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Thromb Haemost 1994; 71(04): 520-525
DOI: 10.1055/s-0038-1642471
Scientific and Standardization Committee Communications
Schattauer GmbH Stuttgart

A Revised Classification of von Willebrand Disease

For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
J Evan Sadler
The Howard Hughes Medical Institute, The Jewish Hospital of St. Louis, Departments of Medicine and of Biochemistry and Molecular Biophysics, Washington University, School of Medicine, St. Louis, MO, USA
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Publication History

Publication Date:
06 July 2018 (online)

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Summary

A simplified phenotypic classification of von Willebrand disease is proposed that is based on differences in pathophysiology. Quantitative defects arc divided into partial deficiency (type 1) and severe deficiency (type 3). Qualitative defects (type 2) are divided into four subcategories. Type 2A refers to variants with decreased platelet-dependent function associated with the loss of high-molecular weight VWF multimers. Type 2B refers to variants with increased affinity for platelet glycoprotein lb. Type 2M refers to qualitatively abnormal variants with decreased platelet-dependent function not associated with the loss of high-molecular weight multimers. Type 2N refers to variants with decreased affinity for factor VIII. When recognized, mixed phenotypes caused by compound heterozygosity are indicated by separate classification of each allele. Standard amino acid and nucleotide numbering schemes are recommended for the description of mutations.

 

  • References

  • 1 Holmberg T, Nilsson TM. Genetic variants of von Willebrand’s disease. Br Med J 1972; 3: 317-320
    CrossrefPubMedGoogle Scholar
  • 2 Kernoff PBA, Gruson R, Rizza CR. A variant of factor VIII related antigen. Br J Haematol 1974; 26: 435-440
    CrossrefPubMedGoogle Scholar
  • 3 Peake IR, Bloom AL, Giddings JC. Inherited variants of factor-VUI-related protein in von Willebrand’s disease. N Engl J Med 1974; 291: 113-117
    CrossrefPubMedGoogle Scholar
  • 4 Meyer D, Obert B, Pietu G, Lavergne JM, Zimmerman TS. Multimeric structure of factor VUI/von Willebrand factor in von Willebrand’s disease. J Lab Clin Med 1980; 95: 590-602
    PubMedGoogle Scholar
  • 5 Ruggeri ZM, Pared FI, Mannucci PM, Ciavarella N, Zimmerman TS. Heightened interaction between platelets and factor VUI/von Willebrand factor in a new subtype of von Willebrand’s disease. N Engl J Med 1980; 302: 1047-1051
    CrossrefPubMedGoogle Scholar
  • 6 Holmberg L, Milsson IM, Borge L, Gunnarson M, Sjorin E. Platelet aggregation induced by l-desamino-8-D-arginine vasopressin (DDAVP) in type IIB von Willebrand’s disease. NEJM 1983; 309: 816-821
    CrossrefPubMedGoogle Scholar
  • 7 Zimmerman TS, Ruggeri ZM. Von Willebrand’s disease. Prog Hemostas Thromb 1982; 6: 203-236
    PubMedGoogle Scholar
  • 8 Ruggeri ZM. Structure and function of von Willebrand factor: Relationship to von Willebrand’s disease. Mayo Clin Proc 1991; 66: 847-861
    CrossrefPubMedGoogle Scholar
  • 9 Ginsburg D, Sadler JE. Von Willebrand disease: A database of point mutations insertions, and deletions. Thromb Haemostas 1993; 69: 177-184
    PubMedGoogle Scholar
  • 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: 149-156
    CrossrefPubMedGoogle Scholar
  • 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: 2169-2177
    CrossrefPubMedGoogle Scholar
  • 12 Nishino M, Girma JP, Rothschild C, Fressinaud E, Meyer D. New variant of von Willebrand disease with defective binding to factor VIII. Blood 1989; 74: 1591-1599
    PubMedGoogle Scholar
  • 13 Mazurier C, Dieval J, Jorieux S, Delobel J, Goudemand M. A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction. Blood 1990; 75: 20-26
    PubMedGoogle Scholar
  • 14 Eikenboom JCJ, Reitsma PH, Peerlinck JM, Briet E. Recessive inheritance of von Willebrand’s disease type I. Lancet. 1993; 341: 982-986
    PubMedGoogle Scholar
  • 15 Cacheris PM, Nichols WC, Ginsburg D. Molecular characterization of a unique von Willebrand disease variant. A novel mutation affecting von Willebrand factor/factor VIII interaction. J Biol Chem 1991; 266: 13499-502
    PubMedGoogle Scholar
  • 16 Kroner PA, Friedman KD, Fahs SA, Scott JP, Montgomery RR. Abnormal binding of factor VIII is linked with the substitution of glutamine for arginine 91 in von Willebrand factor in a variant form of von Willebrand disease. J Biol Chem 1991; 266: 19146-19149
    PubMedGoogle Scholar
  • 17 Weatherall DJ, Clegg JB, Higgs DR, Wood WG. The hemoglobinopathies. In: The Metabolic Basis of Inherited Disease -(sixth ed.). Scrivei CR, Beaudet AL, Sly WS, Valle D. (eds) McGraw-Hill; New York: 1989: 2281-2339
    Google Scholar
  • 18 Shows TB, Alper CA, Rootsma D, Dorf M, Douglas T, Huisman T, Kit S, Klinger HP, Kozak C, Lalley PA, Lindslcy D, McAlpinc FJ, McDougall JK, Meera Khan P, Meisler M, Morton NE, Opitz JM, Partridge CW, Payne R, Roderick TH, Rubinstein T, Ruddle FH, Shaw M, Spmugei JW, Weiss K. International system for human gene nomenclature (1979). ISGN (1979). Cytogenet. Cell Genet 1979; 25: 96-116
    PubMedGoogle Scholar
  • 19 Ruggeri ZM, Zimmerman TS. Von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904
    PubMedGoogle Scholar
  • 20 Miller JL, Castella A. Platelet-type von Willebrand’s disease: Characterization of a new bleeding disorder. Blood 1982; 60: 790-794
    PubMedGoogle Scholar
  • 21 Weiss HJ, Meyer D, Rabinowitz R, Pietu G, Girma TP, Vine WE, Rogers J. Pseudo-von Willebrand’s disease. An intrinsic platelet defect with aggregation by unmodified human factor VUI/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. N Engl J Med 1982; 306: 326-33
    CrossrefPubMedGoogle Scholar
  • 22 Miller CH, Graham JB, Goldin LR, Elston RC. Genetics of classic von Willebrand’s disease I. Phenotypic variation within families. Blood 1979; 54: 117-136
    PubMedGoogle Scholar
  • 23 Bloom AL, Peake IR. Apparent “dominant” and “recessive” inheritance of von Willebrand’s disease within the same kindreds. Possible biochemical mechanisms. Thromb Res 1979; 15: 505-512
    CrossrefPubMedGoogle Scholar
  • 24 Mannucci PM, Lombardi R, Bader R, Vianello L, Federici AB, Solinas S, Mazzucconi MG, Mariani G. Heterogeneity of type I von Willebrand disease: Evidence for a subgroup with an abnormal von Willebrand factor. Blood 1985; 66: 796-802
    PubMedGoogle Scholar
  • 25 Weiss HJ, Pietu G, Rabinowitz R, Girma JP, Rogers J, Meyer D. Heterogeneous abnormalities in the multimeric structure antigenic properties and plasma-platelet content of factor VUI/von Willebrand factor in sub-types of classic (type I) and variant (type IIA) von Willebrand’s disease. J Lab Clin Med 1983; 101: 411-425
    PubMedGoogle Scholar
  • 26 Hoyer LW, Rizza CR, Tuddenham EGD, Carta CA, Armitage H, Rotblat F. Von Willebrand factor multimer patterns in von Willebrand’s disease. Br J Haematol 1983; 55: 493-507
    CrossrefPubMedGoogle Scholar
  • 27 Ruggeri ZM, Nilsson IM, Lombardi R, Holmberg L, Zimmerman TS. Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand’s disease (type IIC). J Clin Invest 1982; 70: 1124-1127
    CrossrefPubMedGoogle Scholar
  • 28 Mannucci PM, Lombardi R, Pared FI, Solinas S, Mazzucconi MG, Mariani G. A variant of von Willebrand’s disease characterized by recessive inheritance and missing triplet structure of von Willebrand factor multimers. Blood 1983; 62: 1000-1005
    PubMedGoogle Scholar
  • 29 Batlle J, Lopez Fernandez MF, Lasierra J, Fernandez Villamor A, Lopez Berges C, Lopez Borrasca A, Ruggeri ZM, Zimmerman TS. Von Wille-brand disease type IIC with different abnormalities of von Willebrand factor in the same sibship. Am J Hematol 1986; 21: 177-188
    CrossrefPubMedGoogle Scholar
  • 30 Batlle J, Lopez Fernandez MF, Fernandez Villamore A, Lopez Berges C, Zimmerman TS. Multimeric pattern discrepancy between platelet and plasma von Willebrand factor in type IIC von Willebrand disease. Am J Hematol 1986; 22: 87-88
    CrossrefPubMedGoogle Scholar
  • 31 Mazurier C, Mannucci PM, Parquet-Gemez A, Goudemand M, Meyer D. Investigation of a case of subtype IIC von Willebrand disease: characterization of the variability of this subtype. Am J Hematol 1986; 22: 301-311
    CrossrefPubMedGoogle Scholar
  • 32 Kinoshita S, Harrison J, Lazerson J, Abildgaard CF. A new variant of dominant type II von Willebrand’s disease with aberrant multimeric pattern of factor VUI-related antigen (type IID). Blood 1984; 63: 1369-1371
    PubMedGoogle Scholar
  • 33 Hill FGH, Enayat MS, George AJ. Investigation of a kindred with a new autosomal dominantly inherited variant type von Willebrand’s disease (possible type IID). J Clin Pathol 1985; 38: 665-670
    CrossrefPubMedGoogle Scholar
  • 34 Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH. Subunit composition of plasma von Willebrand factor: cleavage is present in normal individuals increased in IIA and IIB von Willebrand disease but minimal in variants with aberrant structure of individual oligomers (type IIC, IID, and HE). J Clin Invest 1986; 77: 947-951
    CrossrefPubMedGoogle Scholar
  • 35 Mannucci PM, Lombardi R, Federici AB, Dent JA, Zimmerman TS, Ruggeri ZM. A new variant of type II von Willebrand disease with aberrant multimeric structure of plasma but not platelet von Willebrand factor (type IIF). Blood 1986; 68: 269-274
    PubMedGoogle Scholar
  • 36 Gralnick HR, Williams SB, McKeown LP, Maisonneuve P, Jenneau C, Sultan Y. A Variant of type II von Willebrand disease with an abnormal triplet structure and discordant effects of protease inhibitors on plasma and platelet von Willebrand factor structure. Am J Hematol 1987; 24: 259-266
    CrossrefPubMedGoogle Scholar
  • 37 Federici AB, Mannucci PM, Lombardi R, Lattuada A, Colibretti ML, Dent JA, Zimmerman TS. Type IIH von Willebrand disease: new structural abnormality of plasma and platelet von Willebrand factor in a patient with prolonged bleeding time and borderline levels of ristocetin cofactor activity. Am J Hematol 1989; 32: 287-293
    CrossrefPubMedGoogle Scholar
  • 38 Castaman G, Rodeghiero F, Lattuada A, Mannucci PM. A new variant of von Willebrand disease (type III) with a normal degree of proteolytic cleavage of von Willebrand factor. Thromb Res 1992; 65: 343-351
    CrossrefPubMedGoogle Scholar
  • 39 Lyons SE, Bruck ME, Bowie EJW, Ginsburg D. Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. J Biol Chem 1992; 267: 4424-4430
    PubMedGoogle Scholar
  • 40 Saba HI, Saba SR, Dent J, Ruggeri ZM, Zimmerman TS. Type IIB Tampa: A variant of von Willebrand disease with chronic thrombocytopenia circulating platelet ggregates and spon-taneous platelet aggregation. Blood 1985; 66: 282-286
    PubMedGoogle Scholar
  • 41 Ruggeri ZM, Mannucci PM, Lombardi R, Federici AB, Zimmerman TS. Multimeric composition of factor VUI/von Willebrand factor following administration of DDAVP: Implications for pathophysiology and therapy of von Willebrand’s disease subtypes. Blood 1982; 59: 1272-1278
    PubMedGoogle Scholar
  • 42 Howard MA, Salem HH, Thomas KB, Hau L, Perkin J, Coghlan M, Firkin BG. Variant von Willebrand’s disease type B-revisited. Blood 1982; 60: 1420-1428
    PubMedGoogle Scholar
  • 43 Mannucci PM, Lombardi R, Castaman C, Dent JA, Lattuada A, Rodeghiero F, Zimmerman TS. Von Willebrand disease “Vicenza” with larger-than-normal (supranormal) von Willebrand factor multimers. Blood 1988; 71: 65-70
    PubMedGoogle Scholar
  • 44 Ciavarella G, Ciavarella N, Antoncecchi S, De Mattia D, Ranieri P, Dent J, Zimmerman TS, Ruggeri ZM. High-resolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (type IC). Blood 1985; 66: 1423-1429
    PubMedGoogle Scholar
  • 45 Lopez-Femandez MF, Gonzalez-Boullosa R, Blanco-Lopez MJ, Perez M, Batlle J. Abnormal proteolytic degradation of von Willebrand factor after desmopressin infusion in a new subtype of von Willebrand disease (ID). Am J Hematol 1991; 36: 163-170
    CrossrefPubMedGoogle Scholar
  • 46 Rabinowitz I, Tuley EA, Mancuso DJ, Randi AM, Firkin BG, Howard MA, Sadler JE. Von Willebrand disease type B: A missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein IB. Proc Natl Acad Sci USA 1992; 89: 9846-9849
    CrossrefPubMedGoogle Scholar
  • 47 Bonthron D, Orkin SH. The human von Willebrand factor gene. Structure of the 5' region. Eur J Biochem 1988; 171: 51-57
    CrossrefPubMedGoogle Scholar
  • 48 Assouline Z, Kerbiriou-Nabias DM, Pietu G, Thomas N, Bahnak BR, Meyer D. The human gene for von Willebrand factor Identification of repetitive Alu sequences 5' to the transcription initiation site. Biochem Biophys Res Commun 1988; 153: 1159-1166
    CrossrefPubMedGoogle Scholar
  • 49 Bernardi F, Marchetti G, Guerra S, Casonato A, Gemmati D, Patracchini P, Ballerini G, Conconi F. A de novo and heterozygous gene deletion causing a variant of von Willebrand disease. Blood 1990; 75: 677-683
    PubMedGoogle Scholar
  • 50 Rodeghiero F, Castaman G, Mannucci PM. Clinical indications for desmopressin (DDAVP) in congenital and acquired von Willebrand disease. Blood Reviews 1991; 5: 155-161
    CrossrefPubMedGoogle Scholar
  • 51 López-Fernandez MF, Blanco-Lopez MJ, Castineira MP, Batlle J. Further evidence for recessive inheritance of von Willebrand disease with abnormal binding of von Willebrand factor to factor VIII. Am J Hematol 1992; 40: 20-27
    CrossrefPubMedGoogle Scholar
  • 52 Kyrle PA, Niessner H, Dent J, Panzer S, Brenner B, Zimmerman TS, Lechner K. IB von Willebrand’s disease: pathogenetic and therapeutic studies. Br J Haematol 1988; 69: 55-59
    CrossrefPubMedGoogle Scholar
  • 53 Fowler WE, Berkowitz LR, Roberts HR. DDAVP for type IIB von Willebrand disease. Blood 1989; 74: 1859-1860
    PubMedGoogle Scholar
  • 54 Connaghan DB, Gralnick HR. Beneficial response to desmopressin in type IIB von Willebrand’s disease. Blood 1989; 76: 417a
    PubMedGoogle Scholar
  • 55 Casonato A, Sartori MT, de Marco L. Girolami A. l-Desamino-8-D-arginine vasopressin (DDAVP) infusion in type IIB von Willebrand’s disease: shortening of the bleeding time and induction of a variable pseudothrombocytopenia. Thromb Haemostas 1990; 64: 117-120
    PubMedGoogle Scholar
  • 56 Mazurier C, Gaucher C, Jorieux S, Parquet-Gernez A, Goudemand M. Evidence for a von Willebrand factor defect in factor VIII binding in three members of a family previously misdiagnosed mild haemophilia A and haemophilia A carriers: Consequences for therapy and genetic counselling. Br J Haematol 1990; 76: 372-379
    CrossrefPubMedGoogle Scholar
  • 57 Morfini M, Mannucci PM, Tenconi PM, Longo G, Mazzucconi MG, Rodeghiero F, Ciavarella N, De Rosa V, Arter A. Pharmacokinetics of monoclonally-purified and recombinant factor VIII in patients with severe von Willebrand disease. Thromb Haemostas 1993; 70: 270-272
    PubMedGoogle Scholar