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Thromb Haemost 1996; 75(05): 721-724
DOI: 10.1055/s-0038-1650355
Original Article
Schattauer GmbH Stuttgart

Autoantibodies to Phospholipid-binding Plasma Proteins in Patients with Thrombosis and Phospholipid-reactive Antibodies

V Pengo
Division of Rheumatology, University of Padova, School of Medicine, Padova, Italy
,
A Biasiolo
Division of Rheumatology, University of Padova, School of Medicine, Padova, Italy
,
T Brocco
Division of Rheumatology, University of Padova, School of Medicine, Padova, Italy
,
S Tonetto
1   The Department of Cardiology, Thrombosis Center, School of Medicine, Padova, Italy
,
A Ruffatti
1   The Department of Cardiology, Thrombosis Center, School of Medicine, Padova, Italy
› Author Affiliations
Further Information

Publication History

Received 09 August 1995

Accepted after resubmission 18 December 1995

Publication Date:
10 July 2018 (online)

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Summary

Anti-phospholipid (aPL) antibodies are defined as antibodies detected in systems employing phospholipids (PL). This general definition is misleading as it comprises a large group of autoimmune phospholipid-reactive antibodies that are directed against specific phospholipid-binding plasma proteins, such as β2-glycoprotein I (β2GPI) and prothrombin. Definition of phospholipid-reacting antibodies according to the plasma protein against which they are directed appears more appropriate and could be useful in understanding clinical events and pathogenic mechanisms. Using ELISA systems we have studied the presence of antibodies directed against specific phospholipid-binding proteins in a series of 22 patients with thrombosis and phospholipid-reactive antibodies of the IgG isotype. High levels of anti-β2GPI IgG were detected in all 22 patients. Normal values were calculated on the basis of OD values at 405 nm (OD405) obtained for 22 age- and sex-matched healthy subjects (cut off value = 0.401). Levels of anti-β2GPI antibodies were linearly correlated with those of cardiolipin-reactive (aCL) antibodies. Eleven out of 22 patients (50%) had values of anti-prothrombin antibodies exceeding the cut-off value of 0.250. No relationship was found between the levels of anti-β2GPI and anti-prothrombin antibodies. Tests for antibodies against two natural inhibitors of blood coagulation, protein C and protein S, revealed elevated levels of anti-protein C IgG and anti-protein S IgG in 4 and 12 patients, respectively. A highly significant correlation between anti-protein C IgG and anti-protein S IgG values as well as between antibody titers against the two studied natural coagulation inhibitors and anti-prothrombin IgG was found. When comparing patients positive for aCL and presence or absence of a previous thrombotic episode (aCL+/T+ vs aCL+/T-), the positivity of anti-P2GPI IgG was found to be statistically associated with thrombosis. Conversely, among patients with previous thromboembolism with or without aCL (aCL+/T+ vs aCL-/T+) the positivity of anti-β2GPI IgG was strictly associated with the positivity of aCL, thus identifying the aPL antibody syndrome. These data demonstrate that anti-β2GPI antibodies are a marker of “autoimmune” thrombosis. Anti-prothrombin antibodies are not a marker of thrombosis and are closely associated with antibodies to protein C and protein S.

 

  • References

  • 1 Fiumara NJ. Biologic false positive reaction for syphilis. N Engl J Med 1963; 268: 402-405
    CrossrefPubMedSearch in Google Scholar
  • 2 Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Hemostas Thromb 1972; 1: 75-95
    PubMedSearch in Google Scholar
  • 3 Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CB, Loizou S, Hughes GRV. Anticardiolipin antibodies: detection by radioimmu-noassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2: 1211-1214
    PubMedSearch in Google Scholar
  • 4 Thiagarajan P, Shapiro SS, De Marco L. Monoclonal immunoglobulin MX coagulation inhibitor with phospholipid specificity. J Clin Invest 1980; 66: 397-405
    CrossrefPubMedSearch in Google Scholar
  • 5 Harris EN, Gharavi AE, Tincani A, Chan JKH, Englert H, Mantelli P, Allegro F, Balestrieri G, Hughes GVR. Affinity purified anti-cardiolipin and anti-DNA antibodies. J Clin Lab Immunol 1985; 155-162
    PubMedSearch in Google Scholar
  • 6 Pengo V, Thiagarajan P, Shapiro SS, Heine MJ. Immunologic specificity and mechanism of action of IgG lupus anticoagulant. Blood 1987; 70: 69-76
    PubMedSearch in Google Scholar
  • 7 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: ;2-Glycoprotein-I (Apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4124
    CrossrefPubMedSearch in Google Scholar
  • 8 Galli M, Comfurius P, Maassen C, Hemker HC, De Baets MH, Van Brieda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-1547
    CrossrefPubMedSearch in Google Scholar
  • 9 Matsuura E, Igarashi Y, Fujimoto M, Ichikava K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-178
    PubMedSearch in Google Scholar
  • 10 Matsuura E, Igarashi Y, Yasuda T, Koike T, Triplett DA. Anticardiolipin antibodies recognize β2-Glycoprotein-I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-462
    CrossrefPubMedSearch in Google Scholar
  • 11 Roubey RAS, Eisemberg RA, Harper MF, Winfield JB. “Anticardiolipin” autoantibodies recognize β2-Glycoprotein-I in the absence of phospholipids. J Immunol 1995; 154: 954-960
    PubMedSearch in Google Scholar
  • 12 Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid antibodies are directed against a cryptic epitope expressed when β2-Glycoprotein-I is bound to a suitable surface. Thromb Haemost 1995; 73: 29-34
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Galli M, Comfurius P, Barbui T, Zwaal RFA, Bevers EM. Anticoagulant activity of β2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies. Thromb Haemost 1992; 68: 297-300
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Brandt JT. Antibodies to β2-Glycoprotein-I inhibit phospholipid dependent coagulation reaction. Thromb Haemost 1993; 70: 598-602
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Roubey RAS, Pratt CW, Buyon JP, Winfield JB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon β2-glycoprotein I. J Clin Invest 1992; 90: 1100-1104
    CrossrefPubMedSearch in Google Scholar
  • 16 Matsuura E, Igashi Y, Fujimoto M, Ichikawa K, Suzuki T, Sumida T, Yasuda T, Koike T. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 3885-3891
    PubMedSearch in Google Scholar
  • 17 Fleck RA, Rapaport SI, Visajia Mohan RaoL. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512-519
    CrossrefPubMedSearch in Google Scholar
  • 18 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RFA. Lupus antico-agulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-632
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Janoff AS, Rauch J. The structural specificity of antiphospholipid antibodies in autoimmune disease. Chem Phys Lipids 1986; 40: 315-332
    CrossrefPubMedSearch in Google Scholar
  • 20 Harris EN. Syndrome of the Black swan. Br J Rheumatol 1987; 26: 324-326
    CrossrefPubMedSearch in Google Scholar
  • 21 Asherson RA. A “primary” antiphospholipid syndrome. J Rheumatol 1988; 15: 1742-1744
    PubMedSearch in Google Scholar
  • 22 Viard JP, Amoura Z, Bach JF. Association of anti-β2-glycoprotein I anti-bodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med 1992; 93: 181-186
    CrossrefPubMedSearch in Google Scholar
  • 23 Oosting JD, Derksen RHWM, Bobbink IWG, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipid with prothrombin, protein C or protein S: an explanation for their pathogenetic mechanism?. Blood 1993; 81: 2618-2625
    CrossrefPubMedSearch in Google Scholar
  • 24 Biasiolo A, Pengo V. Antiphospholipid antibodies are not present in the membrane of gel-filtered platelets of patients with IgG anticardiolipin antibodies, lupus anticoagulant and thrombosis. Blood Coag Fibrinol 1993; 4: 425-428
    CrossrefPubMedSearch in Google Scholar
  • 25 Harris EN, Gharavi AE, Patel SP, Hughes GVR. Evaluation of the anticardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol 1987; 68: 215-222
    PubMedSearch in Google Scholar
  • 26 Thiagarajan P, Pengo V, Shapiro SS. The use of dilute Russell Viper Venom Time for the diagnosis of lupus anticoagulants. Blood 1986; 68: 869-873
    PubMedSearch in Google Scholar
  • 27 Miletich JP, Jackson CM, Majerus PW. Properties of the factor Xa binding site on human platelets. J Biol Chem 1978; 253: 6908-6916
    PubMedSearch in Google Scholar
  • 28 Wagenknecht DR, McIntyre JA. Changes in β2-glycoprotein I antigenicity induced by phospholipid binding. Thromb Haemost 1993; 69: 361-365
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of anti-phospholipid antibodies by ELISA using β2-glycoprotein I as an antigen. J Immunol Meth 1991; 143: 223-229
    CrossrefPubMedSearch in Google Scholar
  • 30 Bajaj SP, Rapaport SI, Fierer DS, Herbst KD, Schwartz DB. A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-Lupus Anticoagulant syndrome. Blood 1983; 61: 684-692
    CrossrefPubMedSearch in Google Scholar
  • 31 Edson JR, Vogt JM, Hasegawa DK. Abnormal prothrombin crossed-immunoelectro-phoresis in patients with lupus inhibitors. Blood 1984; 64: 807-816
    PubMedSearch in Google Scholar
  • 32 Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992; 326: 800-806
    CrossrefPubMedSearch in Google Scholar
  • 33 Pengo V, Biasiolo A, Fior MG. Binding of autoimmune cardiolipin-reactive antibodies to heparin: a mechanism of thrombosis?. Thromb Res 1995; 78: 371-378
    CrossrefPubMedSearch in Google Scholar