Congenital Plasminogen Deficiency Research Articles

HTRS2023.O8C.4 Subject with infertility due to congenital plasminogen deficiency type 1: results of plasminogen replacement therapy and impact of varying dosage regimen during treatment and maintenance phases

HTRS2023.O8C.4 Subject with infertility due to congenital plasminogen deficiency type 1: results of plasminogen replacement therapy and impact of varying dosage regimen during treatment and maintenance phases

Plasmin-Mediated Fibrinolysis in Periodontitis Pathogenesis.

The hemostatic and inflammatory systems work hand in hand to maintain homeostasis at mucosal barrier sites. Among the factors of the hemostatic system, fibrin is well recognized for its role in mucosal homeostasis, wound healing, and inflammation. Here, we present a basic overview of the fibrinolytic system, discuss fibrin as an innate immune regulator, and provide recent work uncovering the role of fibrin-neutrophil activation as a regulator of mucosal/periodontal homeostasis. We reason that the role of fibrin in periodontitis becomes most evident in individuals with the Mendelian genetic defect, congenital plasminogen (PLG) deficiency, who are predisposed to severe periodontitis in childhood due to a defect in fibrinolysis. Consistent with plasminogen deficiency being a risk factor for periodontitis, recent genomics studies uncover genetic polymorphisms in PLG, encoding plasminogen, being significantly associated with periodontal disease, and suggesting PLG variants as candidate risk indicators for common forms of periodontitis.

A Successful Treatment Approach in 2 Patients With Type 1 Plasminogen Deficiency: Intratracheal Application of Fresh Frozen Plasma and Tissue Plasminogen Activator.

Respiratory system involvement is common in congenital plasminogen deficiency. Although many treatment approaches have been tried, there is still no definitive treatment for respiratory system involvement. We report 2 congenital plasminogen deficiency cases, who presented with severe respiratory symptoms, for whom a novel treatment modality was tried. After intravenous administration of FFP (fresh frozen plasma), tissue plasminogen activator and FFP were administered intratracheally, and respiratory system findings improved. Intratracheal administration of tissue plasminogen activator and FFP is an available treatment modality for patients with lung involvement. Fibrin plaques should be carefully removed and new lesion formation should be prevented.

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.

Computer Modeling Using Historical Data Demonstrates a Significant Reduction in Expected Extravascular Fibrinous Lesions Due to Congenital Plasminogen Deficiency While Receiving Intravenous Plasminogen (PLG) Replacement

Background: Congenital plasminogen deficiency (PLGD) caused by mutations in the PLG gene is a rare disorder associated with extravascular fibrinous deposits on mucous membranes that may impair tissue and organ function (Tefs 2006; Mehta 2008). Prometic has developed an intravenous (IV) PLG product derived from human plasma (Prometic's-PLG) as replacement therapy for treatment and prevention of extravascular fibrinous (ligneous) lesions in children and adults with PLGD. Due to the rarity of this disorder and the complexity of its clinical manifestations, randomized, blinded, controlled trials are not practical. Statistical modeling comparing historical lesion data to the occurrence of lesions while on plasminogen replacement therapy may provide evidence for efficacy.Aims: Using historical data computer modeling to determine whether replacement therapy with Prometic's-PLG results in a reduction of expected ligneous lesions in children and adults with PLGD.Methods: Fifteen pediatric and adult subjects aged 2 to 80 years with PLGD were enrolled in an open-label study to receive multiple IV doses of Prometic's-PLG for at least 48 weeks. Subjects were dosed every 2, 3, or 4 days based upon a pharmacokinetic (PK) profile to maintain target PLG activity trough levels > 10% (absolute) above baseline values. Extravascular ligneous lesions (visible and non-visible) were assessed at baseline, weeks 4, 8, 12, and every subsequent 12 weeks up to 48 weeks. Detailed medical histories of extravascular ligneous lesions were also obtained at baseline. A model incorporating the historical visible lesion behavior of patients and their reaction to treatment is implemented. Second, simulations studies are realized based on the same data to assess the treatment effect. Furthermore, a Bayesian methodology is also implemented. The following allows for various assessments and predictions based on the predictive distributions of the parameters obtained from a longitudinal inflated Poisson Mixed Model.Results: Historical lesion data were available on 12 subjects at the time of the analysis. Figure 1 presents the fitted model showing the expected historical behavior of extravascular ligneous lesions in the absence of treatment with Prometic's-PLG. After 12 weeks of treatment with Prometic's-PLG, there was a statistically significant reduction (p< 0.05) in the expected number of extravascular ligneous lesions in both pediatric and adult subjects with PLGD (Figure 2).The Bayesian modeling strategy shows that the posterior distribution of the treatment effect is highly negative (very small probability of being zero or positive), which is associated with a decrease in the number of lesions and confirms the frequency model (p< 0.05). Furthermore, using the Bayesian modeling strategy, it is possible to assess the probability of having observed the reduction of lesions after the start of treatment. The model including the treatment effect shows a superiority in comparison to the model without treatment. This leads us to further believe in a departure from a usual behavior and thus a treatment effect. These models can also be used to assess the frequency of observed lesions after 2 weeks (Figure 3) under treatment and no treatment, and the time to first reoccurrence (Figure 4).Conclusions: Historical data computer modeling highlights the significant treatment effect by Prometic's-PLG in reducing the extravascular ligneous lesions in pediatric and adult subjects with PLGD.

Approvisionnement hospitalier en plasminogène humain substitutif pour le traitement de la conjonctivite ligneuse : comment faire en pratique ?

In order to treat a pediatric patient with ligneous conjunctivitis secondary to congenital plasminogen deficiency, a supply of topically administered replacement human plasminogen has been required. In the absence of market approval, this blood-derived drug is managed by a temporary authorisation for nominative use, allowing monthly hospital dispensations. To ensure regulatory compliance and proper use of the drug, it took two years of interactions between various hospital departments and the laboratory to define the pharmaceutical supply chain in our hospital and allow the patient to receive treatment. The main difficulties lie in respecting the cold chain of this drug stored frozen in the bottles not ready for use. Transportation from the laboratory to the patient's home via the hospital pharmacy is carried out in calibrated conditions, ensuring a temperature below -20°C for 72h. Reception and dispensing steps were combined into a single pharmaceutical service in order to optimise transport time while ensuring the safety and traceability of the drug lots. Each month, a date is scheduled between the hospital pharmacy, the laboratory and the family to ensure that delivery and dispensing take place on the same day. Appropriate use and handling are explained to the family. However, two issues remain to be addressed by the manufacturer to facilitate future use of human plasminogen: the thermostability problem, which does not allow stays away from home longer than three days, and self-administration by the child, which is unlikely to be feasible due to handling difficulties.

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.

Acute Airway Obstruction in 4 Pediatric Patients with Congenital Plasminogen Deficiency (C-PLGD) Treated with Intravenous Plasminogen (Human) Replacement Therapy Under an Expanded Access Protocol

C-PLGD is a rare autosomal recessive multisystem disorder of the fibrinolytic system. Mutations in the PLG gene result in extravascular fibrinous deposits, termed ligneous for their woody appearance, that accumulate on mucous membranes such as the conjunctiva and airways, with resultant tissue injury or organ dysfunction. Ligneous conjunctivitis (LC) is the most common manifestation (&amp;gt; 80%) of C-PLGD. Ligneous lesions affecting the respiratory system have been reported in 20% of patients in a large case series (Schuster et. al. JTH 2007). We report 3 new cases in addition to a previously reported case of airway obstruction with respiratory distress successfully treated with intravenous Glu-plasminogen concentrate (Human) (IV-PLG). Case 1: A 16-month-old female with C-PLGD, with onset of LC at 3 weeks of age, developed a febrile illness with upper respiratory tract symptoms and exacerbation of LC. Four weeks after the exacerbation presented, she developed wheezing unresponsive to bronchodilator and corticosteroid treatment. She progressed to stridor, tachypnea and hypercapnia and was treated with fresh frozen plasma (FFP) infusions. She underwent a bronchoscopy which revealed friable airways and fibrinous lesions in the right mainstem bronchus (Figure 1). Computed tomography (CT) of the chest revealed airway narrowing (R&amp;gt;L) with distal air trapping. She was admitted to the pediatric intensive care unit (PICU) for monitoring and continued FFP treatment every 12 hours without relief. Compassionate use of IV-PLG was requested and she initiated urgent treatment under an expanded access protocol. Significant improvement in stridor and tachypnea occurred within 48 hours of starting therapy and was discharged from the PICU after 2 weeks without symptom recurrence. 10 days post treatment repeat bronchoscopy showed improvement in obstructing airway lesions (Figure 2), and CT scan revealed improvement in airway narrowing and air trapping. She is currently continuing treatment administered every 5 days. Case 2: A 16-month-old male with C-PLGD and shunted congenital hydrocephalous, presented with worsening LC (onset at 7 months) and hoarseness from suspected ligneous airway disease. He was admitted to the PICU for monitoring, supplemental oxygen therapy for hypoxemia, and FFP infusions every 12 hours with only minimal relief. Chest CT revealed bronchiectasis and possible airway lesions. IV-PLG compassionate use was requested; he initiated urgent treatment under an expanded access protocol. Four days after starting treatment he underwent bronchoscopy confirming airway ligneous involvement, and ophthalmologic membranes were also stripped. He responded to treatment with improvement of both respiratory and eye symptoms without further requirement for supplemental oxygen; he was discharged from PICU after 8 days total, and 6 days after starting IV-PLG. His eyes healed without lesion recurrence. He continues to receive IV plasminogen replacement infusions every 5 days. Case 3: A 3-year-old C-PLGD male, diagnosed at 7 weeks of age with LC, developed an upper respiratory infection with persistent hoarseness over a 3-week period. Due to potential airway involvement concern, he underwent upper airway laryngoscopy; a right vocal cord small polyp and a papillomatous mass noted below vocal cords were observed. Compassionate use of IV-PLG was requested; he initiated urgent treatment under an expanded access protocol. The patient experienced resolution of hoarseness in 4 weeks, with significant improvement in his LC. He has had no further clinical respiratory symptoms or LC exacerbations and is currently continuing treatment administered every 5 days. Plasminogen replacement has previously been reported in a fourth C-PLGD pediatric patient (22-month-old male) who had experienced cardiopulmonary arrest due to airway obstruction (Hassenpflug et. al. Blood 2016). This patient required ongoing ventilator support; treatment with IV-PLG assisted in weaning from ventilator support. These cases demonstrate the potential role for IV-PLG treatment in C-PLGD patients with airway obstruction due to fibrinous lesions, to prevent progression of obstruction resulting in respiratory failure; additional controlled studies would need to be performed to further support these observations. Disclosures Nakar: Prometic Biotherapeutics: Research Funding; Kedrion SpA: Research Funding. McDaniel:Prometic Biotherapeutics: Consultancy, Other: Investigator Clinical Trial. Parker:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Trybul:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Shapiro:Sangamo: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; BioMarin: Research Funding; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding.

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.

Clinical Course of Two Children with Congenital Plasminogen Deficiency Type 1

Clinical Course of Two Children with Congenital Plasminogen Deficiency Type 1

PB2442 BRONCHOSCOPIC TREATMENT WITH FRESH FROZEN PLASMA AND TISSUE PLASMINOGEN ACTIVATOR FOR A CHILD WITH TYPE 1 PLASMINOGEN DEFICIENCY

Background:Congenital plasminogen deficiency is a genetic disease with autosomal recessive inheritance pattern. Fibrous plaques that accumulate in the mucosal surfaces of oral cavity, eye and respiratory tract.Aims:We aimed to report the first bronchoscopic usage of fresh frozen plasma (FFP) and tissue plasminogen activator (t‐PA) for respiratory complications of a child with plasminogen deficiency.Methods:A child with plasminogen deficiency treated with FFP, t‐PA is reported.Results:A one‐year‐old male patient was admitted to the hospital for 1 week with cough and increased respiratory distress. Antibiotic therapy was started for bronchopneumonia.From his medical history it was learned that he had lingous conjunctivitis, in addition a ventriculo‐peritoneal shunt was inserted due to hydrocephalus in the antenatal period. His parents were cousins. The patient had significant paracardiac infiltrations, linear infiltrations in the parenchyma of the chest x ray. The patient was thought to have plasminogen deficiency by clinical findings and his plasminogen level was found to be 14% (N: 70‐130%).Type 1 plasminogen deficiency and related pulmonary involvement were considered. Bronchoscopy was performed. There were fibrin deposits in the trachea and bronchi. Recurrent pulmonary lavage was performed with FFP and t‐PA. Fibrin plugs occluding the bronchial cuffs were decreased and some of them disappeared.The patient recovered from respiratory distress that required high flow oxygen therapy, and discharged. Homozygous frameshift mutation in the PLG gene was detected.Summary/Conclusion:In this case, it has been firstly reported that total pulmonary lavage treatment with FFP and t‐PA can be a useful treatment method for paitents with plasminogen deficiency in the English literature.

Human Plasminogen Replacement Therapy Vs. Best Supportive Care in Patients with Congenital Plasminogen Deficiency: A Comparison of Health Care Resource Use over a 48-Week Period

Background: Congenital plasminogen deficiency (CPD), is an ultra-rare autosomal recessive disorder that causes severe and debilitating clinical sequelae. Clinical signs are characterized by ligneous conjunctivitis, gingivitis, otitis media, impaired wound healing and even hydrocephalus. Current disease management includes surgery and systemic/topical therapies, but successful clinical responses are few and recurrences are typically rapid. Intravenous (IV) human plasminogen is a new treatment for CPD currently undergoing regulatory review in the United States. A recent clinical trial demonstrated that regular infusions of plasminogen IV (every 2 to 4 days) induced near complete and long term durable responses in affected patients. The current study compared overall health care resource use required to manage clinical manifestations of CPD for patients treated with human plasminogen in the clinical trial relative to a historical control group.Methods: The registration trial database was used to extract health care resource data in CPD patients (n=14) who received human plasminogen IV therapy throughout a 48-week period. Total health care resource use was compared to a control sample consisting of CPD patients (n=16) who did not receive human plasminogen IV and were managed with only best supportive care (BSC) over a one year period from the date of diagnosis. Health care resource extraction consisted of topical and systemic therapies such as fresh frozen plasma (FFP), clinic visits, surgical interventions and hospital admissions related to CPD.Results: A total of 16 patients who received BSC in either the United States (n=3), Spain (n=3) and Turkey (n=10) were identified and formed the control group. Over a 12-month assessment period, there were 304 clinic visits and 65 days of hospitalization for CPD related complications. IV FFP was given to 12 of 16 (75%) patients, which translated to 246 individual FFP doses administered (dose range = 5 to 15 mg/kg) over 12 months. Furthermore, there were 54 eye surgeries performed on the 16 control patients to remove ligneous membranes. In contrast, none of the 14 patients treated with plasminogen IV required surgical interventions, hospital admissions or FFP infusions over the 48-week treatment period (p < 0.001). There were also significant reductions in all types of supportive therapy in the human plasminogen treated patients relative to their utilization at baseline (p < 0.05).Conclusions: Human plasminogen replacement therapy was able to significantly offset health care resource use compared to patients receiving BSC only. Patients in the trial were also able to incorporate IV human plasminogen therapy into their weekly routine, with administrations often performed at home. DisclosuresDranitsaris:Prometic Life Sciences Inc.: Consultancy. Dorward:Prometic Life Sciences Inc.: Employment.

Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency

AbstractCongenital plasminogen deficiency is caused by mutations in PLG, the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.

Pivotal Trial with Intravenous Plasminogen Replacement in Patients with Plasminogen Deficiency Demonstrates Long-Term Efficacy for Treatment and Prevention of Ligneous Lesions

Background: Congenital plasminogen deficiency (PLGD) caused by mutations in the PLG gene is a rare genetic disorder that leads to clinical manifestations due to extravascular fibrinous deposits on mucous membranes with disruption of tissue or organ function (Tefs 2006; Mehta 2008). Prometic has developed an intravenous (IV) plasminogen (PLG) product (Prometic's-PLG) derived from human plasma as replacement therapy for treatment and prevention of extravascular fibrinous (ligneous) lesions in children and adults with PLGD.Aims: To determine whether Prometic's-PLG is safe and effective in pediatric and adult subjects with PLGD over 48 weeks of replacement therapy.Methods: Fifteen pediatric and adult subjects aged 2 to 80 years with PLGD were enrolled in an open-label study to receive multiple IV doses of 6.6 mg/kg Prometic's-PLG for at least 48 weeks. An analysis was performed after 10 subjects completed 48 weeks of treatment. Subjects were dosed every 2, 3, or 4 days based upon a pharmacokinetic (PK) profile to maintain target trough PLG activity levels > 10% (absolute) above baseline values. Extravascular ligneous lesions (visible and non-visible) were assessed at baseline, weeks 4, 8, 12, and every subsequent 12 weeks up to 48 weeks. Safety, tolerability and quality of life were also assessed.Results: Subject baseline characteristics are included in Table 1. Six of 10 subjects had 15 visible lesions at baseline. After 12 weeks, 14 of 15 lesions (93.3%) completely resolved; the remaining lesion shrank to an unmeasurable size. After 48 weeks, all 15 lesions had completely resolved. There were no new lesions or recurrences of previous lesions (Table 2). There were no deaths, serious adverse events (AEs), or AEs resulting in study drug discontinuation. The most frequent AE was nasopharyngitis.Conclusions: Repeated IV doses of 6.6 mg/kg Prometic's-PLG demonstrated excellent efficacy in the resolution of lesions due to PLGD with no recurrences or new lesions while on replacement therapy for 48 weeks, with no safety concerns. Prometic's-PLG represents a pivotal breakthrough in the treatment of this very rare coagulation deficiency and an important therapeutic advance for affected patients who have suffered under the burden of their disease due to lack of an available efficacious therapy.

Treatment of plasminogen deficiency patients with fresh frozen plasma.

Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment.

Plasminogen deficiency.

Plasminogen plays an important role in fibrinolysis as well as wound healing, cell migration, tissue modeling and angiogenesis. Congenital plasminogen deficiency is a rare autosomal recessive disorder that leads to the development of thick, wood-like pseudomembranes on mucosal surfaces, mostly seen in conjunctivas named as ''ligneous conjunctivitis''. Local conjunctival use of fresh frozen plazma (FFP) in combination with other eye medications such as cyclosporin and artificial tear drops may relieve the symptoms. Topical treatment with plasminogen eye drops is the most promising treatment that is not yet available in Turkey.

Laryngeal obstruction in congenital plasminogen deficiency

Type 1 congenital plasminogen deficiency (CPD) is a rare autosomal recessive disease which causes formation of fibrin pseudomembranes that affect multiple systems/organs: the eyes, respiratory system, urinary and genital systems, gastrointestinal system, and the central nervous system. We present a rare manifestation of the disease-severe upper airway obstruction due to a rapidly growing mass in the supraglottic region-6 months after dental treatment under general anesthesia. The management of such a manifestation has not been discussed in the current literature. Due to deterioration in his clinical status, the patient eventually underwent both a tracheotomy in order to bypass the obstruction, and excision of the supraglottic mass. Within a few days the mass recurred with complete obstruction of the upper airway.

The first two Japanese cases of severe type I congenital plasminogen deficiency with ligneous conjunctivitis: Successful treatment with direct thrombin inhibitor and fresh plasma

A 71-year-old woman and her elder sister developed ligneous conjunctivitis after ocular surgery. Laboratory tests demonstrated that the proband and her sister had 6.6% and 8.1% of plasminogen activity, and 1.2 and 1.4 mg/dl of antigen, respectively. Thus, they were diagnosed as having severe type I plasminogen deficiency, for the first time, in Japan. DNA sequencing and PCR-RFLP analyses revealed that these two cases are homozygotes of a novel A-to-G mutation at the obligatory splicing acceptor site in intron-C. Both cases were satisfactorily treated with a direct thrombin inhibitor, topical Argatroban, and topical plasma obtained from their healthy family members.

Ligneous conjunctivitis secondary to a congenital plasminogen deficiency in a dog

A 7-month-old 16.6-kg (36.5-lb) sexually intact female Golden Retriever was evaluated because of progressive severe bilateral membranous conjunctivitis, oral lesions, nasal discharge, and cough. Histologic examination of conjunctival biopsy specimens revealed findings consistent with ligneous conjunctivitis. Circulating plasminogen activity was repeatedly low, and congenital plasminogen deficiency was identified as the underlying cause of the ocular, oral, and respiratory lesions. Topical and subconjunctival administrations of fresh frozen plasma (FFP), topical administration of cyclosporine, and oral administration of azathioprine had no effect on the conjunctival membranes. Excision of the membranes followed by intensive treatment with topical applications of heparin, tissue plasminogen activator, corticosteroid, and FFP and IV administration of FFP prevented membrane regrowth. Intravenous administration of FFP increased plasma plasminogen activity to within reference limits, improved respiratory and oral lesions, and resulted in weight gain; discontinuation of this treatment resulted in weight loss, signs of depression, and worsening of lesions. After euthanasia because of disease progression, necropsy findings included mild hydrocephalus; multifocal intestinal hemorrhages; and fibrinous plaques in the oral cavity, nasopharynx, trachea, esophagus, and pericardium. Microscopically, the plaques were composed of fibrin and poorly organized granulation tissue. Fibrin thrombi were present within vessels in the lungs, oral cavity, and trachea. In dogs, congenital plasminogen deficiency can occur and may be the underlying cause of ligneous conjunctivitis. A combination of surgical and medical treatments may improve conjunctival membranes, and administration of FFP IV appears to be effective in treating nonocular signs of plasminogen deficiency.

International Abstracts of Pediatric Surgery

Congenital plasminogen deficiency is a rare disorder that usually becomes symptomatic as ligneous conjunctivitis. However, pseudomembranous lesions in the pharyngeal mucosa, the tracheobronchial tree, and the peritoneum may also occur. An accompanying hydrocephalus is extremely rare, with only 16 cases reported in the literature. The existing reports indicate that hydrocephalus, even treated by ventriculo-peritoneal (VP) cerebrospinal fluid shunting, worsens the prognosis substantially. Thus, VP cerebrospinal fluid shunting does not seem the optimal therapy for hydrocephalic children with plasminogen deficiency. The authors are adding 2 cases to the literature and, on the basis of their experience, propose a management strategy for the hydrocephalus. Both children were initially treated with VP shunts and had a very similar clinical course with multiple shunt malfunctions because of nonabsorption by the peritoneum. In the first child, the attempt to treat the hydrocephalus with a ventriculoatrial shunt failed because of catheter thrombosis. Finally, a ventriculo-cholecystic shunt was placed in both children. Thus, in patients with plasminogen deficiency and associated hydrocephalus, special care must be taken. The absorptive capacity of the peritoneum is reduced by pseudomembrane formation, which results in shunt malfunction. The plasminogen deficiency also results in early thrombus formation if atrial catheters are used. Therefore, it is recommended that ventriculo-cholecystic shunting should be considered early in the course of the disease.