The Effects of Low-intensity Warfarin on Coagulation Activation in Patients with Antiphospholipid Antibodies and Systemic Lupus Erythematosus

Summary

The optimal intensity of oral anticoagulant therapy for the prevention of thromboembolism in patients with antiphospholipid antibodies (APLA) and systemic lupus erythematosus is controversial. Retrospective studies have suggested that patients with APLA are resistant to oral anticoagulant therapy, with a targeted International Normalization Ratio (INR) of 2.0 to 3.0, and that a higher intensity of anticoagulation (INR: 2.6 to 4.5) is required to prevent recurrent thromboembolism. To investigate if patients with APLA are resistant to the anticoagulant effect of low intensities of warfarin therapy, we performed a randomized trial in which 21 patients with APLA and systemic lupus erythematosus were allocated to receive one of three intensities of warfarin (INR: 1.1 to 1.4, 1.5 to 1.9 or 2.0 to 2.5) or placebo for four months. The main outcome was the effect of each intensity of warfarin therapy on prothrombin fragment 1+2 level (F1+2), that was used as a marker of coagulation activation. When F1+2 levels in patients allocated to the three warfarin intensities were compared to F1+2 levels in the placebo group, there was a statistically significant decrease (p <0.05) in the patient group receiving warfarin with a targeted INR of 2.0 to 2.5 at two, three and four months, and in the patient group with a targeted of INR 1.5 to 1.9 at three months. We conclude that in patients with APLA and systemic lupus erythematosus, warfarin therapy, with a targeted INR of 2.0 to 2.5, is effective in suppressing coagulation activation, and therefore, might be effective in preventing thromboembolism.

Keywords

Thromboembolism - antiphospholipid antibodies - anticoagulation

• 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 1996; 112: 682-98.
• 2 Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-91.
• 3 Asherson RA, Baguley E, Pal C, Hughes GRV. Antiphospholipid syndrome: five year follow-up. Ann Rheum Dis 1991; 50: 805-10.
• 4 Derkson RHWM, de Groot PhG, Kater L, Nieuwenhuis HK. Patients with antiphospholipid antibodies and venous thrombosis should receive long term anticoagulant treatment. Ann Rheum Dis 1993; 52: 689-92.
• 5 Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117: 303-8.
• 6 Rousseau A, Berube C. Prevention of thrombotic recurrences after an initial thrombotic event in antiphospholipid syndrome: a retrospective study. Lupus 1996; 5: 557.
• 7 Khamashta MA, Cuadrado MJ, Munic F, Taub NA, Hunt BJ, Hughes GRV. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-7.
• 8 Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-32.
• 9 Turpie AG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988; 1: 1242-5.
• 10 Hull R, Hirsh J, Jay R, Carter C, England C, Gent M, Turpie AGG, McLoughlin D, Dodd P, Thomas M, Raskob G, Ockelford P. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-81.
• 11 Prandoni P, Simioni P, Girolami A. Antiphospholipid antibodies, recurrent thromboembolism, and intensity of warfarin anticoagulation. Thromb Haemost 1996; 75: 859.
• 12 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50.
• 13 Aronson DL, Stevan L, Ball AP, Franza Jr BR, Finlayson JS. Generation of the combined activation peptide (F1.2) during the clotting of blood and plasma. J Clin Invest 1977; 60: 1410-8.
• 14 Tan EM, Cohen AS, Fries JF, Massie AT, McShane DJ, Rothfield NF, Green Schaller J, Talal N, Winchester RJ. The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum 1988; 31: 315-24.
• 15 Loizou S, McCrea JD, Rudge AC. et al. Measurement of anticardiolipin antibodies by an enzyme linked immunosorbent assay (ELISA): Standardization and quantitation of results. Clin Exp Immunol 1985; 62: 738-45.
• 16 Proctor RR, Rapaport SI. The partial thromboplastin time with kaolin. Am J Clin Path 1961; 36: 212-9.
• 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: 869-74.
• 18 Triplett DA, Barna LK, Unger GA. A hexagonal (II) phase phospholipid neutralization assay for lupus anticoagulant identification. Thromb Haemost 1993; 70: 787-93.
• 19 Miller GJ, Bauer KA, Barzegar S, Foley AJ, Mitchell JP, Cooper JA, Rosenberg RD. The effects of quality and timing of venepuncture on markers of blood coagulation in healthy middle-aged men. Thromb Haemost 1995; 73: 82-6.
• 20 Dunnett CW. A multiple comparison procedure for comparing several treatments with a control. JASA 1955; 50: 482-9.
• 21 Elias A, Bonfils S, Daoud-Elias M, Gauthier B, Sie P, Boccalon H, Boneu B. Influence of long term oral anticoagulants upon F1+2, thrombin-antithrombin III complex and D-dimer levels in patients affected by proximal deep vein thrombosis. Thromb Haemost 1993; 69: 302-5.
• 22 Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-8.
• 23 Kyrle PA, Stumpflen A, Hirschl M, Bialonczyk C, Herkner K, Speiser W, Weltermann A, Kaider A, Pabinger I, Lechner K, Eichinger S. Levels of prothrombin fragment F1+2 in patients with hyperhomocysteinemia and a history of venous thromboembolism. Thromb Haemost 1997; 78: 1327-31.
• 24 Martinelli I, Bottasso B, Duca F, Faioni E, Mannucci PM. Heightened thrombin generation in individuals with resistance to activated protein C. Thromb Haemost 1996; 75: 703-5.
• 25 Conard J, Bauer KA, Gruber A, Griffin JH, Schwarz HP, Horellou MH, Sammama MM, Rosenberg RD. Normalization of markers of coagulation activation with a purified protein C concentrate in adults with homozygous protein C deficiency. Blood 1993; 82: 1159-64.
• 26 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou MH, Sammama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Blood 1988; 71: 1418-26.
• 27 Mannucci PM, Tripodi A, Bottasso B, Baudo F, Finazzi G, De Stefano V, Palareti G, Manotti C, Nazzucconi MG, Castaman G. Markers of procoagulant imbalance in patients with inherited thrombophilic syndromes. Thromb Haemost 1992; 67: 200-2.
• 28 Ginsberg JS, Demers C, Brill-Edwards P, Johnston M, Bona R, Burrows RF, Denburg JA. Increased thrombin generation and activity in patients with systemic lupus erythematosus and anticardiolipin antibodies: evidence for a prothrombotic state. Blood 1993; 81: 2958-63.
• 29 Ames PRJ, Tommasino C, Iannaccone L, Brillante M, Cimino R, Brancaccio V. Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies – A crucial role for acquired free protein S deficiency. Thromb Haemost 1996; 76: 190-4.
• 30 Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Stewart D, Goodwin P. Double-blind randomized trial of very-low dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: 886-9.
• 31 Falanga A, Levine MN, Consonni R, Gritti G, Delaini F, Oldani E, Julian JA, Barbui T. The effect of very-low-dose warfarin on markers of hyper-coagulation in metastatic breast cancer: results from a randomized trial. Thromb Haemost 1998; 79: 23-7.
• 32 Stroke Prevention and Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: stroke prevention in atrial fibrillation III randomized clinical trial. Lancet 1996; 348: 633-8.
• 33 Kistler JP, Singer DE, Millenson MM, Bauer KA, Gress DR, Barzegar S, Hughes RA, Sheehan MA, Maraventano S, Oertel LB, Rosner B, Rosenberg RD. Effect of low-intensity warfarin anticoagulation on level of activity of the hemostatic system in patients with atrial fibrillation. Stroke 1993; 24: 1360-5.
• 34 Miller GJ, Bauer KA, Barzegar S, Foley AJ, Mitchell JP, Cooper JA, Rosenberg RD. The effects of quality and timing of venepuncture on markers of blood coagulation activation in healthy middle-aged men. Thromb Haemost 1995; 73: 82-6.
• 35 Rance A, Emmerich J, Fiessinger J-N. Anticardiolipin antibodies and recurrent thromboembolism. Thromb Haemost 1997; 77: 221-2.
• 36 Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson D, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA, Johnston M, Douketis J, van Nguyen P, Kassis J, Dolan S, Demers C, Desjardins L, Solymoss S, Trowbridge A, Roberts R. Extended anticoagulation compared to placebo after three months of therapy for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-7.
• 37 Schulman S, Svenungsson E, Granqvist S. and the Duration of Anticoagulation Study Group. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998; 104: 332-8.
• 38 Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anti-coagulants. Ann Intern Med 1997; 127: 177-85.