Fine Mapping of Inhibitory Anti-factor V Antibodies Using Factor V C2 Domain Mutants

Tomonori Izumi; Suhng Wook Kim; Anne Greist; Sandra Macedo-Ribeiro; Pablo Fuentes-Prior; Wolfram Bode; William H. Kane; Thomas L. Ortel

doi:10.1055/s-0037-1615962

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 85(06): 1048-1054
DOI: 10.1055/s-0037-1615962

Review Article

Schattauer GmbH

Fine Mapping of Inhibitory Anti-factor V Antibodies Using Factor V C2 Domain Mutants

Identification of Two Antigenic Epitopes Involved in Phospholipid Binding

Tomonori Izumi

¹Division of Hematology, Departments of Medicine and Pathology, Duke University Medical Center, Durham, North Carolina, USA

,

Suhng Wook Kim^*

¹Division of Hematology, Departments of Medicine and Pathology, Duke University Medical Center, Durham, North Carolina, USA

,

Anne Greist

²Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USA

,

Sandra Macedo-Ribeiro^†

³Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Martinsried, Germany

,

Pablo Fuentes-Prior

³Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Martinsried, Germany

,

Wolfram Bode

³Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Martinsried, Germany

,

William H. Kane

¹Division of Hematology, Departments of Medicine and Pathology, Duke University Medical Center, Durham, North Carolina, USA

,

Thomas L. Ortel

¹Division of Hematology, Departments of Medicine and Pathology, Duke University Medical Center, Durham, North Carolina, USA

› Institutsangaben

Abstract

Summary

Hemorrhagic factor V inhibitors frequently bind to the second C-type (C2) domain of factor V and interfere with phospholipid binding. To define specific residues recognized by inhibitors from four patients (one bovine thrombin-induced and three spontaneous antibodies), epitope mapping was performed using recombinant human factor V lacking most of the B-type domain (FV des B) and alanine-substituted mutants within the C2 domain (FV des B C2 mutants). FV des B C2 mutants located in the region between Lys²⁰⁶⁰ and Glu²⁰⁶⁹ were resistant to inhibition by three IgG preparations including the bovine thrombin-induced antibody in both prothrombinase and phospholipid-binding assays. In contrast, mutations at Lys²⁰⁸⁷ and Lys²⁰⁹²/ Glu²⁰⁹⁶ were significantly resistant to inhibition by the fourth IgG preparation in both prothrombinase and phospholipid-binding assays. These results confirm interference of phospholipid binding by hemorrhagic factor V inhibitors and support the role(s) of these residues in phospholipid binding.

Presented in part at the 41st Annual Meeting of the American Society of Hematology, New Orleans, Louisiana, December 3–7, 1999

Key words

Factor V - hemorrhagic inhibitor - epitope mapping - C2 domain - phospholipid binding

Volltext

Referenzen

References
1 Ortel TL, Keller FG, Kane WH. Factor V. In: Molecular Biology of Thrombosis and Hemostasis. High KA, Roberts HR. eds. New York, NY: Dekker; 1995: 119-46.
2 Kane WH, Davie EW. Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 1988; 71: 539-55.
3 Ortel TL. Clinical and laboratory manifestations of anti-factor V antibodies. J Lab Clin Med 1999; 133: 326-34.
4 Nesheim ME, Nichols WL, Cole TL, Houston JG, Schenk RB, Mann KG, Bowie EJ. Isolation and study of an acquired inhibitor of human coagulation factor V. J Clin Invest 1986; 77: 405-15.
5 Ortel TL, Moore KD, Quinn-Allen MA, Okamura T, Sinclair AJ, Lazarchick J, Govindan R, Carmagnol F, Kane WH. Inhibitory anti-factor V antibodies bind to the factor V C2 domain and are associated with hemorrhagic manifestations. Blood 1998; 91: 4188-96.
6 Zehnder JL, Leung LL. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood 1990; 76: 2011-6.
7 Rapaport SI, Zivelin A, Minow RA, Hunter CS, Donnelly K. Clinical significance of antibodies to bovine and human thrombin and factor V after surgical use of bovine thrombin. Am J Clin Pathol 1992; 97: 84-91.
8 Cmolik BL, Spero JA, Magovern GJ, Clark RE. Redo cardiac surgery: late bleeding complications from topical thrombin- induced factor V deficiency. J Thorac Cardiovasc Surg 1993; 105: 222-7.
9 Ortel TL, Charles LA, Keller FG, Marcom PK, Oldham Jr HN, Kane WH, Macik BG. Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis. Am J Hematol 1994; 45: 128-35.
10 Ortel TL, Neal MC, Thames EH, Moore KD, Lawson JH. Immunologic Impact and Clinical Outcomes after Surgical Exposure to Bovine Thrombin. Ann Surg 2001; 233: 88-96.
11 Coots MC, Muhleman AF, Glueck HI. Hemorrhagic death associated with a high titer factor V inhibitor. Am J Hematol 1978; 4: 193-206.
12 Smid WM, de Wolf JT, Nijland JH, Bom VJ, van der Meer J. Severe bleeding caused by an inhibitor to coagulation factor V: a case report. Blood Coagul Fibrinolysis 1994; 5: 133-7.
13 Suehisa E, Toku M, Akita N, Fushimi R, Takano T, Tada H, Iwatani Y, Amino N. Study on an antibody against F1F2 fragment of human factor V in a patient with Hashimoto‘s disease and bullous pemphigoid. Thromb Res 1995; 77: 63-8.
14 Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, Bourenkov GP, Bartunik HD, Stubbs MT, Kane WH, Fuentes-Prior P. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature 1999; 402: 434-9.
15 Kim SW, Quinn-Allen MA, Camp T, Macedo-Ribeiro S, Fuentes-Prior P, Bode W, Kane WH. Identification of functionally important amino acid residues within C2 domain of human factor V using alanine scanning mutagenesis. Biochemistry 2000; 39: 1951-8.
16 Kane WH, Devore-Carter D, Ortel TL. Expression and characterization of recombinant human factor V and a mutant lacking a major portion of the connecting region. Biochemistry 1990; 29: 6762-8.
17 Ortel TL, Quinn-Allen MA, Keller FG, Peterson JA, Larocca D, Kane WH. Localization of functionally important epitopes within the second C-type domain of coagulation factor V using recombinant chimeras. J Biol Chem 1994; 269: 15898-905.
18 Ortel TL, Quinn-Allen MA, Charles LA, Devore-Carter D, Kane WH. Characterization of an acquired inhibitor to coagulation factor V. Antibody binding to the second C-type domain of factor V inhibits the binding of factor V to phosphatidylserine and neutralizes procoagulant activity. J Clin Invest 1992; 90: 2340-7.
19 Lewis DA, Moore KD, Ortel TL. Characterization of the phospholipid binding site in the second C-type domain of factor VIII [abstract]. Thromb Haemost 1999; 82: 235a.
20 Fasmann GD. Handbook of Biochemistry and Molecular Biology. Ohio: CRC press; 1976. p 383.
21 Ortel TL, Devore-Carter D, Quinn-Allen M, Kane WH. Deletion analysis of recombinant human factor V. Evidence for a phosphatidylserine binding site in the second C-type domain. J Biol Chem 1992; 267: 4189-98.
22 Nicolaes GAF, Villoutreix BO, Dahlbäch B. Mutations in a potential phospholipid binding loop in the C2 domain of factor V affecting the assembly of the prothrombinase complex. Blood Coagul Fibrinolysis 2000; 11: 89-100.
23 Guinto ER, Esmon CT, Mann KG, MacGillivray RT. The complete cDNA sequence of bovine coagulation factor V. J Biol Chem 1992; 267: 2971-8.
24 Lecompte MF, Bouix G, Mann KG. Electrostatic and hydrophobic interactions are involved in factor Va binding to membranes containing acidic phospholipids. J Biol Chem 1994; 269: 1905-10.
25 Bardelle C, Furie B, Furie BC, Gilbert GE. Membrane binding kinetics of factor VIII indicate a complex binding process. J Biol Chem 1993; 268: 8815-24.
26 Pipe SW, Kaufman RJ. Factor VIII C2 domain missense mutations exhibit defective trafficking of biologically functional proteins. J Biol Chem 1996; 271: 25671-6.
27 Arai M, Scandella D, Hoyer LW. Molecular basis of factor VIII inhibition by human antibodies. Antibodies that bind to the factor VIII light chain prevent the interaction of factor VIII with phospholipid. J Clin Invest 1989; 83: 1978-84.
28 Shima M, Scandella D, Yoshioka A, Nakai H, Tanaka I, Kamisue S, Terada S, Fukui H. 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: 240-6.
29 Pratt KP, Shen BW, Takeshima K, Davie EW, Fujikawa K, Stoddard BL. Structure of the C2 domain of human factor VIII at 1.5 Å resolution. Nature 1999; 402: 439-42.
30 Ortel TL, Moore KD. Factor VIII inhibitors that bind to the N-terminal region of the C2 domain neutralize procoagulant activity and block binding to phosphatidylserine [abstract]. Blood 1996; 83: 322a.
31 Hay CR, Ludlam CA, Colvin BT, Hill FG, Preston FE, Wasseem N, Bagnall R, Peake IR, Berntorp E, Mauser Bunschoten EP, Fijnvandraat K, Kasper CK, White G, Santagostino E. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation. Thromb Haemost 1998; 79: 762-6.