molecular analysis of VWF: mutational changes 2A 2A (IIA) p.(f1514c) exon 28 Gaucher et al p.(r1597w) Lyons et al p.(s1506l) Lyons et al 20 ; Jacobi et al p.(g1505r) Lyons et al 20 ; Hassenpflug et al p.(i1628t) Iannuzzi et al 23 2A (IID) p.(c2771w) exon 52 Goodeve et al 24 2A (IIC) p.(c1099y) exon 25 Schneppenheim et al 25 2M 2M p.(r1315q) exon 28 Not published p.(g1324s) Rabinowitz et al 26 2M- 2A- like p.(r1374h) Hilbert et al p.(r1374c) Hilbert et al 27 ; Penas et al 15 2B p.(p1337l) exon 28 Kroner et al p.(r1308c) Hilbert et al p.(p1266l) Goodeve et al p.(r1379c) Casaña et al VWD, von Willebrand disease; VWF, von Willebrand factor; RCo, VWF ristocetin cofactor activity; Ag, VWF antigen; CB, VWF collagen binding.
4 80 JOUSSELME et al. 2-3 hours. The within- run CV was 12.5% for the control and 8.4% once diluted (n = 12), and the between- run CV was 6.8% for the control and 9.1% once diluted (n = 16). 3.3 Comparison of the two assays Comparison between AcuStar VWF:CB and ELISA VWF:CB yielded a slope of and an intercept of Pearson s correlation coefficient (r²) was Agreement between the 2 VWF:CB assays was evaluated using Bland and Altman plots; there were slightly higher values for AcuStar VWF:CB (bias +5.1 U/dL; Figure 1A). There was a greater difference for the values >51 U/dL (bias +20.2/dL; Figure 1B) and a lesser difference for values <51 U/dL (bias 1.2/dL; Figure 1C). Values of VWF:RCo, VWF:Ag and VWF:CB using ELISA and AcuStar assays obtained in both VWD patient samples and healthy controls are reported in Table 2. The low linearity thresholds were 6.3 and 0.5 U/dL for the ELISA VWF:CB assay and the AcuStar VWF:CB assay, respectively. VWF:CB results were under the linearity threshold in 6 patients using the ELISA method, and these patients were excluded from the statistical analysis because we needed paired values for paired tests. Both VWF:CB assays gave nonsignificantly different results for all samples, except for the samples from patients with type 2M VWD who had lower values with AcuStar assay (AcuStar VWF:CB: 11.6 U/dL; ELISA VWF:CB: 17.9 U/dL; Wilcoxon matched pairs test, P =.0313). All samples of patients with type 1 VWD had a VWF:CB/VWF:Ag ratio >0.6 using both VWF:CB assays. In patients with type 2 VWD, VWF:CB/VWF:Ag ratios were <0.6 in 20/28 (71%) with the HemosIL assay and in 16/28 (57%) with the ELISA assay. Discrepancies were observed only in type 2M VWD (Figure 2). Among the 7 samples from patients with type 2M VWD, ratios were >0.6 with both VWF:CB assays for the 2 samples from classical type 2M VWD whereas VWF:CB/ VWF:Ag ratios were <0.6 only with AcuStar VWF:CB in 4/5 samples with type 2M- 2A- like VWD, corresponding to missense mutation p.r1374h and p.r1374c (Table 1). The VWF:CB/VWF:Ag ratios were <0.6 in all type 2A VWD samples (n = 10/10, 100%) and in 7/12 (58%) type 2B VWD samples. 4 DISCUSSION This study compared results obtained on VWD plasma previously diagnosed through molecular analysis of VWF, with the HemosIL AcuStar VWF:CB assay to the ELISA ASSERACHROM VWF:CB assay. The fully automated AcuStar VWF:CB assay is less time- consuming than the manual ELISA method, with a lower linearity threshold, and is easier to perform (calibration curve not performed for each measurement series, results quickly obtained and reagents always on board with reported long stability by the manufacturer [5 weeks]). In this study, the CVs of within- run and between- run of AcuStar VWF:CB assay were lower than those of ELISA VWF:CB assay but were slightly higher than those previously reported by Favaloro et al 11. The results FIGURE 1 Bland and Altman plot comparing the difference between VWF:CB assays (AcuStar vs ELISA). (A) n = 58; all plasma samples (>linearity threshold of ELISA). (B) n = 17; plasma samples with VWF:CB (average of assays) > 51 U/dL. (C) n = 41; plasma samples with VWF:CB (average of assays) <51 U/dL. VWF:CB, VWF collagen binding were, however, in accordance with the CVs indicated by the manufacturer (CV of within- run <8%, and between- run <12%). Bias observed on Bland and Altman plots was under CV of within- subject (25.6%) 13 which mean no clinical relevance of the differences between the 2 assays whatever normal or abnormal values. So, we found no relevant different performance to ELISA VWF:CB assay, but by performing quickly and easily VWF:CB assay, this tool might be used by several laboratories. Moreover, as reported, 11 the assay will participate to improve the
5 JOUSSELME et al. 81 TABLE 2 Median and interquartile range for healthy volunteers and patients with VWD for the different assays: ELISA VWF:CB; AcuStar VWF:CB; AcuStar VWF:RCo; AcuStar VWF:Ag ELISA AcuStar n VWF:CB (U/dL) VWF:CB (U/dL) VWF:RCo (U/dL) VWF:Ag (U/dL) Healthy volunteers ( ) ( ) Undetermined Undetermined Type 1 VWD ( ) 32.4 ( ) 28.0 ( ) 24.3 ( ) Type 2 VWD 2A ( ) a 9.9 ( ) a 9.8 ( ) 25.7 ( ) 2M ( )* 11.6 ( )* 6.9 ( ) c 19.0 ( ) 2B ( ) b 26.8 ( ) b 23.9 ( ) 36.5 ( ) VWD, von Willebrand disease; VWF:CB, VWF collagen binding. a n = 5: type 2A VWD (paired values with VWF:CB ELISA > linearity threshold). b n = 10: type 2B VWD (paired values with VWF:CB ELISA > linearity threshold). c n = 6: type 2M VWD (paired values with VWF:RCo AcuStar > linearity threshold). *Significant difference (P- value <.05). FIGURE 2 VWF:CB/VWF:Ag ratios for type 2 VWD plasma samples (n = 43; results > linearity threshold of ELISA) using both assays (VWF:CB AcuStar vs ELISA). Type 1 VWD, Type 2M VWD, Type 2A VWD, Type 2B VWD, Circled data population: type 2M- 2A- like VWD; VWF:CB, von Willebrand factor collagen binding; VWF:Ag, von Willebrand factor antigen diagnosis of VWD by performing the 3 main tests: VWF:Ag and the 2 activities VWF:RCo and VWF:CB on the same system. Statistical analysis found a good correlation between AcuStar VWF:CB and ELISA assays for normal plasma and VWD patients, as previously reported. 11 Concordant results were obtained for all type 1, 2A and 2B VWD samples regardless of the assay using VWF:CB/ VWF:Ag ratios. The AcuStar VWF:CB assay was able to discriminate samples with type 1 VWD (ratios VWF:Rco/VWF:Ag and VWF:CB/ VWF:Ag >0.6) vs type 2A (and most cases of 2B) according to molecular diagnosis of patients. We observed that several cases of type 2B VWD did not show VWF:CB/VWF:Ag discordance regardless of the assay used. However, this may be explained by heterogeneity of the multimeric pattern in type 2B VWD as the VWF:CB assay is dependent on the presence of VWF multimers. Low VWF:CB/VWF:Ag ratios were associated with partial loss of the HMW observed on multimer analysis of VWF and normal ratios to normal distributions. Therefore, the main phenotype diagnosis criteria with type 2B VWD is the RIPA test. 2,14 Discordant results between AcuStar and ELISA VWF:CB assays were found for 4 samples with a VWF:CB/VWF:Ag ratio <0.6 using AcuStar VWF:CB. All of these patients carried a missense mutation affecting the residue 1374, also known as type 2M- 2A- like VWD. Multimeric analysis of plasma VWF in patients carrying the p.r1374c mutation showed an abnormal distribution that is also different to that found in type 2M VWD but also different to that found in type 2A VWD which is characterized by the absence of HMW multimeric VWF. 15 As this complete absence of HMW multimers is required for type 2A VWD, it has been recommended to include mutation affecting the residue p.1374 in type 2M VWD. 16,17 These discordant results may be explained by the difference source of collagen used in the 2 assays: type III human placental collagen for the ELISA assay and synthetic peptides for AcuStar VWF:CB. Discordant VWF:CB results in some type 2 VWD have been previously reported to be dependent on the source of collagen used in the assay. 18 Thus, the phenotype characterization of AcuStar VWF:CB seemed to be more able to detect patients with type 2M- 2A- like VWD which had not classical type 2M phenotypes, at least for those mutations who are affected the p.1374 residue. Furthermore, the only 2 plasma samples with classical type 2M were well differentiated from type 2A. Taken together, the AcuStar VWF:CB assay provided results that were more in accordance with genetic tests, and this may be in relation to the use of a synthetic collagen type III peptide. One limitation of this study is the sample size of our population. Thus, complete phenotype and genotype characterization could be obtained in only 49 samples, but this population is representative of the variability of the VWD. In conclusion, we have demonstrated good performance to detect VWF mutational changes with capacity to discriminate quickly principal types of VWD: type 1 from type 2 VWD and classical type 2A from classical type 2M VWD. The HemosIL AcuStar VWF:CB assay evaluated in this study improved diagnosis of VWD.
6 82 JOUSSELME et al. ADDENDUM Jousselme E designed and performed the project, analysed the data, wrote the manuscript and approved the submission of the manuscript. Jourdy Y analysed the data, wrote the manuscript and approved the submission of the manuscript. Rugeri L and Nougier C designed the project and approved the submission of the manuscript. ACKNOWLEDGEMENTS This study has been supported by Instrumentation Laboratory (test reagents). The author would like to thank Guillaume Lesavre, Fabien Oliver, Sylvie Marin and Claire Chatelain for the technical assistance, the French reference centre in Lille (CRMW) for the genetic evaluations and reports of VWD samples, and Philip Robinson for its careful review. CONFLICT OF INTEREST Instrumentation laboratory provided test reagents. ORCID E. Jousselme REFERENCES 1. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand s disease. 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7 JOUSSELME et al Kroner PA, Kluessendorf ML, Scott JP, Montgomery RR. Expressed full- length von Willebrand factor containing missense mutations linked to type IIB von Willebrand disease shows enhanced binding to platelets. Blood. 1992;79: Hilbert L, Gaucher C, Abgrall JF, Parquet A, Trzeciak C, Mazurier C. Identification of new type 2B von Willebrand disease mutations: Arg543 Gln, Arg545Pro and Arg578Leu. Br J Haematol. 1998;103: Casaña P, Martínez F, Haya S, Tavares A, Aznar JA. New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand s disease. Haematologica. 2001;86: How to cite this article: Jousselme E, Jourdy Y, Rugeri L, Négrier C, Nougier C. Comparison of an automated chemiluminescent assay to a manual ELISA assay for determination of von Willebrand Factor collagen binding activity on VWD plasma patients previously diagnosed through molecular analysis of VWF. Int J Lab Hem. 2018;40:
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