Skip to main content
Log in

Inflammatory markers in thrombosis associated with primary antiphospholipid syndrome

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

The role of inflammation in thrombotic complications of primary antiphospholipid syndrome (PAPS) is controversial. The aim of this study was to evaluate levels of inflammation and coagulation markers in patients with thrombotic PAPS (t-PAPS). Patients with t-PAPS and individuals with no history of thrombosis were enrolled. The association of t-PAPS with levels of tumor necrosis factor (TNF)-α, C-reactive protein (hs-CRP), interferon (IFN)-α, interleukins (IL)-6, -8, factor VIII (FVIII), von Willebrand factor (VWF) and tissue factor (TF) was evaluated by regression models. The levels of these markers were also compared between controls and subgroups of t-PAPS patients with triple positivity, recently diagnosed thrombosis, recurrent thrombosis and venous thrombosis. Patients with t-PAPS (n = 101) had a 8.6-fold increased levels of TNF-α, 90% increased levels of hs-CRP, 80% increased levels of IL-6, 30% increased levels of FVIIIAg, 50% increased levels of VWF and 66% increased levels of TF as compared to controls (n = 131), and the differences did not change after adjustments for sex, age and cardiovascular risk factors. Inflammatory markers were elevated in t-PAPS regardless of the aPL profile, number of previous thrombosis or time elapsed since diagnosis. TNF-α and IL-8 levels were higher in t-PAPS patients with venous thrombosis, in comparison with those with arterial thrombosis and controls. Patients with t-PAPS presented with increased levels of inflammatory and coagulation markers, which suggests that t-PAPS is associated not only with hypercoagulability but also with a persistent inflammatory state.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA (2010) Antiphospholipid syndrome. Lancet 376(9751):1498–1509. https://doi.org/10.1016/s0140-6736(10)60709-x

    Article  CAS  PubMed  Google Scholar 

  2. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Lakos G, Tincani A, Kontopoulou-Griva I, Galeazzi M, Meroni PL, Derksen RH, de Groot PG, Gromnica-Ihle E, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quere I, Hachulla E, Vasconcelos C, Roch B, Fernandez-Nebro A, Boffa MC, Hughes GR, Ingelmo M (2002) Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 46(4):1019–1027

    Article  Google Scholar 

  3. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera RH, Derksen RH, de Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4(2):295–306. https://doi.org/10.1111/j.1538-7836.2006.01753.x

    Article  CAS  Google Scholar 

  4. Bertero MT, Bazzan M, Carignola R, Montaruli B, Silvestro E, Sciascia S, Vaccarino A, Baldovino S, Roccatello D (2012) Antiphospholipid syndrome in northwest Italy (APS Piedmont Cohort): demographic features, risk factors, clinical and laboratory profile. Lupus 21(7):806–809. https://doi.org/10.1177/0961203312446974

    Article  CAS  PubMed  Google Scholar 

  5. Cervera R, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Kiss E, Zeher MM, Tincani A, Kontopoulou-Griva I, Galeazzi M, Bellisai F, Meroni PL, Derksen RH, de Groot PG, Gromnica-Ihle E, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quere I, Hachulla E, Vasconcelos C, Roch B, Fernandez-Nebro A, Piette JC, Espinosa G, Bucciarelli S, Pisoni CN, Bertolaccini ML, Boffa MC, Hughes GR (2009) Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 68(9):1428–1432. https://doi.org/10.1136/ard.2008.093179

    Article  CAS  PubMed  Google Scholar 

  6. Saraiva Sda S, Custodio IF, Mazetto Bde M, Collela MP, de Paula EV, Appenzeller S, Annichino-Bizzachi J, Orsi FA (2015) Recurrent thrombosis in antiphospholipid syndrome may be associated with cardiovascular risk factors and inflammatory response. Thromb Res 136(6):1174–1178. https://doi.org/10.1016/j.thromres.2015.10.029

    Article  CAS  PubMed  Google Scholar 

  7. Ames PR, Antinolfi I, Ciampa A, Batuca J, Scenna G, Lopez LR, Delgado Alves J, Iannaccone L, Matsuura E (2008) Primary antiphospholipid syndrome: a low-grade auto-inflammatory disease? Rheumatology (Oxford) 47(12):1832–1837. https://doi.org/10.1093/rheumatology/ken382

    Article  CAS  Google Scholar 

  8. Meroni PL, Borghi MO, Grossi C, Chighizola CB, Durigutto P, Tedesco F (2018) Obstetric and vascular antiphospholipid syndrome: same antibodies but different diseases? Nat Rev Rheumatol 14(7):433–440. https://doi.org/10.1038/s41584-018-0032-6

    Article  CAS  PubMed  Google Scholar 

  9. Salmon JE, Girardi G, Lockshin MD (2007) The antiphospholipid syndrome as a disorder initiated by inflammation: implications for the therapy of pregnant patients. Nat Clin Pract Rheumatol 3 (3):140–147; quiz 141 p following 187. https://doi.org/10.1038/ncprheum0432

  10. de Groot PG, Urbanus RT (2015) Antiphospholipid syndrome-not a noninflammatory disease. Semin Thromb Hemost 41(6):607–614. https://doi.org/10.1055/s-0035-1556725

    Article  CAS  PubMed  Google Scholar 

  11. Averina M, Johannesen S, Brox J (2016) Diagnostic accuracy of silica clotting time method for lupus anticoagulant in a clinical population with various symptoms of antiphospholipid syndrome. Lupus 25(4):418–422. https://doi.org/10.1177/0961203315617540

    Article  CAS  PubMed  Google Scholar 

  12. Freire PV, Watanabe E, dos Santos NR, Bueno C, Bonfa E, de Carvalho JF (2014) Distinct antibody profile: a clue to primary antiphospholipid syndrome evolving into systemic lupus erythematosus? Clin Rheumatol 33(3):349–353. https://doi.org/10.1007/s10067-013-2472-3

    Article  PubMed  Google Scholar 

  13. Font J, Cervera R (1993) 1982 revised criteria for classification of systemic lupus erythematosus–ten years later. Lupus 2(5):339–341. https://doi.org/10.1177/096120339300200512

    Article  CAS  PubMed  Google Scholar 

  14. American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Suppl 1):S81–S90. https://doi.org/10.2337/dc14-S081

    Article  Google Scholar 

  15. Forastiero RR, Martinuzzo ME, de Larranaga GF (2005) Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies. Lupus 14(2):129–136. https://doi.org/10.1191/0961203305lu2048oa

    Article  CAS  PubMed  Google Scholar 

  16. Swadzba J, Iwaniec T, Musial J (2011) Increased level of tumor necrosis factor-alpha in patients with antiphospholipid syndrome: marker not only of inflammation but also of the prothrombotic state. Rheumatol Int 31(3):307–313. https://doi.org/10.1007/s00296-009-1314-8

    Article  CAS  PubMed  Google Scholar 

  17. Medzhitov R (2007) Recognition of microorganisms and activation of the immune response. Nature 449(7164):819–826. https://doi.org/10.1038/nature06246

    Article  CAS  Google Scholar 

  18. Rauch J, Dieude M, Subang R, Levine JS (2010) The dual role of innate immunity in the antiphospholipid syndrome. Lupus 19(4):347–353. https://doi.org/10.1177/0961203310361492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sorice M, Longo A, Capozzi A, Garofalo T, Misasi R, Alessandri C, Conti F, Buttari B, Rigano R, Ortona E, Valesini G (2007) Anti-beta2-glycoprotein I antibodies induce monocyte release of tumor necrosis factor alpha and tissue factor by signal transduction pathways involving lipid rafts. Arthritis Rheum 56(8):2687–2697. https://doi.org/10.1002/art.22802

    Article  CAS  PubMed  Google Scholar 

  20. Manganelli V, Capozzi A (2017) Elevated serum level of HMGB1 in patients with the antiphospholipid syndrome. J Immunol Res 2017:4570715. https://doi.org/10.1155/2017/4570715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sacre K, Criswell LA, McCune JM (2012) Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 14(3):R155. https://doi.org/10.1186/ar3895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Willis R, Seif AM, McGwin G Jr, Martinez-Martinez LA, Gonzalez EB, Dang N, Papalardo E, Liu J, Vila LM, Reveille JD, Alarcon GS, Pierangeli SS (2012) Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort. Lupus 21(8):830–835. https://doi.org/10.1177/0961203312437270

    Article  CAS  PubMed  Google Scholar 

  23. Ugolini-Lopes MR, Torrezan GT, Gandara APR, Olivieri EHR, Nascimento IS, Okazaki E, Bonfa E, Carraro DM, de Andrade DCO (2019) Enhanced type I interferon gene signature in primary antiphospholipid syndrome: association with earlier disease onset and preeclampsia. Autoimmun Rev 18(4):393–398. https://doi.org/10.1016/j.autrev.2018.11.004

    Article  CAS  PubMed  Google Scholar 

  24. Palli E, Kravvariti E, Tektonidou MG (2019) Type I interferon signature in primary antiphospholipid syndrome: clinical and laboratory associations. Front Immunol 10:487. https://doi.org/10.3389/fimmu.2019.00487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kawecki C, Lenting PJ, Denis CV (2017) von Willebrand factor and inflammation. J Thromb Haemost 15(7):1285–1294. https://doi.org/10.1111/jth.13696

    Article  CAS  PubMed  Google Scholar 

  26. Levi M, van der Poll T, ten Cate H (2006) Tissue factor in infection and severe inflammation. Semin Thromb Hemost 32(1):33–39. https://doi.org/10.1055/s-2006-933338

    Article  CAS  PubMed  Google Scholar 

  27. Habe K, Wada H, Matsumoto T, Ohishi K, Ikejiri M, Matsubara K, Morioka T, Kamimoto Y, Ikeda T, Katayama N, Mizutani H (2016) Presence of antiphospholipid antibodies as a risk factor for thrombotic events in patients with connective tissue diseases and idiopathic thrombocytopenic purpura. Intern Med 55(6):589–595. https://doi.org/10.1177/1076029616643820

    Article  CAS  PubMed  Google Scholar 

  28. Tobaldini LQ, Arantes FT, Saraiva SDS, Mazetto BM, Colella MP, de Paula EV, Annichino-Bizzachi J, Orsi FA (2018) Circulating levels of tissue factor and the risk of thrombosis associated with antiphospholipid syndrome. Thromb Res 171:114–120. https://doi.org/10.1016/j.thromres.2018.09.058

    Article  CAS  PubMed  Google Scholar 

  29. Ng CJ, McCrae KR, Ashworth K, Sosa LJ, Betapudi V, Manco-Johnson MJ, Liu A, Dong JF, Chung D, White-Adams TC, Lopez JA, Di Paola J (2018) Effects of anti-beta2GPI antibodies on VWF release from human umbilical vein endothelial cells and ADAMTS13 activity. Res Pract Thromb Haemost 2(2):380–389. https://doi.org/10.1002/rth2.12090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hernandez C, Orbe J, Roncal C, Alvarez-Hernandez M, Martinez de Lizarrondo S, Alves MT, Garcia Mata J, Paramo JA (2013) Tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients. Thromb Haemost 110(3):598–608. https://doi.org/10.1160/TH13-02-0122

    Article  CAS  PubMed  Google Scholar 

  31. Brambilla M, Rossetti L, Zara C, Canzano P, Giesen PLA, Tremoli E, Camera M (2018) Do methodological differences account for the current controversy on tissue factor expression in platelets? Platelets 29(4):406–414. https://doi.org/10.1080/09537104.2017.1327653

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the São Paulo Research Foundation, FAPESP [Grant Number 2016/14172-6] and by Brazilian Federal Agency for the Support and Evaluation of Graduate Education, CAPES [to Fernanda T. Arantes and Laís Q. Tobaldini].

Author information

Authors and Affiliations

Authors

Contributions

FTA performed the laboratory and statistical analyses and drafted the manuscript; BMM was responsible for the laboratory analyses and revised the manuscript; LQT and APRdS performed the laboratory analyses and revised the manuscript; SSS and JA-B revised the manuscript and FAO designed the study, the analyses and revised the manuscript.

Corresponding author

Correspondence to Fernanda A. Orsi.

Ethics declarations

Competing interests:

The author(s) declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arantes, F.T., Mazetto, B.M., Saraiva, S.S. et al. Inflammatory markers in thrombosis associated with primary antiphospholipid syndrome. J Thromb Thrombolysis 50, 772–781 (2020). https://doi.org/10.1007/s11239-020-02155-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-020-02155-y

Keywords

Navigation