scholarly journals Characterization of Von Willebrand Factor Multimer Structure in Patients With Severe Aortic Stenosis

2017 ◽  
Vol 24 (3) ◽  
pp. 496-501 ◽  
Author(s):  
Joerg Kellermair ◽  
Helmut W. Ott ◽  
Michael Spannagl ◽  
Josef Tomasits ◽  
Juergen Kammler ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Aortic Stenosis ◽  
Von Willebrand Factor ◽  
Severe Aortic Stenosis ◽  
Von Willebrand Disease ◽  
Acquired Von Willebrand Syndrome ◽  
Triplet Structure ◽  
Von Willebrand ◽  
Willebrand Factor

Acquired von Willebrand syndrome (AVWS) associated with severe aortic stenosis (AS) has been frequently subclassified into a subtype 2A based on the deficiency of high-molecular-weight (HMW) multimers as it is seen in inherited von Willebrand disease (VWD) type 2A. However, the multimeric phenotype of VWD type 2A does not only include an HMW deficiency but also a decrease in intermediate-molecular-weight (IMW) multimers and an abnormal inner triplet band pattern. These additional characteristics have not been evaluated in AVWS associated with severe AS. Therefore, we recruited N = 31 consecutive patients with severe AS and performed a high-resolution Western blot with densitometrical band quantification to characterize the von Willebrand factor (VWF) multimeric structure and reevaluate the AVWS subtype classification. Study patients showed an isolated HMW VWF multimer deficiency without additional abnormalities of the IMW portions and the inner triplet structure in 65%. In conclusion, the multimeric pattern of AVWS associated with severe AS does neither resemble that seen in AVWS type 2A nor that seen in inherited VWD type 2A. Therefore, a subclassification into a type 2A should not be used.

Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation in patients with aortic stenosis

2010 ◽  
Vol 103 (02) ◽  
pp. 408-414 ◽  
Author(s):  
Roza Badr Eslam ◽  
Alexandra Schneller ◽  
Alexandra Kaider ◽  
Daniela Koren ◽  
Beate Eichelberger ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Aortic Stenosis ◽  
Valve Replacement ◽  
Platelet Function ◽  
Von Willebrand Factor ◽  
Severe Aortic Stenosis ◽  
High Shear ◽  
Acquired Von Willebrand Syndrome ◽  
Von Willebrand ◽  
Willebrand Factor

SummarySevere aortic stenosis is associated with a haemostatic abnormality that resembles acquired von Willebrand syndrome type 2. It is assumed that high shear conditions render large von Willebrand factor (VWF) multimers accessible to cleavage by ADAMTS-13. However, whether loss of these large multimers affects platelet function by impairing adhesion, aggregate formation, or both has not been evaluated in clinical studies. We prospectively enrolled 47 patients with severe aortic stenosis, and studied them prior to aortic valve surgery and at a median of six months after valve replacement. We investigated levels of large VWF multimers, platelet function under high shear conditions, and residual response to suboptimal concentrations of ADP to express P-selectin. As expected, there was a significant reduction of VWF large multimers before surgery that resolved thereafter in most patients (p<0.0001). The closure time of the ADP cartridge of the PFA-100 was also corrected in most patients after the operation (p<0.0001). We used the cone and plate(let) analyser Impact-R to differentiate between adhesion and aggregation. Both adhesion (p=0.03) and ADP-inducible platelet aggregation (p=0.002) improved considerably after valve replacement. Consequently, ADP-inducible expression of P-selectin was higher after valve replacement (p=0.001). We conclude that reduced levels of large VWF multimers associated with aortic stenosis lead to impairment of both adhesion and, especially, ADP-inducible platelet aggregation.

Diagnosis of Subtype 2B von Willebrand Disease in a Patient with 2A Phenotype of Plasma von Willebrand Factor

1995 ◽  
Vol 73 (04) ◽  
pp. 610-616 ◽  
Author(s):  
Christine Gaucher ◽  
Christophe de Romeuf ◽  
Michéle Rauïs-Morret ◽  
Francis Corazza ◽  
Pierre Fondu ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Diagnosis And Classification ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType 2A of von Willebrand disease refers to qualitative variants with decreased platelet dependent function that is associated with the absence of high molecular weight forms of von Willebrand factor (vWF) multimers. Type 2B refers to qualitative variants with increased affinity for platelet glycoprotein lb. In this report we describe the study of a patient who has been previously diagnosed as having subtype 2A von Willebrand disease (vWD), because she had no heightened ristocetin-induced platelet aggregation, no large and intermediate molecular weight von Willebrand factor (vWF) multimers in plasma, and no increase in plasma vWF capacity to bind to normal platelets in the presence of low ristocetin concentrations. The DNA sequencing of the 3’ part of the exon 28 of the vWF gene where most of the subtype 2A mutations have already been identified, did not detect any nucleotide change. At variance, a G to A transition changing the encoded amino acid residue from Val 553 to Met in mature vWF, was found in the 5’ part of this exon. This mutation which has already been found in several unrelated families with 2B vWD and the increased binding of the patient platelet vWF on normal platelets in the presence of low ristocetin concentrations provide evidence for subtype 2B vWD. This study thus illustrates the importance of the molecular characterization of patients in the correct diagnosis and classification of type 2 vWD.

Characterization of Partial Gene Deletions in Type III von Willebrand Disease with Alloantibody Inhibitors

1994 ◽  
Vol 72 (02) ◽  
pp. 180-185 ◽  
Author(s):  
David J Mancuso ◽  
Elodee A Tuley ◽  
Ricardo Castillo ◽  
Norma de Bosch ◽  
Pler M Mannucci ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Pcr Analysis ◽  
Gene Deletions ◽  
Factor Gene ◽  
Type Iii ◽  
Large Deletions ◽  
Von Willebrand ◽  
Willebrand Factor

Summaryvon Willebrand factor gene deletions were characterized in four patients with severe type III von Willebrand disease and alloantibodies to von Willebrand factor. A PCR-based strategy was used to characterize the boundaries of the deletions. Identical 30 kb von Willebrand factor gene deletions which include exons 33 through 38 were identified in two siblings of one family by this method. A small 5 base pair insertion (CCTGG) was sequenced at the deletion breakpoint. PCR analysis was used to detect the deletion in three generations of the family, including two family members who are heterozygous for the deletion. In a second family, two type III vWD patients, who are distant cousins, share an -56 kb deletion of exons 22 through 43. The identification and characterization of large vWF gene deletions in these type III vWD patients provides further support for the association between large deletions in both von Willebrand factor alleles and the development of inhibitory alloantibodies.

Further specificity characterization of von Willebrand factor inhibitors developed in two patients with severe von Willebrand disease

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 116-120 ◽  
Author(s):  
MF Lopez-Fernandez ◽  
R Martin ◽  
C Lopez-Berges ◽  
F Ramos ◽  
N Bosch ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Complex Structure ◽  
Relative Proportion ◽  
Von Willebrand Disease ◽  
Rabbit Antibody ◽  
Human Factor Viii ◽  
Rabbit Polyclonal Antibody ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Circulating inhibitors against von Willebrand factor (vWF) that show the properties of heterologous IgG antibodies have been described in a few patients with severe von Willebrand disease (vWD). The present study provides further characterization of inhibitors from two patients with severe vWD. Inhibitors in both, like polyclonal rabbit antibody, detected all sizes of multimers and the complex structure of each multimer from platelets and plasma of normal individuals as well as from plasma of patients with IIA, IIB, and IIC vWD. Both inhibitors and the rabbit antibody reacted mainly with the intact 225-Kd vWF subunit and the 189-H and 140-Kd fragments in contrast to monoclonal antibodies specific for vWF fragments that detected a higher relative proportion of 176-Kd fragment. Furthermore, all these antibodies recognized fragment III, although one inhibitor and rabbit polyclonal antibody reacted poorly and the other inhibitor did not react at all with reduced fragment II of vWF digested with Staphylococcus aureus V-8 protease. These data suggest that although human inhibitors from severe vWD patients may behave, to some extent, as polyclonal heterologous antibodies against native vWF, the former show striking differences in their target specificity as well as a much broader specificity than that described for human factor VIII inhibitors.

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

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 560-568 ◽  
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.

scholarly journals 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

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 169-175 ◽  
Author(s):  
MR Ledford ◽  
I Rabinowitz ◽  
JE Sadler ◽  
JW Kent ◽  
F Civantos
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Autosomal Dominant ◽  
Disease Type ◽  
Von Willebrand Disease ◽  
Dominant Inheritance ◽  
New Variant ◽  
Von Willebrand ◽  
Willebrand Factor

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.

Singularities of haemorrhagic syndrome in children with native and acquired deficiencies of von Willebrand factor

2013 ◽  
Vol 4 (1) ◽  
pp. 78-85
Author(s):  
Kseniya Ivanovna Pshenichnaya ◽  
Yegor Viktorovich Lyugayev ◽  
Olga Georgiyevna Golovina
Keyword(s):  
Clinical Manifestation ◽  
Von Willebrand Factor ◽  
Clinical Studies ◽  
Clinical Manifestations ◽  
Underlying Disease ◽  
Von Willebrand Disease ◽  
Acquired Von Willebrand Syndrome ◽  
Different Types ◽  
Von Willebrand ◽  
Willebrand Factor

Deficiencies of content in blood and activity of von Willebrand factor can be inborn or acquired with diseases of different nature. Acquired deficiencies of von Willebrand factor or acquired von Willebrand syndrome in children have been described in several clinical studies. This research paper contains data on clinical manifestation and dynamics of haemorrhagic syndrome in 30 children between 13 months and 18 years of age with acquired von Willebrand factor, suffering from different types of pathology. Similarly, clinical manifestations and dynamics of angiostaxis have been studied in 33 children with von Willebrand disease. It has been determined that clinical manifestations of microcirculatory angiostaxis are the same for children from both groups; however, children with acquired von Willebrand syndrome showed dominating limited numbers of haemorrhagical symptoms that were shorter in duration and less intense. Besides, hematomic component of haemorrhagic syndrome was absent. Eventually, accompanied by positive dynamic of the underlying disease, relapses of haemorrhagic syndrome cease, which does not happen in case of the patients with von Willebrand disease.

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