Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis

Jeannine Kassis; Carolyn Neville; Joyce Rauch; Lambert Busque; Erika R. Chang; Lawrence Joseph; Martine Le Comte; Rebecca Subang; Paul R. Fortin

doi:10.1160/TH04-03-0138

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(06): 1312-1319
DOI: 10.1160/TH04-03-0138

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis

Authors

Jeannine Kassis

¹Department of Hematology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
Carolyn Neville

²Division of Clinical Epidemiology, The Montreal General Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Joyce Rauch

³Division of Rheumatology, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
Lambert Busque

¹Department of Hematology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
Erika R. Chang

⁴Division of Outcomes and Population Health, University Health Network, University of Toronto, Toronto, Ontario, Canada
Lawrence Joseph

²Division of Clinical Epidemiology, The Montreal General Hospital, McGill University Health Centre, Montreal, Quebec, Canada

⁵Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada
Martine Le Comte

²Division of Clinical Epidemiology, The Montreal General Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Rebecca Subang

³Division of Rheumatology, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
Paul R. Fortin

⁴Division of Outcomes and Population Health, University Health Network, University of Toronto, Toronto, Ontario, Canada

⁶Division of Rheumatology, University Health Network, University of Toronto, Toronto, Ontario, Canada

Abstract

Summary

Although antiphospholipid antibodies (aPL) are associated with thrombosis, it is not known who with aPL is at higher risk for thrombosis. It was the aim of this cross-sectional study to investigate how thrombophilic factors contribute to venous or arterial thrombosis in aPL-positive individuals. In outpatient test centres at two tertiary care hospitals, two hundred and eight (208) persons requiring aPL testing were matched by age, gender and centre to 208 persons requiring a complete blood count. Persons were classified as aPL-positive (having anticardiolipin, lupus anticoagulant and/or anti-β₂-glycoprotein I antibodies) or aPL-negative. Several thrombophilic factors were studied using logistic regression modelling. Results showed that the aPL-positive group had three-fold more events (37%) than the aPL-negative group (12%). In unadjusted analyses, clinically important associations were observed between factor V Leiden and venous thrombosis, hyperhomocysteinemia and arterial thrombosis, and activated protein C resistance (APCR) and venous thrombosis (OR, 95% CI = 4.00, 1.35-11.91; 4.79, 2.03-11.33; and 2.03, 1.03-3.97, respectively). After adjusting for recruitment group, persons with both APCR and aPL had a three-fold greater risk (OR, 95% CI = 3.31, 1.30-8.41) for venous thrombosis than those with neither APCR nor aPL. Similarly, after adjusting for hypertension, family history of cardiovascular disease, gender and recruitment group, persons with both hyperhomocysteinemia and aPL had a five-fold increased risk (OR, 95% CI = 4.90, 1.37-17.37) for arterial thrombosis compared to those with neither risk factor. In conclusion, APCR phenotype and hyperhomocysteinemia are associated with a higher risk of venous and arterial thrombosis, respectively, in the presence of aPL.

Keywords

Antiphospholipid antibodies - antiphospholipid syndrome - thrombosis - activated protein C resistance - hyperhomocysteinemia

Full Text

References

References
1 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752-63.
2 Wilson WA, Gharavi AE, Koike T. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-11.
3 Lockshin MD, Sammaritano LR, Schwartzman S. Validation of the Sapporo criteria for antiphospholipid syndrome. Arthritis Rheum 2000; 43: 440-3.
4 Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105: 91-99.
5 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: 423-8.
6 Emmerich J, Rosendaal FR, Cattaneo M. et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism—pooled analysis of 8 casecontrol studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb Haemost 2001; 86: 809-16.
7 Ridker PM, Hennekens CH, Selhub J. et al. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997; 95: 1777-82.
8 Neville C, Rauch J, Kassis J. et al. Thromboembolic risk in patients with high titre anticardiolipin and multiple antiphospholipid antibodies. Thromb Haemost 2003; 90: 108-15.
9 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: 936-41.
10 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, De Ronde H. et al Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
11 Frosst P, Blom HJ, Milos R. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-13.
12 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: 3698-703.
13 The SAS System for Windows. Windows. Cary, North Carolina: The SAS Institute; 2002
14 S-PLUS (version 6.0). Seattle, WA: Insightful Corporation; 2001
15 Tait RC, Walker ID, Reitsma PH. et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87-93.
16 Tait RC, Walker ID, Perry DJ. et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-12.
17 Zoller B, Svensson PJ, He X. et al. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-4.
18 Oosting JD, Derkson RHWM, Bobbink WG. et al. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?. Blood 1983; 81: 2618-25.
19 Marciniak E, Romond EH. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood 1989; 74: 2426-32.
20 Male C, Mitchell L, Julian J. et al. Acquired activated protein C resistance is associated with lupus anticoagulants and thrombotic events in pediatric patients with systemic lupus erythematosus. Blood 2001; 97: 844-9.
21 Bokarewa MI, Blomback M. Combination of activated protein C resistance and antibodies to phospholipids in the development of thrombosis. Semin Hematol 1997; 34: 235-43.
22 Chopra N, Koren S, Greer WL. et al. Factor V Leiden, prothrombin gene mutation, and thrombosis risk in patients with antiphospholipid antibodies. J Rheumatol 2002; 29: 1683-8.
23 Eikelboom JW, Lonn E, Genest J. et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999; 131: 363-75.
24 Hussein WI, Green R, Jacobsen DW. et al. Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann Intern Med 1999; 131: 348-51.
25 Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986; 77: 1909-16.
26 Khajuria A, Houston DS. Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis. Blood 2000; 96 (03) 966-972.
27 Undas A, Williams EB, Butenas S. et al. Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem 2001; 276: 4389-97.
28 Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 1993; 92: 1381-6.
29 Stampfer MJ, Malinow MR, Willett WC. et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992; 268: 877-81.
30 Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies. J Cardiovasc Risk 1998; 05: 229-32.
31 Eichinger S, Stumpflen A, Hirschl M. et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80: 566-9.
32 Petri M, Roubenoff R, Dallal GE. et al. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996; 348: 1120-24.
33 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: 2385-91.