Fresh frozen plasma as a source of plasminogen for ligneous conjunctivitis: Case report and a review of the literature

Purpose: To describe management of a patient with ligneous conjunctivitis secondary to plasminogen defi ciency and review the literature on treatment with plasminogen. Design: Interventional case report. Methods: A 6-year-old Caucasian girl developed ligneous conjunctivitis recalcitrant to debridement and treatment with topical cyclosporin A and steroids. The literature was reviewed regarding treatment of ligneous conjunctivitis with plasminogen. Results: The patient was treated with plasminogen containing drops derived from her father’s fresh frozen plasma. The ligneous conjunctivitis resolved, and the patient was managed on these drops for the following 8 years, initiating treatment for fl ares and tapering according to clinical response. Conclusions: Plasminogen drops concentrated from fresh frozen plasma are a safe and effective option for long-term treatment of ligneous conjunctivitis. Case Report Fresh frozen plasma as a source of plasminogen for ligneous conjunctivitis: Case report and a review of the literature Benjamin J Park1, David Camoriano2, Mark C Vital3, Patricia Chévez-Barrios4, John D Goosey3 and Marcel Belloso3* 1Department of Ophthalmology and Visual Sciences, the Ohio State University, Columbus, Ohio, USA 2University of Manitoba, Winnipeg, Canada 3Houston Eye Associates, Houston, Texas, USA 4Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA Received: 05 July, 2021 Accepted: 17 July, 2021 Published: 19 July, 2021 *Corresponding authors: Marcel Belloso, Houston Eye Associates, 2855 Gramercy Street, Houston, TX 77025, Texas, USA, Tel: 832-553-7100; Fax: 832-553-7154; Email: ORCID: https://orcid.org/0000-0001-7119-5632


Clinical presentation
A 6-year-old Caucasian girl was referred to our clinic by a local ophthalmologist for management of a left, pseudomembranous conjunctivitis. A diagnosis had been given of adenoviral conjunctivitis and the patient had been using moxifl oxacin drops for 10 days. The parents noted that neither time, nor the antibiotics drops were helping. Additionally, the parents noted that the thick white membranes had been increasing until the father manually removed exposed membranes that were described as ''removing a contact lens made out of cooked shell pasta".
The patient is the youngest of three otherwise healthy children. She was born by cesarean section at term with APGARs of 9 / 9. Her peri-natal history was complicated by an arrest in her developmental milestones after the age of six months, at which time she was diagnosed with infantile spasms, even after seeing multiple specialists. The etiology of her spasms was never diagnosed. She was started on felbamate and a Citation: Park  ketogenic diet involving carnitine, by a pediatric neurologist.
There was a decrease of the number of seizures, from approximately four hundred per day, to fi fty per day. Her past medical history was also signifi cant for a hypotonic episode requiring airway intubation for eight days and subsequent tracheomalacia, which was not repaired. Her past surgical history was remarkable for placement of a feeding tube. The patient had a medical diagnosis of cerebral palsy. When she was seen at the clinic, the patient was wheelchair bound and communicated by cooing.

Visual exam
The patient was noted to fi x and follow poorly in each eye, but no nystagmus was present. The pupils were equal, round, and reactive to light, with no relative afferent pupillary defect noted. Slit lamp examination revealed swelling and an erythematous area limited to the left upper and lower lids, with fi ne telangiectasias seen along the eye lid margins. No follicles were present on the bulbar or tarsal conjunctiva. A thick, white, avascular pseudo-membrane was noted on the left, inferior lateral palpebral conjunctiva extending over the lateral one third of the lower lid. All other areas of the areas of the conjunctiva for both eyes were clear. There was no intraocular infl ammation, auricular lymphadenopathy, or oral mucosal lesions. There was no vaginal or anal mucous membrane pathology.

Diagnosis and management
Very minimal bleeding was noted when the pseudomembrane was gently debrided with a cotton swab under topical anesthesia. The clinical picture and history suggested a diagnosis of ligneous conjunctivitis. The father had saved the original membrane that he had removed; we sent our sample and the membrane that the father had removed to pathology. The pathology evaluation revealed strips of epithelium making pseudomembranes, composed of fi brin and eosinophilic dense material infi ltrated by neutrophils and lymphocytes, consistent with the diagnosis of ligneous conjunctivitis. In an initial effort to suppress infl ammation and further pseudomembrane production, the patient was placed on cyclosporin A drops and topical steroids as frequently as every hour without improvement. Although it was known that plasminogen has completely resolved some cases of ligneous conjunctivitis, there was diffi culty in quickly fi nding a preparation for our patient.
Consultation was sought with a hematologist for work up of possible plasminogen defi ciency as has been described in the literature [1][2][3][4][5][6]. The reference levels of plasminogen activity are 70% to 113%. The hematologic evaluation revealed plasminogen activity levels for the parents as follows: father 105% (normal) and mother 100% (normal). The patient's plasminogen activity was 11% (low).
After discussion with the hematologist about plasminogen levels in Fresh Frozen Plasma (FFP), we decided to try treating the patient with her father's FFP. Since he was found to have adequate plasminogen activity levels, we felt that his FFP might have enough plasminogen to be effective. Plasminogen drops were concentrated from the FFP, and we had the patient use these drops every hour while awake. The cyclosporine A drops were continued, and the topical steroids were tapered over one month.
Clinical improvement was fi rst evident at two weeks after starting the plasminogen drops. Signifi cant improvement was noted at fi ve weeks, and the conjunctivitis and pseudomembranes were totally resolved by seven weeks. The patient also received a few courses of intravenous FFP and the parents subjectively noted that the patient seemed to have fewer seizures after receiving these infusions.
The patient was followed over the next 8 years, during which she had four more fl ares. These fl ares were managed each time with the plasminogen drops derived from her father's FFP. The longest interval the patient went between fl ares was 32 months.

Discussion
Ligneous conjunctivitis is rare, painful, chronic, fi brinous infl ammation of the bulbar and/or tarsal conjunctiva. Systemic associations include other mucosal involvement (gingival, cervix, and vagina), juvenile colloid milium, hydrocephalus and potentially life-threatening laryngeal and tracheabronchial membranes [7]. Known ocular complications of this disease include eye lid scarring, corneal ulceration, corneal perforation and possible deprivation amblyopia [8]. Ample evidence, points to systemic Type I plasminogen defi ciency as the etiology of ligneous conjunctivitis [1][2][3][4][5][6]. Plasminogen appears to be an important factor mediating tissue remodeling in the conjunctiva, an exposed mucosal surface vulnerable to environmental irritants and micro-trauma. This remodeling is a balance between the deposition of extracellular matrix proteins and their removal by fi brinolysis. Plasminogen defi ciency skews this delicate balance in favor of the former with resultant pseudomembrane formation [8].
Treatment modalities aimed at restoring local fi brinolysis have included topical hyaluronidase, 6 -chemotrypsine [1,6,9], and cyclosporin A [10,11] all with varying success. In addition, surgical debridement of these lesions often leads to their recurrence within days to weeks [8]. Amniotic membrane grafts have been used to facilitate epithelization and reduce infl ammation [12,13]. Heparin has been used as a cost-effective option to prevent recurrences [9,[13][14][15]. Many interventional case reports and series have shown that topical therapy with plasminogen containing drops is an effective treatment for ligneous conjunctivitis. These cases are summarized in Table 1.
When used as an adjuvant to surgical debridement, topical plasminogen has been shown to be effective at managing ligneous conjunctivitis for over 5 years [25]. Interestingly, plasminogen acts as a necessary precursor, as plasmin is readily inactivated and rendered ineffective when given topically [1]. The diffi culty in treatment comes from issues of availability and cost of plasminogen. The facts that the condition is rare, plasminogen is diffi cult to isolate, and it does not have other large scale uses, results in it not being readily available to clinicians in the treatment of ligneous conjunctivitis.
Citation: Park  Given that ligneous conjunctivitis appears to be a local manifestation of a systemic disease, some groups have attempted to correct the plasminogen defi ciency with donor intravenous FFP in addition to topical drops or sub-conjunctival injections. We chose to use it concurrently because we were unsure of how it would be most effi cacious. Further research needs to be conducted to determine the optimal delivery route for plasminogen.
In our case, we were able to test the parents and use intravenous and topical donor FFP from the father. FFP is an FDA approved blood product known to contain plasminogen.
Although we could not be sure of the exact amount available plasminogen being delivered hourly, topical application of donor FFP from the father resulted in clinical improvement of our patient conjunctivitis. Because the father was the donor, it provided a level of confi dence in the safety of the drops against for ligneous conjunctivitis appears to be safe and effective in the long term. However, this method is costly, so these authors recommend fi rst using topical heparin as it may prevent recurrence, is much cheaper, and is more readily available. Should heparin fail, we recommend treatment with plasminogen. Whether topical therapy with FFP alone is as effective as combined topical and parenteral therapy remains to be elucidated. In the future, gene therapy may play a role in reversing this enzymatic defect.

Method of literature search
Literature was researched on PubMed. Pertinent keywords were searched, including "ligneous conjunctivitis" "plasminogen defi ciency" "fresh frozen plasma" "plasminogen". Articles in English relevant to the discussion were selected from these search results.

Off-label use/unapproved drugs or products
Fresh Frozen Plasma is not labeled by the FDA for the use under discussion.