Antiphospholipid Antibodies, Haemostatic Variables and Thrombosis – A Survey of 144 Patients

Summary

Several clotting abnormalities have been put forth to explain the thrombotic tendency of the antiphospholipid syndrome, but a possible role for fibrinogen and von Willebrand factor has been poorly investigated. The present cross-sectional retrospective study evaluated the relationship of IgG anticardiolipin antibodies, lupus anticoagulants, fibrinogen and von Willebrand factor with the occurrence of arterial and venous thromboses in patients with antiphospholipid antibodies. Among the clotting assays for the detection of lupus anticoagulant, dilute Russell’s viper venom time correlated with a history of venous thrombosis more strongly than activated partial thromboplastin time (p <0.0002 vs p <0.009) and was the only test which correlated with a history of arterial thrombosis (p <0.01), also at low levels of IgG anticardiolipin antibodies (p = 0.003). By regression analysis, and after correction for confounders, serum levels of IgG anticardiolipin antibodies were found to be positively associated with the number of venous events (p <0.001). Plasma levels of fibrinogen and von Willebrand factor were associated with each other (p <0.0001; r: 0.48) and with the occurrence of arterial and venous thromboses (p <0.001). Moreover, plasma levels of fibrinogen and von Willebrand factor in thrombotic patients with antiphospholipid antibodies were significantly higher than those of a control group of thrombotic patients who suffered thrombosis for other reasons (p <0.0001 and p = 0.0008 respectively). Titres of IgG anticardiolipin antibodies correlated with plasma levels of von Willebrand factor (p <0.0001; r: 0.42). These findings support the hypothesis that within the antiphospholipid antibody family, subgroups exist which may preferentially associate with arterial or venous occlusions and raise the possibility that elevated plasma levels of fibrinogen and von Willebrand factor may be implicated in the thrombotic tendency of the antiphospholipid syndrome through an involvement of the vascular endothelium, as the relationship between IgG anticardiolipin and von Willebrand factor suggests. Measurement of fibrinogen and von Willebrand factor in prospective studies, besides anticardiolipin antibodies and lupus anticoagulants, may help assess the risk of developing arterial and venous thrombosis in patients with antiphospholipid antibodies.

• References

• 1 Love PE, Santoro SE. Antiphospholipid antibodies: anticardiolipin antibodies and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682-698
• 2 Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH W M, Machin SJ, Barquinero J, Outt HH, Harris EN, Vilardell-Torres M, Hughes GR V. The “Primary antiphospholipid syndrome”: major clinical and serological features. Medicine 1989; 68: 366-374
• 3 Harris EN, Baguley E, Asherson RA, Hughes GR V. Clinical and serological features of the “antiphospholipid syndrome” (APS). (Abstract): Br J Rheumatol 1987; 26: 19
• 4 Santoro SA. Antiphospholipid antibodies and thrombotic predisposition: underlying pathogenetic mechanisms. Blood 1994; 83: 2389-2391
• 5 Angles-Cano E, Sultan Y, Clauvel JP. Predisposing factor to thrombosis in systemic lupus erythematosus. J Clin Lab Med 1979; 94: 312-315
• 6 Nilsson TK, Lofvenberg E. Decreased fibrinolytic capacity and increased von Willebrand factor levels as indicators of endothelial disfunction in patients with the lupus anticoagulant. Clin Rheumatol 1989; 1: 58-63
• 7 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
• 8 Orlando E, Cortelazzo S, Marchetti M, Sanfratello R, Barbui T. Prolonged bleeding time in patients with lupus anticoagulant. Thromb Haemost 1992; 68: 495-499
• 9 Bums TR, Saleem A. Idiopathic thrombocytopenic purpura. Am J Med 1985; 75: 1001-1007
• 10 Tan EN, 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: 1271-1277
• 11 Exner T, Rickard KA, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol 1978; 40: 143-151
• 12 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
• 13 Schleider NA, Nachman RL, Jaffe EA, Coleman N. A clinical study of the lupus anticoagulant. Blood 1976; 48: 499-509
• 14 Triplett DA, Brandt JT, Kaczar 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
• 15 Rosove MH, 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
• 16 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-242
• 17 Petri M, Rheischmidt N, Withing-O’Keefe Q, Hellmann D, Corash L. The frequency of lupus anticoagulant in systemic lupus erythematosus: A study of sixty consecutive patients by activated partial thromboplastin time, Russell venom viper time and anticardiolipin antibody level. Ann Intern Med 1987; 106: 524-531
• 18 Derksen RH W M, Hasselaar P, Blokziji L, Gmelig Meyling FR J, De Groot PG. Coagulation screen is more specific than the anticardiolipin antibody Elisa in defining a thrombotic subset of lupus patients. Ann Rheum Dis 1988; 47: 364-371
• 19 Padmakumar K, Singh RR, Rai R, Malaviya AN, Saraya AK. Lupus anticoagulants in systemic lupus erythematosus: prevalence and clinical associations. Ann Rheum Dis 1990; 49: 986-989
• 20 McHugh NJ, Moye DA, James IE, Sampson M, Maddison PJ. Lupus anticoagulant: clinical significance in anticardiolipin positive patients with systemic lupus erythematosus. Ann Rheum Dis 1991; 50: 548-552
• 21 Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ W. Lupus anticoagulant: an analysis of the clinical and laboratory features of 219 cases. Am J Haematol 1985; 19: 265-275
• 22 Lechner K, Pabinger-Fasching I. Lupus anticoagulants and thrombosis: a study of 25 cases and review of the literature. Haemostasis 1985; 15: 254-262
• 23 Harris EN, Chan JK, Asherson RA, Aber VR, Gharavi AE, Hughes GR V. Thrombosis recurrent fetal loss and thrombocytopenia Predictive value of the anticardiolipin test. Arch Intern Med 1986; 146: 2153-2156
• 24 Cervera R, Font J, Lopez-Soto A, Casals F, Pallares L, Bove A, Ingelmo M, Urbano MarquezA. Isotype distribution of anticardiolipin antibodies in systemic lupus erythematosus: prospective analysis of 100 patients. Ann Rheum Dis 1990; 49: 109-113
• 25 Long AA, Ginsberg JS, Brill-Edwards P, Johnston M, Turner C, Denburg JA, Bensen WG, Cividino A, Andrew M, Hirsh J. The relationship of anti-phospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross sectional study. Thromb Haemost 1991; 66: 520-524
• 26 Ishii Y, Nagasawa K, Mayumi T, Niho Y. Clinical importance of persistence of anticardiolipin antibodies in systemic lupus erythematosus. Ann Rheum Dis 1990; 49: 387-390
• 27 Vianna JL, Haga HJ, Tripathi P, Cervera R, Kamashta M, Hughes GR V. Reassessing the status of antiphospholipid syndrome in systemic lupus erythematosus. Ann Rheum Dis 1992; 51: 160-161
• 28 Kapiotis S, Speiser W, Pabinger-Fasching I, Kyrle PA, Lechner K. Anticardiolipin antibodies in patients with venous thrombosis. Haemostasis 1991; 21: 19-24
• 29 Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Henne-kens CH, Stampfer MJ. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992; 117: 997-1002
• 30 Sletnes KE, Smith P, Abdelnoor M, Amesen H, Wisloff F. Antiphospholipid antibodies after myocardial infarction and their relation to mortality, reinfarction and non-haemorrhagic stroke. Lancet 1992; 339: 451-453
• 31 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study JAMA 1987; 258: 1183-1186
• 32 Welin L, Svardsudd K, Wilhelmsen K, Larsson B, Tibblin G. Analysis of risk factors for stroke in a cohort of men bom in 1913. New Engl J Med 1987; 317: 521-526
• 33 Wahlberg T, Blomback M, Overmark I. Blood coagulation studies in 45 patients with ischemic cerebrovascular disease and 44 patients with venous thromboembolic disease. Acta Med Scand 1980; 207: 385-390
• 34 Mettinger KI. A study of hemostasis in ischemic cerebrovascular disease. Abnormalities in factor VIII and antithrombin Thromb Res 1982; 26: 183-192
• 35 Jansson JH, Nilsson TK, Johnson O. Von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351-355
• 36 Lindsey NJ, Dawson RA, Henderson FI, Greaves M, Hughes P. Stimulation of von Willebrand factor release by immunoglobulin from thrombosis prone patients with systemic lupus erythematosus and the antiphospholipid syndrome. Br J Rheumatol 1993; 32: 123-126
• 37 Keeling DM, Campbell SJ, Mackie IJ, Machin SJ, Isenberg DA. The fibrinolytic response to venous occlusion and natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus. Br J Haematol 1991; 77: 354-359
• 38 Kordich LC, Forastiero RR, Basilotta E, Porterie P, Carreras LO. Natural inhibitors of blood coagulation and fibrinolysis in patients with lupus anticoagulant. Blood Coagulation and Fibrinolysis 1992; 3: 765-771
• 39 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
• 40 Hill MB, Phipps JL, Malia RG, Greaves M, Hughes P. Characterization and specificity of antiendothelial cell membrane antibodies and their relationship to thrombosis in the primary antiphospholipid syndrome. Lupus 1994; 3: 333 (abstract 83)
• 41 Ribes JA, Francis CW, Wagner DD. Fibrin induces release of von Willebrand factor from endothelial cells. J Clin Invest 1987; 79: 117-123
• 42 Sironi M, Breviario F, Proserpio P, Biondi A, Vecchi A, Van Damme J, Dejana E, Mantovani A. IL-1 stimulated IL-6 production in endothelial cells. J Immunol 1989; 142: 549-556
• 43 Ceriello A, Pirisi M, Giacomello R, Stel G, Falleti E, Motz E, Lizzio S, Gonano F, Bartoli E. Fibrinogen plasma levels as a marker of thrombin activation: new insights on the role of fibrinogen as a cardiovascular risk factor. Thromb Haemost 1994; 71: 593-595
• 44 Collins PW, Macey MG, Cahill MR, Newland AC. Von Willebrand factor release and P-selectin expression is stimulated by thrombin and trypsin but not IL-1 in cultured human endothelial cells. Thromb Haemost 1993; 70: 346-350
• 45 Ginsberg JS, Demers C, Brill-Edwards P, Johnston M, Bona R, Burrows RF, Weitz J, Denburg JA. Increased thrombin generation in patients with systemic lupus erythematosus and anticardiolipin antibodies: evidence for a prothrombotic state. Blood 1993; 81: 2958-63
• 46 MC Neil HP, Chesterman CN, Krilis SA. Anticardiolipin antibodies and lupus anticoagulants comprise separate antibody subgroups with different phospholipid binding characteristics. Br J Haematol 1989; 73: 506-513
• 47 Exner T, Sahman N, Trudinger B. Separation of anticardiolipin antibodies from lupus anticoagulant on a phospholipid-coated polystyrene column. Biochem Biophys Res Commun 1988; 155: 1001-1007