Structural insights into blood coagulation factor VIII: Procoagulant complexes, membrane binding, and antibody inhibition.
antibody inhibitors
factor VIII
hemophilia A
intrinsic tenase
von Willebrand factor
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
revised:
10
06
2022
received:
01
02
2022
accepted:
16
06
2022
pubmed:
21
6
2022
medline:
17
8
2022
entrez:
20
6
2022
Statut:
ppublish
Résumé
Advances in structural studies of blood coagulation factor VIII (FVIII) have provided unique insight into FVIII biochemistry. Atomic detail models of the B domain-deleted FVIII structure alone and in complex with its circulatory partner, von Willebrand factor (VWF), provide a structure-based rationale for hemophilia A-associated mutations which impair FVIII stability and increase FVIII clearance rates. In this review, we discuss the findings from these studies and their implications toward the design of a recombinant FVIII with improved circulatory half-life. Additionally, we highlight recent structural studies of FVIII bound to inhibitory antibodies that have refined our understanding of FVIII binding to activated platelet membranes and formation of the intrinsic tenase complex. The combination of bioengineering and structural efforts to understand FVIII biochemistry will improve therapeutics for treating hemophilia A, either through FVIII replacement therapeutics, immune tolerance induction, or gene therapy approaches.
Identifiants
pubmed: 35722946
doi: 10.1111/jth.15793
pii: S1538-7836(22)02106-7
doi:
Substances chimiques
Antibodies
0
von Willebrand Factor
0
Factor VIII
9001-27-8
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1957-1970Informations de copyright
© 2022 International Society on Thrombosis and Haemostasis.
Références
Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The recombinate study group. Blood. 1994;83:2428-2435.
Kreuz W, Ettingshausen CE, Zyschka A, et al. Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products. Semin Thromb Hemost. 2002;28:285-290. doi:10.1055/s-2002-32664
Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood. 2008;112:250-255. doi:10.1182/blood-2008-03-143586
Ostergaard H, Lund J, Greisen PJ, et al. A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice. Blood. 2021;138:1258-1268. doi:10.1182/blood.2020010331
Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med. 2016;374:2044-2053. doi:10.1056/NEJMoa1511769
Dargaud Y, Escuriola-Ettingshausen C. Recombinant porcine factor VIII: lessons from the past and place in the management of hemophilia A with inhibitors in 2021. Res Pract Thromb Haemost. 2021;5:e12631. doi:10.1002/rth2.12631
Ettinger RA, Liberman JA, Gunasekera D, et al. FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity. Blood Adv. 2018;2:309-322. doi:10.1182/bloodadvances.2017013482
Nguyen NH, Dingman RK, Balu-Iyer SV. Tolerogenic form of factor VIII to prevent inhibitor development in the treatment of hemophilia A. J Thromb Haemost. 2021;19:2744-2750. doi:10.1111/jth.15497
Winterling K, Martin WD, De Groot AS, Daufenbach J, Kistner S, Schuttrumpf J. Development of a novel fully functional coagulation factor VIII with reduced immunogenicity utilizing an in silico prediction and deimmunization approach. J Thromb Haemost. 2021;19:2161-2170. doi:10.1111/jth.15413
Mahlangu J, Powell JS, Ragni MV, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123:317-325. doi:10.1182/blood-2013-10-529974
Seth Chhabra E, Liu T, Kulman J, et al. BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice. Blood. 2020;135:1484-1496. doi:10.1182/blood.2019001292
Zakas PM, Brown HC, Knight K, et al. Enhancing the pharmaceutical properties of protein drugs by ancestral sequence reconstruction. Nat Biotechnol. 2017;35:35-37. doi:10.1038/nbt.3677
Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991;30:10363-10370.
Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem. 1987;262:8443-8446.
van Dieijen G, Tans G, Rosing J, Hemker HC. The role of phospholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem. 1981;256:3433-3442.
Blajchman MA, Austin RC, Fernandez-Rachubinski F, Sheffield WP. Molecular basis of inherited human antithrombin deficiency. Blood. 1992;80:2159-2171.
Lollar P, Parker CG. pH-dependent denaturation of thrombin-activated porcine factor VIII. J Biol Chem. 1990;265:1688-1692.
Regan LM, O'Brien LM, Beattie TL, Sudhakar K, Walker FJ, Fay PJ. Activated protein C-catalyzed proteolysis of factor VIIIa alters its interactions within factor Xase. J Biol Chem. 1996;271:3982-3987. doi:10.1074/jbc.271.8.3982
Hill-Eubanks DC, Parker CG, Lollar P. Differential proteolytic activation of factor VIII-von Willebrand factor complex by thrombin. Proc Natl Acad Sci USA. 1989;86:6508-6512.
Lollar P, Hill-Eubanks DC, Parker CG. Association of the factor VIII light chain with von Willebrand factor. J Biol Chem. 1988;263:10451-10455.
Pittman DD, Kaufman RJ. Proteolytic requirements for thrombin activation of anti-hemophilic factor (factor VIII). Proc Natl Acad Sci USA. 1988;85:2429-2433. doi:10.1073/pnas.85.8.2429
Regan LM, Fay PJ. Cleavage of factor VIII light chain is required for maximal generation of factor VIIIa activity. J Biol Chem. 1995;270:8546-8552. doi:10.1074/jbc.270.15.8546
Ngo JC, Huang M, Roth DA, Furie BC, Furie B. Crystal structure of human factor VIII: implications for the formation of the factor IXa-factor VIIIa complex. Structure. 2008;16:597-606. doi:10.1016/j.str.2008.03.001
Shen BW, Spiegel PC, Chang CH, et al. The tertiary structure and domain organization of coagulation factor VIII. Blood. 2008;111:1240-1247. doi:10.1182/blood-2007-08-109918
Svensson LA, Thim L, Olsen OH, Nicolaisen EM. Evaluation of the metal binding sites in a recombinant coagulation factor VIII identifies two sites with unique metal binding properties. Biol Chem. 2013;394:761-765. doi:10.1515/hsz-2012-0298
Leksa NC, Chiu PL, Bou-Assaf GM, et al. The structural basis for the functional comparability of factor VIII and the long-acting variant recombinant factor VIII Fc fusion protein. J Thromb Haemost. 2017;15:1167-1179. doi:10.1111/jth.13700
Smith IW, d'Aquino AE, Coyle CW, et al. The 3.2 A structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain. J Thromb Haemost. 2020;18:57-69. doi:10.1111/jth.14621
Doering CB, Denning G, Dooriss K, et al. Directed engineering of a high-expression chimeric transgene as a strategy for gene therapy of hemophilia A. Mol Ther. 2009;17:1145-1154. doi:10.1038/mt.2009.35
Doering CB, Healey JF, Parker ET, Barrow RT, Lollar P. Identification of porcine coagulation factor VIII domains responsible for high level expression via enhanced secretion. J Biol Chem. 2004;279:6546-6552. doi:10.1074/jbc.M312451200
Spencer HT, Denning G, Gautney RE, et al. Lentiviral vector platform for production of bioengineered recombinant coagulation factor VIII. Mol Ther. 2011;19:302-309. doi:10.1038/mt.2010.239
Bihoreau N, Pin S, de Kersabiec AM, Vidot F, Fontaine-Aupart MP. Metal identification in human anti-hemophilia A factor (factor VIII). C R Acad Sci III. 1993;316:536-539.
Tagliavacca L, Moon N, Dunham WR, Kaufman RJ. Identification and functional requirement of Cu(I) and its ligands within coagulation factor VIII. J Biol Chem. 1997;272:27428-27434.
Pipe SW, Saenko EL, Eickhorst AN, Kemball-Cook G, Kaufman RJ. Hemophilia A mutations associated with 1-stage/2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa. Blood. 2001;97:685-691.
Chiu PL, Bou-Assaf GM, Chhabra ES, et al. Mapping the interaction between factor VIII and von Willebrand factor by electron microscopy and mass spectrometry. Blood. 2015;126:935-938. doi:10.1182/blood-2015-04-641688
Shiltagh N, Kirkpatrick J, Cabrita LD, et al. Solution structure of the major factor VIII binding region on von Willebrand factor. Blood. 2014;123:4143-4151. doi:10.1182/blood-2013-07-517086
Fassel H, McGuinn C. Haemophilia: factoring in new therapies. Br J Haematol. 2021;194:835-850. doi:10.1111/bjh.17580
Meeks SL, Lacroix-Desmazes S. Emerging benefits of Fc fusion technology in the context of recombinant factor VIII replacement therapy. Haemophilia. 2020;26:958-965. doi:10.1111/hae.14123
Gale AJ, Pellequer JL. An engineered interdomain disulfide bond stabilizes human blood coagulation factor VIIIa. J Thromb Haemost. 2003;1:1966-1971.
Monaghan M, Wakabayashi H, Griffiths A, Wintermute J, Fay PJ. Enhanced factor VIIIa stability of A2 domain interface variants results from an increased apparent affinity for the A2 subunit. Results from an increased apparent affinity for the A2 subunit. Thromb Haemost. 2014;112:495-502. doi:10.1160/TH14-01-0086
Monaghan M, Wakabayashi H, Griffiths AE, Fay PJ. Stabilizing interactions between D666-S1787 and T657-Y1792 at the A2-A3 interface support factor VIIIa stability in the blood clotting pathway. J Thromb Haemost. 2016;14:1021-1030. doi:10.1111/jth.13292
Wakabayashi H, Monaghan M, Fay PJ. Cofactor activity in factor VIIIa of the blood clotting pathway is stabilized by an interdomain bond between His281 and Ser524 formed in factor VIII. J Biol Chem. 2014;289:14020-14029. doi:10.1074/jbc.M114.550566
Konkle BA, Stasyshyn O, Chowdary P, et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126:1078-1085. doi:10.1182/blood-2015-03-630897
Weiss HJ, Sussman II, Hoyer LW. Stabilization of factor VIII in plasma by the von Willebrand factor. Studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand's disease. J Clin Invest. 1977;60:390-404. doi:10.1172/JCI108788
Mazurier C, Ribba AS, Gaucher C, Meyer D. Molecular genetics of von Willebrand disease. Ann Genet. 1998;41:34-43.
Muczynski V, Casari C, Moreau F, et al. A factor VIII-nanobody fusion protein forming an ultrastable complex with VWF: effect on clearance and antibody formation. Blood. 2018;132:1193-1197. doi:10.1182/blood-2018-01-829523
Chia J, Pestel S, Glauser I, et al. Increased potency of recombinant VWF D'D3 albumin fusion proteins engineered for enhanced affinity for coagulation factor VIII. J Thromb Haemost. 2021;19:2710-2725. doi:10.1111/jth.15480
Yee A, Gildersleeve RD, Gu S, et al. A von Willebrand factor fragment containing the D'D3 domains is sufficient to stabilize coagulation factor VIII in mice. Blood. 2014;124:445-452. doi:10.1182/blood-2013-11-540534
Fuller JR, Knockenhauer KE, Leksa NC, Peters RT, Batchelor JD. Molecular determinants of the factor VIII/von Willebrand factor complex revealed by BIVV001 cryo-electron microscopy. Blood. 2021;137:2970-2980. doi:10.1182/blood.2020009197
Dagil L, Troelsen KS, Bolt G, et al. Interaction between the a3 region of factor VIII and the TIL'E' somains of the von Willebrand factor. Biophys J. 2019;117:479-489. doi:10.1016/j.bpj.2019.07.007
Przeradzka MA, Freato N, Boon-Spijker M, et al. Unique surface-exposed hydrophobic residues in the C1 domain of factor VIII contribute to cofactor function and von Willebrand factor binding. J Thromb Haemost. 2020;18:364-372. doi:10.1111/jth.14668
Yee A, Oleskie AN, Dosey AM, et al. Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII. Blood. 2015;126:939-942. doi:10.1182/blood-2015-04-641696
Saenko EL, Shima M, Rajalakshmi KJ, Scandella D. A role for the C2 domain of factor VIII in binding to von Willebrand factor. J Biol Chem. 1994;269:11601-11605.
Dong X, Leksa NC, Chhabra ES, et al. The von Willebrand factor D'D3 assembly and structural principles for factor VIII binding and concatemer biogenesis. Blood. 2019;133:1523-1533. doi:10.1182/blood-2018-10-876300
Eaton D, Rodriguez H, Vehar GA. Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity. Biochemistry. 1986;25:505-512.
Muntean W, Leschnik B, Haas J. Factor VIII coagulant moiety binds to platelets by binding to phospholipids of the platelet membrane. Thromb Res. 1987;45:345-354. doi:10.1016/0049-3848(87)90223-4
Chatterjee M, Meeks S, Novakovic VA, Gilbert GE. Discordance between platelet-supported and vesicle-supported factor VIII activity in the presence of anti-C2 domain inhibitory antibodies. J Thromb Haemost. 2020;18:3184-3193. doi:10.1111/jth.14961
Gilbert GE, Novakovic VA, Shi J, Rasmussen J, Pipe SW. Platelet binding sites for factor VIII in relation to fibrin and phosphatidylserine. Blood. 2015;126:1237-1244. doi:10.1182/blood-2015-01-620245
Scandella D, Gilbert GE, Shima M, et al. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site. Blood. 1995;86:1811-1819.
Pratt KP, Shen BW, Takeshima K, Davie EW, Fujikawa K, Stoddard BL. Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature. 1999;402:439-442. doi:10.1038/46601
Liu Z, Lin L, Yuan C, et al. Trp2313-His2315 of factor VIII C2 domain is involved in membrane binding: structure of a complex between the C2 domain and an inhibitor of membrane binding. J Biol Chem. 2010;285:8824-8829. doi:10.1074/jbc.M109.080168
Macedo-Ribeiro S, Bode W, Huber R, et al. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature. 1999;402:434-439. doi:10.1038/46594
Gilbert GE, Drinkwater D. Specific membrane binding of factor VIII is mediated by O-phospho-L-serine, a moiety of phosphatidylserine. Biochemistry. 1993;32:9577-9585. doi:10.1021/bi00088a009
Gish JS, Jarvis L, Childers KC, et al. Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor. Blood. 2021;137:2981-2986. doi:10.1182/blood.2020008940
Ronayne EK, Peters SC, Gish JS, et al. Structure of blood coagulation factor VIII in complex with an anti-C2 domain non-classical, pathogenic antibody inhibitor. Front Immunol. 2021;12:697602. doi:10.3389/fimmu.2021.697602
Spiegel PC Jr, Jacquemin M, Saint-Remy JM, Stoddard BL, Pratt KP. Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood. 2001;98:13-19. doi:10.1182/blood.v98.1.13
Walter JD, Werther RA, Brison CM, et al. Structure of the factor VIII C2 domain in a ternary complex with 2 inhibitor antibodies reveals classical and nonclassical epitopes. Blood. 2013;122:4270-4278. doi:10.1182/blood-2013-08-519124
Stoilova-McPhie S. Factor VIII and factor V membrane bound complexes. Subcell Biochem. 2021;96:153-175. doi:10.1007/978-3-030-58971-4_2
Hsu TC, Pratt KP, Thompson AR. The factor VIII C1 domain contributes to platelet binding. Blood. 2008;111:200-208. doi:10.1182/blood-2007-01-068957
Lu J, Pipe SW, Miao H, Jacquemin M, Gilbert GE. A membrane-interactive surface on the factor VIII C1 domain cooperates with the C2 domain for cofactor function. Blood. 2011;117:3181-3189. doi:10.1182/blood-2010-08-301663
Gilbert GE, Kaufman RJ, Arena AA, Miao H, Pipe SW. Four hydrophobic amino acids of the factor VIII C2 domain are constituents of both the membrane-binding and von Willebrand factor-binding motifs. J Biol Chem. 2002;277:6374-6381. doi:10.1074/jbc.M104732200
Meems H, Meijer AB, Cullinan DB, Mertens K, Gilbert GE. Factor VIII C1 domain residues Lys 2092 and Phe 2093 contribute to membrane binding and cofactor activity. Blood. 2009;114:3938-3946. doi:10.1182/blood-2009-01-197707
Batsuli G, Deng W, Healey JF, et al. High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors. Blood. 2016;128:2055-2067. doi:10.1182/blood-2016-02-701805
Meeks SL, Healey JF, Parker ET, Barrow RT, Lollar P. Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation. Blood. 2007;110:4234-4242. doi:10.1182/blood-2007-06-096842
Pantazatos D, Gessner CR, Woods VL Jr, Gilbert GE. Changes in the factor VIII C2 domain upon membrane binding determined by hydrogen-deuterium exchange MS. Biochem J. 2014;461:443-451. doi:10.1042/BJ20140121
Kolkman JA, Mertens K. Insertion loop 256-268 in coagulation factor IX restricts enzymatic activity in the absence but not in the presence of factor VIII. Biochemistry. 2000;39:7398-7405. doi:10.1021/bi992735q
Sichler K, Kopetzki E, Huber R, Bode W, Hopfner KP, Brandstetter H. Physiological fIXa activation involves a cooperative conformational rearrangement of the 99-loop. J Biol Chem. 2003;278:4121-4126. doi:10.1074/jbc.M210722200
Zogg T, Brandstetter H. Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa. Structure. 2009;17:1669-1678. doi:10.1016/j.str.2009.10.011
Freato N, Ebberink E, van Galen J, et al. Factor VIII-driven changes in activated factor IX explored by hydrogen-deuterium exchange mass spectrometry. Blood. 2020;136:2703-2714. doi:10.1182/blood.2020005593
Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med. 2009;361:1671-1675. doi:10.1056/NEJMoa0904377
Wu W, Xiao L, Wu X, et al. Factor IX alteration p.Arg338Gln (FIX Shanghai) potentiates FIX clotting activity and causes thrombosis. Haematologica. 2021;106:264-268. doi:10.3324/haematol.2019.216713
Samelson-Jones BJ, Finn JD, Raffini LJ, et al. Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants. Blood Adv. 2021;5:1324-1332. doi:10.1182/bloodadvances.2019000405
Ruben EA, Rau MJ, Fitzpatrick JAJ, Di Cera E. Cryo-EM structures of human coagulation factors V and Va. Blood. 2021;137:3137-3144. doi:10.1182/blood.2021010684
Lechtenberg BC, Murray-Rust TA, Johnson DJ, et al. Crystal structure of the prothrombinase complex from the venom of Pseudonaja textilis. Blood. 2013;122:2777-2783. doi:10.1182/blood-2013-06-511733
Ruben EA, Summers B, Rau MJ, Fitzpatrick J, Di Cera E. Cryo-EM structure of the prothrombin-prothrombinase complex. Blood. 2022;139:3463-3473. doi:10.1182/blood.2022015807
Mutucumarana VP, Duffy EJ, Lollar P, Johnson AE. The active site of factor IXa is located far above the membrane surface and its conformation is altered upon association with factor VIIIa. A fluorescence study. J Biol Chem. 1992;267:17012-17021.
Bajaj SP, Schmidt AE, Mathur A, et al. Factor IXa:factor VIIIa interaction. helix 330-338 of factor IXa interacts with residues 558-565 and spatially adjacent regions of the a2 subunit of factor VIIIa. J Biol Chem. 2001;276:16302-16309. doi:10.1074/jbc.M011680200
Fay PJ, Beattie T, Huggins CF, Regan LM. Factor VIIIa A2 subunit residues 558-565 represent a factor IXa interactive site. J Biol Chem. 1994;269:20522-20527.
Soeda T, Nogami K, Nishiya K, et al. The factor VIIIa C2 domain (residues 2228-2240) interacts with the factor IXa Gla domain in the factor Xase complex. J Biol Chem. 2009;284:3379-3388. doi:10.1074/jbc.M804955200
Mathur A, Bajaj SP. Protease and EGF1 domains of factor IXa play distinct roles in binding to factor VIIIa. Importance of helix 330 (helix 162 in chymotrypsin) of protease domain of factor IXa in its interaction with factor VIIIa. J Biol Chem. 1999;274:18477-18486. doi:10.1074/jbc.274.26.18477
Wilkinson FH, Ahmad SS, Walsh PN. The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex. J Biol Chem. 2002;277:5734-5741. doi:10.1074/jbc.M107753200
Lacroix-Desmazes S, Voorberg J, Lillicrap D, Scott DW, Pratt KP. Tolerating factor VIII: recent progress. Front Immunol. 2019;10:2991. doi:10.3389/fimmu.2019.02991
Jacquemin MG, Desqueper BG, Benhida A, et al. Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with inhibitor. Blood. 1998;92:496-506.
Shima M, Scandella D, Yoshioka A, et al. A factor VIII neutralizing monoclonal antibody and a human inhibitor alloantibody recognizing epitopes in the C2 domain inhibit factor VIII binding to von Willebrand factor and to phosphatidylserine. Thromb Haemost. 1993;69:240-246.
Saenko EL, Shima M, Gilbert GE, Scandella D. Slowed release of thrombin-cleaved factor VIII from von Willebrand factor by a monoclonal and a human antibody is a novel mechanism for factor VIII inhibition. J Biol Chem. 1996;271:27424-27431. doi:10.1074/jbc.271.44.27424
Kahle J, Orlowski A, Stichel D, et al. Frequency and epitope specificity of anti-factor VIII C1 domain antibodies in acquired and congenital hemophilia A. Blood. 2017;130:808-816. doi:10.1182/blood-2016-11-751347
Walter JD, Werther RA, Polozova MS, et al. Characterization and solution structure of the factor VIII C2 domain in a ternary complex with classical and non-classical inhibitor antibodies. J Biol Chem. 2013;288:9905-9914. doi:10.1074/jbc.M112.424564
Wuerth ME, Cragerud RK, Spiegel PC. Structure of the human factor VIII C2 domain in complex with the 3E6 inhibitory antibody. Sci Rep. 2015;5:17216. doi:10.1038/srep17216
Dimitrov JD, Roumenina LT, Plantier JL, et al. A human FVIII inhibitor modulates FVIII surface electrostatics at a VWF-binding site distant from its epitope. J Thromb Haemost. 2010;8:1524-1531. doi:10.1111/j.1538-7836.2010.03878.x
Markovitz RC, Healey JF, Parker ET, Meeks SL, Lollar P. The diversity of the immune response to the A2 domain of human factor VIII. Blood. 2013;121:2785-2795. doi:10.1182/blood-2012-09-456582
Eubanks J, Baldwin WH, Markovitz R, et al. A subset of high-titer anti-factor VIII A2 domain antibodies is responsive to treatment with factor VIII. Blood. 2016;127:2028-2034. doi:10.1182/blood-2015-09-670034