Antiphospholipid antibodies predict imminent vascular events independently from other risk factors in a prospective cohort

Carolyn Neville; Joyce Rauch; Jeannine Kassis; Susan Solymoss; Lawrence Joseph; Patrick Belisle; Jerrold M. Levine; Paul R. Fortin

doi:10.1160/TH08-06-0384

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 101(01): 100-107
DOI: 10.1160/TH08-06-0384

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Antiphospholipid antibodies predict imminent vascular events independently from other risk factors in a prospective cohort

Authors

Carolyn Neville^*

¹Division of Clinical Epidemiology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
Joyce Rauch^*

²Division of Rheumatology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
Jeannine Kassis

³Department of Hematology, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, Quebec, Canada
Susan Solymoss

⁴Division of Hematology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
Lawrence Joseph

¹Division of Clinical Epidemiology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada

⁵Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada
Patrick Belisle

¹Division of Clinical Epidemiology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
Jerrold M. Levine

⁶Section of Nephrology, Department of Medicine, University of Illinois at Chicago, and Section of Nephrology, Department of Medicine, Jesse Brown Veterans Administration Medical Center, Chicago, Illinois, USA
Paul R. Fortin

⁷Division of Health Care and Outcome Research, Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada

⁸Division of Rheumatology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada

Abstract

Summary

Antiphospholipid antibodies (aPL) are associated with vascular events, but the magnitude of this risk, alone, or in combination with other atherogenic and thrombophilic risk factors, remains unclear. A prospective cohort of 415 persons was studied for arterial and venous events (AE and VE) over a median time of 7.4 years. aPL and coagulation abnormalities were measured upon beginning of the study and annually for the first four years. Within the cohort, a nested case-control study was conducted to investigate the role of endothelial and inflammatory markers in predicting new vascular events. Forty-five individuals had new vascular events: 18 occurred during the first year of follow-up. The proportion of event-free survivors at eight years was 90% (95%CI = 87%, 94%) for aPL-negative and 72% (60%, 85%) for aPL-positive individuals, respectively. Predictors for new AE were previous AE (HR=5.7 [2.7, 12.0]), diabetes (5.6 [2.4, 13.2]), aPL positivity (2.6 ([1.2, 5.9]), and age (1.04 [1.01, 1.07]). New VE were predicted by previous VE (6.1 [1.9, 19.9]), anti-β2-glyco-protein I (aβ2GPI) positivity (5.8 [1.4, 24.1]), activated protein C resistance (APCR) (4.1 [1.1, 15.1]), and gender (3.7 [1.1, 12.9]). In the nested case-control study, similar predictors were observed for AE, while abnormal APCR (OR=5.5 [1.1, 26.6]) and elevated von Willebrand factor (vWF) (OR=5.0 [1.2, 19.8]) best predicted VE. We demonstrate that aPL independently predict new vascular events and discriminate between individuals with and without events in the first two years of follow-up, indicating that aPL are associated with a short-term risk of developing new and recurrent vascular events.

Keywords

Antiphospholipid antibodies - thrombosis - anti-beta2-glycoprotein I - activated protein C resistance - von Willebrand factor

Full Text

References

References
1 Kassis J, Neville C, Rauch J. et al. Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis. Thromb Haemost 2004; 92: 1312-1319.
2 Rauch J, Tannenbaum M, Neville C. et al. Inhibition of lupus anticoagulant activity by hexagonal phase phosphatidylethanolamine in the presence of prothrombin. Thromb Haemost 1998; 80: 936-941.
3 Levine JS, Subang R, Nasr SH. et al. Immunization with an apoptotic cell-binding protein recapitulates the nephritis and sequential autoantibody emergence of systemic lupus erythematosus. J Immunol 2006; 177: 6504-6516.
4 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
5 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3‘-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-3703.
6 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 04: 295-306.
7 Somers E, Magder LS, Petri M. Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheumatol 2002; 29: 2531-2536.
8 Vaarala O, Manttari M, Manninen V. et al. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995; 91: 23-27.
9 Finazzi G, Brancaccio V, Moia M. et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry. Am J Med 1996; 100: 530-536.
10 Bili A, Moss AJ, Francis CW. et al. Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. Thrombogenic Factors, and Recurrent Coronary Events Investigators. Circulation 2000; 102: 1258-1263.
11 Brey RL, Abbott RD, Curb JD. et al. beta(2)-Glyco-protein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the honolulu heart program. Stroke 2001; 32: 1701-1706.
12 Janardhan V, Wolf PA, Kase CS. et al. Anticardiolipin antibodies and risk of ischemic stroke and transient ischemic attack: the Framingham cohort and offspring study. Stroke 2004; 35: 736-741.
13 Toloza SM, Uribe AG, McGwin Jr G. et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXIII. Baseline predictors of vascular events. Arthritis Rheum 2004; 50: 3947-3957.
14 Forastiero R, Martinuzzo M, Pombo G. et al. A prospective study of antibodies to beta2-glycoprotein I and prothrombin, and risk of thrombosis. J Thromb Haemost 2005; 03: 1231-1238.
15 Turiel M, Sarzi-Puttini P, Peretti R. et al. Thrombotic risk factors in primary antiphospholipid syndrome: a 5-year prospective study. Stroke 2005; 36: 1490-1494.
16 Mok CC, Tang SS, To CH. et al. Incidence and risk factors of thromboembolism in systemic lupus erythematosus: a comparison of three ethnic groups. Arthritis Rheum 2005; 52: 2774-2782.
17 Galli M, Borrelli G, Jacobsen EM. et al. Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study. Blood 2007; 110: 1178-1183.
18 Levine SR, Brey RL, Tilley BC. et al. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. J Am Med Assoc 2004; 291: 576-584.
19 Erkkila AT, Narvanen O, Lehto S. et al. Autoanti-bodies against oxidized low-density lipoprotein and cardiolipin in patients with coronary heart disease. Arterioscler Thromb Vasc Biol 2000; 20: 204-209.
20 Heinzlef O, Abuaf N, Cohen A. et al. Recurrent stroke and vascular events in elderly patients with anticardiolipin antibodies: a prospective study. J Neurol 2001; 248: 373-379.
21 Akimoto T, Kobayashi S, Tamura N. et al. Risk factors for recurrent thrombosis: prospective study of a cohort of Japanese systemic lupus erythematosus. Angiology 2005; 56: 601-609.
22 Ahmed E, Stegmayr B, Trifunovic J. et al. Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Vasterbotten cohort project. Stroke 2000; 31: 1289-1293.
23 Levine SR, Salowich-Palm L, Sawaya KL. et al. IgG anticardiolipin antibody titer > 40 GPL and the risk of subsequent thrombo-occlusive events and death. A prospective cohort study. Stroke 1997; 28: 1660-1665.
24 Calvo-Alen J, Toloza SMA, Fernandez M. et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA) – XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum 2005; 52: 2060-2068.
25 van Goor MP, Alblas CL, Leebeek FW. et al. Do antiphospholipid antibodies increase the longterm risk of thrombotic complications in young patients with a recent TIA or ischemic stroke?. Acta Neurol Scand 2004; 109: 410-415.
26 Wittkowsky AK, Downing J, Blackburn J. et al. Warfarin-related outcomes in patients with antiphospholipid antibody syndrome managed in an anticoagulation clinic. Thromb Haemost 2006; 96: 137-141.
27 Brandt JT, Triplett DA, Alving B. et al. 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: 1185-1190.
28 Neville C, Rauch J, Kassis J. et al. Thromboembolic risk in patients with high titre anticardiolipin and multiple antiphospholipid antibodies. Thromb Haemost 2003; 90: 108-115.
29 Hudson M, Herr AL, Rauch J. et al. The presence of multiple prothrombotic risk factors is associated with a higher risk of thrombosis in individuals with anticardiolipin antibodies. J Rheumatol 2003; 30: 2385-2391.
30 Neville C, Rauch J, Kassis J. et al. The persistence of anticardiolipin antibodies is associated with an increased risk of the presence of lupus anticoagulant and anti-beta2-glycoprotein I antibodies. Rheumatology (Oxford) 2006; 45: 1116-1120.
31 Sanmarco M, Gayet S, Alessi MC. et al. Antiphosphatidylethanolamine antibodies are associated with an increased odds ratio for thrombosis. A multicenter study with the participation of the European Forum on antiphospholipid antibodies. Thromb Haemost 2007; 97: 949-954.
32 Tomas JF, Alberca I, Tabernero MD. et al. Natural anticoagulant proteins and antiphospholipid antibodies in systemic lupus erythematosus. J Rheumatol 1998; 25: 57-62.
33 Nojima J, Kuratsune H, Suehisa E. et al. Acquired activated protein C resistance is associated with the coexistence of anti-prothrombin antibodies and lupus anticoagulant activity in patients with systemic lupus erythematosus. Br J Haematol 2002; 118: 577-583.
34 Meesters EW, Hansen H, Spronk HM. et al. The inflammation and coagulation cross-talk in patients with systemic lupus erythematosus. Blood Coagul Fibrinolysis 2007; 18: 21-28.