Semin Thromb Hemost 2019; 45(01): 036-042
DOI: 10.1055/s-0038-1660481
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Evaluation of the Utility of von Willebrand Factor Propeptide in the Differential Diagnosis of von Willebrand Disease and Acquired von Willebrand Syndrome

Francesca Stufano
1   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy
,
Marco Boscarino
1   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy
,
Paolo Bucciarelli
1   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy
,
Luciano Baronciani
1   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy
,
Alberto Maino
1   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy
2   Internal Medicine Unit, Azienda Provinciale per i Servizi Sanitari, Trento, Italy
,
Giovanna Cozzi
1   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy
,
Flora Peyvandi
1   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and Luigi Villa Foundation, Milan, Italy
3   Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
18 June 2018 (online)

Abstract

An increased von Willebrand factor propeptide (VWFpp) to VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) indicates an enhanced clearance of VWF. This finding has been described in von Willebrand disease (VWD) and in acquired von Willebrand syndrome (AVWS). A distinction between these two diseases, one congenital and the other acquired, is primarily based on family and personal history of bleeding. However, if this information is scanty, the diagnosis might be challenging due to the lack of an effective diagnostic biomarker. In this cross-sectional study, we assessed the ability of VWFpp/VWF:Ag for the differential diagnosis between VWD and AVWS. VWFpp/VWF:Ag was measured in a group of 153 patients (125 with VWD and 28 with AVWS). Most patients with AVWS and VWD showed an increased VWFpp/VWF:Ag, although to variable degrees. A marked increase of VWFpp/VWF:Ag was mainly associated with the diagnosis of AVWS and VWD type 1 Vicenza. A receiver operating characteristic curve was used to identify the optimal cutoff of VWFpp/VWF:Ag for discrimination of patients with a modestly increased (most VWD cases) versus those with a markedly increased clearance (AVWS and VWD type 1 Vicenza), and this cutoff was identified at the value of 3.9 (sensitivity: 0.70, specificity: 0.97). The ROC curve sorting from a logistic model containing VWFpp/VWF:Ag, age, and sex had an area under the curve (AUC) of 0.88 (95% confidence interval: 0.80–0.95). A subsequent molecular evaluation discriminated VWD type 1 Vicenza from AVWS. In conclusion, VWFpp/VWF:Ag appears helpful to discriminate patients with a markedly increase VWF clearance (AVWS or VWD type 1 Vicenza) from those with a modestly increased clearance (most VWD patients).

Authors' Contributions

F.S., M.B., P.B., and L.B. wrote the article. A.M. critically revised the article. G.C. performed laboratory analysis. F.P. took part in the discussion and critically revised the article.


 
  • References

  • 1 Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6: 217-246
  • 2 Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003; 1 (07) 1335-1342
  • 3 Borchiellini A, Fijnvandraat K, ten Cate JW. , et al. Quantitative analysis of von Willebrand factor propeptide release in vivo: effect of experimental endotoxemia and administration of 1-deamino-8-D-arginine vasopressin in humans. Blood 1996; 88 (08) 2951-2958
  • 4 Haberichter SL, Balistreri M, Christopherson P. , et al. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood 2006; 108 (10) 3344-3351
  • 5 Haberichter SL, Castaman G, Budde U. , et al. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). Blood 2008; 111 (10) 4979-4985
  • 6 Sztukowska M, Gallinaro L, Cattini MG. , et al. Von Willebrand factor propeptide makes it easy to identify the shorter Von Willebrand factor survival in patients with type 1 and type Vicenza von Willebrand disease. Br J Haematol 2008; 143 (01) 107-114
  • 7 Schooten CJ, Tjernberg P, Westein E. , et al. Cysteine-mutations in von Willebrand factor associated with increased clearance. J Thromb Haemost 2005; 3 (10) 2228-2237
  • 8 Eikenboom J, Federici AB, Dirven RJ. , et al; MCMDM-1VWD Study Group. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. Blood 2013; 121 (12) 2336-2339
  • 9 van Genderen PJJ, Boertjes RC, van Mourik JA. Quantitative analysis of von Willebrand factor and its propeptide in plasma in acquired von Willebrand syndrome. Thromb Haemost 1998; 80 (03) 495-498
  • 10 Sadler JE, Budde U, Eikenboom JCJ. , et al; Working Party on von Willebrand Disease Classification. 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
  • 11 Casonato A, Pontara E, Sartorello F. , et al. Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. Blood 2002; 99 (01) 180-184
  • 12 Mannucci PM, Lombardi R, Castaman G. , et al. von Willebrand disease “Vicenza” with larger-than-normal (supranormal) von Willebrand factor multimers. Blood 1988; 71 (01) 65-70
  • 13 Castaman G, Rodeghiero F, Mannucci PM. The elusive pathogenesis of von Willebrand disease Vicenza. Blood 2002; 99 (11) 4243-4244 , author reply 4244
  • 14 Mannucci PM, Lombardi R, Bader R. , et al. Studies of the pathophysiology of acquired von Willebrand's disease in seven patients with lymphoproliferative disorders or benign monoclonal gammopathies. Blood 1984; 64 (03) 614-621
  • 15 Castaman G, Lattuada A, Ruggeri M, Tosetto A, Mannucci PM, Rodeghiero F. Platelet von Willebrand factor abnormalities in myeloproliferative syndromes. Am J Hematol 1995; 49 (04) 289-293
  • 16 Colella MP, Duarte GC, Marques Jr JF, De Paula EV. Haemostatic management of extreme challenges to haemostasis in acquired von Willebrand syndrome. Haemophilia 2012; 18 (03) e188-e191
  • 17 Federici AB, Rand JH, Bucciarelli P. , et al; Subcommittee on von Willebrand Factor. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000; 84 (02) 345-349
  • 18 Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand disease. Mayo Clin Proc 2002; 77 (02) 181-187
  • 19 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 (04) 536-540
  • 20 Tiede A. Diagnosis and treatment of acquired von Willebrand syndrome. Thromb Res 2012; 130 (Suppl. 02) S2-S6
  • 21 Tosetto A, Castaman G, Rodeghiero F. Assessing bleeding in von Willebrand disease with bleeding score. Blood Rev 2007; 21 (02) 89-97
  • 22 Federici AB, Canciani MT, Forza I. , et al. A sensitive ristocetin co-factor activity assay with recombinant glycoprotein Ib alpha for the diagnosis of patients with low von Willebrand factor levels. Haematologica 2004; 89 (01) 77-85