A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction

The patients with inherited bleeding diathesis related to quantitative, structural, and/or functional abnormalities of von Willebrand factor (vWF) are said to have von Willebrand's disease (vWD). We report here the clinical and laboratory features of a 50-year-old woman with a life- long history of excessive bleeding. Her particular laboratory data are factor VIII (FVIII) deficiency, subnormal bleeding time, and the presence of all plasma and platelet vWF multimers in normal amounts. Infused with FVIII/vWF concentrate, she showed a persistent increase in FVIII that led us to discard hemophilia A carrier or “acquired hemophilia” diagnoses. vWF devoid of FVIII purified from normal and patient's plasma by immunoaffinity on anti-vWF monoclonal antibody (MoAb) was immobilized onto polystyrene tubes that were further incubated with purified normal FVIII. The bound FVIII was evidenced using radiolabeled anti-FVIII MoAb. The data showed that the patient's vWF, in contrast to vWF purified from normal plasma, was unable to bind FVIII. Furthermore, no inhibitor of FVIII/vWF interaction was evidenced in incubating purified normal vWF with the patient's plasma before the addition of FVIII and anti-FVIII MoAb. These results support the concept that the bleeding diathesis of this patient appears to be due mainly to her abnormal vWF preventing FVIII/vWF interaction. This abnormality, which is not yet described in present classification of vWD, could be considered as a new variant of vWD.

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A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction

Blood ◽

10.1182/blood.v75.1.20.20 ◽

1990 ◽

Vol 75 (1) ◽

pp. 20-26 ◽

Cited By ~ 101

Author(s):

C Mazurier ◽

J Dieval ◽

S Jorieux ◽

J Delobel ◽

M Goudemand

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Laboratory Data ◽

Bleeding Diathesis ◽

Excessive Bleeding ◽

New Variant ◽

History Of ◽

Von Willebrand ◽

Willebrand Factor

Abstract The patients with inherited bleeding diathesis related to quantitative, structural, and/or functional abnormalities of von Willebrand factor (vWF) are said to have von Willebrand's disease (vWD). We report here the clinical and laboratory features of a 50-year-old woman with a life- long history of excessive bleeding. Her particular laboratory data are factor VIII (FVIII) deficiency, subnormal bleeding time, and the presence of all plasma and platelet vWF multimers in normal amounts. Infused with FVIII/vWF concentrate, she showed a persistent increase in FVIII that led us to discard hemophilia A carrier or “acquired hemophilia” diagnoses. vWF devoid of FVIII purified from normal and patient's plasma by immunoaffinity on anti-vWF monoclonal antibody (MoAb) was immobilized onto polystyrene tubes that were further incubated with purified normal FVIII. The bound FVIII was evidenced using radiolabeled anti-FVIII MoAb. The data showed that the patient's vWF, in contrast to vWF purified from normal plasma, was unable to bind FVIII. Furthermore, no inhibitor of FVIII/vWF interaction was evidenced in incubating purified normal vWF with the patient's plasma before the addition of FVIII and anti-FVIII MoAb. These results support the concept that the bleeding diathesis of this patient appears to be due mainly to her abnormal vWF preventing FVIII/vWF interaction. This abnormality, which is not yet described in present classification of vWD, could be considered as a new variant of vWD.

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

Blood ◽

10.1182/blood.v79.3.563.563 ◽

1992 ◽

Vol 79 (3) ◽

pp. 563-567 ◽

Cited By ~ 30

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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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 ◽

10.1182/blood.v108.11.4076.4076 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4076-4076 ◽

Cited By ~ 1

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.

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Characterization of human factor VIII and interaction with von Willebrand factor. An electron microscopic study

European Journal of Biochemistry ◽

10.1111/j.1432-1033.1990.tb15643.x ◽

1990 ◽

Vol 194 (2) ◽

pp. 491-498 ◽

Cited By ~ 5

Author(s):

Harry F. G. HEIJNEN ◽

Joost. A. KOEDAM ◽

Helena SANDBERG ◽

Nel H. BEESER-VISSER ◽

Jan. W. SLOT ◽

...

Keyword(s):

Factor Viii ◽

Microscopic Study ◽

Electron Microscopic Study ◽

Von Willebrand Factor ◽

Human Factor ◽

Electron Microscopic ◽

Human Factor Viii ◽

Von Willebrand ◽

Willebrand Factor

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Characterization of Microvasculature in the Stroma of Human Colorectal Carcinoma: An Immunoelectron Microscopic Study on Factor VIII/von Willebrand Factor

Journal of Electron Microscopy ◽

10.1093/oxfordjournals.jmicro.a050626 ◽

1987 ◽

Keyword(s):

Colorectal Carcinoma ◽

Factor Viii ◽

Microscopic Study ◽

Von Willebrand Factor ◽

Human Colorectal Carcinoma ◽

Von Willebrand ◽

Willebrand Factor

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Intracellular interaction of von Willebrand factor and factor VIII depends on cellular context: lessons from platelet-expressed factor VIII

Blood ◽

10.1182/blood-2004-12-4701 ◽

2005 ◽

Vol 105 (12) ◽

pp. 4674-4676 ◽

Cited By ~ 28

Author(s):

Helen Yarovoi ◽

Alan T. Nurden ◽

Robert R. Montgomery ◽

Paquita Nurden ◽

Mortimer Poncz

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Blood Clotting ◽

Immunogold Electron Microscopy ◽

Bleeding Diathesis ◽

Cell Type ◽

Carotid Artery Injury ◽

Cellular Context ◽

Von Willebrand ◽

Willebrand Factor

Abstract We have previously reported that ectopically expressed factor VIII (FVIII) is stored within platelets and is released upon platelet activation. Studies by others in various cell lines have suggested that having von Willebrand factor (VWF) coexpression is necessary for FVIII granular storage and for its secretion. We tested the importance of VWF coexpression for ectopic storage of FVIII in platelets and for its bioavailability. Transgenic mice expressing platelet-specific FVIII were crossed onto a VWF-/- background. Antigenic levels of platelet FVIII in these mice were nearly unchanged whether VWF was present or not. Whole-blood clotting times and FeCl3 carotid artery injury correction demonstrated that platelet FVIII demonstrably improved the bleeding diathesis in FVIIInull mice independent of the platelets' VWF status. Immunogold electron microscopy demonstrated that platelet FVIII is stored in platelet α-granules independent of the presence of VWF. It appears that FVIII's interaction with VWF and its intracellular transportation, storage, and secretion differ greatly depending on the cell type. The molecular basis for these differences now needs to be elucidated. (Blood. 2005;105:4674-4676)

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