The D′ domain of von Willebrand factor requires the presence of the D3 domain for optimal factor VIII binding

2018 ◽  
Vol 475 (17) ◽  
pp. 2819-2830 ◽  
Author(s):  
Małgorzata A. Przeradzka ◽  
Henriet Meems ◽  
Carmen van der Zwaan ◽  
Eduard H.T.M. Ebberink ◽  
Maartje van den Biggelaar ◽  
...  
Keyword(s):  
Factor Viii ◽  
Binding Affinity ◽  
Von Willebrand Factor ◽  
Conformational Changes ◽  
Effective Interaction ◽  
Von Willebrand Disease ◽  
Binding Assays ◽  
Surface Plasmon Resonance Analysis ◽  
Von Willebrand ◽  
Willebrand Factor

The D′–D3 fragment of von Willebrand factor (VWF) can be divided into TIL′-E′-VWD3-C8_3-TIL3-E3 subdomains of which TIL′-E′-VWD3 comprises the main factor VIII (FVIII)-binding region. Yet, von Willebrand disease (VWD) Type 2 Normandy (2N) mutations, associated with impaired FVIII interaction, have been identified in C8_3-TIL3-E3. We now assessed the role of the VWF (sub)domains for FVIII binding using isolated D′, D3 and monomeric C-terminal subdomain truncation variants of D′–D3. Competitive binding assays and surface plasmon resonance analysis revealed that D′ requires the presence of D3 for effective interaction with FVIII. The isolated D3 domain, however, did not show any FVIII binding. Results indicated that the E3 subdomain is dispensable for FVIII binding. Subsequent deletion of the other subdomains from D3 resulted in a progressive decrease in FVIII-binding affinity. Chemical footprinting mass spectrometry suggested increased conformational changes at the N-terminal side of D3 upon subsequent subdomain deletions at the C-terminal side of the D3. A D′–D3 variant with a VWD type 2N mutation in VWD3 (D879N) or C8_3 (C1060R) also revealed conformational changes in D3, which were proportional to a decrease in FVIII-binding affinity. A D′–D3 variant with a putative VWD type 2N mutation in the E3 subdomain (C1225G) showed, however, normal binding. This implies that the designation VWD type 2N is incorrect for this variant. Results together imply that a structurally intact D3 in D′–D3 is indispensable for effective interaction between D′ and FVIII explaining why specific mutations in D3 can impair FVIII binding.

Clinical cases of using coagulation factor VIII with von Willebrand factor in parturient women with type III von Willebrand disease

2020 ◽  
Author(s):  
И.В. Куртов ◽  
Е.С. Фатенкова ◽  
Н.А. Юдина ◽  
А.М. Осадчук ◽  
И.Л. Давыдкин
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Coagulation Factor Viii ◽  
Vitro Fertilization ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Болезнь Виллебранда (БВ) может представлять определенные трудности у рожениц с данной патологией. Приведены 2 клинических примера использования у женщин с БВ фактора VIII свертывания крови с фактором Виллебранда, показана эффективность и безопасность их применения. У одной пациентки было также показано использование фактора свертывания крови VIII с фактором Виллебранда во время экстракорпорального оплодотворения. Von Willebrand disease presents a certain hemostatic problem among parturients. This article shows the effectiveness and safety of using coagulation factor VIII with von Willebrand factor for the prevention of bleeding in childbirth in 2 patients with type 3 von Willebrand disease. In one patient, the use of coagulation factor VIII with von Willebrand factor during in vitro fertilization was also shown.

scholarly journals Selective absence of large forms of factor VIII/von Willebrand factor in acquired von Willebrand's syndrome. Response to transfusion

Blood ◽  
1979 ◽  
Vol 54 (3) ◽  
pp. 600-606 ◽  
Author(s):  
D Meyer ◽  
D Frommel ◽  
MJ Larrieu ◽  
TS Zimmerman
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Procoagulant Activity ◽  
Factor Viii Related Antigen ◽  
Cofactor Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity

Abstract A previously healthy elderly man with mucocutaneous bleeding was found to have a benign monoclonal IgG gammapathy associated with criteria for severe von Willebrand disease (Factor VIII procoagulant activity, Factor-VIII-related antigen, and ristocetin cofactor activity, less than 10% of normal). Associated qualitative abnormalities of factor VIII/von Willebrand factor were demonstrated by radiocrossed immunoelectrophoresis and immunoradiometric assay. The late clinical onset and negative family history are in favor of an acquired form of vWD. The monoclonal gammapathy and abnormalities of factor VIII/von Willebrand factor have been stable over a 10-yr period. No inhibitor to Factor VIII procoagulant activity, ristocetin cofactor activity, or Factor-VIII-related antigen could be demonstrated. Following transfusion of cryoprecipitate (with a normal cross immunoelectrophoretic pattern), there was a rapid removal of the large forms of Factor.-VIII-related antigen, paralleled by a decay of ristocetin cofactor activity. The transfusion study of this patient with acquired von Willebrand disease type II (variant of von Willebrand disease) serves to emphasize the relationship between polydispersity of Factor VIII/von Willebrand Factor and functional heterogeneity.

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

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 563-567 ◽  
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.

scholarly journals Influence of mutations and size of multimers in type II von Willebrand disease upon the function of von Willebrand factor

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3553-3561 ◽  
Author(s):  
O Christophe ◽  
AS Ribba ◽  
D Baruch ◽  
B Obert ◽  
C Rouault ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Point Mutations ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Binding Assays ◽  
Normal Individuals ◽  
Binding Isotherms ◽  
Significant Difference ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We compared the properties of plasma von Willebrand factor (vWF) from normal individuals and from two patients with type IIA (Glu875Lys) and type IIB (duplication of Met 540) von Willebrand disease (vWD) with the corresponding fully multimerized recombinant proteins. We included cryosupernatant from normal human plasma and type IIA plasma (Cys509Arg). Functions of vWF were analyzed by binding assays to platelets in the presence of ristocetin or botrocetin. Parameters of binding (number of binding sites per vWF subunit, and dissociation constant Kd) were quantitatively estimated from the binding isotherms of 125I-botrocetin or glycocalicin to vWF, independently of the size of the multimers. We found that ristocetin- or botrocetin-induced binding to platelets was correlated in all cases with the size of vWF multimers. In the absence of inducer, only type IIB rvWF Met-Met540 spontaneously bound to platelets. No significant difference of binding of purified botrocetin to vWF was found between normal and patients' plasma, or between wild-type rvWF (rvWF-WT) and rvWF-Lys875. In contrast, affinity of botrocetin for type IIB rvWF Met-Met540 was decreased. Botrocetin-induced binding of glycocalicin to vWF from all plasma and cryosupernatant was similar. Compared with rvWF-WT, binding of glycocalicin to rvWF-Lys875 was normal. In contrast, the affinity for type IIB rvWF Met-Met540 was 10-fold greater. Thus, our data suggest that, in the patients tested, the abnormal IIA phenotype results from the lack of large-sized multimers and is independent of the point mutations. In contrast, the type IIB mutation is directly involved by providing a conformation to the vWF subunits that allows the high molecular weight multimers to spontaneously interact with platelet glycoprotein Ib.

Managing Patients with von Willebrand Disease Type 1, 2 and 3 with Desmopressin and von Willebrand Factor-Factor VIII Concentrate in Surgical Settings

2009 ◽  
Vol 121 (2-3) ◽  
pp. 167-176 ◽  
Author(s):  
Jan Jacques Michiels ◽  
Huub H.D.M. van Vliet ◽  
Zwi Berneman ◽  
Wilfried Schroyens ◽  
Alain Gadisseur
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Disease Type ◽  
Von Willebrand Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand Factor Levels Do Not Increase with Age in Patients with Type 1 Von Willebrand Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4028-4028
Author(s):  
Hong I. Tarng ◽  
Lynne Taylor ◽  
Barbara A. Konkle
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Test Results ◽  
Age Related ◽  
One Year ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Over Time

Abstract A number of inherited and acquired factors modulate von Willebrand factor antigen (VWF:Ag) levels, including blood type, race, activity and stress level, thyroid hormone status, and, in women, time in menstrual cycle. In reported studies a positive correlation between VWF:Ag and/or factor VIII levels and age has been demonstrated, with an increase of 5 – 6 IU/dL per decade (Conlan MG et al, 1993; Kamphuisen PW et al, 1998). Those studies have primarily assessed VWF and factor VIII as risk factors for ischemic heart disease, cerebrovascular disease, and venous thromboembolism. None of the subjects had von Willebrand disease (VWD). Their VWF:Ag levels were in the higher normal or elevated range. The purpose of this study was to determine whether there is a relationship between age and VWF:Ag level in patients with Type 1 VWD. We collected the data from 36 patients who were diagnosed with type 1 VWD and followed at the Penn Comprehensive Hemophilia and Thrombosis Program up to a period of 13 years (See Table 1 below). For each patient, date of birth, VWF:Ag levels with corresponding test dates were collected by reviewing the medical histories and the lab results. Test results obtained during pregnancy, DDAVP testing, or during prophylaxis or therapy for bleeding control were excluded. One year was set as the observation period, so the adjacent VWF:Ag levels that were tested less than one year were excluded from the dataset. When two test results were available on a patient within a one-year period, the lower test result was used. To investigate whether there was a relationship between VWF:Ag levels and age, cross-sectional analyses (across each visit) and longitudinal analyses were performed using scatter plots, Spearman and Pearson correlations, and regression analysis. No significant increase in VWF:Ag levels with age was demonstrated. The fact that we did not find an increase in VWF:Ag levels over time in our patients could be due to the relatively small number of patients studied or could reflect a subtype of VWD, due to our selection criteria. Only patients with abnormal values were included. Some patients have a prior diagnosis of VWD and bleeding symptoms, but have normal values when tested. Since these patients are adults, this may be due, at least in part, to an age-related increase. Type 1 VWD may occur secondary to decreased VWF synthesis and/or clearance. It is possible that age-related effects on VWF levels will differ depending on the underlying factor(s) resulting in a lower VWF level. Further studies correlating a patient’s values longitudinally with the underlying pathophysiology of their disease would aid in our understanding of their bleeding risks over time. Patient # Age at Last Visit, range (mean) Females (%) Race % (Cauc/AA/Other) VWF:Ag mean 36 17–70 (34) 89 78/19/3 49%

Safety and Efficacy of Von Willebrand Factor/Factor VIII Concentrate (Humate-P®) for Prophylaxis of Excessive Bleeding during Elective Surgery in Patients with von Willebrand Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4076-4076 ◽  
Author(s):  
Jonathan Bernstein ◽  
Joan Cox Gill ◽  
Cindy A. Leissinger ◽  
Jorge Di Paola ◽  
Margaret V. Ragni ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Elective Surgery ◽  
Von Willebrand Disease ◽  
Loading Dose ◽  
Open Label ◽  
Excessive Bleeding ◽  
Optimal Dosing ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The safety, efficacy, and optimal dosing of a von Willebrand Factor/Factor VIII concentrate (Humate-P®) were evaluated in an open-label, uncontrolled study in patients with von Willebrand disease (VWD) undergoing elective surgery. During an initial pharmacokinetic (PK) phase, a detailed profile of FVIII:C, VWF:RCo, and VWF:AG was obtained for each patient after an infusion of 60 IU VWF:RCo/kg as Humate-P. Individual PK values were used to calculate subsequent loading and maintenance doses. Hemostatic efficacy was characterized using a 4-point scale (excellent, good, moderate/poor, or none) at several time points following surgery. Forty-two adults and children were enrolled in the study (17 VWD type 1; 6 type 2; 13 type 3; 6 type 2M), and 35 of these patients underwent a surgical procedure (classified as 3 oral, 7 minor, and 25 major). The median loading dose administered was 55.6 IU/kg (range 17.4 to 135.3 IU/kg). For patients with more severe VWD (baseline VWF:RCo<12 IU/dL), the median loading dose administered was 70.9 IU/kg (range 38.6 to 135.3 IU/kg). The dosing interval was 8 or 12 hours in most subjects (4 were dosed every 6 hours), and treatment duration ranged from 1 to 6 days depending on surgery type. Effective hemostasis (investigator- rated as “excellent” or “good”) was noted in 91.4% (32/35) of subjects immediately after surgery, 100% (35/35) of subjects 14 days after surgery, and 100% (34/34) of subjects evaluated 24 hours after the last infusion (primary endpoint). Mean blood loss was less than expected, and four patients required transfusions, related to their surgery. Only six adverse events were considered possibly treatment related: headache (3), itching, nausea, and dizziness (1). These results demonstrate that von Willebrand Factor/Factor VIII concentrate is safe and effective in the prevention of excessive bleeding during and after elective surgery in adult and pediatric patients with von Willebrand disease.

Laboratory Response to Desmopressin in Children with Von Willebrand Disease: Results of a Multicenter Survey

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4517-4517
Author(s):  
Bianca Huhn ◽  
Volker Aumann ◽  
Andre Hofmann ◽  
Karim Kentouche ◽  
Axel Sauerbrey ◽  
...  
Keyword(s):  
Partial Response ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Complete Response ◽  
Von Willebrand Disease ◽  
Pituitary Hormone ◽  
Individual Response ◽  
Multicenter Survey ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Desmopressin (DDAVP, 1-deamino-8-D-arginin vasopressin) as synthetic analogue of the pituitary hormone vasopressin affects hemostasis by the release of von Willebrand factor (VWF) and coagulation factor VIII from endothelium. The necessity of DDAVP testing prior to the first therapeutic use is a matter of controversial discussion. Aim of this retrospective study was to evaluate the results of DDAVP testing in children with von Willebrand disease (VWD) in seven pediatric hemostaseologic centers. Patients and Methods: Data from DDAVP tests carried out between 2000 to 2007 were included and obtained using a standardised protocol by personel visits of the centers. DDAVP response criteria matched with those of a recently published multicenter study (Castaman et al., Blood 2008, 3531-9). Complete response to DDAVP after administration was defined as an increase in von Willebrand factor antigen (VWF:Ag), collagen-binding activity (VWF:CB) or ristocetin cofactor activity (VWF:RCo) and factor VIII procoagulant activity (FVIII:C) to 50% or higher. In partial responders VWF:Ag, VWF:CB/VWF:RCo or FVIII:C were lower than 50% but increased at least 3-fold from baseline while in non-responders neither of the before-mentioned criteria were fulfilled. Patients with VWF:Ag, VWF:CB/VWF:RCo or FVIII:C of 50% or higher at time of testing before DDAVP infusion were considered as complete responders if a level of 100% or higher were reached for all parameters. Data from 114 children (each 57 boys and girls, median age: 6.2 years, range: 1.4 to 17.8 years) were evaluated. In 99 patients DDAVP was given intravenously at a dosage ranging from 0.25 to 0.41 μg/kg (mean: 0.32 μg/kg) and in 15 intranasaly at an absolute dosage of 40 to 300 μg. The times for determination of the coagulation parameters after DDAVP infusion varied among the centers and ranged from 30 min to 12 hours. Results: The VWD of type 1 was present in 98 children. Before DDAVP administration the VWF:Ag ranged from 11% to 77% (mean: 51%), VWF:CB from 7% to 99% (mean: 46%), VWF:RCo from 15% to 97% (mean: 53%) and FVIII:C from 27% to 116% (mean: 67%). A complete response was detected in 84 children (86%), a partial response in ten (10%) and a non-response in four (4%) patients. Twelve patients suffered from VWD of type 2A. The range of baseline values was as follows: VWF:Ag 8% to 66% (mean: 34%), VWF:CB 9% to 48% (mean: 25%), VWF:RCo from 5% to 71% (mean: 26%) and FVIII:C from 19% to 90% (mean: 51%). A complete response was observed in five children (42%), a partial response in four (33%) and a non-response in three (25%) patients. In the two patients with VWD of type 2M one showed a complete and the other one a partial response. In both children with VWD of type 2N a complete response was detected. DDAVP side effects were observed only in two out of 114 patients (1.8%) who suffered from nausea, vomiting, headaches and fatigue. Conclusion: DDAVP testing prior to therapeutic administration is recommended to determine its efficiency and the individual response on hemostasis. The non-response in seven (6%) and the partial reponse in 15 (13%) out of a total cohort of 114 children with VWD underlines the necessity of this recommendation in pediatrics. However, a standardisation of the test procedure is needed.

A Novel Mutation in the D3 Domain of von Willebrand Factor Markedly Decreases Its Ability to Bind Factor VIII and Affects Its Multimerization

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4663-4670 ◽  
Author(s):  
S. Jorieux ◽  
C. Gaucher ◽  
J. Goudemand ◽  
C. Mazurier
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Stop Codon ◽  
Novel Mutation ◽  
Von Willebrand Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sequencing Analysis ◽  
Normal Platelet ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract In type 2N von Willebrand disease (vWD), von Willebrand factor (vWF) is characterized by normal multimeric pattern, normal platelet-dependent function, but a markedly decreased affinity for factor VIII (FVIII). In this report, we describe the case of a vWD patient who has an abnormal vWF multimers distribution associated with a markedly decreased vWF ability to bind FVIII. Sequencing analysis of patient’s vWF gene showed, at heterozygous state, a G→A transition resulting in the substitution of Asn for Asp at position 116 of the mature vWF subunit and a C→T transition, changing the codon for Arg 896 into a stop codon. His sister who has a subnormal vWF level, but a normal FVIII/vWF interaction, was found to be heterozygous for the Arg896ter mutation only. Recombinant vWF (rvWF) containing the candidate (Asn116) missense mutation was expressed in COS-7 cells. The expression level of Asn116rvWF was significantly decreased compared with wild-type rvWF. The multimeric pattern of Asn116rvWF was greatly impaired as shown by the decrease in high molecular weight forms. The FVIII binding ability of Asn116rvWF was dramatically decreased. These data show that the Asp116Asn substitution is the cause of both the defective FVIII/vWF interaction and the impaired multimeric pattern observed in the patient’s vWF. The monoclonal antibody 31H3 against D’ domain of vWF (epitope aa 66-76) that partially inhibits the FVIII binding and recognizes only nonreduced vWF, showed a decreased ability to bind Asn116rvWF when used as capture-antibody in enzyme-linked immunosorbent assay (ELISA). This result suggests that a potential conformation change in the D’ domain is induced by the Asp116Asn substitution, which is localized in the D3 domain.

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