A Transfusion Service Medical Director for a health system in the midwest has received a request from their Ophthalmology Department to assist in the production of 'autologous serum eye drops' for patients with certain corneal disorders. The inquiring physician is wondering what is the 'community experience' with this type of activity, particularly as it pertains to quality control, maintenance of sterility, and safety issues involved with the loss of control over the "blood product" once it has been dispensed to the patient. He says that while the following reference is illuminating (Br. J. Ophthalmol. 2004;88;1467-1474), he is concerned about undertaking such a 'project' outside a more formal research setting. Any feedback that colleagues can offer would be helpful.

The following comments have been received.

ADDENDA April 27, 2007

1. Dr. Sheila MacLennan, Consultant in Transfusion Medicine, NHS Blood and Transplant (attribution used with permission), and co-author of the referenced British Journal of Ophthalmology review article reports that they performed a randomized controlled trial on the use of autologous serum eyedrops and showed that for most patients in the study, this treatment was superior to conventional treatment for improving ocular surface health and subjective comfort (Br J Ophthalmol 2004: 88: 647-52; editorial 603-4). She adds that prior to their involvement in this project, it was apparent that some ophthalmology clinics were preparing autologous serum themselves with little knowledge of GMP. They were able to develop a protocol using their expertise in this area, and thus improve the safety and control of the process (Transfusion 2001: 41: 9S, p 67-8S). Since then, they have implemented this procedure in several Blood Centers in England, following approval of the process by the Medicines and Healthcare Regulatory Agency. They are now providing treatment for almost 60 patients, some of whom have reported dramatically beneficial improvement. There have been no reported adverse effects. In their experience, this treatment provides a very effective symptomatic treatment for some patients with a debilitating condition for which treatment options are otherwise limited.

2. Editors' note: Colleagues might find it interesting to look over the 'Grand Rounds' powerpoint presentation entitled Autologous Serum Eye Drops: Fact or Fiction? which is posted on the website of the Texas Tech University Health Sciences Center.

ADDENDA May 2, 2007

3. Marie-Claire Chevrier, Director, Bioproduction at Recherche et Développement, Héma-Québec (attribution used with permission) reports that they have had a demand for plasma eye drops for a young patient with a ligneous conjunctivitis (LC) characterized by type I plasminogen deficiency. The patient was treated with a fresh frozen plasma from the blood bank supply tested for all disease markers (HIV, HBV, HCV, HTLV, Syphilis). The plasma was dispensed in eye drop bottles. For the preparation of eye drop bottles, special safety and ethic issues were considered since the plasma was not prepared under regular GMP standards for blood products.

• All manipulations were performed in sterile conditions under biological safety cabinet.
• The plasma was dispensed in sterile eye drop bottles with a needle.
• The first and last bottles were analysed for sterility testing.
• The negative result of bacterial testing was confirmed before the shipping to the blood bank.
• The documentation was approved by the Quality and Standards department.
• A detailed procedure of thawing and dispensing to the patient was provided to make sure that the product will stay sterile and in good storage conditions.
• For ethic considerations, they obtained inform consents from parents and physician.

4. Bruce Noble FRCS Consultant Ophthalmologist, Leeds UK (attribution used with permission) reports that as co-author with Dr. McLennan on the paper in the British Journal of Ophthalmology, he has always been amazed at the varieties of different ways and means in which autologous serum eye drops are prepared around the world and especially in the USA.

He writes: "The issues of handling blood products in a safe, closed way is essential for best medical practice and greatly reduces the risks to patients, MD's and the staff in their offices (where so much of the ad hoc prepping takes place). Ocular surface disease is a (relatively) recently recognized constellation of problems caused by failure/death of the stem cells at the limbus of the cornea. As a result, the corneal epithelium breaks down leading to recurrent corneal ulceration, vascularized corneas and possible loss of sight through scarring or infection or both. When this happens, later corneal transplantation is much less likely to be successful. The problems are frequently bilateral. Over many months or years this excruciating problem plagues both the patients and their attending ophthalmologists. Autologous serum has led to a dramatic improvement in outcomes for these patients."

He adds: "The numbers of patients with ocular surface disease are many; because the outcomes can be so poor, considerable effort has been made to understand the processes and to develop treatments. For instance, great strides have been made in developing ways of growing corneal limbal stem cells in vitro and then transplanting them into severely damaged eyes. These transplanted cells do best in these sick eyes when the local environment is optimal; and it seems that the various growth factors in the autologous serum provide what is neededto give these eyes the best chance of success."

He concludes: "The great advantage of the 'industrialised' or standardized method of producing autologous serum eye drops is that every patient in the United Kingdom with serious ocular surface disease has been able to have access to autologous serum eye drops; the product is of highest quality, sterile and designed for easy and safe handling. There is no contamination of consulting rooms or office. Blood donations may be repeated and each deposit yields about 3 to 4 months worth of treatment. The benefits have been extraordinary to these people."

ADDENDA May 4, 2007

5. Paula Kelley, MT(ASCP)SBB, of the SCABB Technical/Scientific Program Committee (attribution used with permission) notes that a very interesting and informative abstract on this subject will be presented at the upcoming Joint SCABB/CBBS Annual Meeting in Las Vegas. The authors (David Gremillion et al) worked with the FDA on the manufacturing aspects of the process and the inquiring Midwest transfusion service medical director may find it to be a valuable reference.

ADDENDA June 1, 2007

6. Prof. Dr. Gerd Geerling, Vice Chairman, Deputy Director, and Professor in Ophthalmology at the Department of Ophthalmology at the University of Würzburg in Germany (attribution used with permission) reports that as the first author of the referenced review report 'Autologous serum eye drops for ocular surface disorders' they having evaluated a variety of blood-derived products and found that overall the epitheliotrophic, i. e. wound healing, properties of serum are by far better than those of plasma. According to Dr. Geerling, this can be explained by its higher concentration of various growth factors, such as EGF or fibronectin, a protein that is required for cell migration. Concentrated platelets can alternatively be used to produce an enriched growth factor solution. Serum eyedrops can also be combined with soft bandage contact lenses to enhance ocular surface health.

Some relevant publications on the topic are listed as follows:

1. Geerling G, Daniels JT, Dart JKG, Cree IA, Khaw PT: Toxicity of natural tear substitutes in a fully defined culture model of human corneal epihtelial cells. Invest Ophthalmol Vis Sci 42 (2001) 948-956. IF 4.091 (2002)
2. Poon AC, Geerling G, Dart JKG, Fraenkel G, Daniels JT: Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in-vitro toxicity studies. Br J Ophthalmol 85 (2001) 1188-1197. IF 1.779 (2002)
3. Herminghaus P, Hartwig D, Wedel T, Dibbelt L, Geerling G, Epitheliotrophic capacity of serum- and plasma-eyedrops – influence of the centrifugation. Ophthalmologe 101 (2004) 998-1005. IF 0.601 (2002)
4. Hartwig D, Harloff S, Liu L, Schlenke P, Wedel T, Geerling G. Epitheliotrophic capacity of a growth factor preparation produced from platelet concentrates on corneal epithelial cells: A potential agent for the treatment of ocular surface defects? Transfusion 44 (2004) 1724-31. IF 3.765 (2002)
5. Hartwig D, Herminghaus P, Wedel T, Liu L, Schlenke P, Dibbelt L, Geerling G. Topical treatment of ocular surface defects: Comparison of the epitheliotrophic capacity of fresh frozen plasma and serum on corneal epithelial cells in an in-vitro cell culture model. Transfusion Med 15 (2005) 107-112. IF 1.744 (2002)
6. Liu L, Hartwig D, Harloff S, Herminghaus P, Wedel T, Geerling G. An optimized protocol for the production of autologous serum eyedrops. Graefe`s Arch Clin Exp Ophthalmol (2005) 243:706-14 IF 1,279 (2003)
7. Schrader S, Wedel T, Moll R, Geerling G. Combination of serum eye drops with hydrogel bandage contact lenses in the treatment of persistent epithelial defects Graefe’s Arch Clin Exp Ophthalmol (2006) Mar 17 Epub IF 1,498 (2005)
8. Liu L, Hartwig D, Harloff S, Herminghaus P, Wedel T, Kasper K, Geerling G. Corneal epitheliotrophic capacity of three different blood-derived preparations Inv Ophthalmol Vis Sci (2006) 47 (6) 2438-2444 IF 3,643 (2005)
9. Geerling G, MacLennan S, Hartwig D. Autologous Serum Eye Drops For Ocular Surface Disorders. Br J Ophthalmol 88 (2004) 1467-1474. IF 1.779 (2004)

ADDENDA Sept. 16, 2008

7. The Editors believe that the literature review entitled 'Autologous serum eyedrops: literature review and implications for transfusion medicine specialists', which appears in Transfusion 2008 Jun;48(6):1245-55 is germane to this discussion.

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Ira A. Shulman, MD
CBBS e-Network Forum Editor & Moderator

W. Tait Stevens, MD
CBBS e-Network Forum Assistant Editor & Moderator