Systemic Counterregulatory Response of Placental Growth Factor Levels to Intravitreal Aflibercept Therapy

Invest Ophthalmol Vis Sci. 2015 May;56(5):3279-86. doi: 10.1167/iovs.15-16686.


Purpose: Placental growth factor (PlGF) has been implicated as a contributor to resistance against anti-VEGF therapy. The purpose of the present study was to analyze the systemic levels of PlGF, VEGF-A, and VEGF-B in patients with neovascular age-related macular degeneration (AMD) after treatment with aflibercept, ranibizumab, or bevacizumab.

Methods: Totals of 19 patients were treated with intravitreal aflibercept, 19 with ranibizumab, and 18 with bevacizumab. The cytokine levels were measured by ELISA just before the injection, and 7 days and 1 month thereafter. Age- and sex-matched participants (n = 22) served as controls.

Results: The median PlGF plasma concentration at baseline was <12.0 pg/mL in the control group as well as in all three anti-VEGF treatment cohorts. After intravitreal aflibercept injection, a significant upregulation of systemic PlGF could be observed in all treated patients (38.0 [31.0-44.0] pg/mL after 1 week [P < 0.001] and 16.0 [0.0-19.0] pg/mL [P = 0.005] after 4 weeks). No significant effects on plasma PlGF concentrations could be detected in those treated with ranibizumab and bevacizumab. The systemic VEGF-A levels were significantly reduced 1 and 4 weeks after intravitreal aflibercept (P < 0.001, P < 0.001) and bevacizumab (P < 0.001, P < 0.01) injections. No significant effects on plasma cytokine concentrations could be observed in the ranibizumab cohort. No significant effects on systemic VEGF-B could be observed in any of the treatment groups.

Conclusions: In this study, we report a significant systemic upregulation of the proangiogenic cytokine PlGF after intravitreal administration of aflibercept. This might represent a counter-regulatory response to antiangiogenic therapy.

Publication types

  • Observational Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / administration & dosage*
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Bevacizumab
  • Cytokines / blood
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Intravitreal Injections
  • Macular Degeneration / blood
  • Macular Degeneration / drug therapy*
  • Male
  • Placenta Growth Factor
  • Pregnancy Proteins / blood*
  • Prospective Studies
  • Ranibizumab
  • Receptors, Vascular Endothelial Growth Factor / administration & dosage*
  • Recombinant Fusion Proteins / administration & dosage*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / blood
  • Visual Acuity


  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Cytokines
  • PGF protein, human
  • Pregnancy Proteins
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • Placenta Growth Factor
  • aflibercept
  • Bevacizumab
  • Receptors, Vascular Endothelial Growth Factor
  • Ranibizumab