The molecular genetics of von willebrand disease

BERBER, ERGÜL

The molecular genetics of von willebrand disease

Ergül BERBER (İstanbul Arel Üniversitesi, Moleküler Biyoloji ve Genetik, Anabilim Dalı, İstanbul, Türkiye)

Turkish Journal of Hematology

2 0

Yıl: 2012 Cilt: 29 Sayı: 4 Sayfa Aralığı: 313 - 324 Metin Dili: Türkçe İndeks Tarihi: 29-07-2022

The molecular genetics of von willebrand disease

Öz:

Von Willebrand Faktöründe (vWF) görülen kantitatif azalma veya kalitatif bozukluklar bir kanama diyatezi olan ve oldukça sık rastlanan von Willebrand Hastalığının (VWH) oluşumuna neden olur. VWH klinik ve genetik heterojenite gösteren karmaşık bir hastalıktır. Genetik ve çevresel nedenlere ikincil eksik penetrans ve VWF düzeyinde olan değişiklikler olması VWHnın karmaşık bir yapı göstermesine neden olan faktörlerdir. VWF genindeki mutasyonlardan bazıları biyosentezi ve multimerizasyonu etkilerken, diğer mutasyonlar vWFnin dolaşımdan daha erken uzaklaştırılmasına neden olarak fonksiyonunu etkiler. Belirli bir mutasyon ile birlikte kan grubunun da O olması fenotipin daha ağır olmasına neden olabilir. Bu derlemenin amacı vWHnın moleküler genetiği ile ilgili güncel yayınları inceleyerek onların bir özetini yapmaktır.

Anahtar Kelime:

Konular: Hematoloji

Von Willebrand hastalığı nın moleküler genetiği

Öz:

Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD.

Anahtar Kelime:

Konular: Hematoloji

Belge Türü: Makale Makale Türü: Derleme Erişim Türü: Erişime Açık

1. Lillicrap D. Genotype/phenotype association in von Willebrand disease: Is the glass half ful lor empty?. J Thromb and Haemost 2009; 7:65-70.
2. Von Willebrand EA. Finska Lakarasallsk Hand 1926; 68:87.
3. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrands disease. Blood 1987; 69:454-459.
4. Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123:893-898.
5. Bloom AL. von Willebrand factor: Clinical features of inherited and acquired disorders. Mayo Clin Proc 1991; 66:743-751.
6. Rodeghiero F, Castaman G, Tosetto A. Optimizing treatment of von Willebrand disease by using phenotypic and molecular data. Hematology Am Soc Hematol Educ Program 2009; 113-123.
7. Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB. Update on the pathophysiology and classification of von Willebrand disease: A report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4:2103-2114.
8. Ruggeri ZM. Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation. Best Pract Res Clin Haematol 2001; 14:257-279.
9. Wagner DD. Cell Biology of Von Willebrand factor. Annu Rev Cell Biol. 1990; 6:217-246.
10. Sadler JE. Von Willebrand factor assembly and secretion. J Thromb Haemost 2009; 7:24-27.
11. Verweij CL, Diergaarde PJ, Hart M, Pannekoek H. Full- length von Willebrand factor (vWF) encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO J 1986; 5:1839-1846.
12. Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med 2005; 15:302-308.
13. Rondaij MG, Bierings R, Kragt A, van Mourik JA, Voorberg J. Arterioscler Dynamics and plasticity of Weibel-Palade Bodies in endothelial cells. Arterioscler Thromb Vasc Biol 2006; 26:1002-1007.
14. Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood 2008; 112:957-964.
15. Bonthron DT, Handin RI, Kaufman RJ, Wasley LC, Orr EC, Mitsock LM, Ewenstein B, Loscalzo J, Ginsburg D, Orkin SH. Structure of pre-pro von Willebrand factor and its expression in heterologous cells. Nature 1986; 324:270- 273.
16. Wang JW, Eikenboom J. Von Willebrand disease and Weibel-Palade bodies. Hamostaseologie 2010; 30:150-155.
17. Haberichter SL, Jacobi P, Montgomery RR. Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage. Blood 2003; 101:1384-1391.
18. 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.
19. Millar CM, Brown SA. Oligosaccharide structures of von Willebrand factor and their potential role in von Willebrand disease. Blood Rev 2006; 20:83-92.
20. Matsui T, Titani K, Mizuochi T. Structures of the asparagines-linked oligosaccharide chains of human von Willebrand factor. Occurrence of blood group A, B, and H(O) structures. J Biol Chem 1992; 267:8723-8731.
21. Allen S, Abuzenadah AM, Hinks J, Blagg JL, Gursel T, Ingerslev J, Goodeve AC, Peake IR, Daly ME. A novel von Willebrand disease-causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion. Blood 2000; 96:560-568.
22. Fujikawa K, Suzuki H, McMullen B, Chung D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloprotease family. Blood 2001; 98:1662-1666.
23. Dent JA, Berkowitz SD, Ware J, Kasper CK, Ruggeri ZM. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990; 87:6306-6310.
24. Zhang Q, Zhou YF, Zhang CZ, Zhang X, Lu C, Springer TA. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci USA 2009; 106:9226-9231.
25. Luken BM, Winn LNY, Emsley J, Lane DA, Crawley JTB. The importance of vicinal cysteines, C1669 and C1670, for von Willebrand factor A2 domain function. Blood 2010; 115:4910-4913.
26. Pruss CM, Notley CRP, Hegadorn CA, OBrien L, Lillicrap D. ADAMTS13 cleavage efficiency is altered by mutagenic and to a lesser extent, polymorphic sequence changes in the A1 and A2 domains of von Willebrand factor. Br J Haematol 2008; 143:552-558.
27. 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.
28. Mancuso DJ, Tuley EA, Westfield LA, Lester-Mancuso TL, Le Beau MM, Sorace JM, Sadler JE. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30:253-269.
29. Sadler JE, Mannucci PM, Berntorp E, Bochkov N, Boulyjenkov V, Ginsburg D, Meyer D, Peake I, Rodeghiero F, Srivastava A. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84:160-174.
30. Orstavik KH, Magnus P, Reisner H, Berg K, Graham JB, Nance W. FVIII and factor IX in a twin population: Evidence for a major effect of ABO locus on FVIII level. Am J Hum Genet 1985; 37:89-101.
31. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ Jr, Montgomery RR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69:1691-1695.
32. Miller CH, Dilley A, Richardson L, Hooper WC, Evatt BL. Population differences in von Willebrand factor levels affect the diagnosis of von Willebranddisease in African-American women. Am J Hematol 2001; 67:125-129.
33. Bloom AL. Von Willebrand factor: Clinical features of inherited and acquired disorders. Mayo Clin Proc. 1991; 66:743-751.
34. Lenting PJ, Westein E, Terraube V, Ribba AS, Huizinga EG, Meyer D, de Groot PG, Denis CV. An experimental model to study in vivo survibal of von Willebrand factor. J Biol Chem 2004; 279:13:12102-12109.
35. van Schooten CJ, Shahbazi S, Groot E, Oortwijn BD, van den Berg HM, Denis CV, Lenting PJ. Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo. Blood 2008; 112:1704-1712.
36. Bowen DJ, Collins PW. Insights into von Willebrand factor proteolysis: Clinical implications. Br J Haematol 2006; 133:457-467.
37. Lillicrap D. Von Willebrand disease-Phenotype versus genotype: Deficiency versus disease. Thromb Res 2007; 120:S11-S16.
38. Lak M, Peyvandi F, Manucci PM. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 VWD. Br J Haematol 2000; 111:1236-1239.
39. Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24:123-134.
40. Castaman G, Bertoncello K, Bernardi M, Eikenboom JCJ, Budde U, Rodeghiero F. Autosomal recessive von Willebrand Disease Associated With Compound Heterozygosity for a Novel Nonsense Mutation (2908 Del C) and the Missense Mutation C2362F: Definite Evidence for the Non-Penetrance of the C2362F Mutation. Am J Hematol. 2007; 82:376-380.
41. ISTH-SSC VWF Online Database [homepage on the internet] ©2007 The University of Sheffield [Updated 2010 August 07: cited October 2010] Available from: http://vWF. group.shef.ac.uk/
42. Castaman G, Plate M, Giacomelli SH, Rodeghiero F, Duga S. Alterations of mRNA processing and stability as a pathogenic mechanism in von Willebrand factor quantitative deficiencies. J Thromb Haemost 2010; 8:2736-2742.
43. Baronciani L, Cozzi G, Canciani MT, Peyvandi F, Srivastava A, Federici AB, Manucci PM. Molecular defects in type 3 von Willebrand disease: Updated results from 40 multiethnic patients. Blood Cells Mol Dis 2003; 30:264-270.
44. Sutherland MS, Keeney S, Bolton-Maggs PHB, Hay CRM, Will A, Cumming AM. The mutation spectrum associated with type 3 von Willebrand disease in a cohort of patients from North West of England. Haemophilia 2009; 15:1048- 1057.
45. Sutherland MS, Cumming AM, Bowman M, Bolton-Maggs PH, Bowen DJ, Collins PW, Hay CR, Will AM, Keeney S. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood 2009; 114:1091-1098.
46. Mohl A, Boda Z, Jager R, Losonczy H, Marosi A, Masszi T, Nagy E, Nemes L, Obser T, Oyen F, Radványi G, Schlammadinger Á, Szélessy ZS, Várkonyi A, Vezendy K, Vilimi B, Schneppenheim R, Bodó I. Common large partial VWF gene deletion does not cause alloantibody formation in the Hungarian type 3 von Willebrand disease population. J Thromb Haemost 2011; 9:945-952.
47. Federici AB. Clinical and molecular markers of inherited VWD type 3: Are deletions of the VWF gene associated with alloantibodies to VWF?. J Thromb Haemost 2008; 6:1726- 1728.
48. Gupta PK, Adamtziki E, Budde U, Jaiprakash M, Kumar H, Harbeck-Seu A, Kannan M, Oyen F, Obser T, Wedekind I, Saxena R, Schneppenheim R. Gene conversions are a common cause of von Willebrand disease. Br J Haematol 2005; 130:752-758.
49. Eikenboom JC, Vink T, Briët E, Sixma JJ, Reitsma PH. Multiple substitutions in the von Willebrand factor gene that mimic the pseudogene sequence. Proc Natl Acad Sci USA 1994; 91:2221-2224.
50. Hommais A, Stepanian A, Fressinaud E, Mazurier C, Meyer D, Girma JP, Ribba AS. Mutations C1157F and C1234W of von Willebrand factor cause intracellular retention with defective multimerization and secretion. J Thomb Haemost 2006; 4:148-157.
51. Hommais A, Stepanian A, Fressinaud E, Mazurier C, Pouymayou K, Meyer D, Girma JP, Ribba AS. Impaired dimerizattion of von Willebrand factor subunit due to mutation A2801D in the CK domain results in a recessive type 2A subtype IID von Willebrand disease. Thromb Haemost 2006; 95:776-781.
52. 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.
53. OBrien LA, Sutherland JJ, Weaver DF, Lillicrap D. Theoretical structural explanation for group I and group II, type 2A von Willebrand disease mutations. J Thromb Haemost. 2005; 3:796-797.
54. Kashiwagi T, Matsushita T, Ito Y, Hirashima K, Sanda N, Fujimori Y, Yamada T, Okumura K, Takagi A, Murate T, Katsumi A, Takamatsu J, Yamamoto K, Naoe T, Kojima T. L1503R is a member of group I mutation and has dominant- negative effect on secretion of full-length VWF multimers: an analysis of two patients with type 2A von Willebrand disease. Haemophilia 2008; 14:556-563.
55. James PD, and Lillicrap D. The role of Molecular Genetics in Diagnosing von Willebrand Disease. Semin Thromb Hemost. 2008; 34:502-508.
56. Haberichter SL, Budde U, Obser T, Schneppenheim S, Wermes C, Schneppenheim R. The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF. Blood 2010; 115:4580-4587.
57. Hassenpflug WA, Budde U, Obser T, Angerhaus D, Drewke E, Schneppenheim S, Schneppenheim R. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood 2006; 107:2339- 2345.
58. Michiels JJ, van Vliet HH. Dominant von Willebrand disease type 2A groups I and II due to missense mutations in the A2 domain of the von Willebrand factor gene: diagnosis and management. Acta Haematol 2009; 121:154-166.
59. Rayes J, Hollestelle MJ, Legendre P, Marx I, de Groot PG, Christophe OD, Lenting PJ, Denis CV. Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B. Blood 2010; 115:4870-4877.
60. 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 Willebrands disease. N Engl J Med 1980; 302:1047- 1051.
61. 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 Willebrands disease. N Engl J Med 1983; 309:816-821.
62. Nurden P, Debili N, Vainchenker W, Bobe R, Bredoux R, Corvazier E, Combrie R, Fressinaud E, Meyer D, Nurden AT, Enouf J. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood 2006; 108:2587-2595.
63. 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.
64. Rick ME, Williams SB, Sacher RA, McKeown LP. Thrombocytopenia associated with pregnancy in a patient with type IIB von Willebrands disease. Blood 1987; 69:786- 789.
65. Hultin MB, Sussman II. Postoperative thrombocytopenia in type IIB von Willebrand disease. Am J Hematol 1990; 33:64-68.
66. Federici AB, Mannucci PM, Castaman G, Baronciani L, Bucciarelli P, Canciani MT, Pecci A, Lenting PJ, De Groot PG. 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; 113:526-534.
67. Golder M, Pruss CM, Hegadorn C, Mewburn J, Laverty K, Sponagle K, Lillicrap D. Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions. Blood 2010; 115:4862- 4869.
68. Ozeki M, Kunishima S, Kasahara K, Funato M, Teramoto T, Kaneko H, Fukao T, Kondo N. A family having type 2B von Willebrand disease with an R1306W mutation: Severe thrombocytopenia leads to the normalization of high molecular weight multimers. Thromb Res 2010; 125:e17- e22.
69. James PD, Notley C, Hegadorn C, Poon MC, Walker I, Rapson D, Lillicrap D. Association of Hemophilia Clinic Directors of Canada. Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study. J Thromb Haemost 2007; 5:1914-1922.
70. Ribba AS, Loisel I, Lavergne JM, Juhan-Vague I, Obert B, Cherel G, Meyer D, Girma JP. Ser968Thr mutation within the A3 domain of von Willebrand factor (VWF) in two related patients leads to a defective binding of VWF to collagen. Thromb Haemost 2001; 86:848-854.
71. Riddell AF, Gomez K, Millar CM, Mellars G, Gill S, Brown SA, Sutherland M, Laffan MA, McKinnon TA. Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. Blood 2009; 114:3489-3496.
72. 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.
73. 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.
74. Hilbert L, Nurden P, Caron C, Nurden AT, Goudemand J, Meyer D, Fressinaud E, Mazurier C. INSERM Network on Molecular Abnormalities in von Willebrand Disease. 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.
75. Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major factor VIII binding domain resides within the amino- terminal 272 amino acid residues of von Willebrand factor. J Biol Chem 1987; 262:8443-8446.
76. Hilbert L, Jorieux S, Proulle V, Favier R, Goudemand J, Parquet A, Meyer D, Fressinaud E, Mazurier C. Two novel mutations, Q1053H and C1060R, located in the D3 domain of von Willebrand factor, are responsible for decreased FVIII-binding capacity. Br J Haematol 2003; 120:627-632. Berber E, : The Molecular Genetics of von Willebrand Disease
77. Hilbert L, DOiron R, Fressinaud E, Meyer D, Mazurier C; INSERM Network on Molecular Abnormalities in von Willebrand Disease. First identification and expression of a type 2N von Willebrand disease mutation (E1078K) located in exon 25 of von Willebrand factor gene. J Thromb Haemost 2004; 2:2271-2273.
78. Mazurier C, Goudemand J, Hilbert L, Caron C, Fressinaud E, Meyer D. Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biology. Best Pract Res Clin Haematol 2001; 14:337-347.
79. Collins PW, Cumming AM, Goodeve AC, Lillicrap D. Type 1 von Willebrand disease: application of emerging data to clinical practice. Haemophilia 2008; 14:685-696.
80. Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Schneppenheim R, Budde U, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Hashemi Soteh M, Baronciani L, Hallden C, Guilliatt A, Lester W, Peake I. 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.
81. James PD, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, OBrien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007; 109:145-154.
82. Cumming A, Grundy P, Keeney S, Lester W, Enayat S, Guilliatt A, Bowen D, Pasi J, Keeling D, Hill F, Bolton-Maggs PH, Hay C, Collins P; UK Haemophilia Centre Doctors Organisation. An investigation of the von Willebrand factor genotype in UK patients diagnosed to have type 1 von Willebrand disease. Thromb Haemost 2006; 96:630-641.
83. Eikenboom JC, Matsushita T, Reitsma PH, Tuley EA, Castaman G, Briët E, Sadler JE. Dominant type 1 von Willebrand disease caused by mutated cysteine residues in the D3 domain of von Willebrand factor. Blood 1996; 88:2433-2441.
84. Bodó I, Katsumi A, Tuley EA, Eikenboom JC, Dong Z, Sadler JE. Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: A possible general mechanism for dominant mutations of oligomeric proteins. Blood 2001; 98:2973- 2979.
85. Eikenboom J, Hilbert L, Ribba AS, Hommais A, Habart D, Messenger S, Al-Buhairan A, Guilliatt A, Lester W, Mazurier C, Meyer D, Fressinaud E, Budde U, Will K, Schneppenheim R, Obser T, Marggraf O, Eckert E, Castaman G, Rodeghiero F, Federici AB, Batlle J, Goudemand J, Ingerslev J, Lethagen S, Hill F, Peake I, Goodeve A. Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from MCMDM-1VWD study. J Thromb Haemost 2009; 7:1304-1312.
86. Casonato A, Pontara E, Sartorello F, Cattini MG, Sartori MT, Padrini R, Girolami A. Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. Blood 2002; 99:180-184.
87. Haberichter SL, Balistreri M, Christopherson P, Morateck P, Gavazova S, Bellissimo DB, Manco-Johnson MJ, Gill JC, Montgomery RR. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood 2006; 108:3344-3351.
88. Castaman G, Tosetto A, Rodeghiero F. Reduced von Willebrand factor Survival in von Willebrand disease: pathophysiologic and clinical relevance. J Thromb Haemost 2009; 7:71-74.
89. Bowen DJ, Collins PW. An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Blood 2004; 103:941-947.
90. OBrien LA, James PD, Othman M, Berber E, Cameron C, Notley CR, Hegadorn CA, Sutherland JJ, Hough C, Rivard GE, OShaunessey D, Lillicrap D; Association of Hemophilia Clinic Directors of Canada. Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease. Blood 2003; 102:549-557.
91. Davies JA, Collins PW, Hathaway LS, Bowen DJ. Von Willebrand factor: evidence for variable clearance in vivo according to Y/C1584 phenotype and ABO blood group. J Thromb Haemost 2008; 6:97-103.
92. Davies JA, Collins PW, Hathaway LS, Bowen DJ. The effect of von Willebrand factor Y/C1584 on in vivo protein level and function, and interaction with ABO blood group. Blood 2007; 109:2840-2846.
93. Castaman G, Rodeghiero F, Manucci PM. The elusive pathogenesis of von Willebrand disease Vicenza. Blood 2002; 99:4243-4245.
94. Lester W, Guilliatt A, Grundy P, Enayat S, Millar C, Hill F, Cumming T, Collins P. Is VWF R924Q a benign polymorphism, a marker of a null allele or a factor VIII-binding defect? The debate continues with results from the UKHCDO vWD study. Thromb Haemost 2008; 100:716-718.
95. Berber E, James PD, Hough C, Lillicrap D. An assessment of the pathogenic significance of the R924Q von Willebrand factor substitution. J Thromb Haemost 2009; 7:1672-1679.
96. Keeney S, Bowen D, Cumming A, Enayat S, Goodeve A, Hill M. The molecular analysis of von Willebrand disease: A guideline from the UK Haemophilia Centre Doctors Organisation Haemophilia Genetics Laboratory Network. Haemophilia. 2008; 14:1099-1111.
97. Peake IR, Goodeve AC. Genetic testing for von Willebrand disease: The case for. J Thromb Haemost 2010; 8:13-16.
98. Flavaloro EJ. Rethinking the diagnosis of von Willebrand disease. Thromb Res 2011; 127:S17-S21.

APA	BERBER E (2012). The molecular genetics of von willebrand disease. , 313 - 324.
Chicago	BERBER ERGÜL The molecular genetics of von willebrand disease. (2012): 313 - 324.
MLA	BERBER ERGÜL The molecular genetics of von willebrand disease. , 2012, ss.313 - 324.
AMA	BERBER E The molecular genetics of von willebrand disease. . 2012; 313 - 324.
Vancouver	BERBER E The molecular genetics of von willebrand disease. . 2012; 313 - 324.
IEEE	BERBER E "The molecular genetics of von willebrand disease." , ss.313 - 324, 2012.
ISNAD	BERBER, ERGÜL. "The molecular genetics of von willebrand disease". (2012), 313-324.

APA	BERBER E (2012). The molecular genetics of von willebrand disease. Turkish Journal of Hematology, 29(4), 313 - 324.
Chicago	BERBER ERGÜL The molecular genetics of von willebrand disease. Turkish Journal of Hematology 29, no.4 (2012): 313 - 324.
MLA	BERBER ERGÜL The molecular genetics of von willebrand disease. Turkish Journal of Hematology, vol.29, no.4, 2012, ss.313 - 324.
AMA	BERBER E The molecular genetics of von willebrand disease. Turkish Journal of Hematology. 2012; 29(4): 313 - 324.
Vancouver	BERBER E The molecular genetics of von willebrand disease. Turkish Journal of Hematology. 2012; 29(4): 313 - 324.
IEEE	BERBER E "The molecular genetics of von willebrand disease." Turkish Journal of Hematology, 29, ss.313 - 324, 2012.
ISNAD	BERBER, ERGÜL. "The molecular genetics of von willebrand disease". Turkish Journal of Hematology 29/4 (2012), 313-324.