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Thromb Haemost 2001; 86(01): 83-91
DOI: 10.1055/s-0037-1616204
Research Article
Schattauer GmbH

Antiphospholipid Syndrome: Diagnostic Aspects of Lupus Anticoagulants

J. Arnout
1   Center for Molecular and Vascular Biology University of Leuven, Belgium
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Publication History

Publication Date:
12 December 2017 (online)

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Summary

Antiphospholipid syndrome (APS) is an autoimmune disorder in which antiphospholipid antibodies (aPL) are thought to be involved in the development of venous and/or arterial thrombosis. APL found in this syndrome are antibodies directed against a variety of phospholipid (PL) binding-proteins of which β2-glycoprotein I (β2GPI) and prothrombin are considered to be the major antigens. Some of these antibodies prolong PL-dependent clotting reactions and are termed lupus anticoagulants (LA). Autoimmune aPL which bind through β2GPI to cardiolipin are called anticardiolipin antibodies (aCL). Clinical studies indicate that LA is a stronger risk factor for thrombosis than aCL. The production of monoclonal antibodies against β2GPI and prothrombin has enabled us to understand the mechanism by which LA prolong coagulation in vitro. LA form bivalent antigen-antibody complexes with increased affinity for PL which compete with coagulation factors for the same catalytic surface. These LA positive monoclonal antibodies may be helpful in further improving the laboratory diagnosis of LA.

Key words

Lupus anticoagulant - antiphospholipid antibodies - beta-2-glycoprotein I - antiprothrombin antibodies
 

  • References

  • 1 Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, Triplett DA, Khamashta MA. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-11.
    CrossrefPubMedGoogle Scholar
  • 2 Moore JE, Lutz WB. The natural history of systemic lupus erythematosus: an approach to its study through chronic biologic false-positive reactions. J Chronic Dis 1955; 1: 297-316.
    CrossrefPubMedGoogle Scholar
  • 3 Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 1952; 31: 621-2.
    PubMedGoogle Scholar
  • 4 Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Hemost Thromb 1972; 1: 75-95.
    PubMedGoogle Scholar
  • 5 Bowie EJW, Thompson Jr JH, Pascuzzi CA, Owen Jr CA. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med 1963; 62: 416-30.
    PubMedGoogle Scholar
  • 6 Laurell AB, Nilsson IM. Hypergammaglobulinaemia, circulating anticoagulant, and biologic false positive Wassermann reaction: a study of 2 cases. J Lab Clin Med 1957; 49: 694-707.
    PubMedGoogle Scholar
  • 7 Thiagarajan P, Shapiro SS, De Marco L. Monoclonal immunoglobulin M coagulation inhibitor with phospholipid specificity. Mechanism of lupus anticoagulant. J Clin Invest 1980; 66: 397-405.
    CrossrefPubMedGoogle Scholar
  • 8 Triplett DA, Brandt JT, Kaczor D, 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: 678-82.
    CrossrefPubMedGoogle Scholar
  • 9 Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GRV. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2: 1211-4.
    PubMedGoogle Scholar
  • 10 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: 682-98.
    CrossrefPubMedGoogle Scholar
  • 11 Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-4.
    CrossrefPubMedGoogle Scholar
  • 12 Alarcon-Segovia D, Sanchez-Guerrero J. Primary antiphospholipid syndrome. J Rheumatol 1989; 16: 482-8.
    PubMedGoogle Scholar
  • 13 Carreras LO, Vermylen JG. Lupus anticoagulant and thrombosis – possible role of inhibition of prostacyclin formation. Thromb Haemost 1982; 48: 38-40.
    PubMedGoogle Scholar
  • 14 Elias M, Eldor A. Thromboembolism in patients with the “lupus”-type circulating anticoagulant. Arch Intern Med 1984; 144: 510-5.
    CrossrefPubMedGoogle Scholar
  • 15 Lechner K, Pabinger-Fasching I. Lupus anticoagulants and thrombosis. A study of 25 cases and review of the literature. Haemostasis 1985; 15: 254-62.
    PubMedGoogle Scholar
  • 16 Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ. Lupus anticoagulant: an analysis of the clinical and laboratory features of 219 cases. Am J Hematol 1985; 19: 265-75.
    CrossrefPubMedGoogle Scholar
  • 17 Triplett DA, Brandt JT, Maas RL. The laboratory heterogeneity of lupus anticoagulants. Arch Pathol Lab Med 1985; 109: 946-51.
    PubMedGoogle Scholar
  • 18 Harris EN, Gharavi AE, Patel SP, Hughes GRV. Evaluation of the anticardiolipin antibody test: report of an international workshop held on April 1986. Clin Exp Immunol 1987; 68: 215-22.
    PubMedGoogle Scholar
  • 19 Wahl DG, Guillemin F, de Maistre E, Perret C, Lecompte T, Thibaut G. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus – a meta-analysis. Lupus 1997; 6: 467-73.
    CrossrefPubMedGoogle Scholar
  • 20 Wahl DG, Guillemin F, de Maistre E, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7: 15-22.
    CrossrefPubMedGoogle Scholar
  • 21 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta-2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4.
    CrossrefPubMedGoogle Scholar
  • 22 Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van BredaVriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-7.
    CrossrefPubMedGoogle Scholar
  • 23 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-8.
    PubMedGoogle Scholar
  • 24 Galli M, Comfurius P, Barbui T, Zwaal RF, Bevers EM. Anticoagulant activity of beta 2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies. Thromb Haemost 1992; 68: 297-300.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Oosting JD, Derksen RH, Entjes HT, Bouma BN, de Groot PhG. Lupus anticoagulant activity is frequently dependent on the presence of beta 2-glycoprotein I. Thromb Haemost 1992; 67: 499-502.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Roubey RA, Pratt CW, Buyon JP, Winfield JB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon beta 2-glycoprotein I. J Clin Invest 1992; 90: 1100-4.
    CrossrefPubMedGoogle Scholar
  • 27 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-32.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Permpikul P, Rao LV, Rapaport SI. Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. Blood 1994; 83: 2878-92.
    PubMedGoogle Scholar
  • 29 McIntyre JA, Wagenknecht DR, Sugi T. Phospholipid binding plasma proteins required for antiphospholipid antibody detection-an overview. Am J Reprod Immunol 1997; 37: 101-10.
    CrossrefPubMedGoogle Scholar
  • 30 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-32.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?. Blood 1993; 81: 2618-25.
    PubMedGoogle Scholar
  • 32 Matsuda J, Saitoh N, Gohchi K, Gotoh M, Tsukamoto M. Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody. Am J Hematol 1994; 47: 56-8.
    CrossrefPubMedGoogle Scholar
  • 33 Willems GM, Janssen MP, Pelsers MMAL, Comfurius P, Galli M, Zwaal RFA, Bevers EM. Role of divalency in the high-affinity binding of anticardiolipin antibody-2-glycoprotein I complexes to lipid membranes. Biochemistry 1996; 35: 13833-42.
    CrossrefPubMedGoogle Scholar
  • 34 Takeya H, Mori T, Gabazza EC, Kuroda K, Deguchi H, Matsuura E, Ichikawa K, Koike T, Suzuki K. Anti-2-Glycoprotein I (2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the 2GPI binding to phospholipids. J Clin Invest 1997; 99: 2260-8.
    CrossrefPubMedGoogle Scholar
  • 35 Arnout J, Wittevrongel C, Vanrusselt M, Hoylaerts M, Vermylen J. Beta-2-glycoprotein I dependent lupus anticoagulants form stable bivalent antibody-beta-2-glycoprotein I complexes on phospholipid surfaces. Thromb Haemost 1998; 79: 79-86.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Lutters BC, Meijers JC, Derksen RH, Arnout J, de Groot PG. Dimers of beta-2-glycoprotein I mimic the in vitro effects of beta-2-glycoprotein I-anti-beta-2-glycoprotein I antibody complexes. J Biol Chem 2001; 276: 3060-7.
    CrossrefPubMedGoogle Scholar
  • 37 Harper MF, Hayes PM, Lentz B, Roubey RAS. Characterization of ß2-glycoprotein I binding to phospholipid membranes. Thromb Haemost 1998; 80: 610-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Wurm H. Beta 2-glycoprotein I (apolipoprotein H) interactions with phospholipid vesicles. Int J Biochem 1984; 16: 511-5.
    CrossrefPubMedGoogle Scholar
  • 39 Arnout J, Vanrusselt M, Nevens C, Smans K, Wittevrongel C, Vermylen J. Murine monoclonal antibodies against prothrombin with lupus anticoagulant activity: mechanism of action and reactivity. (manuscript in preparation).
    PubMedGoogle Scholar
  • 40 Exner T, Triplett DA, Taberner D, Machin SJ. Guidelines for testing and revised criteria for lupus anticoagulants. Thromb Haemost 1991; 65: 320-2.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995; 74: 1185-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Exner T, Rickard KA, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol 1978; 40: 143-51.
    CrossrefPubMedGoogle Scholar
  • 43 Alving BM, Baldwin PE, Richards RL, Jackson BJ. The dilute phospholipid APTT: a sensitive assay for verification of lupus anticoagulants. Thromb Haemost 1985; 54: 709-12.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Arnout J, Vanrusselt M, Huybrechts E, Vermylen J. Optimisation of the dilute prothrombin time for the detection of the lupus anticoagulant by use of a recombinant tissue thromboplastin. Br J Haematol 1994; 87: 94-9.
    CrossrefPubMedGoogle Scholar
  • 45 Schleider MA, Nachman RL, Jaffe EA, Coleman M. A clinical study of the lupus anticoagulant. Blood 1976; 48: 499-509.
    PubMedGoogle Scholar
  • 46 Thiagarajan P, Pengo V, Shapiro SS. The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 1986; 68: 869-74.
    PubMedGoogle Scholar
  • 47 Triplett DA, Stocker KF, Unger GA, Barna LK. The Textarin/Ecarin ratio: a confirmatory test for lupus anticoagulants. Thromb Haemost 1993; 70: 925-32.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Blanco AN, Grand BE, Pieroni G, Penalva LB, Voto LS, Lazzari MA. Behavior of diluted activated partial thromboplastin time in pregnant women with a lupus anticoagulant. Am J Clin Pathol 1993; 100: 99-102.
    CrossrefPubMedGoogle Scholar
  • 49 Galli M, Finazzi G, Bevers EM, Barbui T. Kaolin clotting time and dilute Russell’s viper venom time distinguish between prothrombin-dependent and beta-2-glycoprotein I-dependent antiphospholipid antibodies. Blood 1995; 86: 617-23.
    PubMedGoogle Scholar
  • 50 Arnout J, Vanrusset M, Wittevrongel C, Vermylen J. Monoclonal Antibodies against beta-2-Glycoprotein I: Use as reference material for lupus anticoagulant tests. Thromb Haemost 1998; 79: 955-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Arnout J, Vanrusselt M, Nevens C, Smans K, Wittevrongel C, Vermylen J. Some murine monoclonal antibodies against human prothrombin have lupus anticoagulant activity. Thromb Haemost. 1999 Suppl August: 65a (abstr).
    PubMedGoogle Scholar
  • 52 Robert A. Two different incubation times for the activated partial thromboplastin time (APTT): a new criterion for diagnosis of lupus anticoagulant. Thromb Haemost 1994; 71: 220-4.
    CrossrefPubMedGoogle Scholar
  • 53 Pengo V, Brocco T, Biasiolo A, Rampazzo P, Carraro P, Zamarchi R. Procoagulant effect of anti-beta2-glycoprotein I antibodies with lupus anticoagulant activity. Blood 1999; 94: 3814-9.
    PubMedGoogle Scholar
  • 54 Arnout J, Meijer P, Vermylen J. Lupus anticoagulant testing in Europe: an analysis of results from the first European Concerted Action on Thrombophilia (ECAT) survey using plasmas spiked with monoclonal antibodies against human beta2-glycoprotein I. Thromb Haemost 1999; 81: 929-34.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Triplett DA. Use of the dilute Russell viper venom time (dRVVT): Its importance and pitfalls. J Autoimmun 2000; 15: 173-8.
    CrossrefPubMedGoogle Scholar
  • 56 Petri M, Rheinschmidt M, Whiting-O’Keefe Q, Hellmann D, Corash L. The frequency of lupus anticoagulant in systemic lupus erythematosus. A study of sixty consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987; 106: 524-31.
    CrossrefPubMedGoogle Scholar
  • 57 Galli M, Finazzi G, Norbis F, Marziali S, Marchioli R, Barbui T. The risk of thrombosis in patients with lupus anticoagulants is predicted by their specific coagulation profile. Thromb Haemost 1999; 81: 695-700.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Exner T. Conceptions and misconceptions in testing for lupus anticoagulants. J Autoimmun 2000; 15: 179-83.
    CrossrefPubMedGoogle Scholar
  • 59 Male C, Lechner K, Speiser W, Pabinger I. Transient lupus anticoagulants in children: stepwise disappearance of diagnostic features. Thromb Haemost 2000; 83: 174-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Clyne LP, White PF. Time dependency of lupuslike anticoagulants. Arch Intern Med 1988; 148: 1060-3.
    CrossrefPubMedGoogle Scholar
  • 61 Arnout J, Huybrechts E, Vanrusselt M, Vermylen J. A new lupus anticoagulant neutralization test based on platelet-derived vesicles. Br J Haematol 1992; 80: 341-6.
    CrossrefPubMedGoogle Scholar
  • 62 Triplett DA, Brandt JT, Kaczor D, 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: 678-82.
    CrossrefPubMedGoogle Scholar
  • 63 Moore GW, Savidge GF, Smith MP. Improved detection of lupus anticoagulants by the dilute Russell’s Viper venom time. Blood Coagul Fibrinolysis 2000; 11: 767-74.
    CrossrefPubMedGoogle Scholar
  • 64 Rauch J, Tannenbaum M, Janoff AS. Distinguishing plasma lupus anticoagulants from anti-factor antibodies using hexagonal (II) phase phospholipids. Thromb Haemost 1989; 62: 892-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 65 Triplett DA, Barna LK, Unger GA. A hexagonal (II) phase phospholipid neutralization assay for lupus anticoagulant identification. Thromb Haemost 1993; 70: 787-93.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Rauch J, Tannenbaum M, Neville C, Fortin PR. Inhibition of lupus anticoagulant activity by hexagonal phase phosphatidylethanolamine in the presence of prothrombin. Thromb Haemost 1998; 80: 936-41.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Safa O, Crippa L, Della Valle P, Sabbadini MG, Vigano D’Angelo S, D’Angelo A. IgG reactivity to phospholipid-bound beta-2-glycoprotein I is the main determinant of the fraction of lupus anticoagulant activity quenched by addition of hexagonal (II) phase phospholipid in patients with the clinical suspicion of antiphospholipid-antibody syndrome. Haematologica 1999; 84: 829-38.
    PubMedGoogle Scholar
  • 68 Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the Second International Workshop for Identification of Lupus Anticoagulants. On behalf of the Subcommittee on Lupus Anticoagulants/Antiphospholipid Antibodies of the ISTH. Thromb Haemost 1995; 74: 1597-603.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Arnout J, Meijer P, Vermylen J. Misdiagnosis of LA. Results from a European Concerted Action on Thrombophilia (ECAT) survey using plasma with a spontaneous factor VIII inhibitor. (manuscript in preparation)
    PubMedGoogle Scholar
  • 70 Denis-Magdelaine A, Flahault A, Verdy E. Sensitivity of sixteen aPTT reagents for the presence of lupus anticoagulants. Haemostasis 1995; 25: 98-105.
    PubMedGoogle Scholar
  • 71 Brandt JT, Triplett DA, Musgrave K, Orr C. The sensitivity of different coagulation reagents to the presence of lupus anticoagulant. Arch Pathol Lab Med 1987; 111: 120-4.
    PubMedGoogle Scholar
  • 72 Brancaccio V, Ames PRJ, Glynn J, Iannaccone L, Mackie IJ. A rapid screen for lupus anticoagulant with good discrimination from oral anticoagulants, congenital factor deficiency and heparin, is provided by comparing a sensitive and an insensitive aPTT reagent. Blood Coagul Fibrinolysis 1997; 8: 155-60.
    CrossrefPubMedGoogle Scholar
  • 73 Erkan D, Bateman H, Lockshin MD. Lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus: report of 2 cases and review of literature. Lupus 1999; 8: 560-4.
    CrossrefPubMedGoogle Scholar
  • 74 Jones DW, Gallimore MJ, MacKie IJ, Harris SL, Winter M. Reduced factor XII levels in patients with the antiphospholipid syndrome are associated with antibodies to factor XII. Br J Haematol 2000; 110: 721-6.
    CrossrefPubMedGoogle Scholar
  • 75 Roussi J, Roisin JP, Goguel A. Lupus anticoagulants. First French inter-laboratory etalanorme survey. Am J Clin Pathol 1996; 105: 788-93.
    CrossrefPubMedGoogle Scholar
  • 76 Jennings I, Kitchen S, Woods TAL, Preston FE, Greaves M. Clinically important inaccuracies in testing for the lupus anticoagulant: an analysis of results from three surveys of the UK national external quality assessment scheme (NEQAS) for blood coagulation. Thromb Haemost 1997; 77: 934-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 Gray E, Mackie I, Greaves M. Calibration of the 1st British reference plasma panel for lupus anticoagulants. Br J Haematol 1998; 105 (Suppl. 01) 97.
    PubMedGoogle Scholar
  • 78 A Le Querrec, J Arnout, D Arnoux, JY Borg, C Caron, L Darnige, B Delahousse, G Reber and P Sié, for the Groupe d’Etudes sur l’Hémostase et la Thrombose (GEHT).. Quantification of lupus anticoagulants in clinical samples using anti-α2GP1 and anti-prothrombin monoclonal antibodies. Thromb Haemost. (In press).
    PubMedGoogle Scholar