Ligneous conjunctivitis associated with type I plasminogen deficiency: A rare case

Ligneous conjunctivitis is a rare form of chronic, recurrent conjunctivitis characterized by wood-like, fibrinous pseudomembranes, which may be associated with systemic disease manifestations. It has been associated with congenital plasminogen (PLG) deficiency that is inherited with an autosomal recessive pattern due to mutations in the PLG gene and a variety of other genes, leading to disturbed wound healing. In this case report, we present the clinical, laboratory, and histopathological findings of a 36-year-old female patient who presented at the ophthalmology department with complaints of redness, irritation for the previous few weeks, and appearance of membranous lesions mainly on the tarsal conjunctivae. During biomicroscopic examination we found thick, yellowish-white pseudomembranes, and conjunctival proliferation with ligneous induration on the conjunctiva, located on the upper eyelids. Histopathological evaluations showed up ligneous conjunctivitis and laboratory evaluation confirmed a severe plasminogen deficiency (PLG < 2%). The patient was treated with topical fresh frozen plasma (FFP), topical steroids, heparin eye drops, and artificial tear drops daily, without systemic therapy.

FC 015LACK OF PLASMINOGEN RELATES TO A HYPERCOAGULABLE STATE IN MICE WITH EXPERIMENTAL NEPHROTIC SYNDROME

Background and Aims Urinary excretion of the fibrinolytic enzyme plasminogen has been identified as a characteristic feature of nephrotic syndrome (NS) in both human and experimental mouse models. Lack of plasminogen may lead to a hypercoagulable state and thrombosis, and mice with plasminogen deficiency have been shown to suffer from developing spontaneous thrombosis. However, the role of plasminogen in hypercoagulable state and thrombosis in an experimental nephrotic syndrome has not been investigated before. Method We investigated the relationship between plasminogen and a hypercoagulable state in an inducible nephrotic mouse model with conditional podocyte-specific podocin deletion (Nphs2Δipod * Plg+/+, n=12). The Nphs2Δipod mice with constitutive plasminogen knockout were used as negative plasminogen control (Nphs2Δipod * Plg-/-, n=15). All mice received a daily oral doxycycline administration for 2 weeks for NS induction. The last day of doxycycline treatment was set as day 0. Spot urine was collected daily for proteinuria and urinary plasmin activity measurement. Citrate blood was collected from each mouse before induction of NS, 7 days and 21 days after induction, respectively (Nphs2Δipod * Plg+/+ mice, n=4/timepoint; Nphs2Δipod * Plg-/- mice, n=5/timepoint). A global assessment of coagulation (extrinsic coagulation test, EX test) was examined by ClotPro® system. Besides, fibrinolysis was tested by adding tissue plasminogen activator (TPA test). Results According to the EX test, uninduced mice with plasminogen deficiency showed a significantly reduced clotting time (CT, Plg-/- vs. Plg+/+, 42 ± 1s vs. 54 ± 4s, p=0.0213), and decreased clot formation time (CFT, Plg-/- vs. Plg+/+, 82 ± 5s vs. 206 ± 28s p&lt;0.0001) with a larger alpha-angle (Plg-/- vs. Plg+/+, 75 ± 1° vs. 66 ± 2°, p=0.0041). The maximum clot firmness (MCF) was significantly increased in uninduced plasminogen knockout mice (Plg-/- vs. Plg+/+, 45 ± 0.5mm vs. 32 ± 2.5mm p&lt;0.0001). According to the TPA test, uninduced Nphs2Δipod *Plg-/-mice had a faster velocity of clot formation (α-angle, 75.6 ± 0.2° vs. 66.5 ± 1.6°, p=0.0254) and did not show any clot lysis in contrast to uninduced nphs2Δipod * plg+/+mice. After induction of NS, both Nphs2Δipod * Plg-/-mice and Nphs2Δipod * Plg+/+ mice developed massive proteinuria to a comparable extent (Plg-/- vs. Plg+/+on day 21, 218 ± 46mg/mg crea vs. 203 ± 28mg/mg crea), and plasminuria was detectable in nephrotic nphs2Δipod * plg+/+ mice. With the ongoing loss of plasminogen in the urine, CT and CFT was significantly reduced in nephrotic Nphs2Δipod * Plg+/+ mice. MCF was significantly increased with a faster velocity of clot formation measured by both the EX and TPA test. Moreover, clot lysis was significantly reduced. In nephrotic nphs2Δipod *plg-/-mice at day 21, there was also a tendency towards a decrease in CT, CFT and an increased velocity of clot formation. According to both EX and TPA test, there were no significant differences between the genotypes in nephrotic mice any more. Conclusion The results highlight that loss of plasminogen in the nephrotic state contributes to a hypercoagulable state with shortened clotting time, clot formation time, increased clot firmness, and most strikingly, loss of clot lysis. Changes in nephrotic wild-type mice were similar to mice with constitutive plasminogen deficiency, indicating that loss of plasminogen plays a role in the hypercoagulable state of nephrotic syndrome.

Painting the Clinical Picture of Congenital Plasminogen Deficiency (C-PLGD) through a Comprehensive Case Study Review

C-PLGD is a rare autosomal recessive multisystem disorder of the fibrinolytic system with a diverse spectrum of clinical manifestations, and is underdiagnosed and difficult to treat. Caused by mutations in thePLGgene, C-PLGD is characterized by extravascular fibrinous deposits on mucous membranes such as the conjunctiva, gingiva, linings of airways and genitourinary tract. The abnormal accumulation or growth of fibrin-rich pseudomembranous lesions have been termed ligneous for their "woody" appearance, and often result in tissue injury and/or organ dysfunction in C-PLGD patients. We present here the results of an exhaustive MEDLINE literature database review undertaken with the PubMed search engine using the key words; 'plasminogen deficiency,' 'hypoplasminogenemia' and 'ligneous conjunctivitis'. Objective:The goal of this review was 1) to achieve a better understanding of the type and prevalence of clinical manifestations of C-PLGD and their outcomes, and 2) to evaluate whether a relationship exists between endogenous plasminogen activity levels and disease manifestations in C-PLGD patients. Methodology: A MEDLINE literature search was conducted by three independent investigators. Publications containing the key words 'plasminogen deficiency,' 'hypoplasminogenemia' and/or 'ligneous conjunctivitis' and reporting human clinical information were selected. Patients' age, sex, endogenous plasminogen levels, and clinical manifestations were tabulated. Results: The search retrieved 414 total citations, and 130 papers with relevant human clinical data were identified for full-length text review. From these, 301 unique C-PLGD patients (237 pediatric and 64 adults) were found to be reported over an 80-year period (from 1957 to 2017) and presented the following outcomes and most common and/or serious clinical manifestations: ligneous conjunctivitis (255 cases), ligneous periodontitis (71 cases), tracheobronchial obstructions (53 cases), hydrocephalus (42 cases), other corneal lesion (15 cases), ligneous vaginitis (24 cases), blindness (6 cases), and death (10 cases). Differences in disease seriousness and prevalence were observed between pediatric and adult patient populations (Table1). Of note, death or hydrocephalus were reported only in pediatric patients. Historical information indicated that 62% of the 301 reported patients were females and 36% males, while 2% of them did not have their gender disclosed. The median age of reported onset of symptoms (and/or diagnosis) was 1 year old for the 176 patients with available data. Of the 130 papers retained and analyzed, 2 studies (Klammt et. al. Thromb Haemost 2011; Tefs et. al. Blood 2006) were selected for additional in-depth analysis. These studies included a subset of 58 C-PLGD patients whose clinical, molecular and plasminogen activity data were available and reliably reported. These patients had a spectrum of plasminogen activity level ranging from 2% to 59% and presented the main following clinical manifestations: ligneous conjunctivitis (52/58), ligneous periodontitis (16/58), tracheobronchial involvement (14/58), ligneous vaginitis (6/58), and hydrocephalus (4/58) (Table 2). Out of this 58-patient cohort, 26 reported a single lesion and had an average plasminogen activity level of 22% while the 32 remaining had 2 or more lesions and an average activity level of 20%, indicating that the level of plasminogen activity may not correlate with the clinical manifestations burden/seriousness. Conclusion:This comprehensive review confirmed that the heterogeneity challenges in clinical evaluation and the overall rarity of C-PLGD can contribute to delayed diagnosis, treatment variability and less than optimal outcomes. With lack of natural history studies or reports of C-PLGD, the data described here can be used to highlight the seriousness of long-term morbidity, promote early and effective management of C-PLGD, and support the ongoing development of novel plasminogen replacement therapy to address the primary underlying drivers of morbidity in C-PLGD. The implementation of natural history studies may play an important role in addressing the knowledge gap in phenotypic expression and long-term impact of C-PLGD on the quality of life of impacted patients. Disclosures Thibaudeau: Liminal BioSciences:Current Employment, Current equity holder in publicly-traded company.Robitaille:Liminal BioSciences:Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.Ledsham:Liminal BioSciences:Current Employment.Sandset:Liminal BioSciences:Other: Investigator Clinical Trial.

Successful Pregnancy in a Patient with Infertility Due to Congenital Plasminogen Deficiency Treated with Intravenous Plasminogen (Human) Replacement Therapy

Congenital plasminogen deficiency (C-PLGD) is a rare autosomal recessive multisystem disorder of the fibrinolytic system that is often underdiagnosed. It is caused by mutations in the PLG gene and is characterized by extravascular fibrinous deposits on mucus membranes resulting in tissue injury or organ dysfunction. The abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes, such as the conjunctiva, gingiva, linings of airways and genitourinary tract have been termed ligneous for their "woody" appearance. Ligneous conjunctivitis is the most common manifestation of C-PLGD occurring in greater than 80% of affected patients. Ligneous lesions affecting the female reproductive system have been reported in one large case series in 9% of patients (Shuster et. al. JTH 2007). An extensive review of the literature (Baithun et. al. Haemophilia 2018) identified 30 cases of C-PLGD patients with gynecologic involvement. A diagnosis of infertility, when performed, was reported in 8 (26.7%) of these females of child-bearing age. Due to the rarity of the disease, infertility may be under diagnosed and under reported in the literature as no natural history studies of this disease have been conducted. We report a case of a patient with C-PLGD with a documented diagnosis of infertility who received intravenous plasminogen therapy. Although the protocol stated that adequate contraceptive measures be taken to avoid becoming pregnant during the study, she became pregnant, went to term and had a successful delivery of a healthy child. She was a 33-year-old woman with a diagnosis of C-PLGD in childhood, after developing ligneous conjunctivitis before the age of 1, developed uterine ligneous lesions and dysmenorrhea as a teenager. At age 27, a hysteroscopy was attempted and laparoscopy was performed which revealed fibrosis and web-like fibrin-rich adhesions in the uterus and fallopian tubes. She was referred to the Oslo University Hospital, Norway, for evaluation and management of her infertility and eye lesions at the age of 28. She was treated with fresh frozen plasma (FFP) infusions with improvement in eye symptoms and dysmenorrhea. At the age of 29, a vaginoscopy and hysteroscopy were performed which again demonstrated fibrin membranes in the uterus. A repeat evaluation at the age of 30 revealed fibrin membranes in the cervix, fibrin accumulation in the uterus, and tube ostia obstructed. At age 33 she was enrolled in a clinical trial, an open-label phase 2/3 study of human Glu-plasminogen administered intravenously at 6.6 mg/kg every 2-4 days in 15 patients with plasminogen deficiency, registered at www.clinicaltrials.gov as #NCT02690714. She received intravenous plasminogen replacement therapy, starting in October 2016. At baseline, she had ligneous conjunctivitis and gynecologic lesions with regular, but atypical menstrual bleeding, discharging very small amounts of thick, mucus-like material over 1-2 days. Her eye lesions had resolved by week 12 of treatment. At the end of the first menstrual cycle on plasminogen treatment, she discharged a large mucus-like plug from the vagina, and had regular and normal menstrual bleeds after that. Approximately 20 weeks into treatment, she reported being pregnant to the investigator. After discussion with the clinical study sponsor, regulatory agencies and the regional ethical committee, the patient and her physician, it was agreed to continue plasminogen replacement therapy through the pregnancy, delivery and recovery period. After approximately 55 weeks into the study treatment, the patient had an uncomplicated pregnancy and delivered a healthy child with APGAR score of 9. The patient remained on PLG treatment post-partum, and her PLG activity trough levels were maintained until she came off the study when her levels went back to baseline. (Figure 1) This is the first reported case of intravenous plasminogen used in a patient with C-PLGD and documented infertility who subsequently became pregnant and delivered a healthy child. Figure Disclosures Parker: Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Trybul:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Sandset:Liminal BioSciences: Other: Investigator Clinical Trial.