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Thromb Haemost 1996; 76(04): 598-602
DOI: 10.1055/s-0038-1650628
Original Article
Schattauer GmbH Stuttgart

Results of a Screening for von Willebrand Disease Type 2N in Patients with Suspected Haemophilia A or von Willebrand Disease Type 1

Reinhard Schneppenheim
1   The Universitats-Kinderklinik Kiel, Germany
,
Ulrich Budde
2   Allgemeines Krankenhaus Harburg, Germany
,
Sonja Krey
1   The Universitats-Kinderklinik Kiel, Germany
,
Elke Drewke
2   Allgemeines Krankenhaus Harburg, Germany
,
Frauke Bergmann
3   Kinderklinik der Medizinischen Hochschule Hannover, Germany
,
Eberhard Lechler
4   Medizinische Universitats-Klinik Koln, Germany
,
Johannes Oldenburg
5   Institut fur Humangenetik der Universitat Wurzburg, Germany
,
Rainer Schwaab
6   Institut für Experimentelle Hamatologie und Transfusionsmedizin, Universitats-Klinik Bonn, Germany
› Author Affiliations
Further Information

Publication History

Received: 28 February 1996

Accepted after revision17 June 1996

Publication Date:
26 July 2018 (online)

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Summary

A screening program for the detection of patients with von Willebrand disease type 2N (VWD 2N) was carried out in 177 unrelated patients previously diagnosed with haemophilia A and in 199 unrelated patients with VWD type 1 in comparison. By measuring the factor VIII (FVIII) binding capacity of von Willebrand factor (VWF), we detected 13 patients with VWD 2N within 8 unrelated families. The former diagnosis has been haemophilia A in 5 index patients, and VWD in the remaining 3. Included in this study were 14 patients with suspected haemophilia A, whose molecular analysis for mutations in the FVIII gene was unsuccessful. Five of them had VWD 2N. In all patients with the VWD 2N phenotype we were able to identify specific molecular defects in the corresponding DNA sequence of the FVIII binding domain of VWF. The most common defect was R91Q. Four patients from 4 families were homozygous for R91Q, six patients from 3 families were compound heterozygous for R91Q and a silent yet unidentified allele. The VWD 2N phenotype of father, daughter, and son in one family, was based on 2 different genotypes, compound heterozygosity for R91Q and VWD type 1 in the father and the daughter, and homozygosity for R91Q in the son. Two patients from one family were compound heterozygous for T28M and ΔC2680-2685 in exon 18, and one patient was compound heterozygous for a novel candidate missense mutation in exon 18 (E24K) and ΔC2680-2685 in exon 18 which is regarded the most common defect causing severe VWD type 3. FVIII:C values of 0.07 and 0.14 IU/ml were observed in patients with the genotype T28MIΔC2680-2685 whereas in patients being homozygous or compound heterozygous for R91Q, FVIII:C was 0.19 ° 0.071 IU/ml. In contrast to the other genotypes, E24KIΔC2680-2685 is correlated with a more severe haemophilic phenotype with a FVIII residual activity of only 0.01-0.02 IU/ml. This emphasizes the need for inclusion of the factor VIII binding assay in the diagnostic workup of suspected haemophilia A.

 

  • References

  • 1 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
  • 2 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
  • 3 Mazurier C. von Willebrand disease masquerading as haemophilia A. Thromb Haemost 1992; 67: 391-396
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Lopez Fernandez MF, Blanco Lopez MJ, Castineira MP, Battle J. Further evidence for recessive inheritance of von Willebrand disease with abnormal binding of von Willebrand factor to factor VIII. Am J Haematol 1992; 40: 20-27
    CrossrefPubMedGoogle Scholar
  • 5 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
    PubMedGoogle Scholar
  • 6 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
    PubMedGoogle Scholar
  • 7 Takahashi Y, Kalafatis M, Girma JP, Sewerin K, Andersson LO, Meyer D. Localization of a factor VIII binding domain on a 34 kilodalton fragment of the N-terminal portion of von Willebrand factor. Blood 1987; 70: 1679-1682
    PubMedGoogle Scholar
  • 8 Kroner PA, Foster PA, Fahs SA, Montgomery RR. The defective interaction between von Willebrand factor and factor VIII in a patient with type 1 von Willebrand disease is caused by substitution of Argl9 and His54 in mature von Willebrand factor. Blood 1996; 87: 1013-1021
    PubMedGoogle Scholar
  • 9 Gaucher C, Jorieux S, Mercier B, Oufkir D, Mazurier C. The “Normandy” variant of von Willebrand disease: characterization of a point mutation in the von Willebrand factor gene. Blood 1991; 77: 1937-1941
    PubMedGoogle Scholar
  • 10 Gaucher C, Mercier B, Jorieux S, Oufkir D, Mazurier C. Identification of two point mutations in the von Willebrand factor gene of three families with the “Normandy” variant of von Willebrand disease. J Haematol 1991; 78: 506-514
    CrossrefPubMedGoogle Scholar
  • 11 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: 13499-13502
    PubMedGoogle Scholar
  • 12 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
  • 13 Peerlinck K, Eikenboom JC, Ploos van Amstel HK, Sangtawesin W, Amout J, Reitsma PH, Vermylen J, Briet E. A patient with von Willebrand’s disease characterized by a compound heterozygosity for a substitution of Arg854 by Gin in the putative factor-VUI-binding domain of von Willebrand factor (vWF) on one allele and very low levels of mRNA from the second vWF allele. Br J Haematol 1992; 80: 358-363
    CrossrefPubMedGoogle Scholar
  • 14 Lavergne JM, Piao Y, Ribba AS, Girma JP, Siguret V, Pietu G, Boyer-Neumann C, Schandelong A, Bahnak BR, Meyer D. Functional analysis of the Arg91Gln substitution in the factor VIII binding domain of von Wille-brand factor demonstrates variable phenotypic expression. Thromb Haemost 1993; 70: 691-696
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Siguret V, Lavergne JM, Cherel G, Boyer-Neumann C, Ribba AS, Bahnak BR, Meyer D, Pietu G. A novel case of compound heterozygosity with “Normandy’Vtype I von Willebrand disease (vWD). Direct demonstration of the segregation of one allele with a defective expression at the mRNA level causing type I vWD. Hum Genet 1994; 93: 95-102
    PubMedGoogle Scholar
  • 16 Schwaab R, Oldenburg J, Schwaab U, Johnson DJD, Schmidt W, Olek K, Brackmann H-H, Tuddenham EGD. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Brit J Haematol 1995; 91: 458-464
    CrossrefPubMedGoogle Scholar
  • 17 Cejka J. Enzyme immunoassay for factor VUI-related antigen. Clin Chem 1982; 28: 1356-1358
    PubMedGoogle Scholar
  • 18 Schneppenheim R, Plendl H, Budde U. Luminography - an alternative assay for detection of von Willebrand factor multimers. Thromb Haemost 1988; 60: 133-136
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Ruggeri ZM, Zimmerman TS. The complex multimeric composition of factor VUI/von Willebrand factor. Blood 1981; 57: 1140-1143
    PubMedGoogle Scholar
  • 20 Nishino S, Nishino M, Nishimura T, Miura S, Sugimoto M, Yoshioka A. A quantitative assay for factor VIII binding capacity of von Willebrand factor in plasma. Thromb Haemost 1995; 73: 1173
    PubMedGoogle Scholar
  • 21 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: 487-491
    CrossrefPubMedGoogle Scholar
  • 22 Lowe T, Sharefkin J, Yang SQ, Dieffenbach CW. A computer program for selection of oligonucleotide primers for polymerase chain reactions. Nucleic Acids Res 1990; 18: 1757-1761
    CrossrefPubMedGoogle Scholar
  • 23 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
    CrossrefPubMedGoogle Scholar
  • 24 Vieira J, Messing J. Production of single-stranded plasmid DNA. Meth Enzymol 1987; 153: 3-11
    PubMedGoogle Scholar
  • 25 Budowle B, Chakrabarty R, Giusti AM, Eisenberg AJ, Allen RC. Analysis of the VNTR locus DIS80 by the PCR followed by high resolution PAGE. Am J Hum Genet 1991; 48: 137-144
    PubMedGoogle Scholar
  • 26 Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71: 520-525
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Myers RM, Maniatis T, Lerman LS. Detection and localisation of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol 1987; 155: 501-527
    PubMedGoogle Scholar
  • 28 Cotton RG, Rodrigues NR, Campbell RD. Reactivity of cytosine and thymine in single-base pair mismatches with hydroxylamine and osmiumtetroxyde and its application to the study of mutations. Proc Natl Acad Sci USA 1988; 85: 43397-43401
    PubMedGoogle Scholar
  • 29 David D, Moreira J, Lalloz MRA, Rosa HAV, Schwaab R, Morais S, Diniz MJ, de Deus G, Campos M, Lavinha J, Johnson D, Tuddenham EGD. Analysis of essential sequences of the factor VIII gene in twelve haemophilia A patients by single stranded conformational polymorphism. Blood Coagul Fibrinol 1993; 5: 257-264
    PubMedGoogle Scholar
  • 30 Schneppenheim R, Thomas KB, Krey S, Budde U, Jessat U, Sutor AH, Zieger B. Identification of a candidate missense mutation in a family with von Willebrand disease type IIC. Hum Genet 1995; 95: 681-686
    PubMedGoogle Scholar
  • 31 Kunkel GR, Graham JB, Fowlkes DM, Lord ST. Rsal polymorphism in von Willebrand factor (vWF) at codon 789. Nucleic Acids Res 1990; 18: 4961
    PubMedGoogle Scholar
  • 32 Mercier B, Gaucher C, Mazurier C. An MspI polymorphism in the von Willebrand factor gene. Nucleic Acids Res 1990; 18: 7467
    PubMedGoogle Scholar
  • 33 Donner M, Holmberg L, Kristoffersson AC, Nilsson IM. An Hphl-polymor-phism in exon 28 of the von Willebrand factor gene, and its frequency among patients with various forms of von Willebrand’s disease. Br J Haematol 1991; 78: 403-407
    CrossrefPubMedGoogle Scholar
  • 34 Peake IR, Bowen D, Bignell P, Liddell MB, Sadler JE, Standen G, Bloom AL. Family studies and prenatal diagnosis in severe von Willebrand disease by polymerase chain reaction amplification of a variable number tandem repeat region of the von Willebrand factor gene. Blood 1990; 76: 555-561
    PubMedGoogle Scholar
  • 35 Ploos van Amstel HK, Reitsma PH. Tetranucleotide repeat polymorphism in the vWF gene. Nucleic Acids Res 1990; 18: 4957
    PubMedGoogle Scholar
  • 36 Zhang ZP, Falk G, Blomback 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; 1: 767-798
    CrossrefPubMedGoogle Scholar
  • 37 Schneppenheim R, Krey S, Bergmann F, Bock D, Budde U, Lange M, Linde R, Mittler U, Meili E, Mertes G, Olek K, Plendl H, Simeoni E. Genetic heterogeneity of severe von Willebrand disease type III in the German population. Hum Genet 1994; 94: 640-652
    PubMedGoogle Scholar
  • 38 Bird AP. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 1980; 8: 1499-1504
    CrossrefPubMedGoogle Scholar
  • 39 Mazurier C, Gaucher C, Jorieux S, Goudemand M. Biological effect of desmopressin in eight patients with type 2N (“Normandy”) von Willebrand disease. Collaborative Group. Br J Haematol 1994; 88: 849-854
    CrossrefPubMedGoogle Scholar