Sir,

We thank Anitua et al. for their stimulating comments and welcome further discussion.1

We note most of their comments are based on the effect of growth factors on epithelial defects, whereas our study2 was on treating chronic dry eyes.

We agree that the growth factor concentration in platelet-rich plasma (PRP) is likely greater than in plasma of fresh whole blood. Despite this, our preliminary results suggest fingerprick autologous blood (FAB) efficacy is comparable to that of autologous serum.3 We propose two possible explanations for this. Firstly, platelet activation may occur in the process of FAB draw and application, and the authors are correct that quantitative characterisation of the degree and reliability to which this occurs requires further study. Additionally, fresh platelets may be able to adhere to areas of the inflamed dry eye anterior surface, allowing for a targeted activation and release of growth factors, as opposed to simply coating the eye momentarily with growth factors from PRP. Secondly, we propose that FAB efficacy might relate to other factors in whole blood, such as fibronectin, vitamins, and other chemicals at physiological level, and their interaction than just growth factors alone. We also note that although Anitua et al recommend from their experience higher concentrations of growth factors than blood for optimal therapeutic effect, long-term safety data are lacking. Higher concentrations may induce harmful effects such as corneal neovascularisation from greater epidermal growth factor4 or impaired epithelial wound healing from high concentrations of transforming growth factor beta.5 Anitua et al rightly mention that non-activated PRP was less effective than its activated counterpart;6 however, this was a laboratory study only looking at corneal wound healing on rabbit eyes and therefore cannot be directly extrapolated to real-life conditions of human severe dry eye patients. As mentioned in our paper discussion, there may also be release of growth factors by red blood cells,7 providing an additional source of and possibly different growth factors than just platelet activation. Only fresh blood has the potential to offer an orchestrated response with its additional adaptive cellular composition to the ever-changing ocular surface environment, particularly in dry eyes. The exact mechanisms will need to be elucidated. Speculation on superior efficacy and putative mechanisms of different blood-derived products is limited by a lack of mechanistic studies and direct comparisons between them. We encourage such studies and suggest FAB be included in these comparisons.

The potential variability in cellular composition from drop to drop has been considered by the authors and again further work is suggested to evaluate this.

Anitua et al propose an interesting approach of 'inactivation protocol for the immune component of the eye drops' for diseases such as Sjogren's. We agree, but this might affect the antimicrobial properties and any unknown beneficial effect of these inactivated components. The increased use of allogenic serum in Sjogren's patients may give us a better understanding in this area.

The authors note the valid concern regarding viability of long-term compliance in light of repeated fingerpricks during treatment. The subjective improvement noted by these patients has resulted in all continuing treatment after study conclusion (the longest for over 3 years). This would suggest that the discomfort of regular fingerpricks is outweighed by the improvement in quality of life provided by relief from severe dry eye syndrome. We feel a major advantage that FAB presents is not being impeded by many of the barriers experienced by other blood-derived therapies such as cost, repeat venesections, and storage.