New variant of von Willebrand disease type II with markedly increased levels of von Willebrand factor antigen and dominant mode of inheritance: von Willebrand disease type IIC Miami

A variant of von Willebrand disease (vWD) was identified in six members of a kindred spanning four generations. The proband was a 46-year-old woman with a lifelong history of bleeding, a prolonged bleeding time (> 15 minutes), markedly elevated von Willebrand factor (vWF) antigen (vWF:Ag = 2.09 U/mL), slightly reduced ristocetin cofactor activity, and a plasma vWF multimer pattern similar to that of vWD type IIC. Similar findings were observed in her three children, mother, and brother. In affected family members, platelet and plasma vWF multimer patterns were discrepant with higher molecular weight multimers observed in platelet vWF. Following a 1-Des-amino-8-D-arginine vasopressin (DDAVP) challenge, the proband failed to normalize her bleeding time even though vWF: Ag rose by 70% and higher molecular weight multimers were increased slightly. Genetic studies were consistent with autosomal dominant inheritance of a mutation within the vWF gene. By sequencing of cloned genomic DNA, mutations were excluded in exons 4, 5, 14, and 15, which encode regions of the vWF propeptide proposed to be important in multimer biosynthesis. Mutations also were excluded in exons 28 to 31, which encompass the known mutations that cause vWD types IIA, IIB, and B. This new variant of vWD, characterized by autosomal dominant inheritance, a qualitative defect that resembles vWD type IIC, and increased plasma vWF:Ag, was tentatively designated vWD type IIC Miami.

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High-resolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (type IC)

Blood ◽

10.1182/blood.v66.6.1423.1423 ◽

1985 ◽

Vol 66 (6) ◽

pp. 1423-1429 ◽

Cited By ~ 44

Author(s):

G Ciavarella ◽

N Ciavarella ◽

S Antoncecchi ◽

D De Mattia ◽

P Ranieri ◽

...

Keyword(s):

High Resolution ◽

Von Willebrand Factor ◽

Bleeding Time ◽

Von Willebrand Disease ◽

Structural Abnormality ◽

Type I ◽

New Variant ◽

Recurrent Epistaxis ◽

Von Willebrand ◽

Willebrand Factor

Abstract In Type I von Willebrand disease, the whole series of von Willebrand factor (vWF) multimers is present in plasma, but all are decreased in quantity. No structural abnormality of individual multimers has been demonstrated so far in these patients. We now describe five individuals, from two unrelated families, who had this form of the disease and in whom the complex banding pattern of each vWF multimer was markedly abnormal. Inheritance was autosomal dominant and the clinical expression was mild. A bleeding history was elicited in three of the patients and included recurrent epistaxis, menometrorrhagia, and bleeding following tooth extraction. Replacement therapy had never been required. Although vWF levels in plasma were within the normal range in all of them, the ristocetin cofactor activity was decreased in four, and the bleeding time was prolonged in three. Analysis of vWF multimeric structure by agarose gel electrophoresis, including a newly developed high-resolution technique, demonstrated that the main band of each multimer was present, but a second, well-defined band always seen in normal individuals was missing in the patients. Two additional bands had altered mobility and were less well defined than in normal subjects, and a fifth, less intense band was also undetectable in the patients. Treatment with 1-deamino-8-D-arginine vasopressin (DDAVP) was assessed in two patients. It caused the circulating levels of vWF to increase and correct the bleeding time, but did not alter the structural abnormality. This study describes, therefore, a new variant form of Type I von Willebrand disease with aberrant structure of individual repeating multimers and an associated functional abnormality of vWF. In keeping with previously accepted terminology, the designation of Type IC von Willebrand disease has been adopted for this new variant.

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High-resolution analysis of von Willebrand factor multimeric composition defines a new variant of type I von Willebrand disease with aberrant structure but presence of all size multimers (type IC)

Blood ◽

10.1182/blood.v66.6.1423.bloodjournal6661423 ◽

1985 ◽

Vol 66 (6) ◽

pp. 1423-1429

Author(s):

G Ciavarella ◽

N Ciavarella ◽

S Antoncecchi ◽

D De Mattia ◽

P Ranieri ◽

...

Keyword(s):

High Resolution ◽

Von Willebrand Factor ◽

Bleeding Time ◽

Von Willebrand Disease ◽

Structural Abnormality ◽

Type I ◽

New Variant ◽

Recurrent Epistaxis ◽

Von Willebrand ◽

Willebrand Factor

In Type I von Willebrand disease, the whole series of von Willebrand factor (vWF) multimers is present in plasma, but all are decreased in quantity. No structural abnormality of individual multimers has been demonstrated so far in these patients. We now describe five individuals, from two unrelated families, who had this form of the disease and in whom the complex banding pattern of each vWF multimer was markedly abnormal. Inheritance was autosomal dominant and the clinical expression was mild. A bleeding history was elicited in three of the patients and included recurrent epistaxis, menometrorrhagia, and bleeding following tooth extraction. Replacement therapy had never been required. Although vWF levels in plasma were within the normal range in all of them, the ristocetin cofactor activity was decreased in four, and the bleeding time was prolonged in three. Analysis of vWF multimeric structure by agarose gel electrophoresis, including a newly developed high-resolution technique, demonstrated that the main band of each multimer was present, but a second, well-defined band always seen in normal individuals was missing in the patients. Two additional bands had altered mobility and were less well defined than in normal subjects, and a fifth, less intense band was also undetectable in the patients. Treatment with 1-deamino-8-D-arginine vasopressin (DDAVP) was assessed in two patients. It caused the circulating levels of vWF to increase and correct the bleeding time, but did not alter the structural abnormality. This study describes, therefore, a new variant form of Type I von Willebrand disease with aberrant structure of individual repeating multimers and an associated functional abnormality of vWF. In keeping with previously accepted terminology, the designation of Type IC von Willebrand disease has been adopted for this new variant.

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A new variant of von willebrand disease (type II I) with a normal degree of proteolytic cleavage of von Willebrand factor

Thrombosis Research ◽

10.1016/0049-3848(92)90165-7 ◽

1992 ◽

Vol 65 (3) ◽

pp. 343-351 ◽

Cited By ~ 8

Author(s):

G. Castaman ◽

F. Rodeghiero ◽

A. Lattuada ◽

P.M. Mannucci

Keyword(s):

Von Willebrand Factor ◽

Proteolytic Cleavage ◽

Disease Type ◽

Von Willebrand Disease ◽

Type Ii ◽

Normal Degree ◽

New Variant ◽

Von Willebrand ◽

Willebrand Factor

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The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651575 ◽

1993 ◽

Vol 69 (02) ◽

pp. 173-176 ◽

Cited By ~ 5

Author(s):

Anna M Randi ◽

Elisabetta Sacchi ◽

Gian Carlo Castaman ◽

Francesco Rodeghiero ◽

Pier Mannuccio Mannucci

Keyword(s):

Von Willebrand Factor ◽

Autosomal Dominant ◽

Genetic Defect ◽

Von Willebrand Disease ◽

Type I ◽

Bleeding Tendency ◽

Factor Gene ◽

Low Levels ◽

Von Willebrand ◽

Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

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Polymorphism in the promoter region of von Willebrand factor gene and von Willebrand disease type 1

Genetics and Molecular Biology ◽

10.1590/s1415-47572003000400001 ◽

2003 ◽

Vol 26 (4) ◽

pp. 397-401 ◽

Cited By ~ 3

Author(s):

Daniel Simon ◽

Eliane Bandinelli ◽

Israel Roisenberg

Keyword(s):

Von Willebrand Factor ◽

Promoter Region ◽

Disease Type ◽

Von Willebrand Disease ◽

Factor Gene ◽

Von Willebrand ◽

Willebrand Factor

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A novel von Willebrand disease–causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion

Blood ◽

10.1182/blood.v96.2.560 ◽

2000 ◽

Vol 96 (2) ◽

pp. 560-568 ◽

Cited By ~ 41

Author(s):

Simon Allen ◽

Adel M. Abuzenadah ◽

Joanna Hinks ◽

Joanna L. Blagg ◽

Turkiz Gursel ◽

...

Keyword(s):

Molecular Weight ◽

High Molecular Weight ◽

Von Willebrand Factor ◽

Family Members ◽

Amino Acid Position ◽

Von Willebrand Disease ◽

Molecular Defect ◽

Wild Type ◽

Von Willebrand ◽

Willebrand Factor

Abstract In this report we describe the molecular defect underlying partial and severe quantitative von Willebrand factor (VWF) deficiencies in 3 families previously diagnosed with types 1 and 3 Von Willebrand-disease. Analysis of the VWF gene in affected family members revealed a novel C to T transition at nucleotide 1067 of the VWF complemetary DNA (cDNA), predicting substitution of arginine by tryptophan at amino acid position 273 (R273W) of pre–pro-VWF. Two patients, homozygous for the R273W mutation, had a partial VWF deficiency (VWF:Ag levels of 0.06 IU/mL and 0.09 IU/mL) and lacked high-molecular weight VWF multimers in plasma. A third patient, also homozygous for the R273W mutation, had a severe VWF deficiency (VWF:Ag level of less than 0.01 IU/mL) and undetectable VWF multimers in plasma. Recombinant VWF having the R273W mutation was expressed in COS-7 cells. Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). Multimer analysis showed that rVWFR273W failed to form high-molecular-weight multimers present in wild-type rVWF. We concluded that the R273W mutation is responsible for the quantitative VWF deficiencies and aberrant multimer patterns observed in the affected family members. To identify factors that may function in the intracellular retention of rVWFR273W, we investigated the interactions of VWF expressed in COS-7 cells with molecular chaperones of the ER. The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells.

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The "Normandy" variant of von Willebrand disease: characterization of a point mutation in the von Willebrand factor gene

Blood ◽

10.1182/blood.v77.9.1937.1937 ◽

1991 ◽

Vol 77 (9) ◽

pp. 1937-1941 ◽

Cited By ~ 47

Author(s):

C Gaucher ◽

S Jorieux ◽

B Mercier ◽

D Oufkir ◽

C Mazurier

Keyword(s):

Amino Acid ◽

Point Mutation ◽

Von Willebrand Factor ◽

Binding Capacity ◽

Von Willebrand Disease ◽

Normal Individuals ◽

New Variant ◽

Functional Defect ◽

Von Willebrand ◽

Willebrand Factor

Abstract We previously reported a functional defect of von Willebrand factor (vWF) in a new variant of von Willebrand disease (vWD) tentatively named vWD “Normandy.” The present work has attempted to characterize the molecular abnormality of this vWF that fails to bind factor VIII (FVIII). The immunopurified vWF from normal and patient's plasma were digested by trypsin and the resulting peptides were compared. The electrophoresis of ““vWF Normandy” showed a shift in the band corresponding to a polypeptide from amino acid 1 to 272. Consequently, we performed the molecular analysis of the portion of the vWF gene of this patient encoding this amino acid sequence. Exons 18–24 were amplified by the use of polymerase chain reaction and their nucleotide sequences corresponding to 1.8 kb were determined. Our analysis showed a point mutation C to T at codon 791, resulting in the substitution of Methionine for Threonine at position 28 of the mature vWF subunit. Because this nucleotide substitution destroyed a Mae II restriction site, this mutation was conveniently sought in various individual DNAs. The patterns obtained were consistent with the homozygous and heterozygous state of this mutation in the patient and in her son, respectively, and with its absence in 28 normal individuals. We conclude that Threonine at position 28 in plasma vWF may be crucial for the conformation and FVIII-binding capacity of its cystine-rich N- terminal domain.

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The mutation Arg (53)----Trp causes von Willebrand disease Normandy by abolishing binding to factor VIII. Studies with recombinant von Willebrand factor

Blood ◽

10.1182/blood.v79.3.563.563 ◽

1992 ◽

Vol 79 (3) ◽

pp. 563-567 ◽

Cited By ~ 30

Author(s):

S Jorieux ◽

EA Tuley ◽

C Gaucher ◽

C Mazurier ◽

JE Sadler

Keyword(s):

Amino Acid ◽

Factor Viii ◽

Von Willebrand Factor ◽

Protein Complex ◽

Von Willebrand Disease ◽

Cho Cell ◽

Fviii Activity ◽

New Variant ◽

Von Willebrand ◽

Willebrand Factor

Abstract von Willebrand factor (vWF) and factor VIII (FVIII) circulate in plasma as a noncovalently linked protein complex. The FVIII/vWF interaction is required for the stabilization of procoagulant FVIII activity. Recently, we reported a new variant of von Willebrand disease (vWD) tentatively named “Normandy,” characterized by plasma vWF that appears to be structurally and functionally normal except that it does not bind FVIII. Three patients from one family were found to be homozygous for a C----T transition at codon 816 converting Arg 53 to Trp in the mature vWF subunit. To firmly establish a causal relationship between this missense mutation and vWD Normandy phenotype, we have characterized the corresponding recombinant mutant vWF(R53W). Expressed in COS-7 cells or CHO cell lines, normal vWF and vWF(R53W) were processed and formed multimers with equal efficiency. However, vWF(R53W) exhibited the same defect in FVIII binding as did plasma vWF from patients with vWD Normandy, confirming that this mutation is responsible for the vWD Normandy phenotype. These results illustrate the importance of Arg 53 of the mature vWF subunit for the binding of FVIII to vWF, and identify an amino acid residue within a disulfide loop not previously known to be involved in this interaction.

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