Semin Thromb Hemost 2016; 42(05): 478-482
DOI: 10.1055/s-0036-1579638
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Type 2B von Willebrand Disease: A Matter of Plasma Plus Platelet Abnormality

Giancarlo Castaman
1   Center for Bleeding Disorders, Department of Heart and Vessels, Careggi University Hospital, Firenze, Italy
,
Augusto B. Federici
2   Department of Oncology and Hematology, University of Milan, Hematology and Transfusion Medicine, L. Sacco University Hospital, Milan, Italy
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
05. Mai 2016 (online)

Abstract

Type 2B von Willebrand disease (VWD2B) is a rare, autosomal-dominant inherited bleeding disorder, characterized by an enhanced ristocetin-induced platelet aggregation in platelet-rich plasma and often with variable degree of thrombocytopenia and loss of high-molecular-weight multimers von Willebrand factor (VWF). All these phenomena are caused by a mutant VWF, normally synthesized and assembled by endothelial cells, but with heightened affinity binding to the platelet receptor glycoprotein Ib-α (GpIb-α). When this abnormal VWF is released into the circulation and under specific clinical circumstances, in vivo platelet clumping is observed. Mutations, invariably clustered in exon 28 of the VWF gene encoding for the VWF A1 domain involved in VWF binding to GpIb-α, are responsible for VWD2B phenotype. Clinical and laboratory phenotype appears strongly related to the type of VWF-causative mutations. However, recent evidences suggest that a true platelet defect is also present in this type, with several morphological and functional abnormalities being detected in a subset of VWD2B patients.

 
  • References

  • 1 Sadler JE, Budde U, Eikenboom JC , 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
  • 2 Ruggeri ZM. Type IIB von Willebrand disease: a paradox explains how von Willebrand factor works. J Thromb Haemost 2004; 2 (1) 2-6
  • 3 Ruggeri ZM, Pareti FI, Mannucci PM, Ciavarella N, Zimmerman TS. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. N Engl J Med 1980; 302 (19) 1047-1051
  • 4 Ruggeri ZM, Zimmerman TS. Variant von Willebrand's disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest 1980; 65 (6) 1318-1325
  • 5 Holmberg L, Nilsson IM, Borge L, Gunnarsson M, Sjörin E. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in Type IIB von Willebrand's disease. N Engl J Med 1983; 309 (14) 816-821
  • 6 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
  • 7 Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest 1991; 87 (4) 1220-1226
  • 8 Cooney KA, Nichols WC, Bruck ME , et al. The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. J Clin Invest 1991; 87 (4) 1227-1233
  • 9 Castaman G, Federici AB, Rodeghiero F, Mannucci PM. Von Willebrand's disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment. Haematologica 2003; 88 (1) 94-108
  • 10 Weiss HJ, Sussman II. A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Willebrand factor containing the full range of multimers. Blood 1986; 68 (1) 149-156
  • 11 Holmberg L, Dent JA, Schneppenheim R, Budde U, Ware J, Ruggeri ZM. von Willebrand factor mutation enhancing interaction with platelets in patients with normal multimeric structure. J Clin Invest 1993; 91 (5) 2169-2177
  • 12 Nurden AT, Federici AB, Nurden P. Altered megakaryocytopoiesis in von Willebrand type 2B disease. J Thromb Haemost 2009; 7 (Suppl. 01) 277-281
  • 13 Jackson SC, Sinclair GD, Cloutier S, Duan Z, Rand ML, Poon MC. The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation. Blood 2009; 113 (14) 3348-3351
  • 14 Nurden P, Gobbi G, Nurden A , et al. Abnormal VWF modifies megakaryocytopoiesis: studies of platelets and megakaryocyte cultures from patients with von Willebrand disease type 2B. Blood 2010; 115 (13) 2649-2656
  • 15 Casari C, Du V, Wu Y-P , et al. Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B-associated thrombocytopenia. Blood 2013; 122 (16) 2893-2902
  • 16 van Schooten CJ, Shahbazi S, Groot E , et al. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood 2008; 112 (5) 1704-1712
  • 17 Castro-Núñez L, Dienava-Verdoold I, Herczenik E, Mertens K, Meijer AB. Shear stress is required for the endocytic uptake of the factor VIII-von Willebrand factor complex by macrophages. J Thromb Haemost 2012; 10 (9) 1929-1937
  • 18 Castaman G. 2B or not 2B: when VWF is not a good platelet friend. Blood 2013; 122 (16) 2772-2773
  • 19 Casari C, Berrou E, Lebret M , et al. von Willebrand factor mutation promotes thrombocytopathy by inhibiting integrin αIIbβ3. J Clin Invest 2013; 123 (12) 5071-5081
  • 20 Ware J. Thrombocytopathy and type 2B von Willebrand disease. J Clin Invest 2013; 123 (12) 5004-5006
  • 21 Hulstein JJ, de Groot PG, Silence K, Veyradier A, Fijnheer R, Lenting PJ. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. Blood 2005; 106 (9) 3035-3042
  • 22 Wohner N, Legendre P, Casari C, Christophe OD, Lenting PJ, Denis CV. Shear stress-independent binding of von Willebrand factor-type 2B mutants p.R1306Q & p.V1316M to LRP1 explains their increased clearance. J Thromb Haemost 2015; 13 (5) 815-820
  • 23 Rastegarlari G, Pegon JN, Casari C , et al. Macrophage LRP1 contributes to the clearance of von Willebrand factor. Blood 2012; 119 (9) 2126-2134
  • 24 Castaman G, Tosetto A, Rodeghiero F. Reduced von Willebrand factor survival in von Willebrand disease: pathophysiologic and clinical relevance. J Thromb Haemost 2009; 7 (Suppl. 01) 71-74
  • 25 Casari C, Lenting PJ, Wohner N, Christophe OD, Denis CV. Clearance of von Willebrand factor. J Thromb Haemost 2013; 11 (Suppl. 01) 202-211
  • 26 Miller JL. Platelet-type von Willebrand disease. Thromb Haemost 1996; 75 (6) 865-869
  • 27 Favaloro EJ. Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: a question of 2B or not 2B? A story of nonidentical twins? Or two sides of a multidenominational or multifaceted primary-hemostasis coin?. Semin Thromb Hemost 2008; 34 (1) 113-127
  • 28 Othman M, Kaur H, Emsley J. Platelet-type von Willebrand disease: new insights into the molecular pathophysiology of a unique platelet defect. Semin Thromb Hemost 2013; 39 (6) 663-673
  • 29 Kaur H, Ozelo M, Scovil S, James PD, Othman M. Systematic analysis of bleeding phenotype in PT-VWD compared to type 2B VWD using an electronic bleeding questionnaire. Clin Appl Thromb Hemost 2014; 20 (8) 765-771
  • 30 Satoh Y, Kita H, Kihira K , et al. Gastrointestinal angiodysplasia in a patient with type 2 von Willebrand's disease and analysis of exon 28 of the von Willebrand factor gene. Am J Gastroenterol 2004; 99 (12) 2495-2498
  • 31 Giles AR, Hoogendoorn H, Benford K. Type IIB von Willebrand's disease presenting as thrombocytopenia during pregnancy. Br J Haematol 1987; 67 (3) 349-353
  • 32 Pareti FI, Federici AB, Cattaneo M, Mannucci PM. Spontaneous platelet aggregation during pregnancy in a patient with von Willebrand disease type IIB can be blocked by monoclonal antibodies to both platelet glycoproteins Ib and IIb/IIIa. Br J Haematol 1990; 75 (1) 86-91
  • 33 Castaman G, Goodeve A, Eikenboom J ; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica 2013; 98 (5) 667-674
  • 34 Castaman G, Rodeghiero F. Desmopressin and type II B von Willebrand disease. Haemophilia 1996; 2: 73-76
  • 35 James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood 2013; 122 (5) 636-640
  • 36 Baaij M, van Galen KPM, Urbanus RT, Nigten J, Eikenboom JHC, Schutgens REG. First report of inhibitory von Willebrand factor alloantibodies in type 2B von Willebrand disease. Br J Haematol 2015; 171 (3) 424-427