Clusters of disease manifestations in patients with antiphospholipid syndrome demonstrated by factor analysis

Abstract

The antiphospholipid syndrome (APS) is now recognized as a multi-system disease, the clinical expression of which may include various target-organs involvements. Despite the reported heterogeneity in clinical presentation of APS, the interrelations between various manifestations of the disease has not yet been studied. We evaluated the principle associations between a variety of clinical manifestations in APS patients, applying factor analysis. Two-hundred and forty-six APS patients were studied. The following disease manifestations were used for the factor analysis: recurrent fetal loss, intrauterine growth restriction (IUGR), venous and arterial thrombosis, cardiac valves thickening/dysfunction, valvular vegetations, stroke, epilepsy, migraine, arthritis, livedo reticularis, thrombocytopenia, leukopenia and autoimmune hemolytic anemia (AIHA). The results were further analysed in relation to sex and to primary APS versus APS associated with SLE. Five factors were derived, which accounted for 59.7% of the variance of the matrix. Factor 1 (which explained 18.5% of variance of the original matrix) represented the association between cardiac valves abnormalities, livedo reticularis and AIHA. Factor 2 (13.8% of variance) represented association between arthritis, thrombocytopenia and leukopenia. Factor 3 (10.3% of variance) represented an association between recurrent fetal loss and IUGR. Factor 4 (9.3% of variance) represented inverse correlation between arterial and venous thrombosis. Factor 5 (7.8% of variance) represented an association between epilepsy and migraine. Application of factor analysis revealed specific clusters of cardiac, cutaneous, hematological and neurological manifestations. Our result also point to a possible divergence of arterial and venous thrombotic tendency. Awareness of these patterns might give us a better understanding of the disease.

Keywords

autoimmune hemolytic anaemia epilepsy livedo reticularis systemic lupus erythematosus thrombosis cardiac valves

Get full access to this article

View all access options for this article.

References

Asherson RA , Khamashta MA , Ordi Ros J et al. The primary antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989; 68: 366–374.

Alarcon Segovia D. The antiphospholipid story. J Rheumatol 2003; 30: 1893–1896.

Alarcon Segovia D , Deleze M , Oria CV et al. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients. Medicine (Baltimore) 1989; 68: 353–365.

Hughes GR , Harris NN , Gharavi AE . The anticardiolipin syndrome. J Rheumatol 1986; 13: 486–489.

Shoenfeld Y. Systemic antiphospholipid syndrome. Lupus 2003; 12: 497–498.

Cervera R , Piette JC , Font J et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019–1027.

Chapman J , Rand JH , Brey RL , Levine SR , Blatt I , Khamashta MA , Shoenfeld Y . Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies. Lupus 2003; 12: 514–517.

Lev S , Shoenfeld Y. Cardiac valvulopathy in the antiphospholipid syndrome. Clin Rev Allergy Immunol 2002; 23: 341–348.

Levine JS , Branch DW , Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752–763.

10.

Shoenfeld Y , Lev S , Blatt I et al. Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol 2004; 31: 1344–1348.

11.

Rosove MH , Brewer PM . Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117: 303–308.

12.

Asherson RA , Baguley E , Pal C , Hughes GR . Antiphospholipid syndrome: five year follow up. Ann Rheum Dis 1991; 50: 805–810.

13.

Khamashta MA , Cuadrado MJ , Mujic F , Taub NA , Hunt BJ , Hughes GR . The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993–997.

14.

Crowther MA , Ginsberg JS , Julian J et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349: 1133–1138.

15.

Gorsuch RL . Factor analysis. W.B. Saunders (1974).

16.

Wysenbeek AJ , Leibovici L , Amit M , Weinberger A. Disease patterns of patients with systemic lupus erythematosus as shown by application of factor analysis. J Rheumatol 1992; 19: 1096–1099.

17.

Krause I , Leibovici L , Guedj D , Molad Y , Uziel Y , Weinberger A. Disease patterns of patients with Behcet's disease demonstrated by factor analysis. Clin Exp Rheumatol 1999; 17: 347–350.

18.

Leibovici L , Wysenbeek AJ , Konisberger H , Samra Z , Pitlik SD , Drucker M. Patterns of multiple resistance to antibiotics in gramnegative bacteria demonstrated by factor analysis. Eur J Clin Microbiol Infect Dis 1992; 11: 782–788.

19.

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; 4: 295–306.

20.

Special report from the National Institute of Neurological Disorders and Stroke . Classification of cerebrovascular diseases III. Stroke 1990; 21: 637–676.

21.

Cerny BA , Kaiser HF . A study of a measure of sampling adequacy for factor-analytic correlation matrices. Multivariate Behavioral Research 1977; 12: 43–47.

22.

Toubi E , Krause I , Fraser A et al. Livedo reticularis is a marker for predicting multi-system thrombosis in antiphospholipid syndrome. Clin Exp Rheumatol 2005; 23: 499–504.

23.

Krause I , Lev S , Fraser A et al. Close association between valvar heart disease and central nervous system manifestations in the antiphospholipid syndrome. Ann Rheum Dis 2005; 64: 1490–1493.

24.

Tietjen GE , Gottwald L , Al Qasmi MM , Gunda P , Khuder SA . Migraine is associated with livedo reticularis: a prospective study. Headache 2002; 42: 263–267.

25.

Munoz Rodriguez FJ , Reverter Calatayud JC , Font Franco J , Espinosa Garriga G , Tassies Penella D , Ingelmo Morin M. Cardiopatia valvular en pacientes con sindrome antifosfolipidico. Rev Clin Esp 2002; 202: 529–533.

26.

Rotem M , Krause I , Fraser A , Stojanovich L , Rovensky J , Shoenfeld Y. Autoimmune hemolytic anemia in the antiphospholipid syndrome. Lupus 2006; 15: 473–477.

27.

Tektonidou MG , Ioannidis JP , Boki KA , Vlachoyiannopoulos PG , Moutsopoulos HM . Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. QJM 2000; 93: 523–530.

28.

Yasuda M , Takakuwa K , Tokunaga A , Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol 1995; 86: 555–559.

29.

Meroni PL , Raschi E , Camera M et al. Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome. J Autoimmun 2000; 15: 237–240.

30.

Roubey RA . Tissue factor pathway and the antiphospholipid syndrome. J Autoimmun 2000; 15: 217–220.

31.

Rand JH , Wu XX , Andree HA et al. Pregnancy loss in the antiphospholipid-antibody syndrome–a possible thrombogenic mechanism. N Engl J Med 1997; 337: 154–160.

32.

Horkko S , Miller E , Dudl E et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J Clin Invest 1996; 98: 815–825.

33.

Ames PR . Antiphospholipid antibodies, thrombosis and atherosclerosis in systemic lupus erythematosus: a unifying ‘membrane stress syndrome’ hypothesis. Lupus 1994; 3: 371–377.

34.

Vaarala O , Alfthan G , Jauhiainen M , Leirisalo Repo M , Aho K , Palosuo T. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993; 341: 923–925.

35.

Becarevic M , Andrejevic S , Bonaci Nikolic B , Obradovic I , Miljic P , Majkic Singh N.

Anti-oxLDL antibodies–marker for arterial thromboses in antiphospholipid syndrome?

Clin Lab 2005; 51: 279–283.

36.

Romero FI , Amengual O , Atsumi T , Khamashta MA , Tinahones FJ , Hughes GR . Arterial disease in lupus and secondary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies but not with antibodies against oxidized low-density lipoprotein. Br J Rheumatol 1998; 37: 883–888.

37.

Lopez LR , Dier KJ , Lopez D , Merrill JT , Fink CA . Anti-beta 2-glycoprotein I and antiphosphatidylserine antibodies are predictors of arterial thrombosis in patients with antiphospholipid syndrome. Am J Clin Pathol 2004; 121: 142–149.

38.

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.

39.

Shoenfeld Y , Krause I , Kvapil F et al. Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome. J Clin Immunol 2003; 23: 377–383.