PDF herunterladen
Semin Thromb Hemost 2020; 46(04): 484-500
DOI: 10.1055/s-0039-3402430
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetic Background of von Willebrand Disease: History, Current State, and Future Perspectives

Jana Zolkova
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Juraj Sokol
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Tomas Simurda
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Lubica Vadelova
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Zuzana Snahnicanova
2   Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
,
Dusan Loderer
2   Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
,
Miroslava Dobrotova
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Jela Ivankova
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Ingrid Skornova
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Zora Lasabova
2   Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
,
Peter Kubisz
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
,
Jan Stasko
1   Department of Hematology and Transfusiology, National Centre of Hemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Martin University Hospital, Comenius University in Bratislava, Martin, Slovakia
› Institutsangaben Funding Our work on VWD is supported by grants VEGA1/0187/17, VEGA 1/0168/16, and APVV 16–0020.
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
30. Dezember 2019 (online)

    Lizenzen und Reprints

Abstract

Sequencing of the gene encoding for von Willebrand factor (VWF) has brought new insight into the physiology of VWF as well as its pathophysiology in the context of von Willebrand disease (VWD). Molecular testing in VWD patients has shown high variability in the overall genetic background of this condition. Almost 600 mutations and many disease-causing mechanisms have been described in the 35 years since the VWF gene was identified. Genetic testing in VWD patients is now available in many centers as a part of the VWD diagnostic algorithm. Molecular mechanisms leading to types 2 and 3 VWD are well characterized; thus, information from genetic analysis in these VWD types may be beneficial for their correct classification. However, the molecular basis of type 1 VWD is still not fully elucidated and most likely represents a multifactorial disorder reflecting a combined impact of environmental and genetic factors within and outside of VWF. Regarding sequencing methods, the previous gold-standard Sanger sequencing is gradually being replaced with next-generation sequencing methods that are more cost- and time-effective. Instead of gene-by-gene approaches, gene panels of genes for coagulation factors and related proteins have recently become a center of attention in patients with inherited bleeding disorders, especially because a high proportion of VWD patients, mainly those with low VWF plasma levels (type 1), appear to be free of mutations in VWF. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are accessible in a very limited number of laboratories. Results from these studies have presented several genes other than VWF or ABO possibly affecting VWF levels, and such findings will need further validation studies.

Keywords

von Willebrand disease - von Willebrand factor - genetic background - genetic testing
 

  • References

  • 1 Von Willebrand EA. Hereditär pseudohemofili. Fin Lakaresallsk Handl 1926; 68: 87-112
    PubMedGoogle Scholar
  • 2 Nilsson IM. The history of von Willebrand disease. Haemophilia 1999; 5 (Suppl. 02) 7-11
    CrossrefPubMedGoogle Scholar
  • 3 Ginsburg D, Handin RI, Bonthron DT. , et al. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228 (4706): 1401-1406
    CrossrefPubMedGoogle Scholar
  • 4 Lynch DC, Zimmerman TS, Collins CJ. , et al. Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method. Cell 1985; 41 (01) 49-56
    CrossrefPubMedGoogle Scholar
  • 5 Sadler JE, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci USA 1985; 82 (19) 6394-6398
    CrossrefPubMedGoogle Scholar
  • 6 Verweij CL, de Vries CJ, Distel B. , et al. Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene. Nucleic Acids Res 1985; 13 (13) 4699-4717
    CrossrefPubMedGoogle Scholar
  • 7 Lynch DC, Zimmerman TS, Ruggeri ZM. von Willebrand factor, now cloned. Br J Haematol 1986; 64 (01) 15-20
    CrossrefPubMedGoogle Scholar
  • 8 Federici AB, Berntorp E, Lee CA. The 80th anniversary of von Willebrand's disease: history, management and research. Haemophilia 2006; 12 (06) 563-572
    CrossrefPubMedGoogle Scholar
  • 9 Favaloro EJ. Von Willebrand disease: local diagnosis and management of a globally distributed bleeding disorder. Semin Thromb Hemost 2011; 37 (05) 440-455
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 10 Stasko J, Sokol J, Dobrotova M. , et al. Von Willebrandova choroba – profylaxia a liečba. Vask med 2016; 8 (03) 116-121
    PubMedGoogle Scholar
  • 11 Favaloro EJ. Preface to special issue: diagnosis and management of von Willebrand disease—diverse approaches to a global and common bleeding disorder. Ann Blood 2018; 3: 43
    CrossrefPubMedGoogle Scholar
  • 12 Favaloro EJ. Rare forms of von Willebrand disease. Ann Transl Med 2018; 6 (17) 345
    CrossrefPubMedGoogle Scholar
  • 13 Kubisz P, Sokol J, Simurda T. , et al. Diagnosis and management of von Willebrand disease in Slovakia. Ann Blood 2018; 3: 9
    CrossrefPubMedGoogle Scholar
  • 14 Favaloro EJ, Bonar R, Marsden K. Lower limit of assay sensitivity: an under-recognised and significant problem in von Willebrand disease identification and classification. Clin Lab Sci 2008; 21 (03) 178-183
    PubMedGoogle Scholar
  • 15 de Jong A, Eikenboom J. Von Willebrand disease mutation spectrum and associated mutation mechanisms. Thromb Res 2017; 159: 65-75
    CrossrefPubMedGoogle Scholar
  • 16 Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis 2014; 25 (03) 206-216
    CrossrefPubMedGoogle Scholar
  • 17 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
    CrossrefPubMedGoogle Scholar
  • 18 James PD, Goodeve AC. von Willebrand disease. Genet Med 2011; 13 (05) 365-376
    CrossrefPubMedGoogle Scholar
  • 19 Marder VJ, Aird WC, Bennett JS, Schulman S, White II GC. Hemostasis and Thrombosis: Basic principles and Clinical Practice. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013: 197-207 , 670–683
    Google Scholar
  • 20 Baronciani L, Goodeve A, Peyvandi F. Molecular diagnosis of von Willebrand disease. Haemophilia 2017; 23 (02) 188-197
    CrossrefPubMedGoogle Scholar
  • 21 Mancuso DJ, Tuley EA, Westfield LA. , et al. Human von Willebrand factor gene and pseudogene: structural analysis and differentiation by polymerase chain reaction. Biochemistry 1991; 30 (01) 253-269
    CrossrefPubMedGoogle Scholar
  • 22 Ginsburg D, Bowie EJW. Molecular genetics of von Willebrand disease. Blood 1992; 79 (10) 2507-2519
    CrossrefPubMedGoogle Scholar
  • 23 Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24 (03) 123-134
    CrossrefPubMedGoogle Scholar
  • 24 Gupta PK, Adamtziki E, Budde U. , et al. Gene conversions are a common cause of von Willebrand disease. Br J Haematol 2005; 130 (05) 752-758
    CrossrefPubMedGoogle Scholar
  • 25 Ahmad F, Kannan M, Obser T. , et al. Characterization of VWF gene conversions causing von Willebrand disease. Br J Haematol 2019; 184 (05) 817-825
    CrossrefPubMedGoogle Scholar
  • 26 Tutar Y. Pseudogenes. Comp Funct Genomics 2012; 2012: 424526
    CrossrefPubMedGoogle Scholar
  • 27 Favaloro EJ. Genetic testing for von Willebrand disease: the case against. J Thromb Haemost 2010; 8 (01) 6-12
    CrossrefPubMedGoogle Scholar
  • 28 Campos M, Sun W, Yu F. , et al. Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort. Blood 2011; 117 (19) 5224-5230
    CrossrefPubMedGoogle Scholar
  • 29 Wang QY, Song J, Gibbs RA, Boerwinkle E, Dong JF, Yu FL. Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes. J Thromb Haemost 2013; 11 (02) 261-269
    CrossrefPubMedGoogle Scholar
  • 30 Hickson N, Hampshire D, Castaman G. , et al; MCMDM-1VWD and ZPMCB-VWD Study Groups. Effect of the VWF promoter (GT)n repeat and single-nucleotide polymorphism c.-2527G>A on circulating von Willebrand factor levels under normal conditions. J Thromb Haemost 2011; 9 (03) 603-605
    CrossrefPubMedGoogle Scholar
  • 31 Goodeve A. Diagnosing von Willebrand disease: genetic analysis. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 678-682
    CrossrefPubMedGoogle Scholar
  • 32 Flood VH. New insights into genotype and phenotype of VWD. Hematology (Am Soc Hematol Educ Program) 2014; 2014 (01) 531-535
    CrossrefPubMedGoogle Scholar
  • 33 James PD, Notley C, Hegadorn C. , et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007; 109 (01) 145-154
    CrossrefPubMedGoogle Scholar
  • 34 Castaman G, Eikenboom JCJ. ABO blood group also influences the von Willebrand factor (VWF) antigen level in heterozygous carriers of VWF null alleles, type 2N mutation Arg854GIn, and the missense mutation Cys2362Phe. Blood 2002; 100 (05) 1927-1928
    CrossrefPubMedGoogle Scholar
  • 35 Berber E. The molecular genetics of von Willebrand disease. Turk J Haematol 2012; 29 (04) 313-324
    PubMedGoogle Scholar
  • 36 Cumming A, Grundy P, Keeney S. , et al; 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 (05) 630-641
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 37 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 (01) 112-121
    CrossrefPubMedGoogle Scholar
  • 38 Favaloro EJ. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD): a rebuttal. J Thromb Haemost 2008; 6 (11) 1999-2001 , author reply 2002–2003
    CrossrefPubMedGoogle Scholar
  • 39 James PD, Lillicrap D. The molecular characterization of von Willebrand disease: good in parts. Br J Haematol 2013; 161 (02) 166-176
    CrossrefPubMedGoogle Scholar
  • 40 Keeney S, Bowen D, Cumming A, Enayat S, Goodeve A, Hill M. ; UK Haemophilia Centre Doctors' Organisation (UKHCDO). The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation Haemophilia Genetics Laboratory Network. Haemophilia 2008; 14 (05) 1099-1111
    CrossrefPubMedGoogle Scholar
  • 41 Shen MC, Chen M, Ma GC. , et al. De novo mutation and somatic mosaicism of gene mutation in type 2A, 2B and 2M VWD. Thromb J 2016; 14 (Suppl. 01) 36
    CrossrefPubMedGoogle Scholar
  • 42 Freitas SDS, Rezende SM, de Oliveira LC. , et al. Genetic variants of VWF gene in type 2 von Willebrand disease. Haemophilia 2019; 25 (02) e78-e85
    CrossrefPubMedGoogle Scholar
  • 43 König G, Obser T, Marggraf O. , et al. Alteration in GPIIb/IIIa binding of VWD-associated von Willebrand factor variants with C-terminal missense mutations. Thromb Haemost 2019; 119 (07) 1102-1111
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 44 Pruthi RK. A practical approach to genetic testing for von Willebrand disease. Mayo Clin Proc 2006; 81 (05) 679-691
    CrossrefPubMedGoogle Scholar
  • 45 Hassenpflug WA, Budde U, Obser T. , et al. Impact of mutations in the von Willebrand factor A2 domain on ADAMTS13-dependent proteolysis. Blood 2006; 107 (06) 2339-2345
    CrossrefPubMedGoogle Scholar
  • 46 O'Brien 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 (04) 796-797
    CrossrefPubMedGoogle Scholar
  • 47 Lynch CJ, Cawte AD, Millar CM, Rueda D, Lane DA. A common mechanism by which type 2A von Willebrand disease mutations enhance ADAMTS13 proteolysis revealed with a von Willebrand factor A2 domain FRET construct. PLoS One 2017; 12 (11) e0188405
    CrossrefPubMedGoogle Scholar
  • 48 Baronciani L, Federici AB, Beretta M, Cozzi G, Canciani MT, Mannucci PM. 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 (12) 2689-2694
    CrossrefPubMedGoogle Scholar
  • 49 Casonato A, Daidone V, Galletta E, Bertomoro A. Type 2B von Willebrand disease with or without HMW multimers: a distinction of two sides of the disorder is long overdue. PLoS One 2017; 12 (06) e0179566
    CrossrefPubMedGoogle Scholar
  • 50 Swystun LL, James PD. Genetic diagnosis in hemophilia and von Willebrand disease. Blood Rev 2017; 31 (01) 47-56
    CrossrefPubMedGoogle Scholar
  • 51 Favaloro EJ, Bonar RA, Mohammed S. , et al. Type 2M von Willebrand disease - more often misidentified than correctly identified. Haemophilia 2016; 22 (03) e145-e155
    CrossrefPubMedGoogle Scholar
  • 52 Flood VH, Schlauderaff AC, Haberichter SL. , et al; Zimmerman Program Investigators. Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 2015; 125 (14) 2297-2304
    CrossrefPubMedGoogle Scholar
  • 53 Larsen DM, Haberichter SL, Gill JC, Shapiro AD, Flood VH. Variability in platelet- and collagen-binding defects in type 2M von Willebrand disease. Haemophilia 2013; 19 (04) 590-594
    CrossrefPubMedGoogle Scholar
  • 54 Flood VH, Lederman CA, Wren JS. , et al. Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD. J Thromb Haemost 2010; 8 (06) 1431-1433
    CrossrefPubMedGoogle Scholar
  • 55 Riddell AF, Gomez K, Millar CM. , et al. Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. Blood 2009; 114 (16) 3489-3496
    PubMedGoogle Scholar
  • 56 Ribba AS, Loisel I, Lavergne JM. , et al. 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 (03) 848-854
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 57 Favaloro EJ, Pasalic L, Curnow J. Type 2M and type 2A von Willebrand disease: similar but different. Semin Thromb Hemost 2016; 42 (05) 483-497
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 58 Casonato A, Galletta E, Sarolo L, Daidone V. Type 2N von Willebrand disease: characterization and diagnostic difficulties. Haemophilia 2018; 24 (01) 134-140
    CrossrefPubMedGoogle Scholar
  • 59 Shiltagh N, Kirkpatrick J, Cabrita LD. , et al. Solution structure of the major factor VIII binding region on von Willebrand factor. Blood 2014; 123 (26) 4143-4151
    CrossrefPubMedGoogle Scholar
  • 60 Przeradzka MA, Meems H, van der Zwaan C. , et al. The D' domain of von Willebrand factor requires the presence of the D3 domain for optimal factor VIII binding. Biochem J 2018; 475 (17) 2819-2830
    CrossrefPubMedGoogle Scholar
  • 61 Bowman M, Tuttle A, Notley C. , et al; Association of Hemophilia Clinic Directors of Canada. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles. J Thromb Haemost 2013; 11 (03) 512-520
    CrossrefPubMedGoogle Scholar
  • 62 Baronciani L, Cozzi G, Canciani MT. , et al. Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients. Blood Cells Mol Dis 2003; 30 (03) 264-270
    CrossrefPubMedGoogle Scholar
  • 63 James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood 2013; 122 (05) 636-640
    PubMedGoogle Scholar
  • 64 Federici AB, James P. Current management of patients with severe von Willebrand disease type 3: a 2012 update. Acta Haematol 2012; 128 (02) 88-99
    CrossrefPubMedGoogle Scholar
  • 65 Elayaperumal S, Fouzia NA, Biswas A. , et al. Type-3 von Willebrand disease in India-clinical spectrum and molecular profile. Haemophilia 2018; 24 (06) 930-940
    CrossrefPubMedGoogle Scholar
  • 66 Vangenechten I, Smejkal P, Zapletal O. , et al. Analysis of von Willebrand Disease in the South Moravian Population (Czech Republic): results from the BRNO-VWD Study. Thromb Haemost 2019; 119 (04) 594-605
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 67 Batlle J, Pérez-Rodríguez A, Corrales I. , et al; PCM-EVW-ES Investigators Team. Update on molecular testing in von Willebrand disease. Semin Thromb Hemost 2019; 45 (07) 708-719
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 68 Corrales I, Ramírez L, Altisent C, Parra R, Vidal F. Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost 2009; 101 (03) 570-576
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 69 Peake IR, Goodeve AC. Genetic testing for von Willebrand disease: the case for. J Thromb Haemost 2010; 8 (01) 13-16
    CrossrefPubMedGoogle Scholar
  • 70 Rao ES, Ng CJ. Current approaches to diagnostic testing in von Willebrand disease. Transfus Apheresis Sci 2018; 57 (04) 463-465
    CrossrefPubMedGoogle Scholar
  • 71 Cumming AM, Keeney S, Jenkins PV, Nash MJ, O'Donnell JS. Clinical utility gene card for: von Willebrand disease. Eur J Hum Genet 2011 19(05):
    PubMedGoogle Scholar
  • 72 Atiq F, Fijnvandraat K, van Galen KPM. , et al. BMI is an important determinant of VWF and FVIII levels and bleeding phenotype in patients with von Willebrand disease. Am J Hematol 2019; 94 (08) E201-E205
    PubMedGoogle Scholar
  • 73 Swystun LL, Lillicrap D. Genetic regulation of plasma von Willebrand factor levels in health and disease. J Thromb Haemost 2018; 16 (12) 2375-2390
    CrossrefPubMedGoogle Scholar
  • 74 Kumar KR, Cowley MJ, Davis RL. Next-generation sequencing and emerging technologies. Semin Thromb Hemost 2019; 45 (07) 661-673
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 75 Cabrera N, Casaña P, Cid AR. , et al. First application of MLPA method in severe von Willebrand disease. Confirmation of a new large VWF gene deletion and identification of heterozygous carriers. Br J Haematol 2011; 152 (02) 240-242
    CrossrefPubMedGoogle Scholar
  • 76 Bastida JM, González-Porras JR, Jiménez C. , et al. Application of a molecular diagnostic algorithm for haemophilia A and B using next-generation sequencing of entire F8, F9 and VWF genes. Thromb Haemost 2017; 117 (01) 66-74
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 77 Bastida JM, Del Rey M, Lozano ML. , et al. Design and application of a 23-gene panel by next-generation sequencing for inherited coagulation bleeding disorders. Haemophilia 2016; 22 (04) 590-597
    CrossrefPubMedGoogle Scholar
  • 78 Saes JL, Simons A, de Munnik SA. , et al. Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis. Haemophilia 2019; 25 (01) 127-135
    CrossrefPubMedGoogle Scholar
  • 79 Pezeshkpoor B, Zimmer N, Marquardt N. , et al. Deep intronic 'mutations' cause hemophilia A: application of next generation sequencing in patients without detectable mutation in F8 cDNA. J Thromb Haemost 2013; 11 (09) 1679-1687
    CrossrefPubMedGoogle Scholar
  • 80 Smith NL, Chen MH, Dehghan A. , et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121 (12) 1382-1392
    CrossrefPubMedGoogle Scholar
  • 81 Sabater-Lleal M, Huffman JE, de Vries PS. , et al; INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC). Genome-wide association transethnic meta-analyses identifies novel associations regulating coagulation factor VIII and von Willebrand factor plasma levels. Circulation 2019; 139 (05) 620-635
    CrossrefPubMedGoogle Scholar
  • 82 Ward S, O'Sullivan JM, O'Donnell JS. von Willebrand factor sialylation-a critical regulator of biological function. J Thromb Haemost 2019; 17 (07) 1018-1029
    CrossrefPubMedGoogle Scholar
  • 83 Xiang Y, Cheng J, Wang D. , et al. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 2015; 125 (22) 3377-3387
    CrossrefPubMedGoogle Scholar
  • 84 Xiang Y, Hwa J. Regulation of VWF expression, and secretion in health and disease. Curr Opin Hematol 2016; 23 (03) 288-293
    CrossrefPubMedGoogle Scholar