Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies

Abstract

The antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPL) in patients with thromboembolic complications. In APS, most aPL are autoantibodies to β₂-glycoprotein I and prothrombin, which play a major role in the APS pathogenesis. Nevertheless, antibodies with the same antigen specificity are also found in aPL patients with leprosy, in whom thromboembolic complications are uncommon. The in vivo upregulation of the tissue factor (TF) pathway and the imbalance of cytokines have been proposed as potential mechanisms of thrombosis in the APS. We measured the circulating levels of TF, interleukin 6 (IL-6), IL-6 receptor (sIL-6R), tumor necrosis factor (TNF-a) and interferon g (IFN-g) in 83 patients with autoimmune aPL (42 with and 41 without clinical features of definite primary APS), 48 leprosy patients (33 with aPL) and 48 normal controls. There was a trend (P = 0.06) to higher median sTF in patients with autoimmune aPL (139 pg/mL) compared with leprosy patients (103.5 pg/mL) and controls (123 pg/mL). In addition, the frequency of raised sTF levels (.187 pg/mL) was significantly higher in the group with autoimmune aPL [22.9% (APS 21.4%, non-APS 24.4%)] but not in leprosy (10.4%) compared with controls (4.2%). Elevated levels of IL-6 and TNF-a and a trend to lower IFN-g were found in patients with definite APS. Leprosy patients with aPL, however, had increased TNF-a and IFN-g but normal IL-6 levels. Levels of sIL-6R did not differ between controls and either patients with autoimmune aPL or leprosy. The different cytokine profiles as well as differences in circulating levels of TF might contribute to the high thrombotic risk found in patients with autoimmune aPL but not in leprosy related aPL patients.

Keywords

antiphospholipid syndrome leprosy proinflammatory cytokines tissue factor

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References

Wilson W , Gharavi A , Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Report of an International Workshop . Arthritis Rheum 1999; 42: 1309-1311 .

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

Carreras LO , Forastiero RR , Martinuzzo ME. Which are the best biological markers of the antiphospholipid syndrome ? J Autoimmun 2000; 15: 163-172 .

de Larrañaga G , Forastiero RR , Martinuzzo ME et al. High prevalence of antiphospholipid antibodies in leprosy: evaluation of antigen reactivity . Lupus 2000; 9: 594-600 .

Arvieux J , Renaudineau Y , Mane I , Perraut R , Krilis SA , Youinou P. Distinguishing features of anti-β2 glycoprotein I antibodies between patients with leprosy and the antiphospholipid syndrome . Thromb Haemost 2002; 87: 599-605 .

Santiago M , Martinelli R , Ko A et al. Anti-beta2 glycoprotein I and anticardiolipin antibodies in leptospirosis, syphilis and Kala-azar . Clin Exp Rheumatol 2001; 19: 425-430 .

Loizou S , Cazabon JK , Walport MJ , Tait D , So AK. Similarities of specificity and cofactor dependence in serum antiphospholipid antibodies from patients with human parvovirus B19 infection and from those with systemic lupus erythematosus . Arthritis Rheum 1997; 40: 103-108 .

Panunto-Castelo A , Almeida IC , Rosa JC , Greene LJ , Roque-Barreira M. The Rubino test for leprosy is a β2-glycoprotein I-dependent anti-phospholipid reaction . Immunol 2000; 101: 147-153 .

Goulart IMB , Penna GO , Cunha G. Immunopathology of leprosy: the complexity of the mechanisms of host immune response to Mycobacterium leprae . Rev Soc Bras Med Trop 2002; 35: 365-375 .

10.

Galli M , Luciani D , Bertolini G , Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome . Blood 2003; 102: 2717-2723 .

11.

Amengual O , Atsumi T , Khamashta MA , Hughes GRV. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome . Thromb Haemost 1998; 79: 276-281 .

12.

Dobado-Berrios P , López-Pedrera C , Velasco F , Cuadrado MJ. The role of tissue factor in the antiphospholipid syndrome . Arthritis Rheum 2001; 44: 2467-2476 .

13.

Williams FMK , Parmar K , Hughes GRV , Hunt BJ. Systemic endothelial cell markers in primary antiphospholipid syndrome . Thromb Haemost 2000; 84: 742-746 .

14.

Forastiero RR , Martinuzzo ME , Broze GJ. High titres of autoantibodies to tissue factor pathway inhibitor are associated with the antiphospholipid syndrome . J Thromb Haemost 2003; 1: 718-724 .

15.

Reverter JC , Tassies D , Font J et al. Hypercoagulable state in patients with antiphospholipid syndrome is related to high induced tissue factor expression on monocytes and to low free protein S . Arterioscler Thromb Vasc Biol 1996; 16: 1319-1326 .

16.

Ferro D , Pittoni V , Quintarelli C et al. Coexistence of anti-phospholipid antibodies and endothelial perturbation in systemic lupus erythematosus patients with ongoing prothrombotic state . Circulation 1997; 95: 1425-1432 .

17.

Martinuzzo ME , de Larrañaga GF , Forastiero RR et al. Markers of platelet, endothelial cell and blood coagulation activation markers in leprosy patients with antiphospholipid antibodies . Clin Exp Rheumatol 2002; 20: 477-483 .

18.

Grignani G , Maiolo A. Cytokines and hemostasis . Haematologica 2000; 85: 967-972 .

19.

Esmon CT. Does inflammation contribute to thrombotic events ? Haemostasis 2000; 30: 34-40 .

20.

Forastiero R , Martinuzzo M , Carreras LO. Imbalance towards Th2-type response in patients with definite primary antiphospholipid syndrome . Thromb Haemost 2001; 86: 934-935 (letter).

21.

Brandt JT , Triplett DA , Alving B , Scharrer I. Criteria for the diagnosis of lupus anticoagulant: an update . Thromb Haemost 1995; 74: 1185-1190 .

22.

Forastiero RR , Martinuzzo ME , Cerrato GS , Kordich LC , Carreras LO. Relationship of anti β2-glycoprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies . Thromb Haemost 1997; 78: 1008-1014 .

23.

Ferro D , Saliola M , Moroni PL et al. Enhanced monocyte expression of tissue factor by oxidative stress in patients with antiphospholipid antibodies: effect of antioxidant treatment . J Thromb Haemost 2003; 1: 523-531 .

24.

Dobado-Berrios PM , Lopez-Pedrera C , Velasco F , Aguirre MA , Torres A , Cuadrado MJ. Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome . Thromb Haemost 1999; 82: 1578-1582 .

25.

Martinuzzo ME , Forastiero RR , Kordich L , Carreras LO. Increased lipid peroxidation correlates with platelet activation but not with markers of endothelial cell and blood coagulation activation in patients with antiphospholipid antibodies . Br J Haematol 2001; 114: 845-851 .

26.

Cuadrado MJ , Lopez-Pedrera C , Khamashta MA et al. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression . Arthritis Rheum 1997; 40: 834-841 .

27.

Cuadrado MJ , Dobado-Berrios PM , Lopez-Pedrera C et al. Variability of soluble tissue factor in primary antiphospholipid syndrome . Thromb Haemost 1998; 80: 712-713 (letter).

28.

Forastiero RR , Martinuzzo ME , de Larrañaga G , Broze GJ. Antibodies to tissue factor pathway inhibitor are uncommonly detected in patients with infection-related antiphospholipid antibodies . J Thromb Haemost 2003; 1: 2250-2251 (letter).

29.

Krause I , Blank M , Levi Y , Koike T , Barak V , Shoenfeld Y. Anti-idiotype immunomodulation of experimental anti-phospholipid syndromevia effect on Th1/Th2 expression . Clin Exp Immunol 1999; 117: 190-197 .

30.

Wong CK , Ho CY , Li EK , Lam CWK. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus . Lupus 2000; 9: 589-593 .

31.

Del Papa N , Guidali L , Sala A et al. Endothelial cells as target for antiphospholipid antibodies . Arthritis Rheum 1997; 40: 551-561 .

32.

Simantov R , LaSala JM , Lo SK et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies . J Clin Invest 1995; 96: 2211-2219 .

33.

van Aken BE , den Heijer M , Bos GMJ , van Deventer SJH , Reitsma PH. Recurrent venous thrombosis and markers of inflammation . Thromb Haemost 2000; 83: 536-539 .

34.

Stouthard JML , Levi M , Hack CE et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans . Thromb Haemost 1996; 76: 738-742 .

35.

Jones SA , Rose-John S. The role of soluble receptors in cytokine biology: the agonistic properties of the sIL-6R/IL-6 complex . Biochim Biophys Acta 2002; 1592: 251-263 .

36.

Polgar A , Brozik M , Toth S et al. Soluble interleukin-6 receptor in plasma and in lymphocyte culture supernatants of healthy individuals and patients with systemic lupus erythematosus and rheumatoid arthritis . Med Sci Monit 2000; 6: 13-18 .

37.

Bertolaccini ML , Atsumi T , Lanchbury J et al. Plasma tumor necrosis factor a levels and the 2238 A promoter polymorphism in patients with antiphospholipid syndrome . Thromb Haemost 2001; 85: 198-203 .