Different factor <scp>VIII</scp> neutralizing effects on anti‐factor <scp>VIII</scp> inhibitor antibodies associated with epitope specificity and von <scp>W</scp>illebrand factor

Yada, Koji; Nogami, Keiji; Shima, Midori

doi:10.1111/bjh.12473

Cited by 4 publications

(3 citation statements)

References 25 publications

(31 reference statements)

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“…Furthermore, CWA was used by Yada et al to evaluate the effects of different alloantibodies against different epitopes of FVIII. This helped to understand the variability of responses to FVIII replacement therapy in patients with HA with inhibitors …”

Section: Potential Clinical Indicationsmentioning

confidence: 99%

Clot waveform analysis: Where do we stand in 2017?

Sevenet

Depasse

2017

Int J Lab Hematology

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Section: Potential Clinical Indicationsmentioning

confidence: 99%

Clot waveform analysis: Where do we stand in 2017?

Sevenet

Depasse

2017

Int J Lab Hematology

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“…The Bethesda assay is an in vitro one‐stage clot‐based assay that quantifies the inhibition of FVIII procoagulant activity by antibodies in inhibitor plasma . However, the Bethesda assay has limitations . The Bethesda assay does not account for a diverse spectrum of multidomain inhibitory and non‐inhibitory anti‐FVIII antibodies , or the effect of these antibodies on FVIII binding to von Willebrand factor (VWF), activation of FVIII by thrombin, or FVIII clearance.…”

Section: Introductionmentioning

confidence: 99%

Anti‐C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model

Batsuli

Ito

Mercer

et al. 2018

Journal of Thrombosis and Haemostasis

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Background The development of neutralizing anti-factor VIII (FVIII) antibodies remains a challenging complication of modern hemophilia A care. In vitro assays are the primary method used for quantifying inhibitor titers, predicting bleeding risk, and determining bleeding management. However, other mechanisms of inhibition are not accounted for in these assays, which may result in discrepancies between the inhibitor titer and clinical bleeding symptoms. Objectives To evaluate FVIII clearance in vivo as a potential mechanism for antibody pathogenicity and to determine whether increased FVIII dosing regimens correct the associated bleeding phenotype. Methods FVIII or FVIII /von Willebrand factor (VWF) mice were infused with anti-FVIII mAbs directed against the FVIII C1, C2 or A2 domains, followed by infusion of FVIII. Blood loss via the tail snip bleeding model, FVIII activity and FVIII antigen levels were subsequently measured. Results Pathogenic anti-C1 mAbs that compete with VWF for FVIII binding increased the clearance of FVIII-mAb complexes in FVIII mice but not in FVIII /VWF mice. Additionally, pathogenic anti-C2 mAbs that inhibit FVIII binding to VWF increased FVIII clearance in FVIII mice. Anti-C1, anti-C2 and anti-A2 mAbs that do not inhibit VWF binding did not accelerate FVIII clearance. Infusion of increased doses of FVIII in the presence of anti-C1 mAbs partially corrected blood loss in FVIII mice. Conclusions A subset of antibodies that inhibit VWF binding to FVIII increase the clearance of FVIII-mAb complexes, which contributes to antibody pathogenicity. This may explain differences in the bleeding phenotype observed despite factor replacement in some patients with hemophilia A and low-titer inhibitors.

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“…The antibody could be against the factor VIII receptor, not routinely tested in the Bethesda assay. Another possibility could be antibody against von Willebrand factor (vWF), which binds to and protects factor VIII from degradation [7]. However, her vWF levels were normal.…”

Section: Discussionmentioning

confidence: 99%

Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

Abt

Streiff

Gocke

et al. 2014

Case Reports in Hematology

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Objective. We present the case of a 73-year-old female, with no family or personal history of a bleeding disorder, who had a classic presentation for acquired hemophilia A. Factor VIII activity was low but detectable and a factor VIII inhibitor was undetectable. Methods. The patient's plasma was comprehensively studied to determine the cause of the acquired coagulopathy. Using the Nijmegen modification of the Bethesda assay, no factor VIII autoantibody was measureable despite varying the incubation time from 1 to 3 hours. Results. The aPTT was prolonged at 46.8 seconds, which did not correct in the 4 : 1 mix but did with 1 : 1 mix. Using a one stage factor VIII activity assay, the FVIII activity was 16% and chromogenic FVIII activity was also 16%. The patient was treated with recombinant FVII and transfusion, significantly reducing bleeding. Long-term therapy was initiated with cyclophosphamide and prednisone with normalization of FVIII activity. Conclusions. Physicians can be presented with the challenging clinical picture of an acquired factor VIII inhibitor without a detectable inhibitor by the Bethesda assay. Standard therapy for an acquired hemophilia A should be considered.

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Different factor VIII neutralizing effects on anti‐factor VIII inhibitor antibodies associated with epitope specificity and von Willebrand factor

Cited by 4 publications

References 25 publications

Clot waveform analysis: Where do we stand in 2017?

Clot waveform analysis: Where do we stand in 2017?

Anti‐C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model

Idiopathic Acquired Hemophilia A with Undetectable Factor VIII Inhibitor

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