Genetics of type 2B von Willebrand Disease: “True 2B,” “tricky 2B,” or “Not 2B.” What Are the Modifiers of the Phenotype?

ABSTRACT

Type 2B von Willebrand disease (VWD) is a qualitative type of VWD with a unique feature among VWD types, resulting from an increased binding of von Willebrand factor (VWF) to its platelet receptor glycoprotein 1b-α (GP1BA). This heightened responsiveness takes place in vivo without endothelial injury or shear stress induction, typically resulting in loss of the hemostatically most active high-molecular-weight VWF multimers and leading to a bleeding diathesis. This process also typically leads to clearance of platelets and thus usually mild thrombocytopenia. At least this describes the classic representation of type 2B VWD (i.e., the typical picture we have come to know since the description/classification of this disorder in the early 1990s). Over more recent years, several reports have described individual cases, groups of patients, and families diagnosed with type 2B VWD where this picture was not typical in one or more aspects. This review discusses type 2B–like disorders and sheds light on potential phenotypic modifiers that might be responsible for the variation encountered with the classic picture of type 2B VWD as well as the impact on the diagnostic certainty of type 2B VWD.

KEYWORDS

von Willebrand disease - VWD - von Willebrand factor - VWF - type 2B VWD - platelet type VWD - PT-VWD - ADAMTS13

REFERENCES

• 1 Ginsburg D, Sadler J E. von Willebrand disease: a database of point mutations, insertions, and deletions. For the Consortium on von Willebrand Factor Mutations and Polymorphisms, and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.  Thromb Haemost. 1993;  69 177-184
• 2 Mathew P, Greist A, Maahs J A, Lichtenberg E C, Shapiro A D. Type 2B vWD: the varied clinical manifestations in two kindreds.  Haemophilia. 2003;  9 137-144
• 3 Facey D A, Favaloro E J, Maxwell E, Baker R, Hertzberg M S. Type 2B von Willebrand's disease in thirteen individuals from five unrelated Australian families: phenotype and genotype correlations.  Am J Hematol. 2000;  63 197-199
• 4 Nurden A T, Nurden P. Inherited defects of platelet function.  Rev Clin Exp Hematol. 2001;  5 314-334
• 5 Gomez Garcia E B, Brouwers G J, Kappers-Klunne M C, Leebeek F W, van Vliet H H. Intermittent thrombocytopenia as a manifestation of von Willebrand's disease.  Ned Tijdschr Geneeskd. 2002;  146 1192-1195
• 6 Rauch R, Budde U, Schneppenheim R, Ries M, Girisch M, Klinge J. A 2-year-old boy with recurrent severe bleeding: von Willebrand type 2B and ITP–or von Willebrand type 2B alone?.  Eur J Pediatr. 1999;  158(Suppl 3) S171-S173
• 7 Mauz-Korholz C, Budde U, Kruck H, Korholz D, Gobel U. Management of severe chronic thrombocytopenia in von Willebrand's disease type 2B.  Arch Dis Child. 1998;  78 257-260
• 8 Rodeghiero F, Castaman G, Tosetto A et al.. The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study.  J Thromb Haemost. 2005;  3 2619-2626
• 9 Stakiw J, Bowman M, Hegadorn C et al.. The effect of exercise on von Willebrand factor and ADAMTS-13 in individuals with type 1 and type 2B von Willebrand disease.  J Thromb Haemost. 2008;  6 90-96
• 10 Rodeghiero F, Kadir R A, Tosetto A, James P D. Relevance of quantitative assessment of bleeding in haemorrhagic disorders.  Haemophilia. 2008;  14(Suppl 3) 68-75
• 11 Huizinga E G, Tsuji S, Romijn R A et al.. Structures of glycoprotein Ib alpha and its complex with von Willebrand factor A1 domain.  Science. 2002;  297 1176-1179
• 12 von Willebrand disease database. Available at: http://www.vwf.group.shef.ac.uk/ Accessed August 25, 2008
• 13 Platelet type VWD database and disease registry. http://Available at: www.pt-vwd.org Accessed August 25, 2008
• 14 Meyer D, Girma J P. von Willebrand factor: structure and function.  Thromb Haemost. 1993;  70 99-104
• 15 Roland K, Rapson D, Lillicrap D, James P. The value of genetic testing for type 2B von Willebrand disease.  Clin Lab Haematol. 2006;  28 17-21
• 16 Rabinowitz I, Randi A M, Shindler K S, Tuley E A, Rustagi P K, Sadler J E. Type IIB mutation His-505→Asp implicates a new segment in the control of von Willebrand factor binding to platelet glycoprotein Ib.  J Biol Chem. 1993;  268 20497-20501
• 17 Hilbert L, Gaucher C, de Romeuf C, Horellou M H, Vink T, Mazurier C. Leu 697→Val mutation in mature von Willebrand factor is responsible for type IIB von Willebrand disease.  Blood. 1994;  83 1542-1550
• 18 Martin C, Morales L D, Cruz M A. Purified A2 domain of von Willebrand factor binds to the active conformation of von Willebrand factor and blocks the interaction with platelet glycoprotein Ib alpha.  J Thromb Haemost. 2007;  5 1363-1370
• 19 Casonato A, Sartorello F, Pontara E et al.. A novel von Willebrand factor mutation (I1372S) associated with type 2B-like von Willebrand disease: an elusive phenotype and a difficult diagnosis.  Thromb Haemost. 2007;  98 1182-1187
• 20 Baronciani L, Federici A B, Beretta M, Cozzi G, Canciani M T, Mannucci P M. Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding.  J Thromb Haemost. 2005;  3 2689-2694
• 21 Casana P, Martinez F, Espinos C, Haya S, Lorenzo J I, Aznar J A. Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants.  Am J Hematol. 1998;  59 57-63
• 22 Cooney K A, Nichols W C, Bruck M E 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 1227-1233
• 23 Meyer D, Fressinaud E, Gaucher C et al.. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. INSERM Network on Molecular Abnormalities in von Willebrand Disease.  Thromb Haemost. 1997;  78 451-456
• 24 Takimoto Y, Imanaka F. Type 2B Hiroshima: a variant of von Willebrand disease characterized by chronic thrombocytopenia and the presence of all von Willebrand factor multimers in plasma.  Int J Hematol. 1999;  70 127-131
• 25 Fuse I H, Uesugi Y, Aizawa Y et al.. Variant type 2B von Willebrand disease; no responsible mutations at the von Willebrand factor A1 domain and the surrounding region.  Acta Med Biol. 2001;  49 11-17
• 26 Kroner P A, Kluessendorf M L, Scott J P, Montgomery R R. Expressed full-length von Willebrand factor containing missense mutations linked to type IIB von Willebrand disease shows enhanced binding to platelets.  Blood. 1992;  79 2048-2055
• 27 Baronciani L, Federici A B, Cozzi G, Canciani M T, Mannucci P M. Biochemical characterization of a recombinant von Willebrand factor (VWF) with combined type 2B and type 1 defects in the VWF gene in two patients with a type 2A phenotype of von Willebrand disease.  J Thromb Haemost. 2007;  5 282-288
• 28 Hilbert L, Gaucher C, Mazurier C. Identification of two mutations (Arg611Cys and Arg611His) in the A1 loop of von Willebrand factor (vWF) responsible for type 2 von Willebrand disease with decreased platelet-dependent function of vWF.  Blood. 1995;  86 1010-1018
• 29 Castaman G, Eikenboom J C, Rodeghiero F, Briet E, Reitsma P H. A novel candidate mutation (Arg611→His) in type I 'platelet discordant' von Willebrand's disease with desmopressin-induced thrombocytopenia.  Br J Haematol. 1995;  89 656-658
• 30 Penas N, Perez-Rodriguez A, Torea J H et al.. von Willebrand disease R1374C: type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia).  Am J Hematol. 2005;  80 188-196
• 31 Di Paola J, Murray J, Lentz S et al.. A missense mutation in exon 28 (C4120T) of the von Willebrand factor gene is the cause for von Willebrand disease in a large Amish pedigree. Presented at: the International Society of Thrombosis and Hemostasis August 6–12, 2005 Sydney, Australia;
• 32 Sharthkumar A, Greist A, Di Paola J et al.. Biologic response to subcutaneous and intranasal therapy with desmopressin in a large Amish kindred with type 2M von Willebrand disease.  Haemophilia. 2008;  14 539-548
• 33 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;  109 112-121
• 34 Weiss H J, Sussman I I. 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;  68 149-156
• 35 Holmberg L, Berntorp E, Donner M, Nilsson I M. von Willebrand's disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma.  Blood. 1986;  68 668-672
• 36 Weiss H J. Type 2B von Willebrand disease and related disorders of patients with increased ristocetin-induced platelet aggregation: what they tell us about the role of von Willebrand factor in hemostasis.  J Thromb Haemost. 2004;  2 2055-2056
• 37 Federici A B. Impaired megakaryocytopoiesis in type 2B von Willebrand disease.  Blood. 2006;  108 2498-2499
• 38 Moll S, Lazarowski A R, White II G C. Giant platelet disorder in a patient with type 2B von Willebrand's disease.  Am J Hematol. 1998;  57 62-67
• 39 Loffredo G, Baronciani L, Noris P, Menna F, Federici A B, Balduini C L. von Willebrand disease type 2B must be always considered in the differential diagnosis of genetic thrombocytopenias with giant platelets.  Platelets. 2006;  17 149-152
• 40 Saba H I, Saba S R, Dent J, Ruggeri Z M, Zimmerman T S. Type IIB Tampa: a variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation.  Blood. 1985;  66 282-286
• 41 Nurden P, Chretien F, Poujol C, Winckler J, Borel-Derlon A, Nurden A. Platelet ultrastructural abnormalities in three patients with type 2B von Willebrand disease.  Br J Haematol. 2000;  110 704-714
• 42 Hilbert L, Nurden P, Caron C et al.. Type 2N von Willebrand disease due to compound heterozygosity for R854Q and a novel R763G mutation at the cleavage site of von Willebrand factor propeptide.  Thromb Haemost. 2006;  96 290-294
• 43 Zhang Z P, Blomback M, Egberg N, Falk G, Anvret M. Characterization of the von Willebrand factor gene (VWF) in von Willebrand disease type III patients from 24 families of Swedish and Finnish origin.  Genomics. 1994;  21 188-193
• 44 James P D, Notley C, Hegadorn C et al.. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study.  Blood. 2007;  109 145-154
• 45 Favaloro E J. 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;  34 113-127
• 46 Othman M. Platelet-type von Willebrand disease and type 2B von Willebrand disease: a story of nonidentical twins when two different genetic abnormalities evolve into similar phenotypes.  Semin Thromb Hemost. 2007;  33 780-786
• 47 Hoylaerts M F, Nuyts K, Peerlinck K, Deckmyn H, Vermylen J. Promotion of binding of von Willebrand factor to platelet glycoprotein Ib by dimers of ristocetin.  Biochem J. 1995;  306(Pt 2) 453-463
• 48 Favaloro E J. An update on the von Willebrand factor collagen binding assay: 21 years of age and beyond adolescence but not yet a mature adult.  Semin Thromb Hemost. 2007;  33 727-744
• 49 Hui S R, Biswas T K, Miller J L. Functional ELISA of von Willebrand factor (VWF) activity using His-tagged increase of function recombinant GPIB bound to nickle chelator plates.  J Thromb Hemost. 2007;  5(Suppl 2) , O-T-063
• 50 Montgomery R R, Morateck P A, Christopherson B C et al.. Functional assay of VWF measured by its interaction with platelet GPIb without the use of ristocetin.  Blood. 2007;  110 3158
• 51 Duncan E M, Bonar R, Rodgers S E, Favaloro E J, Marsden K. Methodology and outcomes of platelet aggregation testing in Australia, New Zealand and the Asia-Pacific region: results of a survey from the Royal College of Pathologists of Australasia Haematology Quality Assurance Program.  Int J Lab Hematol. 2008 March 21;  , [Epub ahead of print]
• 52 Favaloro E J, Bonar R, Meiring M, Street A, Marsden K. 2B or not 2B? Disparate discrimination of functional VWF discordance using different assay panels or methodologies may lead to success or failure in the early identification of type 2B VWD.  Thromb Haemost. 2007;  98 346-358
• 53 Novelli E M, Ragni M V. Genetics of bleeding disorders in women.  Semin Thromb Hemost. 2008;  34 509-519
• 54 Sadler J E. New concepts in von Willebrand disease.  Annu Rev Med. 2005;  56 173-191
• 55 Pareti F I, Federici A B, Cattaneo M, Mannucci P M. 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 86-91
• 56 de Romeuf C, Hilbert L, Mazurier C. Platelet activation and aggregation induced by recombinant von Willebrand factors reproducing four type 2B von Willebrand disease missense mutations.  Thromb Haemost. 1998;  79 211-216
• 57 Nurden P, Debili N, Vainchenker W et al.. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia.  Blood. 2006;  108 2587-2595
• 58 Takahashi H, Murata M, Moriki T et al.. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease.  Blood. 1995;  85 727-733
• 59 Bray P F. Sizing up platelet defects.  Blood. 2008;  111 3302-3303
• 60 Italiano Jr J E, Lecine P, Shivdasani R A, Hartwig J H. Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes.  J Cell Biol. 1999;  147 1299-1312
• 61 Okita J R, Frojmovic M M, Kristopeit S, Wong T, Kunicki T J. Montreal platelet syndrome: a defect in calcium-activated neutral proteinase (calpain).  Blood. 1989;  74 715-721
• 62 Milton J G, Frojmovic M M, Tang S S, White J G. Spontaneous platelet aggregation in a hereditary giant platelet syndrome (MPS).  Am J Pathol. 1984;  114 336-345
• 63 Jackson S, Sinclair G, Poon M. Montreal platelet syndrome: revisited.  Haemophilia. 2008;  14(Suppl 2.) 112
• 64 Wang Z J, Onwuzurike N, Callaghan M U, Rajpurkar M, Chitlur M, Lusher J M. Decreased clearance of von Willebrand factor in a patient with type 2B von Willebrand disease following development of immune thrombocytopenia.  Pediatr Blood Cancer. 2008;  51 416-418
• 65 Pruss C M, Hegadorn C, Notley C RP, Chegeni R, Dhala A S, Lillicrap D. Human von Willebrand disease mutations in mouse von Willebrand factor alter cleavage by ADAMTS13.  Blood. 2007;  110 2708
• 66 Rayes J, Hommais A, Legendre P et al.. Effect of von Willebrand disease type 2B and type 2M mutations on the susceptibility of von Willebrand factor to ADAMTS-13.  J Thromb Haemost. 2007;  5 321-328
• 67 Nishio K, Anderson P J, Zheng X L, Sadler J E. Binding of platelet glycoprotein Ibalpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13.  Proc Natl Acad Sci U S A. 2004;  101 10578-10583
• 68 Shim K, Anderson P J, Tuley E A, Wiswall E, Sadler J E. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress.  Blood. 2008;  111 651-657
• 69 Dong J F, Whitelock J, Bernardo A, Ball C, Cruz M A. Variations among normal individuals in the cleavage of endothelial-derived ultra-large von Willebrand factor under flow.  J Thromb Haemost. 2004;  2 1460-1466
• 70 Liu L, Choi H, Bernardo A et al.. Platelet-derived VWF-cleaving metalloprotease ADAMTS-13.  J Thromb Haemost. 2005;  3 2536-2544
• 71 Frenette P S, Denis C V, Weiss L et al.. P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo.  J Exp Med. 2000;  191 1413-1422
• 72 Jurk K, Clemetson K J, de Groot P G et al.. Thrombospondin-1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor.  FASEB J. 2003;  17 1490-1492
• 73 Othman M. Differential identification of PT-VWD from type 2B VWD and GP1BA nomenclature issues.  Br J Haematol. 2008;  , In press
• 74 Kozak M. At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells.  J Mol Biol. 1987;  196 947-950
• 75 Lopez J A, Ludwig E H, McCarthy B J. Polymorphism of human glycoprotein Ib alpha results from a variable number of tandem repeats of a 13-amino acid sequence in the mucin-like macroglycopeptide region. Structure/function implications.  J Biol Chem. 1992;  267 10055-10061
• 76 Veronica H, Flood B CK. Common VWF haplotypes in normal African-Americans and Caucasians recruited into the ZPMCB-VWD and their impact on VWF laboratory testing.  Blood. 2007;  110 714
• 77 Koutts J. A short history of diagnostic tests for von Willebrand disease: in memory of Barry Firkin (1930 to 2001) and Ted Zimmerman (1937 to 1988).  Semin Thromb Hemost. 2006;  32 445-455
• 78 Kunicki T J, Baronciani L, Canciani M T et al.. An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees.  J Thromb Haemost. 2006;  4 137-147
• 79 Bath P, Algert C, Chapman N, Neal B. Association of mean platelet volume with risk of stroke among 3134 individuals with history of cerebrovascular disease.  Stroke. 2004;  35 622-626
• 80 Favaloro E J, Patterson D, Denholm A et al.. Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from Type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis.  Br J Haematol. 2007;  139 623-626