scholarly journals Von Willebrand factor: structure, properties and role in the process of hemostasis

2020 ◽  
pp. 3-13
Author(s):  
N Shurko ◽  
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Functional Ability ◽  
Platelet Adhesion ◽  
The Other ◽  
Hemostasis System ◽  
Other Hand ◽  
Thrombotic Complications ◽  
Von Willebrand ◽  
Willebrand Factor

The article reviews the scientific papars on the structure, function and biological role of von Willebrand factor (vWF). The vWF mainly was considered as the main factor in the development of bleeding disorders (von Willebrand’s disease). On the other hand, it can be able the cause thrombotic complications through to the functional ability of the factor to stimulate platelet adhesion. The aim of this work was to conduct an analysis of the structure of the factor, its role in the process of hemostasis to determine a border between two opposing processes. Von Willebrand factor is a hemostatic, multimeric glycoprotein, one of the key components of the hemostasis system, taking an active part at startup mechanisms of platelet adhesion at the site of vesselendothelial damage. On the other hand, another important function of vWF is co-factor activity related to coagulation factor VIII (FVIII), which is to stabilize its activity, promoting thrombin activation and preventing the cleavage of the molecule by blood plasma proteinases. The human gene of vWF is localized on the short arm of the 12 chromosome, contains 52 exons and covers approximately 180 kb. VWF is made by endothelial cells and by bone marrow megakaryocytes. The factor is preserved in the Weibel-Palade bodies of endotolial cells and α-granules of platelets. The primary pro-polypeptide consists of 2813 amino acid, of which 2050 form the mature peptide. The molecular weight of vWF is 220 kDa. In bloodstreamv WF circulates as a multimeric protein with a molecular weight from 400 to 20,000 kDa. The synthesized molecule has the next domain structure: D1-D2-D’-D3-A1-A2-A3-D4-C1-C2-C3-C4-C5-C6-CK. Domains are responsible for binding various proteins, including FVIII, fibrin, collagen, heparin, complement components etcetra. Von Willebrand disease (vWD) is the most common autosomal inherited disorder of the hemostasis system (from 0.6 to 2.0% of the population) and the cause is a genetic deficiency of quantitative and/or qualitative abnormal multimeric structure of the vWF molecule. There are three main subtypes of vWD. Quite often in such patients there is a decrease in FVIII activity, as an indirect consequence of changes in vWF. The basic principle of vWD treatment is based on the normalization of vWF and/or FVIII levels by increasing the level of external vWF under the action of desmopressin or the introduction of factor concentrates. In contrast to hereditary vWD, acquired von Willebrand syndrome is a relatively rare acquired bleeding of the blood coagulation system (incidence from 0.04 to 0.13 %) associated with various underlying diseases. For today a significant amount of research devoted to the relationship between vWF and thrombotic complications, that is due functional ability of the factor stimulate platelet adhesion. In particular, there are reports of the following complications in: pneumonia caused by Streptococcus pneumoniae; COVID-19; polycythemia vera; chronic kidney disease etcetra.

Purification of the Porcine Platelet GP IIb-IIIa Complex and the Propolypeptide of von Willebrand Factor

1998 ◽  
Vol 80 (08) ◽  
pp. 302-309 ◽  
Author(s):  
Teresa Royo ◽  
Matilde Vidal ◽  
Lina Badimon
Keyword(s):  
Molecular Weight ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Membrane Glycoproteins ◽  
Single Chain ◽  
Inhibitory Effects ◽  
Adhesive Proteins ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Human Receptor

SummaryPlatelet membrane glycoproteins (GP) are involved in platelet adhesion and aggregation. The glycoprotein IIb-IIIa complex (GP IIbIIIa) is a Ca2+-dependent heterodimer that binds fibrinogen and other adhesive proteins, thereby mediating platelet aggregation and adhesion. We have purified two major glycoproteins from pig platelets by Concanavalin A-Sepharose, Heparin-Sepharose and Sephacryl S-300 HR chromatography (Fitzgerald et al. Anal Biochem, 1985): i) the GP IIb-IIIa complex, GP IIb Mr = 140,000 and GP IIIa a single chain of Mr = 95,000-100,000; and ii) a predominant glycoprotein of high molecular weight, the propolypeptide of von Willebrand factor (Mr = 80,000-100,000). Western-blot analysis of the purified GP IIb-IIIa showed that only certain monoclonal antibodies against the human receptor specifically recognize the porcine complex. Differences between the porcine and human GP IIb-IIIa glycoproteins could partially explain the decreased inhibitory effects of GP IIb/IIIa-antagonists (against the human receptor) in porcine platelets.

scholarly journals Adhesion of platelets to human artery subendothelium: effect of factor VIII-von Willebrand factor of various multimeric composition

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 128-139 ◽  
Author(s):  
JJ Sixma ◽  
KS Sakariassen ◽  
NH Beeser-Visser ◽  
M Ottenhof-Rovers ◽  
PA Bolhuis
Keyword(s):  
Molecular Weight ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Bleeding Time ◽  
Low Molecular Weight ◽  
Perfusion Chamber ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adhesion Factor

Abstract The relationship between the multimeric size of factor VIII-von Willebrand factor (FVIII-vWF) and the support of platelet adhesion to subendothelium was studied in an annular perfusion chamber, employing human renal and umbilical arteries. Commercial factor VIII concentrates containing multimers of low molecular weight that had been shown not to correct the bleeding time upon infusion into patients with von Willebrand's disease did not support platelet adhesion in the perfusion chamber. Cryoprecipitate and two experimental FVIII-vWF concentrates containing multimers of high molecular weight supported platelet adhesion. Factor VIII-vWF purified from cryoprecipitate was subdivided into three fractions of different molecular weights (6.0–14.0, 4.0–9.0, and 3.0–7.5 X 10(6) dalton). These fractions appeared to bind equally well and to be equally effective in supporting platelet adhesion. Factor VIII-vWF with multimers of low molecular weight (0.5–1.5 X 10(6) dalton) were prepared by partial reduction. Binding of FVIII-vWF to subendothelium was not impaired, and the support of platelet adhesion appeared to be more resistant to the effect of reduction than the ristocetin cofactor activity. At high shear rate (2,500 sec-1), increased platelet adhesion was observed with partially reduced FVIII- vWF. These data indicate that the ability of FVIII-vWF preparations to correct the bleeding time is reflected in enhanced platelet adhesion to subendothelium in a perfusion chamber. These data also emphasize that multimeric size is not the only factor determining whether FVIII-vWF will support platelet adhesion.

scholarly journals Functional Studies on Platelet Adhesion With Recombinant von Willebrand Factor Type 2B Mutants R543Q and R543W Under Conditions of Flow

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2766-2772 ◽  
Author(s):  
Hanneke Lankhof ◽  
Conchi Damas ◽  
Marion E. Schiphorst ◽  
Martin J.W. IJsseldijk ◽  
Madelon Bracke ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Collagen Type ◽  
Cell Culture Supernatant ◽  
Collagen Type Iii ◽  
Type Iii ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Type 2B von Willebrand disease (vWD) is characterized by the absence of the very high molecular weight von Willebrand factor (vWF ) multimers from plasma, which is caused by spontaneous binding to platelet receptor glycoprotein Ib (GPIb). We studied two mutations in the A1 domain at position 543 in which arginine (R) was replaced by glutamine (Q) or tryptophan (W), respectively. Both mutations were previously identified in vWD type 2B patients. The mutations R543Q and R543W were cloned into a eukaryotic expression vector and subsequently transfected in baby hamster kidney cells overexpressing furin (fur-BHK). Stable cell lines were established by which the mutants were secreted in the cell culture supernatant. The subunit composition and multimeric structure of R543Q and R543W were similar to wild-type (WT) vWF. The mutants showed a spontaneous binding to GPIb. R543Q and R543W showed normal binding to collagen type III or heparin. Both mutants supported platelet adhesion under conditions of flow, usually when preincubated on a collagen type III surface. A low dose (2.5% of the concentration present in normal pooled plasma) of recombinant R543Q or R543W added to normal whole blood inhibited platelet adhesion to collagen type III. No inhibition was found when vWF was used as an adhesive surface. These results indicate that point mutations identified in vWD type 2B cause bleeding symptoms by two mechanisms: (1) the mutants cause platelet aggregation, which in vivo is followed by removal of the aggregates leading to the loss of high molecular weight multimers and thrombocytopenia, (2) on binding to circulating platelets the mutants block platelet adhesion. Relatively few molecules are required for the latter effect.

scholarly journals Adhesion of platelets to human artery subendothelium: effect of factor VIII-von Willebrand factor of various multimeric composition

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 128-139
Author(s):  
JJ Sixma ◽  
KS Sakariassen ◽  
NH Beeser-Visser ◽  
M Ottenhof-Rovers ◽  
PA Bolhuis
Keyword(s):  
Molecular Weight ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Bleeding Time ◽  
Low Molecular Weight ◽  
Perfusion Chamber ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adhesion Factor

The relationship between the multimeric size of factor VIII-von Willebrand factor (FVIII-vWF) and the support of platelet adhesion to subendothelium was studied in an annular perfusion chamber, employing human renal and umbilical arteries. Commercial factor VIII concentrates containing multimers of low molecular weight that had been shown not to correct the bleeding time upon infusion into patients with von Willebrand's disease did not support platelet adhesion in the perfusion chamber. Cryoprecipitate and two experimental FVIII-vWF concentrates containing multimers of high molecular weight supported platelet adhesion. Factor VIII-vWF purified from cryoprecipitate was subdivided into three fractions of different molecular weights (6.0–14.0, 4.0–9.0, and 3.0–7.5 X 10(6) dalton). These fractions appeared to bind equally well and to be equally effective in supporting platelet adhesion. Factor VIII-vWF with multimers of low molecular weight (0.5–1.5 X 10(6) dalton) were prepared by partial reduction. Binding of FVIII-vWF to subendothelium was not impaired, and the support of platelet adhesion appeared to be more resistant to the effect of reduction than the ristocetin cofactor activity. At high shear rate (2,500 sec-1), increased platelet adhesion was observed with partially reduced FVIII- vWF. These data indicate that the ability of FVIII-vWF preparations to correct the bleeding time is reflected in enhanced platelet adhesion to subendothelium in a perfusion chamber. These data also emphasize that multimeric size is not the only factor determining whether FVIII-vWF will support platelet adhesion.

Asialo von Willebrand Factor Enhances Platelet Adhesion to Vessel Subendothelium

1988 ◽  
Vol 60 (01) ◽  
pp. 030-034 ◽  
Author(s):  
Eva Bastida ◽  
Juan Monteagudo ◽  
Antonio Ordinas ◽  
Luigi De Marco ◽  
Ricardo Castillo
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Human Albumin ◽  
Membrane Receptors ◽  
Shear Rates ◽  
High Shear Rates ◽  
Platelet Deposition ◽  
Platelet Spreading ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryNative von Willebrand factor (N-vWF) binds to platelets activated by thrombin, ADP or ristocetin. Asialo vWF (As-vWF) induces platelet aggregation in absence of platelet activators. N-vWF mediates platelet adhesion to vessel subendothelium at high shear rates. We have investigated the role of As-vWF in supporting platelet deposition to rabbit vessel subendothelium at a shear rate of 2,000 sec-1, using the Baumgartner perfusion system. We have studied the effects of the addition of As-vWF (from 2 to 12 μg/ml) to perfusates consisting of washed red blood cells, 4% human albumin and washed platelets. Our results show a significant increase in platelet deposition on subendothelium (p <0.01) in perfusions to which As-vWF had been added. Blockage of the platelet glycoproteins Ib and IIb/IIIa (GPIb and GPIIb/IIIa) by specific monoclonal antibodies (LJIb1 and LJCP8, respectively) resulted in a decrease of platelet deposition in both types of perfusates prepared with N-vWF and As-vWF. Our results indicate that As-vWF enhances platelet deposition to vessel subendothelium under flow conditions. Furthermore, they suggest that this effect is mediated by the binding of As-vWF to platelet membrane receptors, which in turn, promote platelet spreading and adhesion to the subendothelium.

Interventional Thermal Injury of the Arterial Wall: Unfolding of von Willebrand Factor and Its Increased Binding to Collagen after 55° C Heating

1996 ◽  
Vol 75 (03) ◽  
pp. 515-519 ◽  
Author(s):  
Mark J Post ◽  
Anke N de Graaf-Bos ◽  
George Posthuma ◽  
Philip G de Groot ◽  
Jan J Sixma ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Conformational Changes ◽  
Arterial Wall ◽  
Platelet Adhesion ◽  
Type I ◽  
Temperature Dependent ◽  
Collagen Types ◽  
Electron Microscopic ◽  
Von Willebrand ◽  
Willebrand Factor

Summary Purpose. Thermal angioplasty alters the thrombogenicity of the arterial wall. In previous studies, platelet adhesion was found to increase after heating human subendothelium to 55° C and decrease after heating to 90° C. In the present electron microscopic study, the mechanism of this temperature-dependent platelet adhesion to the heated arterial wall is elucidated by investigating temperature-dependent conformational changes of von Willebrand factor (vWF) and collagen types I and III and the binding of vWF to heated collagen. Methods. Purified vWF and/or collagen was applied to electron microscopic grids and heated by floating on a salt-solution of 37° C, 55° C or 90° C for 15 s. After incubation with a polyclonal antibody against vWF and incubation with protein A/gold, the grids were examined by electron microscopy. Results. At 37° C, vWF was coiled. At 55° C, vWF unfolded, whereas heating at 90° C caused a reduction in antigenicity. Collagen fibers heated to 37° C were 60.3 ± 3.1 nm wide. Heating to 55° C resulted in the unwinding of the fibers, increasing the width to 87.5 ± 8.2 nm (p < 0.01). Heating to 90° C resulted in denatured fibers with an enlarged width of 85.1 ± 6.1 nm (p < 0.05). Heating of collagen to 55° C resulted in an increased vWF binding as compared to collagen heated to 37° C or to 90° C. Incubation of collagen with vWF, prior to heating, resulted in a vWF binding after heating to 55° C that was similar to the 37° C binding and a decreased binding after 90° C. Conclusions. After 55° C heating, the von Willebrand factor molecule unfolds and collagen types I and III exhibit an increased adhesiveness for von Willebrand factor. Heating to 90° C denatures von Willebrand factor and collagen. The conformation changes of von Willebrand factor and its altered binding to collagen type I and III may explain the increased and decreased platelet adhesion to subendothelium after 55° C and 90° C heating, respectively.

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.

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