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Semin Thromb Hemost 2007; 33(8): 745-758
DOI: 10.1055/s-2007-1000367
© Thieme Medical Publishers

Time to Think Outside the Box? Proposals for a New Approach to Future Pharmacokinetic Studies of von Willebrand Factor Concentrates in People with von Willebrand Disease

Emmanuel J. Favaloro1 , Geoff Kershaw2 , Andrew J. McLachlan3 , John Lloyd4
  • 1Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia
  • 2Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  • 3Faculty of Pharmacy, University of Sydney, Camperdown, NSW, Australia
  • 4Haematology, Institute of Medical and Veterinary Science (IMVS), Royal Adelaide Hospital, Adelaide, SA, Australia
Further Information

Publication History

Publication Date:
04 January 2008 (online)

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ABSTRACT

Plasma-derived factor concentrates are important in the management of von Willebrand disease (VWD). We review the current literature regarding pharmacokinetic studies of von Willebrand factor (VWF) concentrates used to treat VWD. Using additional local experience of a crossover pharmacokinetic (PK) study comparing a currently licensed double virally inactivated concentrate, Biostate, with that of its single virally inactivated predecessor, AHF (High Purity), we propose that consideration now be given to the use of new and novel test parameters for future PK studies. In particular, we propose that an evaluation of VWF collagen binding (VWF:CB) using an assay confirmed to be sensitive to high-molecular-weight forms of VWF be used in all future studies in addition to standard parameters such as factor VIII coagulant (FVIII:C), VWF antigen (VWF:Ag), and ristocetin cofactor (VWF:RCo). We further propose the use of calculated ratios of VWF:RCo to VWF:Ag and VWF:CB capacity to VWF:Ag as a measure of delivered VWF “functionality.” We also report some new data regarding assessment of VWF:multimers using standard procedures together with densitometry and a novel scoring system to support our proposals. We suggest that these test parameters may be useful in future PK studies to better assess and compare the potential utility and clinical efficacy of VWF factor concentrates for use as therapy for VWD.

KEYWORDS

von Willebrand factor - VWF - von Willebrand disease - VWD - coagulation factor concentrate - pharmacokinetics

REFERENCES

  • 1 Sadler J E, Budde U, Eikenboom J CJ et al.. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor.  J Thromb Haemost. 2006;  4 2103-2114
    CrossrefPubMedSearch in Google Scholar
  • 2 Federici A B. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: results from current studies and surveys.  Blood Coagul Fibrinolysis. 2005;  16(Suppl 1) S17-S21
    CrossrefPubMedSearch in Google Scholar
  • 3 Federici A B. Management of inherited von Willebrand disease in 2006.  Semin Thromb Hemost. 2006;  32 616-620
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Pasi K J, Collins P W, Keeling D M et al.. Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctor's Organization.  Haemophilia. 2004;  10 218-231
    CrossrefPubMedSearch in Google Scholar
  • 5 Mannucci P M. Scientific and Standardization Committee Communication. Recommended protocol for the study of the ex vivo biological effects of virus-inactivated plasma concentrates in patients with von Willebrand disease.  Thromb Haemost. 1992;  68 84-87
    PubMedSearch in Google Scholar
  • 6 Committee for Proprietary Medicinal Products . Guideline on the clinical investigation of human plasma derived von Willebrand factor products (CPMP/BPWG/220/02).  2005;  Available at: http://www.emea.europa.eu/pdfs/human/bpwg/022002en.pdf , Accessed November 22, 2007
    Search in Google Scholar
  • 7 Goudemand J, Mazurier C, Marey A et al.. Clinical and biological evaluation in von Willebrand's disease of a von Willebrand factor concentrate with low factor VIII activity.  Br J Haematol. 1992;  80 214-221
    PubMedSearch in Google Scholar
  • 8 Menache D, Aronson D, Darr F et al.. Pharmacokinetics of von Willebrand factor and factor VIIIC in patients with severe von Willebrand disease (type 3 VWD): estimation of the rate of factor VIIIC synthesis.  Br J Haematol. 1996;  94 740-745
    CrossrefPubMedSearch in Google Scholar
  • 9 Menache D. Pharmacokinetics of von Willebrand factor and FVIII coagulant activity in patients with von Willebrand disease type 2 and 3.  Haemophilia. 1998;  4(Suppl 3) 44-47
    CrossrefPubMedSearch in Google Scholar
  • 10 Dobrkovska A, Krzensk U, Chediak J R. Pharmacokinetics, efficacy and safety of Humate-P in von Willebrand disease.  Haemophilia. 1998;  4(Suppl 3) 33-39
    PubMedSearch in Google Scholar
  • 11 Lubetsky A, Martinowitz U, Luboshitz J, Kenet G, Keller N, Tamarin I. Efficacy and safety of a factor VIII-von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experience.  Haemophilia. 2002;  8 622-628
    CrossrefPubMedSearch in Google Scholar
  • 12 Auerswald G, Eberspacher B, Engl W et al.. Successful treatment of patients with von Willebrand disease using a high-purity double-virus inactivated factor concentrate (Immunate®).  Semin Thromb Hemost. 2002;  28 203-213
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Mannucci P M, Chediak J, Hanna W Alphanate Study Group et al. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study.  Blood. 2002;  99 450-456
    CrossrefPubMedSearch in Google Scholar
  • 14 Ver Elst K MM, van Vliet H DM, Kappers-Klunne M C, Leebeek F WG. In vitro studies, pharmacokinetic studies and clinical use of a high purity double virus inactivated FVIII/VWF concentrate (Immunate) in the treatment of von Willebrand disease.  Thromb Haemost. 2004;  92 67-74
    PubMedSearch in Google Scholar
  • 15 Goudemand J, Scharrer I, Berntorp E et al.. Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods.  J Thromb Haemost. 2005;  3 2219-2227
    CrossrefPubMedSearch in Google Scholar
  • 16 Lethagen S, Kyrle P A, Castaman G, Haertel S, Mannucci P M. for the HAEMATE® P Surgical Study Group. von Willebrand factor/factor VIII concentrate (Haemate® P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery.  J Thromb Haemost. 2007;  5 1420-1430
    CrossrefPubMedSearch in Google Scholar
  • 17 Favaloro E J, Lloyd J, Rowell J et al.. Comparison of the pharmacokinetics of two von Willebrand factor concentrates (Biostate® and AHF (High Purity)) in people with von Willebrand disorder: A randomised cross-over, multi-centre study.  Thromb Haemost. 2007;  97 922-930
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Favaloro E J, Bukuya M, Martinelli T et al.. A comparative multi-laboratory assessment of factor concentrate and implications for clinical efficacy as potential replacement therapy in von Willebrand's Disease (VWD).  Thromb Haemost. 2002;  87 466-476
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Oates A, Polmear E, Herrington R et al.. Willebrand factor characterization of a severe dry-heat treated factor VIII concentrate, AHF (high purity).  Thromb Res. 1992;  65 389-399
    CrossrefPubMedSearch in Google Scholar
  • 20 Shortt J, Dunkley S, Rickard K, Baker R, Street A. Efficacy and safety of a high purity, double virus inactivated factor VIII/von Willebrand factor concentrate (Biostate®) in patients with von Willebrand disorder requiring invasive or surgical procedures.  Haemophilia. 2007;  13 144-148
    CrossrefPubMedSearch in Google Scholar
  • 21 Favaloro E J. von Willebrand factor (VWF) collagen binding (activity) assay (VWF:CBA) in the diagnosis of von Willebrand's disorder (VWD): A 15-year journey.  Semin Thromb Hemost. 2002;  28 191-202
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Favaloro E J. Laboratory identification of von Willebrand disease: technical and scientific perspectives.  Semin Thromb Hemost. 2006;  32 456-471
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Federici A B, Canciani M T, Forza I, Cozzi G. Ristocetin cofactor and collagen binding activities normalized to antigen levels for a rapid diagnosis of type 2 von Willebrand disease. Single center comparison of four different assays.  Thromb Haemost. 2000;  84 1127-1128
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Baronciani L, Federici A B, Cozzi G, Canciani M T, Mannucci P M. von Willebrand factor collagen binding assay in von Willebrand disease type 2A, 2B, and 2M.  J Thromb Haemost. 2006;  4 2088-2090
    CrossrefPubMedSearch in Google Scholar
  • 25 Hubbard A R. von Willebrand factor standards for plasma and concentrate testing.  Semin Thromb Hemost. 2006;  32 522-528
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Budde U, Metzner H J, Muller H-G. Comparative analysis and classification of von Willebrand factor/factor VIII concentrates: impact on treatment of patients with von Willebrand disease.  Semin Thromb Hemost. 2006;  32 626-635
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Mazurier C. Composition, quality control, and labeling of plasma-derived products for the treatment of von Willebrand disease.  Semin Thromb Hemost. 2006;  32 529-536
    Thieme ConnectPubMedSearch in Google Scholar
  • 28 Favaloro E J, Facey D, Grispo L. Laboratory assessment of von Willebrand Factor: use of different assays can influence the diagnosis of von Willebrand's disease, depending on differing sensitivity to sample preparation and differential recognition of high molecular weight VWF forms.  Am J Clin Pathol. 1995;  104 264-271
    CrossrefPubMedSearch in Google Scholar
  • 29 Favaloro E J. Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrand's disease (VWD), and discrimination of VWD subtypes, depends on collagen source.  Thromb Haemost. 2000;  83 127-135
    PubMedSearch in Google Scholar
  • 30 Neugebauer B M, Goy C, Budek I, Seitz R. Comparison of two von Willebrand factor collagen binding assays with different affinities for low, medium and high multimers of von Willebrand factor.  Semin Thromb Hemost. 2002;  28 139-147
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Neugebauer B M, Goy C, Seitz R. A collagen binding assay: an additional method for von Willebrand factor activity in therapeutic concentrates.  Thromb Haemost. 2002;  88 871-872
    PubMedSearch in Google Scholar
  • 32 Hubbard A R, Sands D, Chang A C, Mazurier C. Standardisation of von Willebrand factor in therapeutic concentrates: calibration of the 1st International Standard for von Willebrand Factor Concentrate (00/514).  Thromb Haemost. 2002;  88 380-386
    PubMedSearch in Google Scholar
  • 33 Favaloro E J. An update on the von Willebrand factor collagen binding assay (VWF:CB)-21 years of age and beyond adolescence, but not yet a mature adult.  Semin Thromb Hemost. 2007;  33 727-744
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Favaloro E J. Standardization, regulation, quality assurance and emerging technologies in hemostasis: Issues, controversies, benefits and limitations.  Semin Thromb Hemost. 2007;  33 290-297
    Thieme ConnectPubMedSearch in Google Scholar
  • 35 Hubbard A. Minutes of the International Society on Thrombosis and Haemostasis (ISTH) von Willebrand factor (VWF) Scientific Standardisation Committee (SSC) meeting.  Available at: http://www.med.unc.edu/isth/ssc/07sscminutes/07vwf.htm , Accessed September 4, 2007
    PubMed

Dr. Emmanuel J FavaloroPh.D. M.A.I.M.S. 

Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR)

Westmead Hospital, WSAHS, Westmead, NSW, 2145, Australia

Email: emmanuel.favaloro@swahs.health.nsw.gov.au