Maculopathy after long-term use of fondaparinux, a heparin mimetic and heparanase inhibitor.

Purpose: To report maculopathy associated with the long-term use of fondaparinux, a heparin mimetic and inhibitor of the extracellular matrix enzyme, heparanase. Observations: A 41-year-old woman receiving thrice weekly injections of fondaparinux as prophylaxis against deep vein thrombosis for 9 years noticed gray spots in her vision without metamorphopsias. On exam, there was bilateral altered macular pigmentation with speckled hyperpigmentation. Optical coherence tomography revealed irregular thickening of the retinal pigment epithelium. Blue autofluorescence photography demonstrated symmetric well-defined plaques of hyper-and hypoautofluorescence similar to those described in patients chronically treated with pentosan polysulfate (PPS). Review of 13 years of outside medical records confirmed no prior treatment with PPS. Two years before, optical coherence tomography (OCT) done as part of routine eye examination showed early pigmentary changes which were not felt to be clinically significant. Inherited retinal gene panel testing and mitochondrial DNA testing did not reveal pathogenic variants associated with pattern dystrophies. The maculopathy was attributed to fondaparinux due to a pharmacologic effect shared with PPS of heparanase inhibition. Thirteen months after stopping fondaparinux, there was a significant reduction in macular pigmentary changes and improvement in outer retinal abnormalities on OCT. Conclusions and importance: Fondaparinux is structurally and functionally related to PPS, which is also a heparin mimetic and heparanase inhibitor. Both drugs are now associated with phenotypically similar disruptions of the macular retinal pigment epitheliopathy. Although used for different clinical indications, both fondaparinux and PPS are sulfated oligosaccharides related to heparin that bind and inhibit heparanase, a critical enzyme in the extracellular matrix. This case is relevant for research into pharmacologic uses of heparanase inhibitors and monitoring for retinal disease in patients treated with them.