Skip to main content

Advertisement

SpringerLink
Log in

Soluble endothelial protein C receptor levels in Behçet patients with and without ocular involvement

  • Inflammatory Disorders
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

The protein C system is an important natural anticoagulant mechanism. Endothelial cell-activated protein C receptor (EPCR), which was discovered at the surface of endothelial cells, binds protein C and enhances its activation. The soluble form of EPCR (sEPCR) has been detected in plasma. Behçet’s disease is a chronic inflammatory disorder affecting multiple organs. Arterial and venous thrombosis is a common clinical manifestation of Behçet’s disease and the pathogenic mechanism of thrombotic tendency in the disease is not well known. The aim of this study is to determine sEPCR concentrations in Behçet patients with and without ocular involvement as well as to investigate the association between sEPCR levels and clinical manifestations of Behçet’s disease.

Methods

Sixty patients with Behçet’s disease and 67 healthy control subjects were included in this study. A complete ophthalmic examination was performed by ophthalmologists with an interest in Behçet’s disease. Sixty patients with Behçet’s disease were divided into two groups. Group 1 consisted of 30 patients with ocular involvement and Group 2 consisted of 30 patients without ocular involvement. Soluble EPCR levels were determined in plasma by using sEPCR Asserachrom enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer’s instructions. Differences of the mean sEPCR levels between groups were evaluated using Mann-Whitney U-test. Pearson’s correlation analysis was used for evaluating the correlation between sEPCR levels and age, gender, duration of the disease as well as different clinical manifestations of Behçet’s disease.

Results

Age and gender ratio were not different between patients and controls. Plasma sEPCR concentrations were significantly higher in patients with Behçet’s disease than those in controls (p<0.05). There was no statistically significant difference in serum sEPCR levels between the patients with versus the ones without ocular involvement. There were no statistically significant correlations between sEPCR levels and age, gender, duration of the disease or clinical manifestations.

Conclusions

Our data suggests a possible role of soluble EPCR in the pathogenesis of Behçet’s disease. Further studies by possible mutations and polymorphisms in EPCR gene in patients with Behçet’s disease would be useful to bring to light the pathogenic mechanism of ocular and systemic vascular complications of the disease.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Akar N, Gokdemir R, Ozel D, Akar E (2002) Endothelial cell protein C receptor (EPCR) gene exon III, 23-bp insertion mutation in the Turkish pediatric thrombotic patients. Thromb Haemost 88:1068–1069

    PubMed  CAS  Google Scholar 

  2. Ates A, Duzgun N, Ulu A, Tiryaki AO, Akar N (2003) Factor V gene (1691A and 4070G) and prothrombin gene 20210A mutations in patients with Behcet’s disease. Pathophysiol Haemost Thromb 33:157–163 doi:10.1159/000077824

    Article  PubMed  CAS  Google Scholar 

  3. Batioglu F, Atmaca LS, Karabulut HG, Sayın DB (2003) Factor V Leiden and prothrombin gene G20210A mutations in ocular Behçet disease. Acta Ophthalmol Scand 81:283–285 doi:10.1034/j.1600-0420.2003.00068.x

    Article  PubMed  CAS  Google Scholar 

  4. Biguzzi E, Merati G, Liaw PC, Bucciarelli P, Oganesyan N, Qu D, Gu JM, Fetiveau R, Esmon CT, Mannucci PM, Faioni EM (2001) A 23-bp insertion in the endothelial protein C receptor (EPCR) gene impairs EPCR function. Thromb Haemost 86:945–948

    PubMed  CAS  Google Scholar 

  5. Boomsma MM, Stearns-Kurosawa DJ, Stegeman CA, Raschi E, Meroni PL, Kurosawa S, Tervaert JW (2002) Plasma levels of soluble endothelial cell protein C receptor in patients with Wegener’s granulomatosis. Clin Exp Immunol 128:187–194 doi:10.1046/j.1365-2249.2002.01803.x

    Article  PubMed  CAS  Google Scholar 

  6. Chambers JC, Haskar DO, Kooner JS (2001) Vascular endothelial function and oxidative stress mechanism in patients with Behçet’s syndrome. J Am Coll Cardiol 37:517–520 doi:10.1016/S0735-1097(00)01137-2

    Article  PubMed  CAS  Google Scholar 

  7. Conway EM, Rosenberg RD (1988) Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol Cell Biol 8:5588–5592

    PubMed  CAS  Google Scholar 

  8. Esmon CT, Gu J, Xu J, Qu D, Stearns-Kurosawa DJ, Kurosawa S (1999) Regulation and functions of the protein C anticoagulant pathway. Haematologica 84:363–368

    PubMed  CAS  Google Scholar 

  9. Esmon CT (2003) The protein C pathway. Chest 124:26–32 doi:10.1378/chest.124.3_suppl.26S

    Article  Google Scholar 

  10. Esmon CT (2004) Crosstalk between inflammation and thrombosis. Maturitas 47:305–314 doi:10.1016/j.maturitas.2003.10.015

    Article  PubMed  CAS  Google Scholar 

  11. Esmon CT (2004) Structure and functions of the endothelial cell protein C receptor. Crit Care Med 32:298–301 doi:10.1097/01.CCM.0000126128.64614.81

    Article  Google Scholar 

  12. Esmon CT (2005) Coagulation inhibitors in inflammation. Biochem Soc Trans 33:401–405 doi:10.1042/BST0330401

    Article  PubMed  CAS  Google Scholar 

  13. Espinosa G, Font J, Tassies D, Vidaller A, Deulofeu R, Lopez-Soto A, Cervera R, Ordinas A, Ingelmo M, Reverter J (2002) Vascular involvement in Behçet’s disease: Relation with thrombophilic factors, coagulation activation, and thrombomodulin. Am J Med 112:37–43 doi:10.1016/S0002-9343(01)01048-8

    Article  PubMed  CAS  Google Scholar 

  14. Faioni EM, Ferrero S, Fontana G, Gianelli U, Ciulla MM, Vecchi M, Saibeni S, Biguzzi E, Cordani N, Franchi F, Bosari S, Cattaneo M (2004) Expression of endothelial protein C receptor and thrombomodulin in the intestinal tissue of patients with inflammatory bowel disease. Crit Care Med 32:266–270 doi:10.1097/01.CCM.0000128032.85396.83

    Article  Google Scholar 

  15. Fukudome K, Esmon CT (1994) Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 269:26486–26491

    PubMed  CAS  Google Scholar 

  16. Fukudome K, Kurosawa S, Stearns-Kurosawa DJ, He X, Rezaie AR, Esmon CT (1996) The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor. J Biol Chem 271:17491–17498 doi:10.1074/jbc.271.29.17491

    Article  PubMed  CAS  Google Scholar 

  17. Galligan L, Livingstone W, Volkov Y, Hokamp K, Murphy C, Lawler M, Fukudome K, Smith O (2001) Characterization of protein C receptor expression in monocytes. Br J Haematol 115:408–414 doi:10.1046/j.1365-2141.2001.03187.x

    Article  PubMed  CAS  Google Scholar 

  18. Grey ST, Tsuchida A, Hau H, Orthner CL, Salem HH, Hancock WW (1994) Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-γ or phorbol ester. J Immunol 153:3664–3672

    PubMed  CAS  Google Scholar 

  19. Gul A, Ozbek U, Ozturk C, Inanc M, Koniçe M, Ozçelik T (1996) Coagulation factor V gene mutation increases the risk of venous thrombosis in Behçet’s disease. Br J Rheumatol 35:1178–1180 doi:10.1093/rheumatology/35.11.1178

    Article  PubMed  CAS  Google Scholar 

  20. Gumus K, Kadayifcilar S, Eldem B, Saracbasi O, Ozcebe O, Dundar S, Kirazli S (2006) Is elevated level of soluble endothelial protein C receptor a new risk factor for retinal vein occlusion. Clin Experiment Ophthalmol 34:305–311 doi:10.1111/j.1442-9071.2006.01212.x

    Article  PubMed  Google Scholar 

  21. Haznedaroglu IC, Ozcebe O, Çelik I, Dündar SV, Kirazli S (1996) Haemostatic markers of procoagulant imbalance in Behçet’s disease. Eur J Haematol 57:107–108

    Article  PubMed  CAS  Google Scholar 

  22. Kiraz S, Ertenli I, Ozturk MA, Haznedaroglu IC, Celik I, Calguneri M (1994) Pathological haemostasis and ‘prothrombotic state’ in Behçet’s disease. Thromb Res 105:125–133 doi:10.1016/S0049-3848(02)00006-3

    Article  Google Scholar 

  23. Kosar A, Haznedaroglu IC, Buyukasık Y, Kirazli S, Dundar SV (1998) Activated protein C resistance in Behçet’s disease. Rheumatol Int 17:249–250 doi:10.1007/s002960050043

    Article  PubMed  CAS  Google Scholar 

  24. Kurosawa S, Stearns-Kurosawa DJ, Hidari N, Esmon CT (1997) Identification of functional endothelial protein C receptor in human plasma. J Clin Invest 100:411–418 doi:10.1172/JCI119548

    Article  PubMed  CAS  Google Scholar 

  25. Kurosawa S, Stearns-Kurosawa DJ, Carson CW, D’Angelo A, Della Valle P, Esmon CT (1998) Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: lack of correlation with thrombomodulin suggests involvement of different pathological processes. Blood 91:725–727

    PubMed  CAS  Google Scholar 

  26. Laszik Z, Mitro A, Taylor FB Jr, Ferrell G, Esmon CT (1997) Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 96:3633–3640

    PubMed  CAS  Google Scholar 

  27. Lee YJ, Kang SW, Yang JI, Choi YM, Sheen D, Lee EB, Choi SW, Song YW (1994) Coagulation parameters and plasma total homocysteine levels in Behcet’s disease. Thromb Res 106:19–24 doi:10.1016/S0049-3848(02)00085-3

    Article  Google Scholar 

  28. Liaw PCY, Neuenschwander PF, Smirnov MD, Esmon CT (2000) Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. J Biol Chem 275:5447–5452 doi:10.1074/jbc.275.8.5447

    Article  PubMed  CAS  Google Scholar 

  29. Lie JT (1992) Vascular involvement in Behçet’s disease: arterial and venous and vessels of all sizes. J Rheumatol 19:341–343

    PubMed  CAS  Google Scholar 

  30. Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, Takatsuki K (1996) Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 87:642–647

    PubMed  CAS  Google Scholar 

  31. Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, Takatsuki K (1997) Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 272:197–202

    Google Scholar 

  32. Murphy C, Livingstone WJ, White B (2001) Activated protein C inhibits upregulation of both tissue factor and TNF-α in endotoxin stimulated monocytes. Thromb Haemost Suppl: 509

  33. Oner AF, Gurgey A, Gurler A, Mesci L (1998) Factor V Leiden mutation in patients with Behçet’s disease. J Rheumatol 25:496–498

    PubMed  CAS  Google Scholar 

  34. Regan LM, Mollica JS, Rezaie AR, Esmon CT (1997) The interaction between the endothelial cell protein C receptor and protein C is dictated by the gamma-carboxyglutamic acid domain of protein C. J Biol Chem 272:26279–26284 doi:10.1074/jbc.272.42.26279

    Article  PubMed  CAS  Google Scholar 

  35. Rizzi R, Bruno S, Dammacco R (1997) Behçet’s disease: an immune-mediated vasculitis involving vessels of all sizes. Int J Clin Lab Res 27:225–232 doi:10.1007/s005990050002

    Article  PubMed  CAS  Google Scholar 

  36. Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behçet’s disease. N Eng J Med 341:1284–1291 doi:10.1056/NEJM199910213411707

    Article  CAS  Google Scholar 

  37. Saposnik B, Reny JL, Gaussem P, Emmerich J, Aiach M, Gandrille S (2004) EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis. Blood 103:1311–1318 doi:10.1182/blood-2003-07-2520

    Article  PubMed  CAS  Google Scholar 

  38. Simioni P, Morboeuf O, Tognin G, Gavasso S, Tormene D, Woodhams B, Pagnan A (2006) Soluble endothelial cell protein C receptor (sEPCR) levels and venous thromboembolism in carriers of two dysfunctional protein C variants. Thromb Res 117:523–528 doi:10.1016/j.thromres.2005.04.029

    Article  PubMed  CAS  Google Scholar 

  39. Simmonds RE, Lane DA (2001) The endothelial cell protein C receptor: a candidate genetic risk factor for thrombosis. Thromb Haemost 86:939–941

    PubMed  CAS  Google Scholar 

  40. Sipahi T, Pocan H, Akar N (2006) Effects of various genetic polymorphisms on the incidence and outcome of severe sepsis. Clin Appl Thrombosis/Hemostasis 12:47–54 doi:10.1177/107602960601200108

    Article  CAS  Google Scholar 

  41. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT (1996) The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 93:10212–10216 doi:10.1073/pnas.93.19.10212

    Article  PubMed  CAS  Google Scholar 

  42. Stearns-Kurosawa DJ, Swindle K, D’Angelo A, Della Valle P, Fattorini A, Caron N, Grimaux M, Woodhams B, Kurosawa S (2002) Plasma levels of endothelial protein C receptor respond to anticoagulant treatment. Blood 99:526–530 doi:10.1182/blood.V99.2.526

    Article  PubMed  CAS  Google Scholar 

  43. Sturn DH, Kaneider NC, Feistritzer C, Djanani A, Fukudome K, Wiedermann CJ (2003) Expression and function of the endothelial protein C receptor in human neutrophils. Blood 102:1499–1505 doi:10.1182/blood-2002-12-3880

    Article  PubMed  CAS  Google Scholar 

  44. Taylor FB Jr, Stearns-Kurosawa DJ, Kurosawa S, Ferrell G, Chang AC, Laszik Z, Kosanke S, Peer G, Esmon CT (2000) The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 95:1680–1686

    PubMed  CAS  Google Scholar 

  45. Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT (2001) Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 97:1685–1688 doi:10.1182/blood.V97.6.1685

    Article  PubMed  CAS  Google Scholar 

  46. Toydemir PB, Elhan AH, Tükün A, Toydemir R, Gürler A, Tüzüner A, Bokesoy I (2000) Effects of factor V gene G1691A, methylenetetrahydrofolate reductase gene C677T, and prothrombin gene G20210A mutations on deep venous thrombosis in Behçet’s disease. J Rheumatol 27:2849–2854

    PubMed  CAS  Google Scholar 

  47. Uitte D Willige S, Van Marion V, Rosendaal FR, Vos HL, De Visser MCH, Bertina RM (2004) Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis. J Thromb Haemost 2:1305–1310 doi:10.1046/j.1538-7836.2004.00855.x

    Article  Google Scholar 

  48. Ulu A, Gunal D, Tiras S, Egin Y, Deda G, Akar N (2007) EPCR gene A3 haplotype and elevated soluble endothelial protein C receptor (sEPCR) levels in Turkish pediatric stroke patients. Thromb Res 120:47–52 doi:10.1016/j.thromres.2006.08.004

    Article  PubMed  CAS  Google Scholar 

  49. Verity DH, Vaughan RW, Madanat W, Kondeatis E, Zureikat H, Fayyad F, Kanawati CA, Ayesh I, Stanford MR, Wallace GR (1999) Factor V Leiden mutation is associated with ocular involvement in Behçet’s disease. Am J Ophthalmol 128:352–356 doi:10.1016/S0002-9394(99)00184-1

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by Ankara University Research Fund.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Ankara University Faculty of Medicine, 06100, Ankara, Turkey

    F. Nilüfer Yalçındağ, Figen Batıoğlu, Özden Özdemir & Esra Cansızoğlu

  2. Department of Pediatric Moleculer Genetics, Ankara University Faculty of Medicine, Ankara, Turkey

    Yonca Eğin & Nejat Akar

  3. Esat Caddesi 74/3 Küçükesat, 06660, Ankara, Turkey

    F. Nilüfer Yalçındağ

Authors
  1. F. Nilüfer Yalçındağ
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Figen Batıoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Özden Özdemir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Esra Cansızoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yonca Eğin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nejat Akar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F. Nilüfer Yalçındağ.

Additional information

The authors have no financial interest in any of the products identified herein. We have full control of all primary data and agree to allow Graefes Archive for Clinical and Experimental Ophthalmology to review our data upon request.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yalçındağ, F.N., Batıoğlu, F., Özdemir, Ö. et al. Soluble endothelial protein C receptor levels in Behçet patients with and without ocular involvement. Graefes Arch Clin Exp Ophthalmol 246, 1603–1608 (2008). https://doi.org/10.1007/s00417-008-0873-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-008-0873-9

Keywords

Search

Navigation