Antibodies directed to protein S in patients with systemic lupus erythematosus: prevalence and clinical significance

Summary

Antibodies directed against protein S (anti-ProtS) may be involved in the development of thrombosis in patients with the antiphospholipid syndrome. We assessed the prevalence and clinical significance of anti-ProtS and evaluated their immunological characteristics in 184 patients with SLE and 99 healthy donors. All patients were tested for IgG anti-ProtS by an in-house ELISA. Plasma levels and functional activity of protein S were also tested.

Anti-ProtS were found in 57 patients (31%) and 4 healthy controls (4%). Patients with thrombosis had anti-ProtS more frequently than controls (29% vs 4%, OR 9.5 [95% CI 3.07-29.3], p<0.0001). Anti-ProtS were more frequent in patients with venous thrombosis and in those with arterial thrombosis, than in controls (41% vs. 4%, OR 16.5 [95% CI 5-54], p< 0.0001 and 23% vs. 4%, OR 7 [95%CI 2.1-23.5], p=0.0008, respective-ly). Patients with prematurity, preeclampsia and intra-uterine growth restriction had anti-ProtS more frequently than the control group (36%, 47% and 44% vs. 4%; OR 13.6 [95% CI 2.8-66], p=0.003, OR 21 [95% CI 5-86], p<0.0001 and OR 19 [95% CI 4-99], p=0.0014, respectively). Plasma levels of free protein S were not statistically different between patients with and without anti-ProtS and controls (77.9% [20.7-100] vs. 83.7% [52.7-100] vs. 89% [62-101], respectively). Free protein S functional activity was no different between subgroups (105% [48-230] in anti-ProtS positive vs. 123% [95-283] in anti-ProtS negative vs. 136% [60-174] in controls).

Anti-ProtS are frequent in SLE patients with thrombosis and pregnancy morbidity. These antibodies do not interfere with free protein S in plasma since its level and/or functional activity are not impaired.

Keywords

Antiphospholipid syndrome - pregnancy morbidity - coagulation - thrombosis - lupus anticoagulant

• References

• 1 Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-44.
• 2 Roubey RA. Antigenic specificities of antiphospholipid autoantibodies: implications for clinical laboratory testing and diagnosis of the antiphospholipid syndrome. Lupus 1996; 5: 425-30.
• 3 McNally T, Mackie IJ, Machin SJ, Isenberg DA. Increased levels of beta 2 glycoprotein-I antigen and beta 2 glycoprotein-I binding antibodies are associated with a history of thromboembolic complications in patients with SLE and primary antiphospholipid syndrome. Br J Rheumatol 1995; 34: 1031-6.
• 4 Amengual O, Atsumi T, Khamashta MA, Koike T, Hughes GRV. Specificity of ELISA for antibody to beta 2-glycoprotein I in patients with antiphospholipid syndrome. Br J Rheumatol 1996; 35: 1239-43.
• 5 Schwarz HP, Heeb MJ, Wencel-Drake JD, Griffin JH. Identification and quantitation of protein S in human platelets. Blood 1985; 66: 1452-5.
• 6 Appleby RD, Olds RJ. The inherited basis of venous thrombosis. Pathology 1997; 29: 341-7.
• 7 High KA. Antithrombin III, protein C, and protein S. Naturally occurring anticoagulant proteins. Arch Pathol Lab Med 1988; 112: 28-36.
• 8 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311: 1525-8.
• 9 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-8.
• 10 Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrom-bin, protein C, or protein S: an explanation for their pathogenic mechanism?. Blood 1993; 81: 2618-25.
• 11 Sorice M, Arcieri P, Griggi T. et al. Inhibition of protein S by autoantibodies in patients with acquired protein S deficiency. Thromb Haemost 1996; 75: 555-9.
• 12 Morange PE, Alessi MC, Barthet MC. et al. Acquired protein S deficiency, likely due to anti-PS autoantibodies, following a thrombotic event in a patient with a systemic lupus erythematosus. Thromb Haemost 1997; 78: 1416-17.
• 13 Song KS, Park YS, Kim HK. Prevalence of anti-protein S antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 2000; 43: 557-60.
• 14 Tan EM, Cohen AS, Fries JF. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7.
• 15 Wilson WA, Gharavi AE, Koike T. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-11.
• 16 Erkan D, Zhang HW, Shriky RC, Merrill JT. Dual antibody reactivity to β2-glycoprotein I and Protein S: increased association with thrombotic events in the antiphospholipid syndrome. Lupus 2002; 11: 215-20.
• 17 Harris EN, Pierangeli S, Birch D. Anticardiolipin wet workshop report. Fifth International Symposium on antiphospholipid antibodies. Am J Clin Pathol 1994; 101: 616-24.
• 18 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 the ISTH. Thromb Haemost 1995; 74: 1185-90.
• 19 Moreb J, Kitchens CS. Acquired functional protein S deficiency, cerebral venous thrombosis, and coumarin skin necrosis in association with antiphospholipid syndrome: report of two cases. Am J Med 1989; 87: 207-10.
• 20 Sthoeger ZM, Sthoeger D, Mellnick SD, Steen D, Berrebi A. Transient anticardiolipin antibodies, functional protein S deficiency, and deep vein thrombosis. Am J Hematol 1991; 36: 206-7.
• 21 Ruiz-Arguelles GJ, Ruiz-Arguelles A, Alarcon-Segovia D. et al. Natural anticoagulants in systemic lupus erythematosus. Deficiency of protein S bound to C4bp associates with recent history of venous thromboses, antiphospholipid antibodies, and the antiphospholipid syndrome. J Rheumatol 1991; 18: 552-8.
• 22 Parke AL, Weinstein RE, Bona RD, Maier DB, Walker FJ. The thrombotic diathesis associated with the presence of phospholipid antibodies may be due to low levels of free protein S. Am J Med 1992; 93: 49-56.
• 23 Nojima J, Kuratsune H, Suehisa E. et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clin Chem 2001; 47: 1008-15.
• 24 Merrill JT, Zhang HW, Shen C. et al. Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein. Thromb Haemost 1999; 81: 748-57.
• 25 Matsuda J, Gohchi K, Gotoh M, Tsukamoto M, Saitoh N. Plasma concentrations of total/free and functional protein S are not decreased in systemic lupus erythematosus patients with lupus anticoagulant and/or antiphospholipid antibodies. Ann Hematol 1994; 69: 311-5.
• 26 Guermazi S, Regnault V, Gorgi Y, Ayed K, Lecompte T, Dellagi K. Further evidence for the presence of anti-protein S autoantibodies in patients with systemic lupus erythematosus. Blood Coagul Fibrinolysis 2000; 11: 491-8.