scholarly journals Von Willebrand Factor in Health and Disease

2021 ◽  
Vol 15 (3) ◽  
pp. 201-218
Author(s):  
P. P. Avdonin ◽  
N. V. Tsvetaeva ◽  
N. V. Goncharov ◽  
E. Yu. Rybakova ◽  
S. K. Trufanov ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Thrombus Formation ◽  
The Body ◽  
Pathological Conditions ◽  
Activated Platelets ◽  
History Of ◽  
Health And Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract— Von Willebrand factor (vWF), the key component of hemostasis, is synthesized in endothelial cells and megakaryocytes and released into the blood as high molecular weight multimeric glycoproteins weighing up to 20 million Daltons. Blood plasma metalloprotease ADAMTS13 cleaves ultra-large vWF multimers to smaller multimeric and oligomeric molecules. The vWF molecules attach to the sites of damage at the surface of arterioles and capillaries and unfold under conditions of shear stress. On the unfolded vWF molecule, the regions interacting with receptors on the platelet membrane are exposed. After binding to the vWF filaments, platelets are activated; platelets circulating in the vessels are additionally attached to them, leading to thrombus formation, blocking of microvessels, and cessation of bleeding. This review describes the history of the discovery of vWF, presents data on the mechanisms of vWF secretion and its structure, and characterizes the processes of vWF metabolism in the body under normal and pathological conditions.

Comparison of Tryptic Fragments of von Willebrand Factor Involved in Binding to Thrombin-Activated Platelets with Fragments Involved in Ristocetin-Induced Binding and Binding to Collagen

1986 ◽  
Vol 56 (03) ◽  
pp. 391-396 ◽  
Author(s):  
Wim P M Houdijk ◽  
Jen-pierre Girma ◽  
Jan A van Mourik ◽  
Jan J Sixma ◽  
Dominique Meyer
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Von Willebrand Factor ◽  
Binding Domain ◽  
Large Fragment ◽  
Binding Domains ◽  
Activated Platelets ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Dimensional Electrophoresis

SummaryPreviously we have studied the binding domains on von Willebrand factor (vWF) involved in ristocetin-induced binding to platelets (ristocetin binding domain, RBD) and in the binding of vWF to collagen (collagen binding domain, CBD) using tryptic fragments of 125I-labelled vWF (21, 23). We have also reported on the RBD, CBD and the domain on vWF involved in the binding to thrombin activated platelets (thrombin binding domain, TBD) using vWF-fragments prepared by digestion with staphylococcal protease V8 (25).In the present study, we have digested 125I-vWF with TPCK-trypsin and we have performed at various times of digestion immuno-precipitation with Mab 9, the antibody inhibiting binding of vWF to thrombin activated platelets. The data were compared with the immunoprecipitation patterns simultaneously obtained with CLB-RAg 35 which inhibits binding of vWF in the presence of ristocetin and with CLB-RAg 201, which inhibits binding of vWF to collagen. At 90 min, Mab 9 and CLB-RAg 201 precipitated similar high molecular weight bands, whereas CLB-RAg 35 precipitated bands at 180 and 120 kDa. After 24 h, Mab 9 precipitated bands at 200, 155, 116 and 85 kDa; CLB-RAg 201 precipitated a band at 48 kDa and CLB-RAg 35 a band at 116 kDa. Two-dimensional electrophoresis demonstrated that the high molecular weight bands, precipitated by Mab 9 and CLB-RAg 201 at 90 min, were identical. The 116 kDa fragment recognized by CLB-RAg 35 had a different subunit composition than the 116 kDa fragment precipitated by Mab 9.These data indicate that there is an early split in the vWF subunit which yields a large fragment, containing the CBD and the TBD, and a smaller fragment with the RBD. Later, there is a split in the large fragment and the CBD and the TBD are separated. Comparison with data obtained with Staph protease V8 indicate that the CBD is located between the RBD and TBD.

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.

Lack of Stability of Aggregates after Thrombin-Induced Reaggregation of Thrombin-Degranulated Platelets

1992 ◽  
Vol 67 (04) ◽  
pp. 453-457 ◽  
Author(s):  
Raelene L Kinlough-Rathbone ◽  
Marian A Packham ◽  
Dennis W Perry ◽  
J Fraser Mustard ◽  
Marco Cattaneo
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Aggregate Stability ◽  
Relative Importance ◽  
Platelet Aggregates ◽  
The Stability ◽  
Von Willebrand ◽  
Induced Aggregation ◽  
Willebrand Factor

SummaryThe stability of platelet aggregates is influenced by the extent of the release of granule contents; if release is extensive and aggregation is prolonged, deaggregation is difficult to achieve. The relative importance of the contributions of released substances to aggregate stability are not known, although stable thrombin-induced aggregates form in platelet-rich plasma from patients with barely detectable plasma or platelet fibrinogen, and ADP stabilizes thrombin-induced aggregates of platelets from patients with delta storage pool deficiency which otherwise deaggregate more readily than normal platelets. We degranulated platelets with thrombin (0.9 U/ml caused greater than 90% loss of delta and alpha granule contents) and recovered them as individual platelets in fresh medium. The degranulated platelets were reaggregated by thrombin (2 U/ml). To prevent continuing effects of thrombin, FPRCH2C1 was added when thrombin-induced aggregation of thrombin-degranulated platelets reached its maximum. EDTA (5 mM) or EGTA (5 mM) added at maximum aggregation did not deaggregate these platelets, indicating that the stability of these aggregates does not depend on Ca2+ in the medium. Whereas with control platelets a combination of PGE1 (10 μM) and chymotrypsin(10 U/ml) was required for deaggregation, with thrombin-degranulated platelets either PGE1 or chymo-trypsin alone caused extensive deaggregation. The rate and extent of deaggregation of thrombin-degranulated platelets by a combination of PGE1 and chymotrypsin was greater than with control platelets.Electron microscope gold immunocytochemistry using antihuman fibrinogen IgG, anti-von Willebrand factor and anti-fibronectin showed a) that fibrinogen in the vacuoles of degranulated platelets was visible at focal points of platelet contact in the aggregates, but that large areas of platelet contact had no fibrinogen detectable between them; and b) in comparison to fibrinogen, little fibronectin or von Willebrand factor (vWf) was detectable in the platelets.Since the linkages between thrombin-degranulated platelets reaggregated by thrombin can be disrupted either by raising cAMP (thus making glycoprotein IIb/IIIa unavailable) or by proteolysis, these linkages are less stable than those formed between normal platelets. It might therefore be expected that platelets that take part in thrombus formation and then recirculate are likely to form less stable thrombi than platelets that have not released their granule contents.

scholarly journals Immunohistological Evaluation of Von Willebrand Factor in the Left Atrial Endocardium and Atrial Thrombi from Cats with Cardiomyopathy

Animals ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1240
Author(s):  
Wan-Ching Cheng ◽  
Lois Wilkie ◽  
Tsumugi Anne Kurosawa ◽  
Melanie Dobromylskyj ◽  
Simon Lawrence Priestnall ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Left Atrial ◽  
Thrombus Formation ◽  
Clinical Signs ◽  
Naturally Occurring ◽  
Feline Model ◽  
Von Willebrand ◽  
And Control ◽  
Endocardial Endothelium ◽  
Willebrand Factor

Aortic thromboembolism (ATE) occurs in cats with cardiomyopathy and often results in euthanasia due to poor prognosis. However, the underlying predisposing mechanisms leading to left atrial (LA) thrombus formation are not fully characterised. von Willebrand Factor (vWF) is a marker of endothelium and shows increased expression following endothelial injury. In people with poor LA function and LA remodelling, vWF has been implicated in the development of LA thrombosis. In this study we have shown (1) the expression of endocardial vWF protein detected using immunohistofluorescence was elevated in cats with cardiomyopathy, LA enlargement (LAE) and clinical signs compared to cats with subclinical cardiomyopathy and control cats; (2) vWF was present at the periphery of microthrombi and macrothrombi within the LA where they come into contact with the LA endocardium and (3) vWF was integral to the structure of the macrothrombi retrieved from the atria. These results provide evidence for damage of the endocardial endothelium in the remodelled LA and support a role for endocardial vWF as a pro-thrombotic substrate potentially contributing to the development of ATE in cats with underlying cardiomyopathy and LAE. Results from this naturally occurring feline model may inform research into human thrombogenesis.

Levels of von Willebrand factor and ADAMTS13 determine clinical outcome after cardioversion for atrial fibrillation

2011 ◽  
Vol 105 (03) ◽  
pp. 435-443 ◽  
Author(s):  
Veronika Bruno ◽  
Rudolf Jarai ◽  
Susanne Gruber ◽  
Thomas Höchtl ◽  
Ivan Brozovic ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Independent Predictor ◽  
Thrombus Formation ◽  
Critical Role ◽  
Inverse Correlation ◽  
Von Willebrand ◽  
Rhythm Stability ◽  
Willebrand Factor

SummaryVon Willebrand factor (vWF) plays an essential role in platelet adhesion and thrombus formation. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 antigen levels compared to controls. Little is known about vWF and ADAMTS13 in AF patients treated with cardioversion (CV). Thus we investigated the alterations of plasma vWF and ADAMTS13 after CV and evaluated the predictive value of these parameters for recurrence of AF. In this observational study we determined plasma levels of vWF and ADAMTS13 in 77 patients before and immediately after CV, as well as 24 hours (h) and six weeks thereafter, by means of commercially available assays. The vWF/ ADAMTS13-ratio was significantly elevated immediately after CV (p=0.02) and 24 h after CV (p=0.002) as compared to baseline levels. ADAMTS13, 24 h after CV, exhibited a significant association with recurrence of AF (HR: 0.97; p=0.037). Accordingly, tertiles of ADAMTS13 showed a stepwise inverse correlation with the risk of recurrent AF (HR: 0.50; p=0.009). After adjustment for confounders, ADAMTS13 remained significant as an independent predictor of recurrent AF (HR: 0.61; p=0.047). Similarly, the vWF/ADAMTS13-ratio, 24 h after CV, was associated with rhythm stability and remained an independent predictor of recurrent AF (HR: 1.88; p=0.028). The regulation of vWF and its cleaving protease ADAMTS13 after CV might play a critical role in producing a pro-thrombotic milieu immediately after CV for AF. Since ADAMTS13 plasma concentration and the vWF/ADAMTS13-ratio are independently associated with rhythm stability, these indexes might be used for prediction of recurrence of AF.

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.

Sign in / Sign up

Export Citation Format

Share Document