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.

Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate®) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery

2011 ◽  
Vol 105 (06) ◽  
pp. 1072-1079 ◽  
Author(s):  
Mario von Depka-Prondzinski ◽  
Jerzy Windyga ◽  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Perioperative Management ◽  
Von Willebrand Disease ◽  
Major Surgery ◽  
Open Label ◽  
New Generation ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe aim of this study was to assess the efficacy of Wilate®, a new generation, plasma-derived, high-purity, double virus-inactivated von Willebrand factor (VWF) and factor VIII (FVIII) concentrate (ratio close to physiological 1:1) in the perioperative management of haemostasis in von Willebrand disease (VWD). Data for VWD patients who received Wilate® for perioperative management were obtained from four European, prospective, open-label, non-controlled, non-randomised, multicentre phase II or III clinical trials. A total of 57 surgical procedures were performed (major: n = 27; minor n = 30) in 32 patients. The majority of patients (n = 19, 59.4%) had type 3 VWD, 9 (28.1%) had type 2 VWD and four (12.5%) had type 1 VWD. During major surgery, median daily FVIII dose and mean number of infusions were 25 IU•kg-1 FVIII (VWF:RCô23 IU•kg-1) and 11.0, respectively. Corresponding values for minor surgery were 35 IU•kg-1 (VWF:RCo ~32 IU•kg-1) and 1.5. The efficacy of Wilate® was rated by the investigator as excellent or good in 51 of 53 (96%) procedures. Tolerability was rated as very good or good in 100% of major surgeries (27 of 27) and minor surgeries (29 of 29). Wilate® is an effective and well-tolerated VWF/FVIII replacement therapy in the perioperative management of haemostasis in patients with VWD. It can be administered at a similar FVIII dose, but at a lower VWF dose, as compared to older generation products. Clinical benefits were shown in a population with a high proportion of type 3 VWD patients.

scholarly journals Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery

2018 ◽  
Vol 17 (1) ◽  
pp. 52-62 ◽  
Author(s):  
F. Peyvandi ◽  
A. Mamaev ◽  
J.‐D. Wang ◽  
O. Stasyshyn ◽  
M. Timofeeva ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Elective Surgery ◽  
Von Willebrand Disease ◽  
Phase 3 ◽  
Von Willebrand ◽  
Willebrand Factor

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.

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