Anti-factor VIII Inhibitors and Lupus Anticoagulants in Haemophilia A Patients

Summary

In a study of 170 haemophilia A patients, 43 were found to have an inhibitory effect; seven had anti-factor VIII inhibitors (a-fVIII) (A), 18 had lupus anticoagulants (LAs) with a strong (B: 12) or weak (C: 6) time-dependent effect and 18 had no time-dependent LAs (D). The a-fVIII showed a neutralizing effect only against factor VIII and negative diluted Russell viper venom time (dRVVT). The LAs were diagnosed by dRVVT; the Staclot® LA agreed with the dRVVT. During the study, three patients changed from an a-fVIII to an LA pattern; they also modified their clinical response.

Our prevalence of a-fVIII was low (4%) and we found 21% of LA, with a high (50%) prevalence of time-dependent inhibition. This pattern raises the possibility of the coexistence of LA and a-fVIII, stressing the need to develop specific tests to identify a-fVIII and LA.

• References

• 1 Aledort L. Inhibitors in hemophilia patients: Current status and management. Am J Hematol 1994; 47: 208-217
• 2 Sanchez-Cuenca JM, Carmona E, Villanueva MJ, Aznar JA. Immunological characterization of factor VIII inhibitors by a sensitive micro-ELISA method. Thromb Res 1990; 57: 897-908
• 3 Fulcher CA. Immunochemistry of factor VIII:C inhibitor antibodies. Am J Med 1991; 91 (Suppl. 05) 6S-8S
• 4 Hoyer LW, Gawryl MS, de laFuente B. Immunochemical characterization of factor VIII Inhibitors. In: Factor VIII Inhibitors. Hoyer LW. ed. Alan R Liss; Inc, New York: 1984. pp 73-85
• 5 Fulcher CA, de GraafMahoney S, Roberts JR, Kasper CK, Zimmerman TS. Localization of human factor VIII inhibitor epitopes to two polypeptide fragments. Proc Natl Acad Sci USA 1985; 82: 7728-7732
• 6 Arai M, Scandella D, Hoyer LW. Molecular basis of factor VIII inhibition by human antibodies: Antibodies that bind to factor VIII light chains prevent the interaction of factor VIII with phospholipid. J Clin Invest 1989; 83: 1978-1984
• 7 Biggs R, Austen DEG, Denson KWE, Rizza CR, Borrett R. The mode of action of antibodies which destroy factor VIII: I. Antibodies which have secondorder concentration graphs. Br J Haematol 1972; 23: 125-135
• 8 Biggs R, Austen DEG, Denson KWE, Borrett R, Rizza CR. The mode of action of antibodies which destroy factor VIII: II. Antibodies which give complex concentration graph. Br J Haematol 1972; 23: 137-155
• 9 McMillan CW. Clinical patterns of hemophilic patients who develop inhibitors. Prog Clin Biol Res 1984; 150: 31-44
• 10 McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao VA, Lazerson J. and the Hemophilia Study Group The natural history of factor VIII: C inhibitors in patients with hemophilia A: A National Cooperative Study. II. Observations on the initial development of factor VIII: C inhibitors. Blood 1988; 71: 344-348
• 11 Addiego J, Kasper C, Abildgaard C, Hilgartner M, Lusher J, Glader B, Aledort L. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993; 342: 462-464
• 12 Leyva WH, Knutsen AP, Joist JH. Disappearance of a high responder factor VIII inhibitor in a hemophiliac with AIDS. Am J Clin Pathol 1988; 89: 414-418
• 13 Ragni MV, Bontempo FA, Lewis JH. Dissappearance of inhibitor to factor VIII in HIV-infected hemophiliacs with progession to AIDS or severe ARC. Transfusion 1989; 29: 447-449
• 14 Hoots K. An effect of HIV infection on factor VIII (FVIII) antibodies in hemophiliacs. Blood 1987; 70 (Suppl. 01) 343a (Abstr).
• 15 Bray GL, Kroner BL, Arkin S, Aledort LW, Hilgartner MW, Eyster ME, Ragni MV, Goedert JJ. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: A report from the Multi-Center Hemophilia Cohort Study. Am J Hematol 1993; 42: 375-379
• 16 Cohen H, Mackie JI, Anagnostopoulos N, Savage GF, Machin SJ. Lupus anticoagulant, anticardiolipin antibodies and human immunodeficiency virus in haemophilia. J Clin Pathol 1989; 42: 629-633
• 17 Triplett DA, Brandt JT. Lupus anticoagulants: misnomer, paradox, riddle, epiphenomenon. Hematologic Pathology 1988; 2: 121-143
• 18 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682-698
• 19 Exner T. Some recent developments with lupus anticoagulants. Blood Coagulation and Fibrinolysis 1994; 05: 281-289
• 20 Cohen AJ, Philips TM, Keffler CM. Circulating coagulation inhibitors in the acquired immunodeficiency syndrome. Ann Int Med 1986; 104: 175-180
• 21 Triplett DA. Protean clinical presentation of antiphospholipid-protein antibodies (APA). Thromb Haemost 1995; 74: 329-337
• 22 Triplett DA. Antiphospholipid-protein antibodies: laboratory detection and clinical relevance. Thromb Res 1995; 78: 01-31
• 23 Triplett DA, Brandt JT, Maas RL. The laboratory heterogeneity of lupus anticoagulants. Arch Pathol Lab Med 1985; 109: 946-951
• 24 Triplett DA. Laboratory diagnosis of lupus anticoagulants. Sem Thromb Haemost 1990; 16: 182-192
• 25 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of ISTH. Thromb Haemost 1995; 74: 1185-1190
• 26 Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin. Am J Clin Pathol 1961; 36: 212-218
• 27 Triplett DA, Brandt JT, Kaczor DJ, Schaeffer J. Laboratory diagnosis of lupus inhibitors: A comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983; 79: 678-682
• 28 Blanco AN, Grand BE, Pieroni G, Peñalva LB, Voto LS, Lazzari MA. Behaviour of diluted activated partial thromboplastin time in pregnant women with a lupus anticoagulant. Am J Clin Pathol 1993; 100: 099-102
• 29 Thiagarajan P, Pengo V, Shapiro SS. The use of the diluted Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 1986; 68: 869-874
• 30 Brandt JT, Triplett DA, Rock WA, Bovill EG, Arkin CF. Effect of lupus anticoagulants on the activated partial thromboplastin time: Results of the College of American Pathologists Survey Program. Arch Pathol Lab Med 1991; 115: 109-114
• 31 Green D, Hougie C, Kazmier FJ, Lechner K, Mannucci PM, Rizza CR, Sultan Y. Report of the working party on acquired inhibitors of coagulation: Studies of the “Lupus Anticoagulant”. Thromb Haemost 1983; 49: 144-146
• 32 Rauch J, Tannenbaum M, Janoff AS. Distinguishing plasma lupus anticoagulants from antifactor antibodies using hexagonal (II) phase phospholipids. Thromb Haemost 1989; 62: 892-896
• 33 Triplett DA, Bama LK, Unger GA. A hexagonal (II) phase phospholipid neutralization assay for lupus anticoagulant identification. Thromb Haemost 1993; 70: 787-793
• 34 Kasper CK, Aldedort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro SS, Shulman NR, van EyaJ. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869-872
• 35 Blanco A, Cardozo A, Esteves G, Candela M, Perez BiancoR, Lazzari M. Antifactor VIII inhibitor and lupus anticoagulant in hemophilia. A new diagnostic problem. Thromb Haemost 1995; 73: 1995a (Abstr).
• 36 Foster WM, Triplett DA, Bama LK. Evaluation of-7 dilute Russell viper venom (dRVVT) kits. Lupus 1994; 3: 155a (Abstr).
• 37 Triplett DA. New diagnostic strategies for lupus anticoagulants and antiphospholipid antibodies. Haemostasis 1994; 24: 155-163
• 38 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör T, Krackhardt B, Komhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598
• 39 Barrowcliffe TW, Kemball-Cook G, Gray E. Binding to phospholipid protects factor VIII from inactivation by human antibodies. J Lab Clin Med 1983; 101: 34-43
• 40 Bernard Ch, Bosser C, Exquis B, Tremblet Ch, Reber G, de MoerloosePh. Incidence of anticardiolipin antibodies in hemophiliac and non-hemophiliac patients with HIV-I antibodies. Thromb Haemost 1989; 62: 1176a (Abstr).
• 41 Al-Saeed A, Makris M, Malia RG, Preston FE, Greaves M. The development of antiphospholipid antibodies in haemophilia is linked to infection with hepatitis C. BrJ Haematol 1994; 88: 845-848