Antibodies to β₂-Glycoprotein I Associated with Antiphospholipid Syndrome Suppress the Inhibitory Activity of Tissue Factor Pathway Inhibitor

Summary

Anionic phospholipid membranes have a dual role in blood coagulation: they are essential for the initiation and propagation as well as for the limitation and termination of the blood coagulation process. Patients with the anti-phospholipid syndrome (APS) carrying antibodies against complexes of anionic phospholipids and plasma proteins, show in vitro inhibited phospholipid dependent coagulation reactions, whereas in vivo the presence of these antibodies is associated with an increased risk of thrombosis. In this study we focussed on the effects of these anti-phospholipid antibodies on the regulation of TF-mediated factor Xa (FXa) generation in plasma. We hypothesized that anti-phospholipid antibodies interfere with the phospholipiddependent inhibition by tissue factor pathway inhibitor (TFPI) of TFinduced coagulation. Indeed, total-IgG, anti-cardiolipin-IgG (aCL) and anti-β₂GPI-IgG, isolated from patient plasmas, all stimulated TF-induced FXa generation in normal plasma. This enhanced FXa generation was not observed when the patient’s IgG was depleted of anti-β₂GPI-IgG or when normal plasma was depleted of β₂GPI or TFPI. Taken together, these data indicate that antibodies to β₂GPI, circulating in patients with APS, suppress TFPI-dependent inhibition of TF-induced coagulation, which results in an increased FXa generation.

Key words

Tissue factor - TFPI - FXa generation - anti-β₂-glycoprotein I

• References

• 1 Rapaport SI, Rao LVM. The tissue factor pathway: how it has become a “primaballerina”. Thromb Haemost 1995; 74: 7-17.
• 2 Broze GJ. The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin Hematol 1992; 29: 159-69.
• 3 Kazama Y. The importance of the binding of Factor Xa to phospholipids in the inhibitory mechanism of tissue factor pathway inhibitor: the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory action of tissue factor pathway inhibitor. Thromb Haemost 1997; 77: 492-7.
• 4 Salemink I, Franssen J, Willems GM, Hemker HC, Lindhout T. Inhibition of tissue factor: factor VIIa-catalyzed factor X activation by factor Xa: tissue factor pathway inhibitor. A rotating disc study on the effect of phospholipid membrane composition. J Biol Chem 1999; 274: 28225-32.
• 5 Rauch J. Lupus anticoagulant antibodies: recognition of phospholipidbinding protein complex. Lupus 1998; 07: S29-S31.
• 6 Hughes GRV. Thrombosis, abortion, cerebral disease and the lupus anticoagulant. Br Med J 1983; 287: 1088-9.
• 7 Feinstein DI. Lupus anticoagulant, thrombosis and fetal loss. N Engl J Med 1985; 313: 1348-50.
• 8 Shapiro SS. The lupus anticoagulant/antiphospholipid syndrome. Annu Rev Med 1996; 47: 533-53.
• 9 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7.
• 10 Loizou S, McCrea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN. Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985; 62: 738-44.
• 11 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulant: an update. Thromb Haemost 1995; 74: 1185-90.
• 12 Sandset PM, Abildgaard U, Pettersen M. A sensitive assay of extrinsic pathway inhibitor (EPI) in plasma and plasma fractions. Thromb Res 1987; 47: 389-400.
• 13 Bach R, Gentry R, Nemerson Y. Factor VII binding to tissue factor in reconstituted phospholipid vesicles: induction of cooperativity by phosphatidylserine. Biochemistry 1986; 25: 4007-20.
• 14 Wurm H. β₂-glycoprotein I (apolipoprotein H) interactions with phospholipid vesicles. Int J Biochem 1984; 16: 511-5.
• 15 DiScipio RG, Hermodson MA, Yates SG, Davie EW. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry 1977; 16: 698-706.
• 16 Diaz-Collier JA, Palmier MO, Kretzmer KK, Bishop BF, Combs RG, Obukowicz MG, Frazier RB, Bild GS, Joy WD, Hill SR, Duffin KL, Gustafson ME, Junger KD, Grabner RW, Galluppi GR, Wun TC. Refold and characterization of recombinant tissue factor pathway inhibitor expressed in Escherichia coli. Thromb Haemost 1994; 71: 339-46.
• 17 Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van Breda PJVriesman, Barbui T, Zwaal RF, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-7.
• 18 Willems GM, Janssen MP, Pelsers MM, Comfurius P, Galli M, Zwaal RFA, Bevers E. Role of divalency in the high-affinity binding of anticardiolipin antibody-β₂-glycoprotein I complexes to lipid membranes. Biochemistry 1996; 35: 13833-42.
• 19 Pieters J, Lindhout T. The limited importance of factor Xa inhibition to the anticoagulant property of heparin in thromboplastin-activated plasma. Blood 1988; 72: 2048-52.
• 20 Shi W, Chong BH, Hogg PJ, Chesterman CN. Anticardiolipin antibodies block the inhibition by β₂-glycoprotein 1 of the factor Xa generating activity. Thromb Haemost 1993; 70: 342-5.
• 21 Pieters J, Lindhout T, Hemker HC. In situ generated thrombin is the only enzyme that effectively activates factor VIII and Factor V in thromboplastin-activated plasma. Blood 1989; 74: 1021-4.
• 22 Lindhout T, Franssen J, Willems G. Kinetics of the inhibition of tissue factor-factor VIIa by tissue factor pathway inhibitor. Thromb Haemost 1995; 74: 910-5.
• 23 Baugh RJ, Broze GJ, Krishnaswamy S. Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor. J Biol Chem 1998; 273: 4378-86.
• 24 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.
• 25 Pengo V, Brocco T, Biasiolo A, Rampazzo P, Carraro P, Zamarchi R. Procoagulant effect of anti-β₂2-glycoprotein I antibodies with lupus anticoagulant activity. Blood 1999; 94: 3814-9.
• 26 Willems GM, Janssen MP, Salemink I, Wun TC, Lindhout T. Transient high affinity binding of tissue factor pathway inhibitor-factor Xa complexes to negatively charged phospholipid membranes. Biochemistry 1998; 37: 3321-8.
• 27 Salemink I, Franssen J, Willems GM, Hemker HC, Li AG, Wun TC, Lindhout T. Factor Xa cleavage of tissue factor pathway inhibitor is associated with loss of anticoagulant activity. Thromb Haemost 1998; 80: 273-80.