Coagulation Activation and Fibrinolytic imbalance in Subjects with Idiopathic Antiphospholipid Antibodies -A Crucial Role for Acquired Free Protein S Deficiency

Summary

To explore the coagulation/fibrinolytic balance and its relation with free protein S (f-PS) in subjects with antiphospholipid antibodies (aPLs) outside the setting of autoimmune inflammatory disorders, we carried out a cross-sectional study on 18 thrombotic patients with primary antiphospholipid syndrome and 18 apparently healthy subjects with persistence of idiopathic aPLs. Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and D-Dimer (D-D) were taken as markers of thrombin generation and fibrin turnover. Mean F1+2 levels were higher in thrombotic (p = 0.006) and non-thrombotic subjects (p = 0.0001) than in controls as were those of D-D (p <0.0001 and p = 0.003 respectively). TAT levels did not differ. Lower mean levels of f-PS were found in thrombotic (p = 0.0006) and non-thrombotic subjects (p = 0.002) than in controls. Within both groups, mean Fl+2 levels were higher in subjects who had low f-PS levels compared to those with normal f-PS levels (p = 0.01). Gender analysed data revealed blunted tPA release (venous occlusion test) in thrombotic females (from 16.80 ± 0.79 to 21.3 ± 3.9 ng/nl, NS) but not in thrombotic males (from 18.2 ± 2.0 to 33.7 ± 4.9 ng/ml, p = 0.01) nor in asymptomatic subjects of either sex. Also, in both patient groups females had higher mean PAI than males (p <0.0002) and than control females (p <0.02). Low free protein S was found in 100% of non-thrombotic and in 90% of thrombotic patients with defective fibrinolysis. These data are consistent with increased thrombin generation, accelerated fibrin turnover and fibrinolysis abnormalities also in asymptomatic carriers of aPLs and highlight a central role for acquired f-PS deficiency in the thrombotic tendency of the antiphospholipid syndrome.

• References

• 1 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: 682-698
• 2 Santoro SA. Antiphospholipid antibodies and thrombotic predisposition: underlying pathogenetic mechanisms. Blood 1994; 83: 2389-2391
• 3 Ginsberg JS, Demers C, Brill-Edwards P, Johnston M, Bona R, Burrows RF, Weitz J, Denburg JA. Increased thrombin generation and activity in patients with systemic lupus erythematosus and anticardiolipin antibodies: evidence for a prothrombotic state. Blood 1993; 81: 2958-2963
• 4 Ginsberg JS, Demers C, Brill-Edwards P, Bona R, Johnston M, Wong A, Denburg JA. Acquired free protein S deficiency is associated with increased thrombin generation in patients with systemic lupus erythematosus. Am J Med 1995; 98: 379-383
• 5 Francis RB, McGehee WG, Feinstein DI. Endothelial-dependent fibrinolysis in subjects with the lupus anticoagulant and thrombosis. Thromb Haemost 1988; 59: 412-414
• 6 Kordich L, Forastiero RR, Basilotta E, Porterie P, Carreras LO. Natural inhibitors of blood coagulation and fibrinolysis in patients with lupus anticoagulant. Blood Coag Fibrinol 1992; 3: 765-771
• 7 Violi F, Ferro D, Valesini G, Quintarelli C, Saliola M, Grandilli MA, Balsano F. Tissue plasminogen activator inhibitor in patients with systemic lupus erythematosus. Br Med J 1990; 300: 1099-1102
• 8 Keeling DM, Campbell SJ, Mackie IJ, Machin SJ, Isenberg DA. The fibrinolytic response to venous occlusion and the natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus. Br J Haematol 1991; 77: 354-359
• 9 Jurado M, Paramo JA, Gutierrez-Pimentel M , Rocha E. Fibrinolytic potential and antiphospholipid antibodies in systemic lupus erythematosus and other connective tissue disorders. Thromb Haemost 1992; 68: 516-520
• 10 Matsuda J, Kawasugi K, Gohchi K, Saitoh N, Tsukamoto M, Kazama M, Kinoshita T. Clinical significance of the venous occlusion test in patients with systemic lupus erythematosus: a focus on changes in blood levels of tissue plasminogen activator, von Willebrand factor antigen and thrombomodulin. Acta Haematol 1992; 88: 22-26
• 11 Macworth-Young CG, Andreotti F, Harmer I, Loizou S, Pottinger BE, Pearson JD, Davies GJ, Maseri A, Walport MJ. Endothelium-derived haemostatic factors and the antiphospholipid syndrome. Br J Rheumatol 1995; 34: 201-206
• 12 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258: 1183-1186
• 13 Welin L, Svardsudd K, Wilhelmsen K, Larrson B, Tibblin G. Analysis of risk factors for stroke in a cohort of men born in 1913. N Engl J Med 1987; 317: 521-526
• 14 Smith EB, Thomson WD. Fibrin as a factor in atherogenesis. Thromb Res 1994; 73: 1-19
• 15 Ames PRJ, Pyke S, Iannaccone L, Brancaccio V. Antiphospholipid antibodies, haemostatic variables and thrombosis. A survey on 144 patients. Thromb Haemost 1995; 73: 768-773
• 16 Asherson RA, Khamashta MAS, Ordi-Ros J, Derksen RHWM, Machin SJ, Barquinero J, Outt HH, Harris EN, Vilardell-Torres M, Hughes GRV. The “Primary antiphospholipid syndrome”: major clinical and serological features. Medicine 1989; 68: 366-374
• 17 Thiagarajan P, Pengo V, Shapiro SS. The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 1986; 68: 869-874
• 18 Rosove MN, Ismail M, Koziol BJ, Runge A, Kasper CK. Lupus anticoagulants: improved diagnosis with a kaolin clotting time using rabbit brain phospholipid in standard and high concentrations. Blood 1986; 68: 472-478
• 19 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: 678-682
• 20 Shibata S, Harpel PC, Gharavi A, Rand J, Fillit H. Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes. Blood 1994; 83: 2532-2540
• 21 Yamazaki M, Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E, Aoshima K, Ikeda T, Matsuda T. Plasma levels of lipoprotein(a) are elevated in patients with the antiphospholipid antibody syndrome. Thromb Haemost 1994; 71: 424-427
• 22 Blystone SD, Weston LK, Kaplan JE. Fibronectin dependent macrophage fibrin binding. Blood 1991; 78: 2900-2907
• 23 Juhan-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip-Joet C, Holvoet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep vein thrombosis. Thromb Haemost 1987; 57: 67-72
• 24 Juhan VagueI, Aillaud MF, De Cock F, Philip-Joet C, Amaud C, Serradimigni A, Collen D. The fast-acting inhibitor of tissue type plasminogen activator is an acute phase reactant protein. In: Progress in fibrinolysis Davidson JF, Donati MB, Coccheri S. (eds). Vol VII Churchill Livingstone; Edinburgh - London - Melbourne - New York: 1985: 146-149
• 25 Ridker PM. Plasma concentration of endogenous tissue plasminogen activator and the occurrence of future cardiovascular events. J Thromb Throm-bol 1994; 1: 335-340
• 26 Wieczorek I, Ludlam CA, MacGregor IR. Age dependent changes in the fibrinolytic system are well established in healthy middle aged subjects. Fibrinolysis 1992; 6 (Suppl. 03) 44-46
• 27 Haverkate F, van de Loo JCW, Thompson SG. on behalf of the ECAT Angina Pectoris Study Group. Hemostasis risk markers, inflammatory and endothelial reactions in angina pectoris. Results of the ECAT Angina Pectoris Study. Thromb Haemost 1993; 69: 1537-1546
• 28 Atsumi T, Khamashta M, Ames PRJ, Ichikawa K, Koike T, Hughes GRV. Protein S, C4b-binding protein (C4BP) and beta2-glycoprotein binding interaction: inhibition by human monoclonal anticardiolipin antibody (Mo-aCL). Blood Coag Fibrinol 1995; 6: 594 (abstract)
• 29 Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-344