Download PDF
Thromb Haemost 1995; 73(05): 768-773
DOI: 10.1055/s-0038-1653866
Original Articles
Clinical Studies
Schattauer GmbH Stuttgart

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

Paul R J Ames
1   The Institute of Haematology, 1st Medical School, University of Naples, Italy
,
Stephen Pyke
3   Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK
,
Luigi Iannaccone
2   Department of Haematology, Coagulation Unit, Cardarelli Hospital, Naples, Italy
,
Vincenzo Brancaccio
2   Department of Haematology, Coagulation Unit, Cardarelli Hospital, Naples, Italy
› Author Affiliations
Further Information

Publication History

Received 19 August 1994

Accepted 20 January 1995

Publication Date:
09 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 4 Santoro SA. Antiphospholipid antibodies and thrombotic predisposition: underlying pathogenetic mechanisms. Blood 1994; 83: 2389-2391
    PubMedGoogle Scholar
  • 5 Angles-Cano E, Sultan Y, Clauvel JP. Predisposing factor to thrombosis in systemic lupus erythematosus. J Clin Lab Med 1979; 94: 312-315
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Bums TR, Saleem A. Idiopathic thrombocytopenic purpura. Am J Med 1985; 75: 1001-1007
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 11 Exner T, Rickard KA, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol 1978; 40: 143-151
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 13 Schleider NA, Nachman RL, Jaffe EA, Coleman N. A clinical study of the lupus anticoagulant. Blood 1976; 48: 499-509
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 16 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-242
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 28 Kapiotis S, Speiser W, Pabinger-Fasching I, Kyrle PA, Lechner K. Anticardiolipin antibodies in patients with venous thrombosis. Haemostasis 1991; 21: 19-24
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 31 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study JAMA 1987; 258: 1183-1186
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 34 Mettinger KI. A study of hemostasis in ischemic cerebrovascular disease. Abnormalities in factor VIII and antithrombin Thromb Res 1982; 26: 183-192
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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)
    PubMedGoogle Scholar
  • 41 Ribes JA, Francis CW, Wagner DD. Fibrin induces release of von Willebrand factor from endothelial cells. J Clin Invest 1987; 79: 117-123
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar