Anti‐C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model
Author(s): ,
G. Batsuli
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
,
J. Ito
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
,
R. Mercer
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
,
W. H. Baldwin
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
,
C. Cox
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
,
E. T. Parker
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
,
J. F. Healey
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
,
P. Lollar
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
S. L. Meeks
Affiliations:
Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Emory University, Atlanta, USA
Correspondence: Shannon L. Meeks, MD, Emory Children's Center, 2015 Uppergate Drive, Room 442, Atlanta, GA 30322, USA|Tel.: +1 404 727 1608|E‐mail: smeeks@emory.edu
ISTH Academy. L. Meeks S. Sep 4, 2018; 230981
Shannon L. Meeks
Shannon  L. Meeks

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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.
Keyword(s)
antibody, factor VIII, hemophilia A, inhibitors, von Willebrand factor
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