Download PDF
Hamostaseologie 1994; 14(04): 159-168
DOI: 10.1055/s-0038-1660359
Übersichtsarbeiten/Review Articles
Schattauer GmbH

Hämostaseologische und molekulare Diagnostik des Von-Willebrand-Syndroms

R. Schneppenheim
1   Klinik für Allgemeine Pädiatrie im Klinikum der Christian-Albrechts-Universität Kiel (Direktor: Prof. Dr. med. J. Schaub)
› Author Affiliations
Further Information

Publication History

Publication Date:
26 June 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Seit der Erstbeschreibung des Von-Willebrand-Syndroms (vWS) als »Hereditär Pseudohemofili« durch Erik Adolf von Willebrand 1926 schaffte erst die Verfügbarkeit moderner hämostaseologischer und in letzter Zeit auch molekularer Methoden die Voraussetzung für die heutigen Kenntnisse über die Genetik und die Natur der zugrundeliegenden quantitativen, funktionellen und molekularen Defekte. Die bekannte ausgeprägte Heterogenität der klinischen Symptome und der Laborparameter korrespondiert mit der Natur und der Lokalisation der molekularen Defekte in definierten Regionen des multifunktionellen Von-Willebrand-Faktors. Das diagnostische Vorgehen und die Indikationen für zusätzliche molekulargenetische Untersuchungen zur Charakterisierung der verschiedenen heute bekannten Typen und Subtypen des vWS werden dargestellt.

Schlüsselwörter

Von-Willebrand-Syndrom - Von-Willebrand-Faktor - Diagnose - Genetik - molekulare Defekte
 

  • LITERATUR

  • 1 Anvret M, Blombäck M, Lindstedt M, Söderlind E, Tapper-Persson M, Thelander AC. Genetic and blood coagulation characterization of “Swedish” families with von Willebrand’s disease types I and III: New aspects of heredity. Hum Genet 1992; 89: 147-54.
    PubMedSearch in Google Scholar
  • 2 Bahnak BR, Lavergne JM, Rothschild C, Meyer D. A stop codon in a patient with severe type III von Willebrand disease (letter). Blood 1991; 78: 1148-9.
    PubMedSearch in Google Scholar
  • 3 Bird AP. DNA méthylation and the frequency of CpG in animal DNA. Nucleic Acids Res 1980; 08: 1499-504.
    CrossrefPubMedSearch in Google Scholar
  • 4 Bloom AL, Giddings JC, Wilks CJ. Factor VIII on the vascular intima: Possible importance in haemostasis and thrombosis. Nature New Biology 1973; 241: 217-9.
    CrossrefPubMedSearch in Google Scholar
  • 5 Bonthron D, Orr EC, Mitsock LM, Ginsburg D, Handin RI, Orkin SH. Nucleotide sequence of pre-pro-von Willebrand factor cDNA. Nucleic Acids Res 1986; 14: 7125-7.
    CrossrefPubMedSearch in Google Scholar
  • 6 Brown JE, Bosak JO. An ELISA test for the binding of von Willebrand antigen to collagen. Thromb Res 1986; 43: 303-11.
    CrossrefPubMedSearch in Google Scholar
  • 7 Budde U, Müller N, Hammerstein U, Lüchters G. Vorkommen milder Formen des von Willebrand-Syndroms Typ I in der »Normalbevölkerung«. In: Hämostase, Thrombophilie und Arteriosklerose. De Loo J v, Asbeck F. (Hrsg). Stuttgart: Schattauer; 1982: 505-10.
    Search in Google Scholar
  • 8 Eikenboom JCJ, Ploos HKvan Amstel, Reitsma PH, Briet E. Mutations in severe, type III von Willebrand’s disease in the Dutch population: candidate missense and nonsense mutations associated with reduced levels of von Willebrand factor messenger RNA. Thromb Haemostas 1992; 68: 448-54.
    PubMedSearch in Google Scholar
  • 9 Eriksson AW, Hiepler E, Jürgens R, Lehmann W, Schulz H. Untersuchungen zur Thrombopathie (v. Willebrand-Jürgens). Klin Wochenschr 1961; 39: 32-42.
    CrossrefPubMedSearch in Google Scholar
  • 10 Fay PJ, Kawai Y, Wagner DD, Ginsburg D, Bonthron D, Ohlsson BMWilhelm, Chavin SI, Abraham GN, Handin RI, Orkin SH. Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II. Sciene 1986; 232: 995-8.
    CrossrefPubMedSearch in Google Scholar
  • 11 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: 8443-6.
    PubMedSearch in Google Scholar
  • 12 Fowler WE, Fretto LJ, Hamilton KK, Erickson HP, McKee PA. Substructure of human von Willebrand factor. J Clin Invest 1985; 76: 1491-500.
    CrossrefPubMedSearch in Google Scholar
  • 13 Fulcher CA, Zimmerman TS. Characterization of the human factor VIII procoagulant protein with a heterologous precipitating antibody. Proc Natl Acad Sci USA 1982; 79: 1648-52.
    CrossrefPubMedSearch in Google Scholar
  • 14 Furlan M. Factor VIII/von Willebrand factor: a multivalent ligand binding to platelets and collagen. Blut 1986; 52: 329-36.
    CrossrefPubMedSearch in Google Scholar
  • 15 Ginsburg D, Bowie EJW. Molecular genetics of von Willebrand disease. Blood 1992; 79: 2507-19.
    PubMedSearch in Google Scholar
  • 16 Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GA, Latt SA, Orkin SH. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228: 1401-6.
    CrossrefPubMedSearch in Google Scholar
  • 17 Ginsburg D, Sadler JE. 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: 177-84.
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Girma JP, Meyer D, Verweij CL, Pannekoek H, Sixma JJ. Structure-function relationship of human von Willebrand factor. Blood 1987; 70: 605-11.
    PubMedSearch in Google Scholar
  • 19 Hach-Wunderle V, Vigh Z, Scharrer I. Diagnostik und Therapie des von WillebrandSyndroms. Med Welt 1987; 38: 1654-7.
    PubMedSearch in Google Scholar
  • 20 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 in press..
    PubMedSearch in Google Scholar
  • 21 Holmberg L, Nilsson IM. Von Willebrand disease. Clin Haematol 1985; 14: 461-88.
    PubMedSearch in Google Scholar
  • 22 Hoyer LW, Los Santos RPD, Hoyer JR. Antihemophilic factor antigen. Localization in endothelial cells by immunofluorescent microscopy. J Clin Invest 1973; 52: 2737-44.
    CrossrefPubMedSearch in Google Scholar
  • 23 Hoyer LW, Shainoff JR. Factor VUI-related protein circulates in normal plasma as high molecular weight multimers. Blood 1980; 57: 1056-9.
    PubMedSearch in Google Scholar
  • 24 Jaffe EA, Hoyer LW, Nachman RL. Synthesis of von Willebrand factor by cultured human endothelial cells. Proc Natl Acad Sci USA 1974; 71: 1906-9.
    CrossrefPubMedSearch in Google Scholar
  • 25 Koutts J, Walsh PN, Plow EF, Fenton JW, Bouma BN, Zimmerman TS. Active release of human platelet factor VUI-related antigen by adenosine diphosphate, collagen, and thrombin. J Clin Invest 1978; 62: 1255-63.
    CrossrefPubMedSearch in Google Scholar
  • 26 Laurell CB. Electroimmunoassay. Scand J Clin Lab Invest 1972; 124 (Suppl): 21-37.
    PubMedSearch in Google Scholar
  • 27 Lenk H, Nilsson IM, Holmberg L, Weissbach G. Frequency of different types of von Willebrand’s disease in the GDR. Acta Med Scand 1988; 224: 275-80.
    PubMedSearch in Google Scholar
  • 28 Loesberg C, Gonsalves MD, Zandbergen J, Willems C, von Aken WG, Stel HV, Van Mourik JA, De Groot PG. The effect of calcium on the secretion of factor VUI-related antigen by cultured human endothelial cells. Biochim Biophys Acta 1983; 763: 160-8.
    CrossrefPubMedSearch in Google Scholar
  • 29 Lynch DC, Williams R, Zimmerman TS, Kirby EP, Livingston DM. Biosynthesis of the subunits of factor VIIIR by bovine aortic endothelial cells. Proc Natl Acad Sci USA 1983; 80: 2738-42.
    CrossrefPubMedSearch in Google Scholar
  • 30 Macfarlane DE, Stibbe J, Kirby EP, Zucker MB, Grant RA, McPherson J. Letter: A method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh 1975; 34: 306-8.
    PubMedSearch in Google Scholar
  • 31 Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton BBInloes, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-27.
    PubMedSearch in Google Scholar
  • 32 Mancuso DJ, Tuley EA, Westfield LA, Lester TLMancuso, 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: 253-69.
    CrossrefPubMedSearch in Google Scholar
  • 33 Mannucci PM, Bloom AL, Larrieu MJ, Nilsson IM, West RR. Atherosclerosis and von Willebrand factor. I. Prevalence of severe von Willebrand’s disease in western Europe and Israel. Br J Haematol 1984; 57: 163-9.
    CrossrefPubMedSearch in Google Scholar
  • 34 Mayadas TN, Wagner DD. Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Natl Acad Sci USA 1992; 89: 3531-5.
    CrossrefPubMedSearch in Google Scholar
  • 35 Mazurier C, Parquet AGernez, Goudemand M. Enzyme-linked immunoabsorbent assay of factor VUI-related antigen. Interest in study of Von Willebrand’s disease. Pathol Biol Paris 1977; 25: 18-24.
    PubMedSearch in Google Scholar
  • 36 Mazurier C. von Willebrand disease masquerading as haemophilia A. Thromb Haemost 1992; 67: 391-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 37 Miller CH, Graham JB, Goldin LR, Elston RC. Genetics of classic von Willebrand’s disease. I. Phenotypic variation within families. Blood 1979; 54: 117-36.
    PubMedSearch in Google Scholar
  • 38 Miller CH, Lenzi R, Breen C. Prevalence of von Willebrand’s disease among U.S. adults. Blood 1987; 70: 377a.
    PubMedSearch in Google Scholar
  • 39 Mohri H, Zimmerman TS, Ruggeri ZM. Synthetic peptides inhibit the interaction of von Willebrand factor-platelet membrane glycoproteins. Peptides 1993; 14: 125-9.
    CrossrefPubMedSearch in Google Scholar
  • 40 Myers RM, Lumelsky N, Lerman LS, Maniatis T. Detection of single base substitutions in total genomic DNA. Nature 1985; 313: 495-8.
    CrossrefPubMedSearch in Google Scholar
  • 41 Nachman RL, Jaffe EA. Subcellular platelet factor VIII antigen and von Willebrand factor. J Exp Med 1975; 141: 1101-13.
    CrossrefPubMedSearch in Google Scholar
  • 42 Ngo KY, Glotz VT, Koziol JA, Lynch DC, Gitschier J, Ranieri P, Ciavarella N, Ruggeri ZM, Zimmerman TS. Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease. Proc Natl Acad Sci USA 1988; 85: 2753-7.
    CrossrefPubMedSearch in Google Scholar
  • 43 Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 1989; 86: 2766-70.
    CrossrefPubMedSearch in Google Scholar
  • 44 Peake IR, Liddell MB, Moodie P, Standen G, Mancuso DJ, Tuley EA, Westfield LA, Sorace JM, Sadler JE, Verweij CL, Bloom AL. Severe type III von Willebrand’s disease caused by deletion of exon 42 of the von Willebrand factor gene: family studies that identify carriers of the condition and a compound heterozygous individual. Blood 1990; 75: 654-61.
    PubMedSearch in Google Scholar
  • 45 Rand JH, Sussman II, Gordon RE, Chu SV, Solomon V. Localization of factor-VIII-related antigen in human vascular subendothelium. Blood 1980; 55: 752-6.
    PubMedSearch in Google Scholar
  • 46 Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecular basis of von Willebrand disease type IIB - Candidate mutations cluster in one disulfide loop be-tween proposed platelet Glycoprotein IB binding sequences. J Clin Invest 1991; 87: 1220-6.
    CrossrefPubMedSearch in Google Scholar
  • 47 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69: 454-9.
    PubMedSearch in Google Scholar
  • 48 Ruggeri ZM, Zimmerman TS. Variant von Willebrand’s disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. J Clin Invest 1980; 65: 1318-25.
    CrossrefPubMedSearch in Google Scholar
  • 49 Ruggeri ZM, Zimmerman TS. The complex multimeric composition of factor VIII/ von Willebrand factor. Blood 1981; 57: 1140-3.
    PubMedSearch in Google Scholar
  • 50 Ruggeri ZM. Classification of von Willebrand disease. In: Thrombosis and Haemostasis 1987. Verstraete M, Vermylen J, Lijnen R, Arnout J. (Hrsg). Leuven: Leuven University Press; 1987: 419-45.
    Search in Google Scholar
  • 51 Ruggeri ZM, Zimmerman TS. von Willebrand factor and von Willebrand disease [published erratum appears in Blood 71 (3), 830 (1988)]. Blood 1987; 70: 895-904.
    PubMedSearch in Google Scholar
  • 52 Sadler JE, Ginsburg D. A database of polymorphisms in the von Willebrand factor gene and pseudogene. 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: 185-91.
    Thieme ConnectPubMedSearch in Google Scholar
  • 53 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-5.
    Thieme ConnectPubMedSearch in Google Scholar
  • 54 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-91.
    CrossrefPubMedSearch in Google Scholar
  • 55 Sakariassen KS, Nievelstein PF, Coller BS, Sixma JJ. The role of platelet membrane glycoproteins lb and Ilb-IIIa in platelet adherence to human artery subendothelium. Br J Haematol 1986; 63: 681-91.
    CrossrefPubMedSearch in Google Scholar
  • 56 Santoro SA. Adsorption of von Willebrand factor/factor VIII by the genetically distinct interstitial collagens. Thromb Res 1981; 21: 689-91.
    CrossrefPubMedSearch in Google Scholar
  • 57 Schneppenheim R, Plendl H, Budde U. Luminograph - an alternative assay for detection of von Willebrand factor multimers. Thromb Haemost 1988; 60: 133-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 58 Schneppenheim R, Krey S, Bergmann F, Bock D, Budde U, Lange M, Linde R, Mittler U, Meili GE Mertes, Olek K, Plendl H, Simeoni E. Genetic heterogeneity of severe von Willebrand disease type III in the German population. Hum Genet. 1994 in press..
    PubMedSearch in Google Scholar
  • 59 Shelton BBInloes, Broze GJJ, Miletich JP, Sadler JE. Evolution of human von Willebrand factor: cDNA sequence polymorphisms, repeated domains, and relationship to von Willebrand antigen II. Biochem Biophys Res Commun 1987; 144: 657-65.
    CrossrefPubMedSearch in Google Scholar
  • 60 Shelton BBInloes, Chehab FF, Mannucci PM, Federici AB, Sadler JE. Gene deletions correlate with the development of alloantibodies in von Willebrand disease. J Clin Invest 1987; 79: 1459-65.
    CrossrefPubMedSearch in Google Scholar
  • 61 Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 1975; 98: 503-17.
    CrossrefPubMedSearch in Google Scholar
  • 62 Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46: 185-90.
    CrossrefPubMedSearch in Google Scholar
  • 63 Sussman II, Rand JH. Subendothelial deposition of von Willebrand’s factor requires the presence of endothelial cells. J Lab Clin Med 1982; 100: 526-32.
    PubMedSearch in Google Scholar
  • 64 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: 3171-84.
    CrossrefPubMedSearch in Google Scholar
  • 65 Vehar GA, Davie EW. Preparation and properties of bovine factor VIII (antihemophilic factor). Biochemistry 1980; 19: 401-10.
    CrossrefPubMedSearch in Google Scholar
  • 66 von Willebrand EA. Hereditär Pseudohemofili. Finska Läk Sällsk Handl 1926; 68: 87-112.
    PubMedSearch in Google Scholar
  • 67 von Willebrand EA, Jürgens R. Über ein neues vererbbares Blutungsübel: die konstitutionelle Thrombpathie. Dtsch Arch Klin Med 1933; 175: 453-83.
    PubMedSearch in Google Scholar
  • 68 Wagner DD, Marder VJ. Biosynthesis of von Willebrand protein by human endothelial cells. Identification of a large precursor polypeptide chain. J Biol Chem 1983; 258: 2065-7.
    PubMedSearch in Google Scholar
  • 69 Wagner DD, Marder VJ. Biosynthesis of von Willebrand protein by human endothelial cells: processing steps and their intracellular localization. J Cell Biol 1984; 99: 2123-30.
    CrossrefPubMedSearch in Google Scholar
  • 70 Wagner DD, Mayadas T, Marder VJ. Initial glycosylation and acidic pH in the Golgi apparatus are required for multimerization of von Willebrand factor. J Cell Biol 1986; 102: 1320-4.
    CrossrefPubMedSearch in Google Scholar
  • 71 Wahlbert TB, Blombäck M, Ruggeri ZM. Differences between heterozygous dominant and recessive von Willebrand’s disease type I expressed by bleeding symptoms and combinations of factor VIII variables. Thromb Haemost 1983; 50: 864-8.
    Thieme ConnectPubMedSearch in Google Scholar
  • 72 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 membrane Glycoprotein IB-IX receptor. Proc Natl Acad Sci USA 1991; 88: 2946-50.
    CrossrefPubMedSearch in Google Scholar
  • 73 Zhang ZP, Lindstedt M, Falk G, Blombäck M, Egberg N, Anvret M. Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I. Am J Hum Genet 1992; 51: 850-8.
    PubMedSearch in Google Scholar
  • 74 Zhang ZP, Falk G, Blombäck M, Egberg N, Anvret M. A single cytosine deletion in exon 18 of the von Willebrand factor gene is the most common mutation in Swedish vWD type III patients. Hum Mol Genet 1992; 01: 757-8.
    PubMedSearch in Google Scholar
  • 75 Zimmerman TS, Ratnoff OD, Powell AE. Immunologic differentiation of classic hemophilia (factor 8 deficiency) and von Willebrand’s disease, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and on an acquired circulating anticoagulant against antihemophilic factor. J Clin Invest 1971; 50: 244-54.
    CrossrefPubMedSearch in Google Scholar
  • 76 Zucker MB, Broekman MJ, Kaplan KL. Factor VUI-related antigen in human blood platelets. Localization and release by thrombin and collagen. J Lab Clin Med 1979; 94: 675-82.
    PubMedSearch in Google Scholar