A Type 2b von Willebrand Disease Mutation (lle546→Val) Associated with an Unusual Phenotype

A B Federici; P M Mannucci; F Stabile; M T Canciani; N Di Rocco; S Miyata; J Ware; Z M Ruggeri

doi:10.1055/s-0038-1657699

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1997; 78(03): 1132-1137
DOI: 10.1055/s-0038-1657699

Rapid Communication

Schattauer GmbH Stuttgart

A Type 2b von Willebrand Disease Mutation (lle⁵⁴⁶→Val) Associated with an Unusual Phenotype

A B Federici

¹The Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milano, Italy

,

P M Mannucci

¹The Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milano, Italy

,

F Stabile

¹The Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milano, Italy

,

M T Canciani

¹The Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milano, Italy

,

N Di Rocco

¹The Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milano, Italy

,

S Miyata

²The Roon Research Center for Arteriosclerosis and Thrombosis, Department of Molecular and Experimental Medicine and Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA

,

J Ware

²The Roon Research Center for Arteriosclerosis and Thrombosis, Department of Molecular and Experimental Medicine and Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA

,

Z M Ruggeri

²The Roon Research Center for Arteriosclerosis and Thrombosis, Department of Molecular and Experimental Medicine and Department of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA

› Author Affiliations

Abstract

PDF Download

Summary

Type 2B von Willebrand disease (vWD) is typically characterized by enhanced ristocetin-induced platelet aggregation (RIPA) caused by increased von Willebrand factor (vWF) affinity for platelets. Furthermore, absence of larger vWF multimers in plasma is characteristic of the originally described type IIB patients, now considered a subgroup of type 2B. We describe here three affected members of a family presenting with prolonged bleeding time, thrombocytopenia, markedly enhanced RIPA and spontaneous platelet aggregation, but normal plasma vWF antigen and ristocetin cofactor activity. Larger plasma vWF multimers, albeit decreased, were present in relatively greater proportion than in other type IIB patients. Genetic studies performed in two of these patients resulted in the identification of a previously unreported A→G transition at nucleotide 4175 in the sequence of the pre-pro-vWF cDNA, corresponding to the substitution Ile^546→Val in the mature vWF subunit. This mutation appears to be responsible for an unusual type 2B phenotype, with greater enhancement of the vWF platelet interaction than in typical cases but partial preservation of the larger vWF multimers in plasma.

PDF (1430 kb)

References

References
1 Ruggeri ZM, Pareti 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
2 Ruggeri ZM, Zimmerman TS. Variant von Willebrand’s disease: characterization of two subtypes by analysis of multimeric composition of factor VUI/von Willebrand factor in plasma and platelets. J Clin Invest 1980; 65: 1318-1325
3 Weiss HJ, Sussman II. A new von Willebrand variant (type I, New York): increased ristocetin-induced platelet aggregation and plasma von Wille brand factor containing the full range of multimers. Blood 1986; 68: 149-156
4 Holmberg L, Bemtorp E, Donner M, Nilsson IM. 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
5 Sadler JE. 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. Thromb Haemost 1994; 71: 520-525
6 Mazurier C, Parquet GemezA, Goudemand J, Taillefer MF, Goudemand M. Investigation of a large kindred with type IIB von Willebrand’s disease, dominant inheritance and age-dependent thrombocytopenia. Br J Haematol 1988; 69: 499-505
7 Rick ME, Williams SB, Sacher RA, McKeown LP. Thrombocytopenia associated with pregnancy in a patient with type IIB von Willebrand’s disease. Blood 1987; 69: 786-789
8 Hultin MB, and Sussman II. Postoperative thrombocytopenia in type IIB von Willebrand disease. Am J Hematol 1990; 33: 64-68
9 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 lb and Ilb/IIIa. Br J Haematol 1990; 75: 86-91
10 Holmberg L, Nilsson IM, Borge L, Gunnarsson M, Sjorin E. Platelet aggregation induced by l-desamino-8-D-arginine vasopressin (DDAVP) in Type IIB von Willebrand’s disease. N Engl J Med 1983; 309: 816-821
11 Gralnick HR, Williams SB, McKeown LP, Rick ME, Maisonneuve P, Jenneau C, Sultan Y. von Willebrand’s disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor. J Clin Invest 1985; 76: 1522-1529
12 Saba HI, Saba SR, Dent J, Ruggeri ZM, Zimmerman TS. Type IIB Tampa: A variant of von Willebrand disease with chronic thrombocytopenia, circulating platelet aggregates, and spontaneous platelet aggregation. Blood 1985; 66: 282-286
13 Ruggeri ZM, Mannucci PM, Federici AB, Lombardi R, 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
14 Ruggeri ZM, Lombardi R, Gatti L, Bader R, Valsecchi C, Zimmerman TS. Type IIB von Willebrand’s disease: Differential clearance of endogenous versus transfused large multimer von Willebrand Factor. Blood 1982; 60: 1453-1456
15 Lopez JA. The platelet glycoprotein Ib-IX complex. Blood Coag Fib 1994; 05: 97-119
16 Hickey MJ, Hagen FS, Yagi M, Roth GJ. Human platelet glycoprotein V: Characterization of the polypeptide and the related Ib-V-IX receptor system of adhesive, leucine-rich glycoproteins. Proc Natl Acad Sci, USA 1993; 90: 8327-8331
17 Fujimura Y, Titani K, Holland LZ, Russell SR, Roberts JR, Elder JH, Ruggeri ZM, Zimmerman TS. von Willebrand factor. A reduced and alkylated 52/48 kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein lb. J Biol Chem 1986; 261: 381-385
18 Fujimura Y, Titani K, Holland LZ, Roberts JR, Kostel P, Ruggeri ZM, Zimmerman TS. A heparin-binding domain of human von Willebrand Federici et al.: Type 2b vWD Mutation factor. Characterization and localization to a tryptic fragment extending from amino acid residue Val-449 to Lys-728. J Biol Chem 1987; 262: 1734-1739
19 Ginsburg D, Sadler JE. von Willebrand Disease: A Database of point mutations, insertions and deletions. Thromb Haemost 1993; 69: 177-184
20 Andrews RK, Gorman JJ, Booth WJ, Corino GL, Castaldi PA, Bemdt MC. Cross-linking of a monomeric 39/34-kDa dispase fragment of von Wille brand factor (Leu-480/Val-481 -Gly-718) to the N-terminal region of the a-chain of membrane glycoprotein lb on intact platelets with Lis(sulfosuc- cinimidyl) suberate. Biochemistry 1989; 28: 8326-8336
21 Shelton InloesB, Titani K, Sadler JE. cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry 1986; 25: 3164-3171
22 Federici AB, Mannucci PM, Bader R, Lombardi R, Lattuada A. Heterogeneity in type IIB von Willebrand disease: two unrelated cases with no family history and mild abnormalities of ristocetin-induced interaction between von Willebrand factor and platelets. Am J Hematol 1986; 23: 381-390
23 Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecu lar basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoproteins lb binding sequences. J Clin Invest 1991; 87: 1220-1226
24 Randi AM, Jorieux S, Tuley EA, Mazurier C, Sadler JE. Recombinant von Willebrand factor Arg⁵⁷⁸Gln. A type IIB von Willebrand disease mutation affects binding to glycoprotein lb but not collagen or heparin. J Biol Chem 1992; 267: 21187-21192
25 Handa M, Titani K, Holland LZ, Roberts JR, Ruggeri ZM. The von Wille brand factor-binding domain of platelet membrane glycoprotein lb. Charac terization by monoclonal antibodies and partial amino acid sequence analysis of proteolytic fragments. J Biol Chem 1986; 261: 12579-12585
26 Sugimoto M, Dent J, McClintock RS, Ware J, Ruggeri ZM. Analysis of structure-function relationship in the platelet membrane glycoprotein Ib binding domain of von Willebrand’s factor by expression of deletion mutants. J Biol Chem 1993; 268: 12185-12892
27 Niiya K, Hodson E, Bader R, Byers-Ward V, Koziol JA, Plow EF, Ruggeri ZM. Increased surface expression of the membrane glycoprotein Ilb/EIa complex induced by platelet activation. Relationship to the binding of fibrinogen and platelet aggregation. Blood 1987; 70: 475-4783
28 Ruggeri ZM, Zimmerman TS. The complex multimeric composition of Factor VUI/von Willebrand factor. Blood 1981; 57: 1140-1143
29 Bonthron D, Orkin SH. The human von Willebrand factor gene: structure of the 5’ region. Eur J Biochem 1988; 171: 51-57
30 Assouline Z, Kerbiriou-Nabias DM, Piétu 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 BiophysRes Commun 1988; 153: 1159-1166
31 Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-19527
32 Titani K, Kumar S, Takio K, Ericsson LH, Wade RD, Ashida K, Walsh KA, Chopek MW, Sadler JE, Fujikawa K. Amino acid sequence of human von Willebrand factor. Biochemistry 1986; 25: 3171-3184
33 Fay PJ, Kawai Y, Wagner DD, Ginsburg D, Bonthron D, Ohlsson-Wilhelm BM, Chavin SI, Abraham GN, Handin RI, Orkin SH, Montgomery RR, Marder VJ. Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II. Science 1986; 232: 995-998
34 Blin N, Stafford DW. A general method for isolation of high molecular weight DNA from eukaryocytes. Nucleic Acid Res 1976; 03: 2303-2308
35 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci, USA 1977; 74: 5463-5467
36 Barbui T, Baudo F, Ciavarella N, Mariani G, Capitanio A, Mannucci PM, Pareti FI, Ruggeri ZM. (Italian Working Group). Spectrum of von Willebrand’s disease: a study of 100 cases. Br J Haematol 1977; 35: 101-112
37 Rabinowitz I, Randi AM, Shindler KS, Rustagi PK, Sadler JE, Turley EA. Type IIB mutation His-505(right arrow) Asp implicates a new segment in the control of von Willebrand factor binding to platelet glycoprotein lb. J Biol Chem 1993; 268: 20497-20501
38 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
39 Donner M, Kristofferson AC, Lenk H, Scheibel E, Dahlback B, Milsson IM, and Holmberg L. Type IIB von Willebrand’s disease: gene mutations and clinical presentation in nine families from Dname enmarkme Germany and Sweden. Br J Haematol 1992; 82: 58-65
40 Cooney KA, Ginsburg D. Comparative analysis of Type 2b von Willebrand disease mutations: implications for the mechanism of von Willebrand factor binding to platelets. Blood 1996; 87: 2322-2328
41 Miyata S, Goto S, Federici AB, Ware J, Ruggeri ZM. Conformational changes in the Al domain of von Willebrand factor modulating the interac tion with platelet glycoprotein Ibα. J Biol Chem 1996; 271: 9046-9053
42 Ware J, Dent JA, Azuma H, Sugimoto M, Kyrle PA, Yoshioka A, Ruggeri ZM. Identification of a point mutation in Type IIB von Willebrand disease illustrating the regulation of von Willebrand factor affinity for the platelet GP Ib-IX receptor. Proc Natl Acad Sci, USA 1991; 88: 2946-2950