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Value assignment of the WHO 6th International Standard for blood coagulation factor VIII and von Willebrand factor in plasma (07/316)

2011; Elsevier BV; Volume: 9; Issue: 10 Linguagem: Inglês

10.1111/j.1538-7836.2011.04471.x

1538-7933

A. R. Hubbard, Michelle Hamill, M. BEEHARRY, S. Bevan, Alan Heath,

Myeloproliferative Neoplasms: Diagnosis and Treatment

Harmonization in the diagnosis and monitoring of the bleeding disorders hemophilia A and von Willebrand disease (VWD) relies on the availability of the World Health Organization International Standard (WHO IS) for factor (F)VIII and von Willebrand factor (VWF) in plasma, which provides the primary definition of the International Unit (IU) for five analytes in human plasma [factor VIII:coagulant activity (FVIII:C), factor VIII:antigen (FVIII:Ag), VWF:antigen (VWF:Ag), VWF:ristocetin cofactor (VWF:RCo) and VWF:collagen binding, (VWF:CB)]. The WHO IS provides a common traceable source of calibration in IU for secondary plasma standards throughout the world and the annual demand exceeds 800 ampoules. Depletion of the stocks of the WHO 5th IS (02/150), which was established in 2003 [1Hubbard A.R. Heath A.B. Standardization of factor VIII and von Willebrand factor in plasma: calibration of the WHO 5th International Standard (02/150).J Thromb Haemost. 2004; 2: 1380-4Crossref PubMed Scopus (27) Google Scholar], made it necessary to prepare a replacement standard and this report describes the value assignment of the WHO 6th IS. The candidate WHO 6th IS (07/316) was prepared from recovered plasma from 80 normal healthy donors, pooled and buffered with HEPES, to a final concentration of 40 mmol L−1, before freeze drying under conditions suitable for the preparation of international biological standards [2Campbell P.J. International biological standards and reference preparations. 1. Preparation and presentation of materials to serve as standards and reference preparations.J Biol Stand. 1974; 2: 249-67Crossref PubMed Scopus (59) Google Scholar]. Value assignment of the proposed WHO 6th IS was achieved through assays relative to the WHO 5th IS in an international multi‐center study involving 44 laboratories from 14 countries which comprised 20 clinical laboratories, 21 manufacturers and three regulators. Estimates for FVIII:C, relative to the WHO 5th IS, produced similar mean values for all three methods (0.67 IU per ampoule by 1‐stage clotting, n = 31; 0.72 IU per ampoule by 2‐stage clotting, n = 1; 0.70 IU per ampoule by chromogenic, n = 20) and there was good agreement between laboratories for the overall combined mean of 0.68 IU mL−1 [n = 52, geometric coefficient of variation (GCV) 4.06%] (Table 1). Estimates for FVIII:Ag, relative to the WHO 5th IS, showed good agreement between laboratories with a GCV of 4.24% and an overall mean of 1.04 IU mL−1 (n = 10).Table 1Summary of overall mean estimates and inter‐laboratory variability (GCV%) for the WHO 6th IS factor VIII/VWF Plasma (07/316) calculated relative to the WHO 5th IS factor VIII/VWF Plasma (02/150) and the local normal plasma poolsAnalytevs. WHO 5th IS (02/150)vs. Local normal poolsMean (IU ml−1)GCV%nMean (IU mL−1)GCV%nFVIII:C0.68*4.06520.57 (fresh) 0.72 (frozen)13.90 13.5416 31FVIII:Ag1.04*4.24100.9310.5311VWF:Ag1.00*4.29310.8912.9230VWF:RCo0.87*8.13280.9025.2928VWF:CB1.03*5.80210.9912.2420*These values were assigned to the WHO 6th IS factor VIII/VWF Plasma (07/316) on establishment. FVIII:C, factor VIII:coagulant activity; FVIII:Ag, factor VIII:antigen; VWF:Ag, VWF:antigen; VWF:RCo, VWF:ristocetin cofactor; VWF:CB, VWF:collagen binding. Open table in a new tab *These values were assigned to the WHO 6th IS factor VIII/VWF Plasma (07/316) on establishment. FVIII:C, factor VIII:coagulant activity; FVIII:Ag, factor VIII:antigen; VWF:Ag, VWF:antigen; VWF:RCo, VWF:ristocetin cofactor; VWF:CB, VWF:collagen binding. Estimates for VWF:Ag, relative to the WHO 5th IS, showed excellent agreement between the ELISA (mean 1.00 IU per ampoule, n = 21) and immuno‐turbidimetric (mean 1.00 IU per ampoule, n = 10) methods and produced an overall mean of 1.00 IU mL−1 (n = 31) with low inter‐laboratory variability (GCV 4.29%) (Table 1). Estimates for VWF:RCo relative to the WHO 5th IS by the automated aggregometric methods were less variable (mean 0.86 IU per ampoule, GCV 6.52%) but not significantly different to estimates by manual visual agglutination (mean 0.90 IU per ampoule, GCV 12.0%). A combination of all estimates relative to the 5th IS produced a mean of 0.87 IU mL−1 (n = 28) with acceptable inter‐laboratory variability (GCV) of 8.13%. Estimates for VWF:CB, relative to the WHO 5th IS, were associated with very good agreement between laboratories using type 3 (mean 1.04 IU per ampoule) and type 1/3 mix collagen reagents (mean 1.02 IU per ampoule) and produced an overall mean of 1.03 IU mL−1 (n = 21) with an inter‐laboratory variability (GCV) of 5.80%. Estimates relative to local normal plasma pools were also calculated for the proposed WHO 6th IS as a check on possible drift of the IU away from the ‘plasma unit’ where 1 IU mL−1 represents the amount of analyte in 1 mL of fresh, normal pooled plasma (Table 1). However, these estimates have a limited value as the normal pools differ between laboratories and between collaborative studies. Moreover, there was a significant difference (P < 0.0001) for FVIII:C estimates in the proposed WHO 6th IS where mean values of 0.57 and 0.72 IU mL−1 were calculated relative to fresh and frozen local pools, respectively. This was consistent with the loss of FVIII:C on freeze‐thawing of the local pools. Estimates for all analytes, calculated relative to the locally collected normal plasma pools, were associated with larger inter‐laboratory variability and produced significantly different results compared with estimates vs. the WHO 5th IS for FVIII:C, FVIII:Ag and VWF:Ag but not for VWF:RCo and VWF:CB. Previous studies have also shown similar discrepancies between estimates relative to the WHO IS and local pools and these have recurred in spite of efforts of correction by adjusting the value of the IU [1Hubbard A.R. Heath A.B. Standardization of factor VIII and von Willebrand factor in plasma: calibration of the WHO 5th International Standard (02/150).J Thromb Haemost. 2004; 2: 1380-4Crossref PubMed Scopus (27) Google Scholar, 3Hubbard A.R. Rigsby P. Barrowcliffe T.W. Standardisation of Factor VIII and von Willebrand Factor in plasma: calibration of the 4th International Standard.Thromb Haemost. 2001; 85: 634-8Crossref PubMed Scopus (31) Google Scholar, 4Hubbard A.R. von Willebrand Factor standards for plasma and concentrate testing.Semin Thromb Hemost. 2006; 32: 522-8Crossref PubMed Scopus (17) Google Scholar]. It was therefore agreed by the participants in the study, the experts associated with the SSC sub‐committees (FVIII/FIX and VWF) and the Expert Committee on Biological Standardization (ECBS) of WHO, that continuity of the IU was of primary importance and that the assigned values should be calculated relative to the WHO 5th IS. The excellent stability of the WHO 5th IS further validated this route of value assignment. The preparation coded 07/316 was established as the WHO 6th International Standard FVIII/VWF, Plasma by WHO in October 2009 with the following assigned values: FVIII:C 0.68 IU per ampoule, FVIII:Ag 1.04 IU per ampoule, VWF:Ag 1.00 IU per ampoule, VWF:RCo 0.87 IU per ampoule and VWF:CB 1.03 IU per ampoule [5Hubbard AR, Hamill M, Beeharry M, Bevan S, Heath AB. Value assignment of the proposed 6th International Standard for blood coagulation factor VIII and von Willebrand factor in plasma, human (07/316). WHO/BS/09.2116 World Health Organization Expert Committee on Biological Standardization 2009. http://whqlibdoc.who.int/hq/2009/WHO_BS_09.2116_eng.pdf; Accessed 9 September 2011.Google Scholar]. The authors state that they have no conflict of interest. M. Shima, Nara Medical University, Kashihara City, Japan. K. Sukhu/P. Giangrande, Churchill Hospital, Oxford, UK. A. Federici/M. Canciani/R. Bader, ABB Hemophilia & Thrombosis Centre, Milan, Italy. E. Duncan, Institute of Medical & Veterinary Science, Adelaide, Australia. K. Friedman/J. Endres, Blood Center of SE Wisconsin, Milwaukee WI, USA. C. Eby, Washington University School of Medicine, Saint Louis MO, USA. B. Woodhams, Diagnostica Stago, Gennevilliers, France. A. Lichte/J. Patzke/M. Timme, Siemens Healthcare GmbH, Marburg, Germany. C. Andreini, Instrumentation Laboratory, Milan, Italy. S. Rosén, Rossix, Molndal, Sweden. S. Duff/M. Boylan, Precision Biologic Inc, Dartmouth, Nova Scotia, Canada. S. Cinotti, Centro Emofilia, Azienda Ospedaliera Careggi, Florence, Italy. C. Watson, Royal Infirmary, Leicester, UK. B. Kerbl, Technoclone GmbH, Vienna, Austria. M. G. Riera, Instituto Grifols S.A., Barcelona, Spain. F. Rodeghiero/A. Tosetto, San Bortolo Hospital, Vicenza, Italy. M. Chitlur/J. M. Lusher, Children’s Hospital of Michigan, Detroit MI, USA. M. Wolf, Hôpital Antoine‐Béclère, Clamart, France. P. Turecek/H. Gritsch, Baxter Innovations GmbH, Vienna, Austria. E. J. Favaloro, ICPMR, Westmead Hospital, Australia. A. Hunfeld/J. Fötisch/A. Schroda/R. Nawroth, Paul‐Ehrlich‐Institut, Langen, Germany. K. Trumbull, Instrumentation Laboratory, Lexington MA, USA. B. Samor, LFB Biotechnologies, Lille, France. S. Bevan/M. Beeharry, NIBSC, Potters Bar, UK. C. A. Ludlam/L Germain, Royal Infirmary, Edinburgh, UK. S. Kitchen/K. Goodfellow, Royal Hallamshire Hospital, Sheffield, UK. A. Riddell, Royal Free Hospital, London, UK. S. Berrier, Diagnostica Stago QC, Franconville, France. C. Caron, Centre de Biologique Pathologie, Lille, France. C. M. Eckmann, Sanquin Plasma Supply Foundation, Amsterdam, The Netherlands. P. Gärtner, Baxter AG, Vienna, Austria. D. Elmlinger, Octapharma SA QC, Lingolsheim, France. M. Blum, Baxter AG, Orth/Donau, Austria. J. Amiral, Hyphen Biomed SAS, Neuville‐sur‐Oise, France. M. Bono, Diagnostic Grifols, Barcelona, Spain. J. C. J. Eikenboom, Leiden University Medical Center, Leiden, the Netherlands. K. Pock, Octapharma R & D, Vienna, Austria. J. Conkie/G. Hickman, Royal Infirmary, Glasgow, UK. M. Telesca, Presbyterian Hospital, New York NY, USA. G. Longin, CAF‐DCF Red Cross, Neder‐Over‐Heembeek (Brussels), Belgium. G. Rautmann/C. Raphalen, EDQM Council of Europe, Strasbourg, France. D. Krause, Octapharma Prod. GmbH, Vienna, Austria. A. Blande, Bio Products Laboratory, Elstree, UK. We are very grateful to the participants in this calibration exercise for their considerable efforts in performing the assays; to the Standards Processing Division (NIBSC) for preparing the ampouled materials and dispatching the samples, and to the chairs and members of the ISTH/SSC sub‐committees for FVIII/FIX and von Willebrand factor for their support.