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• W2875193073 abstract "Essentials•Inhibitor formation remains a challenging complication of hemophilia A care.•The Bethesda assay is the primary method used for determining bleeding risk and management.•Antibodies that block factor VIII binding to von Willebrand factor can increase FVIII clearance.•Antibodies that increase clearance contribute to antibody pathogenicity.AcknowledgementsThis research was supported by Atlanta Pediatric Scholars Program K12 HD072245 (G. Batsuli), the 2016 HTRS/Novo Nordisk Mentored Research Award in Hemophilia and Rare Bleeding Disorders from the Hemostasis and Thrombosis Research Society (HTRS) supported by an educational grant from Novo Nordisk Inc. (G. Batsuli), NIH grant U54 HL112309 (P. Lollar and S. L. Meeks), and Hemophilia of Georgia, Inc. (P. Lollar and S. L. Meeks). We thank J. Voorberg for providing the human‐derived anti‐FVIII C1 antibody KM33 and D. Wagner for the FVIII−/−/VWF−/− mice.Atlanta Pediatric Scholars ProgramK12 HD072245Hemostasis and Thrombosis Research SocietyNIHU54 HL112309Hemophilia of Georgia, Inc.Summary: BackgroundThe 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.ObjectivesTo 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.MethodsFVIII−/− 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.ResultsPathogenic 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.ConclusionsA 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. Essentials•Inhibitor formation remains a challenging complication of hemophilia A care.•The Bethesda assay is the primary method used for determining bleeding risk and management.•Antibodies that block factor VIII binding to von Willebrand factor can increase FVIII clearance.•Antibodies that increase clearance contribute to antibody pathogenicity.AcknowledgementsThis research was supported by Atlanta Pediatric Scholars Program K12 HD072245 (G. Batsuli), the 2016 HTRS/Novo Nordisk Mentored Research Award in Hemophilia and Rare Bleeding Disorders from the Hemostasis and Thrombosis Research Society (HTRS) supported by an educational grant from Novo Nordisk Inc. (G. Batsuli), NIH grant U54 HL112309 (P. Lollar and S. L. Meeks), and Hemophilia of Georgia, Inc. (P. Lollar and S. L. Meeks). We thank J. Voorberg for providing the human‐derived anti‐FVIII C1 antibody KM33 and D. Wagner for the FVIII−/−/VWF−/− mice.Atlanta Pediatric Scholars ProgramK12 HD072245Hemostasis and Thrombosis Research SocietyNIHU54 HL112309Hemophilia of Georgia, Inc. •Inhibitor formation remains a challenging complication of hemophilia A care.•The Bethesda assay is the primary method used for determining bleeding risk and management.•Antibodies that block factor VIII binding to von Willebrand factor can increase FVIII clearance.•Antibodies that increase clearance contribute to antibody pathogenicity. This research was supported by Atlanta Pediatric Scholars Program K12 HD072245 (G. Batsuli), the 2016 HTRS/Novo Nordisk Mentored Research Award in Hemophilia and Rare Bleeding Disorders from the Hemostasis and Thrombosis Research Society (HTRS) supported by an educational grant from Novo Nordisk Inc. (G. Batsuli), NIH grant U54 HL112309 (P. Lollar and S. L. Meeks), and Hemophilia of Georgia, Inc. (P. Lollar and S. L. Meeks). We thank J. Voorberg for providing the human‐derived anti‐FVIII C1 antibody KM33 and D. Wagner for the FVIII−/−/VWF−/− mice.Atlanta Pediatric Scholars ProgramK12 HD072245Hemostasis and Thrombosis Research SocietyNIHU54 HL112309Hemophilia of Georgia, Inc. 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. 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. 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. 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. 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." @default.
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• W2875193073 date "2018-09-01" @default.
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• W2875193073 title "Anti‐C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model" @default.
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• W2875193073 doi "https://doi.org/10.1111/jth.14233" @default.
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