Download PDF
Semin Thromb Hemost 2011; 37(5): 511-521
DOI: 10.1055/s-0031-1281037
© Thieme Medical Publishers

Management of Inherited von Willebrand Disease in Italy: Results from the Retrospective Study on 1234 Patients

Augusto B. Federici1 , 2 , Paolo Bucciarelli2 , Giancarlo Castaman3 , Luciano Baronciani2 , Maria T. Canciani2 , Maria G. Mazzucconi4 , Massimo Morfini5 , Angiola Rocino6 , Mario Schiavoni7 , Emily Oliovecchio8 , Alfonso Iorio8 , Pier M. Mannucci9
  • 1Division of Hematology and Transfusion Medicine, L. SACCO University Hospital and Department of Internal Medicine, University of Milan, Milan, Italy
  • 2A. Bianchi BONOMI Hemophilia and Thrombosis Center, IRCCS Cà Granda Foundation, Policlinico Hospital, Milan, Italy
  • 3Division of Hematology, San BORTOLO Hospital, Vicenza, Italy
  • 4Hemophilia Center, Department of Hematology, University of Rome, Rome, Italy
  • 5Hemophilia Center, CAREGGI Hospital, Florence, Italy
  • 6Hemophilia Center, PELLEGRINI Hospital, Naples, Italy
  • 7Hemophilia Thrombosis Center, POLICLINICO Hospital, Bari, Italy
  • 8Hemophilia Center, University of Perugia, Perugia, Italy
  • 9Scientific Direction IRCCS Ca GRANDA Foundation Maggiore Policlinico Hospital, Milan, Italy
Further Information

Publication History

Publication Date:
18 November 2011 (online)

    Permissions and Reprints

ABSTRACT

von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD.

KEYWORDS

von Willebrand disease - mucosal bleeding - von Willebrand factor assays - clinical - laboratory and molecular markers - desmopressin - VWF/FVIII concentrates

REFERENCES

  • 1 Sadler JE, Budde U, Eikenboom JC Working Party on von Willebrand Disease Classification 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 (10) 2103-2114
    Search in Google Scholar
  • 2 Federici AB, Mannucci PM. Management of inherited von Willebrand disease in 2007.  Ann Med. 2007;  39 (5) 346-358
    Search in Google Scholar
  • 3 Federici AB, Castaman G, Mannucci PM. Guidelines for the diagnosis and management of VWD in Italy.  Haemophilia. 2002;  8 607-621
    Search in Google Scholar
  • 4 Pasi KJ, Collins PW, Keeling DM et al.. Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization.  Haemophilia. 2004;  10 (3) 218-231
    Search in Google Scholar
  • 5 Nichols WL, Hultin MB, James AH et al.. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA).  Haemophilia. 2008;  14 (2) 171-232
    Search in Google Scholar
  • 6 Mannucci PM, Franchini M, Castaman G, Federici AB. Italian Association of Hemophilia Centers . Evidence-based recommendations on the treatment of von Willebrand disease in Italy.  Blood Transfus. 2009;  7 (2) 117-126
    Search in Google Scholar
  • 7 Tosetto A, Castaman G, Rodeghiero F. Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes theorem approach.  Blood. 2008;  111 (8) 3998-4003
    Search in Google Scholar
  • 8 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease.  Blood. 1987;  69 (2) 454-459
    Search in Google Scholar
  • 9 Goodeve A, Eikenboom J, Castaman G et al.. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD).  Blood. 2007;  109 (1) 112-121
    Search in Google Scholar
  • 10 James PD, Notley C, Hegadorn C et al.. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study.  Blood. 2007;  109 (1) 145-154
    Search in Google Scholar
  • 11 Barbui T, Baudo F, Ciavarella N Italian Working Group et al. Spectrum of von Willebrand's disease: a study of 100 cases.  Br J Haematol. 1977;  35 (1) 101-112
    Search in Google Scholar
  • 12 Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases.  Lancet. 1977;  1 (8017) 869-872
    Search in Google Scholar
  • 13 Iorio A, Oliovecchio E, Morfini M, Mannucci PM. Association of Italian Hemophilia Centres Directors . Italian Registry of Haemophilia and Allied Disorders. Objectives, methodology and data analysis.  Haemophilia. 2008;  14 (3) 444-453
    Search in Google Scholar
  • 14 Federici AB, Canciani MT, Forza I et al.. A sensitive ristocetin co-factor activity assay with recombinant glycoprotein Ibalpha for the diagnosis of patients with low von Willebrand factor levels.  Haematologica. 2004;  89 (1) 77-85
    Search in Google Scholar
  • 15 Baronciani L, Cozzi G, Canciani MT et al.. Molecular characterization of a multiethnic group of 21 patients with type 3 von Willebrand disease.  Thromb Haemost. 2000;  84 (4) 536-540
    Search in Google Scholar
  • 16 Tosetto A, Rodeghiero F, Castaman G et al.. A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD).  J Thromb Haemost. 2006;  4 (4) 766-773
    Search in Google Scholar
  • 17 Federici AB, Canciani MT. Clinical and laboratory versus molecular markers for a correct classification of von Willebrand disease.  Haematologica. 2009;  94 (5) 610-615
    Search in Google Scholar
  • 18 Federici AB, Mazurier C, Berntorp E et al.. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study.  Blood. 2004;  103 (6) 2032-2038
    Search in Google Scholar
  • 19 Castaman G, Lethagen S, Federici AB et al.. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD.  Blood. 2008;  111 (7) 3531-3539
    Search in Google Scholar
  • 20 Federici AB, Baudo F, Caracciolo C et al.. Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study.  Haemophilia. 2002;  8 (6) 761-767
    Search in Google Scholar
  • 21 Federici AB, Castaman G, Franchini M et al.. Clinical use of Haemate P in inherited von Willebrand's disease: a cohort study on 100 Italian patients.  Haematologica. 2007;  92 (7) 944-951
    Search in Google Scholar
  • 22 Federici AB, Barillari G, Zanon E et al.. Efficacy and safety of highly purified, doubly virus-inactivated VWF/FVIII concentrates in inherited von Willebrand's disease: results of an Italian cohort study on 120 patients characterized by bleeding severity score.  Haemophilia. 2010;  16 (1) 101-110
    Search in Google Scholar
  • 23 Federici AB. Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of von Willebrand disease: the PRO. WILL Study.  Haemophilia. 2007;  13 (Suppl 5) 15-24
    Search in Google Scholar
  • 24 Nitu-Whalley IC, Riddell A, Lee CA et al.. Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling.  Thromb Haemost. 2000;  84 (6) 998-1004
    Search in Google Scholar
  • 25 Schneppenheim R, Budde U. Phenotypic and genotypic diagnosis of von Willebrand disease: a 2004 update.  Semin Hematol. 2005;  42 (1) 15-28
    Search in Google Scholar
  • 26 Favaloro EJ. Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrands disease (VWD), and discrimination of VWD subtypes, depends on collagen source.  Thromb Haemost. 2000;  83 (1) 127-135
    Search in Google Scholar
  • 27 Federici AB, Canciani MT, 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 (6) 1127-1128
    Search in Google Scholar
  • 28 Favaloro EJ. Evaluation of commercial von Willebrand factor collagen binding assays to assist the discrimination of types 1 and 2 von Willebrand disease.  Thromb Haemost. 2010;  104 (5) 1009-1021
    Search in Google Scholar
  • 29 Federici AB, Mannucci PM, Castaman G et al.. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients.  Blood. 2009;  113 (3) 526-534
    Search in Google Scholar
  • 30 Shelton-Inloes BB, Chehab FF, Mannucci PM, Federici AB, Sadler JE. Gene deletions correlate with the development of alloantibodies in von Willebrand disease.  J Clin Invest. 1987;  79 (5) 1459-1465
    Search in Google Scholar
  • 31 Mannucci PM, Tamaro G, Narchi G et al.. Life-threatening reaction to factor VIII concentrate in a patient with severe von Willebrand disease and alloantibodies to von Willebrand factor.  Eur J Haematol. 1987;  39 (5) 467-470
    Search in Google Scholar
  • 32 Bergamaschini L, Mannucci PM, Federici AB, Coppola R, Guzzoni S, Agostoni A. Posttransfusion anaphylactic reactions in a patient with severe von Willebrand disease: role of complement and alloantibodies to von Willebrand factor.  J Lab Clin Med. 1995;  125 (3) 348-355
    Search in Google Scholar
  • 33 Schneppenheim R, Federici AB, Budde U et al.. von Willebrand disease type 2M “Vicenza” in Italian and German patients: identification of the first candidate mutation (G3864A; R1205H) in 8 families.  Thromb Haemost. 2000;  83 (1) 136-140
    Search in Google Scholar
  • 34 Castaman G, Missiaglia E, Federici AB, Schneppenheim R, Rodeghiero F. An additional unique candidate mutation (G2470A; M740I) in the original families with von Willebrand disease type 2 M Vicenza and the G3864A (R1205H) mutation.  Thromb Haemost. 2000;  84 (2) 350-351
    Search in Google Scholar
  • 35 Federici AB. Clinical and molecular markers of inherited von Willebrand disease type 3: are deletions of the VWF gene associated with alloantibodies to VWF?.  J Thromb Haemost. 2008;  6 (10) 1726-1728
    Search in Google Scholar
  • 36 Federici AB. The use of desmopressin in von Willebrand disease: the experience of the first 30 years (1977–2007).  Haemophilia. 2008;  14 (Suppl 1) 5-14
    Search in Google Scholar
  • 37 Federici AB, Santagostino E, Rumi MG et al.. The natural history of hepatitis C virus infection in Italian patients with von Willebrand's disease: a cohort study.  Haematologica. 2006;  91 (4) 503-508
    Search in Google Scholar

Augusto B FedericiM.D. 

Division of Hematology and Transfusion Medicine, Department of Internal Medicine University of Milan

L. SACCO University Hospital, Via G. B. Grassi, 76 – 20154 Milan, Italy

Email: augusto.federici@unimi.it