scholarly journals Rapid Restoration of Thrombus Formation and High-Molecular-Weight von Willebrand Factor Multimers in Patients with Severe Aortic Stenosis After Valve Replacement

2016 ◽  
Vol 23 (10) ◽  
pp. 1150-1158 ◽  
Author(s):  
Keigo Yamashita ◽  
Hideo Yagi ◽  
Masaki Hayakawa ◽  
Takehisa Abe ◽  
Yoshihiro Hayata ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Aortic Stenosis ◽  
High Molecular Weight ◽  
Valve Replacement ◽  
Von Willebrand Factor ◽  
Thrombus Formation ◽  
Severe Aortic Stenosis ◽  
Rapid Restoration ◽  
Von Willebrand ◽  
Willebrand Factor

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.

High-molecular-weight von Willebrand Factor multimer ratio differentiates true-severe from pseudo-severe classical low-flow, low-gradient aortic stenosis

2020 ◽  
Vol 21 (10) ◽  
pp. 1123-1130
Author(s):  
Joerg Kellermair ◽  
Sahrai Saeed ◽  
Helmut W Ott ◽  
Juergen Kammler ◽  
Hermann Blessberger ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Aortic Stenosis ◽  
High Molecular Weight ◽  
Von Willebrand Factor ◽  
Imaging Techniques ◽  
Dobutamine Stress ◽  
Low Flow ◽  
Predictive Values ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Aims Upon high wall shear stress, high-molecular-weight (HMW) von Willebrand Factor (VWF) multimers are degraded, thus, HMW VWF multimer deficiency mirrors haemodynamics at the site of aortic stenosis (AS). The aim of the present study was to analyse the role of HMW VWF multimer ratio for subcategorization of classical low-flow, low-gradient (LF/LG) AS. Methods and results Eighty-three patients with classical LF/LG AS were prospectively recruited and HMW VWF multimer pattern was analysed using a densitometric quantification of western blot bands. Patients were subclassified into true-severe (TS) and pseudo-severe (PS) classical LF/LG AS based on dobutamine stress echocardiography (DSE). Positive and negative predictive values (PPV/NPV) of HMW VWF multimer ratio for diagnosis of the TS subtype were calculated. HMW VWF multimer ratio in TS classical LF/LG AS was significantly decreased compared to PS classical LF/LG AS (0.86 ± 0.27 vs. 1.06 ± 0.09, P < 0.001). HMW VWF multimer deficiency occurred exclusively in the TS subtype with an optimal PPV of 1.000 and NPV of 0.379. HMW VWF multimer ratio showed a strong correlation with mean transvalvular pressure gradients during DSE (r = −0.616; P < 0.001). HMW VWF multimer ratio measured at baseline was higher compared to levels measured after DSE (0.87 ± 0.27 vs. 0.84 ± 0.31; P = 0.031) indicating DSE-induced increased proteolysis. Conclusion HMW VWF multimer ratio represents a valuable biomarker for classical LF/LG AS subclassification and mirrors haemodynamics during DSE. HMW VWF multimer ratio identifies the TS subtype without the use of other imaging techniques.

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.

COAGULATION STUDIES IN THROMBOTIC THROMBOCYTOPENIC PURPURA, WITH SPECIAL REFERENCE TO VON WILLEBRAND FACTOR ABNORMALITIES

1987 ◽  
Author(s):  
Hoyu Takahashi ◽  
Wataru Tatewaki ◽  
Tadao Nakamura ◽  
Masaharu Hanano ◽  
Ken Wada ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Thrombus Formation ◽  
Tissue Type ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Plasmin Inhibitor

The profile of blood coagulation and fibrinolysis was studied in detail in 8 patients with thrombotic thrombocytopenic purpura (TTP), who had most of the characteristic findings such as fluctuating neurologic signs, schistocytic hemolytic anemia, marked thrombocytopenia, renal abnormalities and fever. Fibrinogen (2.2-3.6 g/L) and factor XIII levels were normal in all patients, while FDP values were slightly elevated (from below 5 to 4-0 mg/L). Anti thrombin III, alpha 2-plasmin inhibitor and plasminogen were normal in all patients except one with elevated FDP. Alpha 2-macroglobulin was normal as well. Plasmin-alpha 2-plasmin inhibitor complex measured by an enzyme-immunoassay was either normal or marginally elevated. Tissue-type plasminogen activator antigen was elevated to 5.2-14.5 μg/L. Protein C activity and antigen were either normal or elevated, while protein S antigen was decreased in 3 patients. Factor VIII activity and von Willebrand factor antigen (vWf:Ag) and ristocetin cofactor (RCcf) were either normal or elevated, but RCof/vWf:Ag ratio was decreased (mean 0.546 ± SD 0.1876). Crossed immunoelectrophoresis and SDS-agarose gel electrophoresis revealed that the hemostatically most active, high-molecular-weight vWf multimers were absent from or relatively decreased in TTP plasma. In addition, a vWf fragment with a faster mobility than the major vWf was demonstrated in some patients. Histidine-rich glycoprotein and fibronectin were decreased in 3 and 4 patients, respectively. Most of these abnormal findings were nearly normalized in remission. Although the pathogenesis of TTP is still uncertain, these results indicate that in contrast to disseminated intravascular coagulation, the intravascular generation of thrombin and plasmin was minimal in TTP, and suggest that the high-molecular-weight multimer vWf and fibronectin are consumed probably due to their participation in platelet thrombus formation in addition to platelet aggregating factor.

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.

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