Antiphospholipid antibody-mediated interference with annexin-V anticoagulant activity

Summary

The antiphospholipid (aPL) syndrome is a disorder in which vascular thrombosis and/or recurrent pregnancy losses occur together with serologic and coagulation evidence for antibodies directed against anionic phospholipid-protein complexes. Evidence has been developed for the idea that thrombosis in this syndrome may result from disruption of the binding of annexin-V to the phospholipids which line the placental and systemic vasculatures. We hypothesize that annexin-V, a protein known to have high affinity for anionic phospholipids, plays a thromboregulatory role at the vascular-blood interface by shielding anionic phospholipids from complexation with coagulation proteins in circulating blood. We propose that the thrombotic manifestations of the antiphospholipid syndrome are due to disruption of this annexin-V shield by antiphospholipid antibodies, thereby resulting in a net increase of thrombogenic phospholipids exposed to circulating blood. The accumulated data from tissue immunohistochemistry, trophoblast and endothelial cell culture studies, coagulation studies using noncellular phospholipids, and competition studies on artificial phospholipid bilayer are consistent with the hypothesis that the interference with the binding of annexin-V to anionic phospholipid surfaces plays an important role in the mechanism of thrombosis and in pregnancy loss in the antiphospholipid syndrome.

Zusammenfassung

Das Antiphospholipid-(aPL-)Syndrom ist eine Störung, die mit Gefäßthrombosen und/oder wiederholten Schwangerschaftsverlusten einhergeht und bei der in serologischen und Gerinnungstests Antikörper nachgewiesen werden können, die gegen anionische Phospholipid-Komplexe gerichtet sind. Es gibt Hinweise, die die Vorstellung unterstützen, dass die mit diesem Syndrom einhergehende Thrombose durch die Bindungsstörung von Annexin-V an die das systemische und das plazentale Gefäßsystem auskleidenden Phospholipide verursacht sein könnte. Wir nehmen an, dass Annexin-V, ein Protein mit bekanntermaßen hoher Affinität für anionische Phospholipide, im Bereich der Grenzfläche zwischen Gefäß und Blut eine thromboregulatorische Funktion zukommt, indem es anionische Phospholipide von einer Komplexbildung mit im Blut zirkulierenden Gerinnungsproteinen abschirmt. Unserer Meinung nach könnten die mit dem Antiphospholipid-Syndrom einhergehenden thrombotischen Ereignisse dadurch verursacht sein, dass Antiphospholipid-Antikörper dieses Annexin-V-Schild stören, was einen Nettoanstieg an thrombogenen Phospholipiden im zirkulierenden Blut zur Folge hätte. Die sich mehrenden Ergebnisse aus immunhistochemischen Gewebeuntersuchungen, Zellkulturstudien an Trophoblast- und Endothelzellen, Gerinnungsstudien an nichtzellulären Phospholipiden sowie kompetitiven Testverfahren zu artifiziellen Phospholipid-Doppelschichten unterstützen die Hypothese, dass die Beeinflussung der Bindung von Annexin-V an anionische Phospholipid-Oberflächen bei Thrombose-Entstehung und Schwangerschaftsverlusten im Rahmen des Antiphospholipid-Syndroms eine wichtige Rolle spielt.

Keywords

Antiphospholipid syndrome - lupus anticoagulant - thrombosis - annexin-V

Schlüsselwörter

Antiphospholipid-Syndrome - Lupusantikoagulanz - Thrombose - Annexin-V

• References

• 1 Rand JH. Antiphospholipid Antibody-mediated Disruption of the Annexin-V Antithrombotic Shield: a Thrombogenic Mechanism for the Antiphospholipid Syndrome. J Autoimmun 2000; 15: 107-11.
• 2 Rand JH. Lupus Anticoagulants and Ralated Disorders. In: Williams’ Hematology. Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U. eds. New York: McGraw-Hill; 2000
• 3 Hughes GR. The anticardiolipin syndrome. Clin Exp Rheumatol 1985; 3: 285-6.
• 4 Harris EN, Hughes GRV, Gharavi AE. The antiphospholipid antibody syndrome. J Rheumatol 1987; (Suppl. 13) 210.
• 5 Hughes GR, Khamashta MA, Gharavi AE, Wilson WA. Lupus (Special Issue, 8th International Symposium on Antiphospholipid Antibodies, vol 7, Suppl 2). New Orleans: Stockton Press; 1998
• 6 Shapiro SS. The lupus anticoagulant/antiphospholipid syndrome. Annu Rev Med 1996; 47: 533-53.
• 7 Triplett DA. Lupus anticoagulants/antiphospholipid-protein antibodies: the great imposters. Lupus 1996; 5: 431-5.
• 8 Shapiro SS, Thiagarajan P. Lupus anticoagulants. Prog Hemost Thromb 1982; 6: 263-85.
• 9 Goldsmith GH, Pierangeli SS, Branch DW, Gharavi AE, Harris EN. Inhibition of prothrombin activation by antiphospholipid antibodies and beta 2-glycoprotein 1. Br J Haematol 1994; 87: 548-54.
• 10 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.
• 11 Galli M, Bevers EM, Comfurius P, Barbui T, Zwaal RF. Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles. Br J Haematol 1993; 83: 466-72.
• 12 Ginsberg JS, Wells PS, Brill Edwards P. et al. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-91.
• 13 Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC. The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 1989; 161: 369-73.
• 14 Horbach DA, van Oort E, Donders RC, Derksen RH, de Groot PG. Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus. Comparison between different assays for the detection of antiphospholipid antibodies. Thromb Haemost 1996; 76: 916-24.
• 15 Andree HAM, Hermens WT, Hemker HC, Willems GM. Displacement of factor Va by annexin V. In: Phospholipid Binding and Anticoagulant Action of Annexin V. Andree HAM. ed. Maastricht. The Netherlands: Universitaire Pers Maastricht; 1992: 73-5.
• 16 Rand JH. “Annexinopathies” – A new class of disease. N Engl J Med 1999; 340: 1035-6.
• 17 Voges D, Berendes R, Burger A, Demange P, Baumeister W, Huber R. Three-dimensional structure of membrane-bound annexin V. A correlative electron microscopy-X-ray crystallography study. J Mol Biol 1994; 238: 199-13.
• 18 Reviakine I, Bergsma-Schutter W, Brisson A. Growth of Protein 2-D Crystals on Supported Planar Lipid Bilayers Imaged in Situ by AFM. J Struct Biol 1998; 121: 356-61.
• 19 Lyden TW, Vogt E, Ng AK, Johnson PM, Rote NS. Monoclonal antiphospholipid antibody reactivity against human placental trophoblast. J Reprod Immunol 1992; 22: 1-14.
• 20 Krikun G, Lockwood CJ, Wu XX. et al. The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: immunolocalization and in vitro regulation. Placenta 1994; 15: 601-12.
• 21 Vogt E, Ng AK, Rote NS. Antiphosphatidylserine antibody removes annexin-V and facilitates the binding of prothrombin at the surface of a choriocarcinoma model of trophoblast differentiation. Am J Obstet Gynecol 1997; 177: 964-72.
• 22 Rand JH, Wu XX, Andree HAM. et al. Pregnancy loss in the antiphospholipid-antibody syndrome – a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154-60.
• 23 Wang X, Campos B, Kaetzel MA, Dedman JR. Annexin V is critical in the maintenance of murine placental integrity. Am J Obstet Gynecol 1999; 180: 1008-16.
• 24 Rand JH, Wu XX, Guller S. et al. Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol 1994; 171: 1566-72.
• 25 Rand JH, Wu XX, Guller S, Scher J, Andree HAM, Lockwood CJ. Antiphospholipid immunoglobulin G antibodies reduce annexin-V levels on syncytiotrophoblast apical membranes and in culture media of placental villi. Am J Obstet Gynecol 1997; 177: 918-23.
• 26 Rand JH, Wu XX, Andree HAM. et al. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a “lupus procoagulant” phenomenon. Blood 1998; 92: 1652-60.
• 27 Rand JH, Wu XX, Giesen P. A possible solution to the paradox of the “lupus anticoagulant”: Antiphospholipid antibodies accelerate thrombin generation by inhibiting annexin-V. Thromb Haemost 1999; 82: 1376-7.
• 28 Hanly JG, Smith SA. Anti-beta2-glycoprotein I (GPI) autoantibodies, annexin V binding and the anti-phospholipid syndrome. Clin Exp Immunol 2000; 120: 537-43.
• 29 Willems GM, Janssen MP, Comfurius P, Galli M, Zwaal RF, Bevers EM. Competition of annexin V and anticardiolipin antibodies for binding to phosphatidylserine containing membranes. Biochemistry 2000; 39: 1982-9.
• 30 Bevers EM, Janssen MP, Willems GM, Zwaal FA. No evidence for enhanced thrombin formation through displacement of annexin V by antiphospholipid antibodies. Thromb Haemost 2000; 83: 792-4.
• 31 Flaherty MJ, West S, Heimark RL, Fujikawa K, Tait JF. Placental anticoagulant protein-I: measurement in extracellular fluids and cells of the hemostatic system. J Lab Clin Med 1990; 115: 174-81.
• 32 Hughes GR, Harris NN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13: 486-9.