Graefe's Archive for Clinical and Experimental Ophthalmology

, Volume 251, Issue 7, pp 1723–1733

Factor Xa and thrombin stimulate proinflammatory and profibrotic mediator production by retinal pigment epithelial cells: a role in vitreoretinal disorders?


    • The Rotterdam Eye Hospital
    • Department of ImmunologyErasmus MC
  • Jan C. van Meurs
    • The Rotterdam Eye Hospital
    • Department of OphthalmologyErasmus MC
  • Conny van Holten-Neelen
    • Department of ImmunologyErasmus MC
  • Marja Smits-te Nijenhuis
    • Department of ImmunologyErasmus MC
  • Marion J. Kolijn-Couwenberg
    • Department of ImmunologyErasmus MC
  • P. Martin van Hagen
    • Department of ImmunologyErasmus MC
    • Department of Internal MedicineErasmus MC
  • Robert W. A. M. Kuijpers
    • Department of OphthalmologyErasmus MC
  • Herbert Hooijkaas
    • Department of ImmunologyErasmus MC
  • Willem A. Dik
    • Department of ImmunologyErasmus MC
Basic Science

DOI: 10.1007/s00417-013-2335-2

Cite this article as:
Bastiaans, J., van Meurs, J.C., van Holten-Neelen, C. et al. Graefes Arch Clin Exp Ophthalmol (2013) 251: 1723. doi:10.1007/s00417-013-2335-2



Vitreoretinal disorders, including proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR) and exudative age-related macular degeneration (AMD), are a major cause of visual impairment worldwide and can lead to blindness when untreated. Loss of blood-retinal barrier (BRB) integrity associated with vitreoretinal fibrin deposition, inflammation, fibrosis and neovascularization contribute to the pathophysiological processes in these disorders. Retinal pigment epithelial (RPE) cells are well recognized to contribute to vitreoretinal inflammation/fibrosis and are likely to encounter contact with coagulation factor upon loss of BRB integrity.


An extensive study was performed in which we examined the effect of factor Xa and thrombin on the production of a broad panel of cytokines/chemokines and growth factors by RPE cells. For this purpose we used the ARPE-19 cell line as well as primary RPE cells, a glass slide based array that allows simultaneous detection of 120 cytokines/chemokines and growth factors, ELISA and real-time-quantitative PCR. The involved signaling cascade was examined using specific inhibitors for protease activated receptor (PAR)1, PAR2 and nuclear factor kappa-B (NF-κB).


Factor Xa and thrombin regulated the production of cytokines and growth factors (including GM-CSF, IL-6, IL-8, MCP-3, PDGF-AA, PDGF-BB, TIMP-1 and TGF-α) that fit well in the pathobiology of vitreoretinal disease. Blocking studies revealed that the effects were mediated via PAR1 induced NF-κB activation.


Our findings suggest that factor Xa and thrombin can drive vitreoretinal inflammation and fibrosis and should be considered as treatment targets in vitreoretinal disorders such as PVR, PDR and AMD.


Factor XaThrombinRetinal pigment epitheliumVitreoretinal fibrotic disordersCytokine antibody arrayInflammationFibrosis

Supplementary material

417_2013_2335_MOESM1_ESM.doc (248 kb)
ESM 1(DOC 248 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013