Development of a Plasminogen Population PK model supporting prophylactic replacement therapy for Plasminogen deficient patients within the WAPPS-Hemo platform.

INTRODUCTION: Plasminogen deficiency is an ultra rare disease whose patients may develop ligneous lesions if untreated. Prophylactic replacement therapy with plasma derived plasminogen, Ryplazim, is efficient in treating lesions and could benefit from pharmacokinetic (PK) tailoring. AIM: The objectives of this study are to develop, evaluate and integrate into the WAPPS-Hemo platform a Population PK model supporting prophylactic replacement therapy for Plasminogen deficient patients. METHODS: Population PK modelling and evaluations followed the same protocol performed for factor VIII and IX concentrates. Limited sampling analysis used dosing and sampling scenarios in accordance with recommended treatment for Ryplazim. RESULTS: The population PK model, derived from 16 participants included in previous clinical studies, was a 2-compartment model whose variability was best described by fat-free mass. Evaluations showed that the model described well the data and Bayesian forecasting in limited sampling environment led to acceptable precision for PK parameters relevant to plasminogen treatment. CONCLUSION: The model was integrated into the WAPPS-Hemo webservice to help individualize prophylactic treatment in plasminogen deficient patients. Prospective PK data to be collected through the WAPPS-Hemo database will be used to better understand plasminogen PK and improve patient care.

Plasminogen, human-tvmh for the treatment of children and adults with plasminogen deficiency type 1.

AIM: An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted. Interim data was previously reported. The final data on 15 subjects who completed the study up to a maximum of 124 weeks are reported here. METHODS: The primary objectives were to evaluate efficacy of plasminogen replacement therapy on clinically evident or visible lesions during 48 weeks of dosing and to achieve an increase in trough plasminogen activity levels by at least an absolute 10% above baseline during 12 weeks of treatment. RESULTS: The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non-visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human-tvmh. All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12. Plasminogen, human-tvmh at a dose of 6.6 mg/kg administered every 2-5 days for 48 weeks and every 1-7 days for up to 124 weeks was well tolerated. CONCLUSION: This study provides additional evidence regarding the long-term safety and clinical utility of replacement therapy with human plasminogen for the treatment of children and adults with type 1 plasminogen deficiency. Plasminogen, human-tvmh received marketing approval on June 4, 2021. This trial was registered at www. CLINICALTRIALS: gov as #NCT02690714.

Ligneous periodontitis exacerbated by Behçet's disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report.

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency.

INTRODUCTION: Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI-1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI-1 do not provide an accurate correlation with clinical phenotype. METHODS: The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI-1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls. RESULTS: Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI-1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect. CONCLUSION: Patients with either PLGD or PAI-1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.

Prophylactic protocol for dental care in ligneous gingivitis due to severe plasminogen deficiency: Case report and review of literature.

INTRODUCTION: Severe plasminogen (PLG) deficiency causes ligneous conjunctivitis, a rare disease characterized by the growth of fibrin-rich pseudomembranes on mucosal surfaces; gums involvement leads to ligneous gingivitis (LG). Specific therapy for LG is not available yet. We report a prophylactic treatment with enoxaparin and fresh frozen plasma (FFP) for invasive dental procedures in a patient with LG, and a review of literature on LG treatment. METHODS: A 43-year-old female with LG was studied. In order to prevent LG recurrence after dental care, FFP before and the day after the procedure, and enoxaparin were administered in addition to proper minimally invasive dentistry techniques and implant surgery. RESULTS: Plasminogen deficiency was confirmed by reduced PLG antigen (25 µg/mL) and activity (20%) levels, and genetic analysis. PLG levels rose to 46% after FFP transfusion and returned to baseline after 48 hours. Minimally invasive dental procedures and implants were performed. Small gingival pseudomembranes developed soon thereafter in some cases but disappeared within a few weeks; no bleeding complications were observed. CONCLUSIONS: In our patient with LG, the adoption of combined haematological and dentistry protocols appeared to be safe and effective in preventing abnormal gingival pseudomembranes growth after dental interventions, maintaining a healthy periodontal condition.

Ligneous cervicitis and endometritis: A gynaecological presentation of congenital plasminogen deficiency.

BACKGROUND: Congenital plasminogen deficiency is a rare autosomal recessive condition. Plasminogen deficiency is thought to result in an inability of fibrin breakdown and therefore accumulation of fibrin and formation of ligneous changes. Ligneous lesions can form on a number of mucosal membranes including the cervix and endometrium. METHODS: We report the case of a 25-year-old woman with type 1 plasminogen deficiency with ligneous cervicitis and endometritis and her treatment and clinical course over the last few years. We then review the current literature of ligneous cases of the female genital tract and discuss available treatment options. KEY RESULTS: We found 30 reported cases of ligneous lesions affecting the female genital tract, with the cervix being the most affected part. A number of treatment options have been tried by our patient and other cases in the literature. These include use of the combined oral contraceptive pill, fresh frozen plasma infusion, topical plasmin and plasminogen and trial use of plasminogen concentrate. CONCLUSIONS: This is a chronic condition requiring a multidisciplinary approach. There is currently no definitive treatment for the condition, current trials with plasminogen concentrate replacement therapy may provide a promising option for these patients in the future.

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.

Beyond hemostasis: the challenge of treating plasminogen deficiency. A report of three cases.

Congenital plasminogen deficiency is a rare autosomal recessive disorder, characterized by chronic mucosal membranous lesions. Although the most common clinical manifestation is eye involvement as ligneous conjunctivitis, extra-ocular lesions affecting other mucosal surfaces indicates a systemic disease. In this report we describe two cases with atypical extra-ocular involvement that includes pericarditis and recurrent hematocolpos, and one with paradoxical correlation between ocular lesions and plasminogen levels. In ligneous conjunctivitis, although different treatment strategies have been tried with mild success, the only effective therapy is topical or systemic plasminogen concentrates that are not commercially available. Unfortunately there is not either effective management for cases with multisystemic disease. Hence, treatment for plasminogen deficiency is still a challenge and the variability of the clinical spectrum in this pathology makes necessary a multidisciplinary approach.

Molecular pathogenesis of plasminogen Hakodate: the second Japanese family case of severe type I plasminogen deficiency manifested late-onset multi-organic chronic pseudomembranous mucositis.

A 64-year-old man first developed ligneous conjunctivitis at the age of 58 years after right pulmonary resection because of suspected cancer; otherwise, he had been healthy. Since then, he began to suffer from various forms of chronic pseudomembranous mucositis. Laboratory tests demonstrated that he had 7.8 % of plasminogen activity and 5.9 % of the normal antigen level. Thus, he was diagnosed as having severe type I plasminogen deficiency, making him the third case in Japan. DNA sequencing and PCR-restriction fragment length polymorphism analyses revealed that this patient was a compound heterozygote of a G-to-A missense mutation (G266E) in exon VIII and a g-to-a mutation at the obligatory splicing acceptor site in intron 12 (IVS12-1g>a). These two mutations were confirmed to be novel. Molecular modeling and splice site strength calculation predicted conformational disorder(s) for the Glu266 mutant and a drastic decrease in splicing efficiency for intron 12, respectively. Western blot analysis demonstrated that the patient contained a small amount of the normal-sized plasminogen protein. Mass spectrometric analysis of the patient's plasminogen revealed a peptide containing the wild-type Gly266 residue and no peptides with mutations at Glu266. However, he had never suffered from thrombosis. Low levels of fibrinogen/fibrin degradation products (FDP), D-dimer, and plasmin-α2-plasmin inhibitor complex clearly indicated a hypo-fibrinolytic condition. However, his plasma concentration of elastase-digested crosslinked FDPs was 4.8 U/mL, suggesting the presence of an on-going plasmin(ogen)-independent "alternative" fibrinolytic system, which may protect the patient from thrombosis. The patient has been free from recurrence of ligneous conjunctivitis for approximately 2.5 years.

Persistent Hydrocephalus, Shunt, and Subglottic Stenosis in a Newborn with Plasminogen Deficiency due to Delayed Treatment with Plasminogen Concentrates: A Case Report.

INTRODUCTION: Here we present the case of a newborn baby boy with severe plasminogen deficiency causing occlusive hydrocephalus and ligneous conjunctivitis. CASE PRESENTATION: Shortly after birth, the hydrocephalus was treated with a ventriculoperitoneal shunt implantation. However, the child had to be readmitted soon afterward because of shunt obstruction. Subglottic microtrauma caused by the necessary intubations then led to another life-threatening complication - subglottic stenosis with pseudomembrane formation. Microsurgical removal had to be performed to secure the airway. Initially, regular plasma transfusions achieved slightly elevated plasminogen activity levels and short-term improvement of the respiratory situation. However, shunt dysfunction reoccurred, and alternative treatment options were needed. Since therapy with plasminogen concentrate is already available in the USA with encouraging results, this treatment option was organized in hopes of equally good results for this patient. Fortunately, under short-term substitution with plasminogen concentrates, the implantation of a new ventriculoperitoneal shunt was successful, and respiratory problems resolved. CONCLUSION: Plasminogen concentrates are critically needed in Europe and other parts of the world to improve the care of and prevent complications among patients with plasminogen deficiency.

[Colonic pseudotumoral involvement as an expression of severe plasminogen deficiency]. / Compromiso pseudotumoral colónico como expresión de déficit grave de plasminogéno.

Plasminogen deficiency is a very rare multisystem entity that affects different tissues of the economy through the deposition of fibrin-rich pseudomembrane and determines a heterogeneous and diverse clinical presentation. It is transmitted in an autosomal recessive manner by mutations of the PLG gene on chromosome 6 and can be divided into hypoplasminogenemia or type I and dysplasminogenemia or type II, the latter not related to clinical pathology. Severe plasminogen deficiency has a prevalence of 1.6 individuals per million inhabitants and although it can be diagnosed in adulthood, the most severe symptoms are observed in infants and children. The most common form of onset is the so-called woody conjunctivitis, characterized by fibrin membranes that are deposited on the eyelids since childhood, causing exophytic lesions that affect vision. It can also affect other mucous membranes such as the gingival, respiratory, oropharyngeal, digestive and genital mucosa, among others. We present a rare case of severe plasminogen deficiency with conjunctivitis and woody cervicitis who was admitted with clinical acute abdominal symptoms, associated with a tumor mass due to pseudomembranous deposition in the ascending colon that simulated inflammatory bowel disease and resolved spontaneously.

La deficiencia de plasminógeno es una entidad multisistémica, muy infrecuente, que afecta diferentes tejidos de la economía mediante el depósito de pseudo membranas ricas en fibrina y que determina una presentación clínica heterogénea y diversa. Se transmite en forma autosómica recesiva por mutaciones del gen PLG del cromosoma 6 y se puede dividir en hipoplasminogenemia o tipo I y displasminogenemia o tipo II, esta última no relacionada con patología clínica. El déficit grave de plasminógeno tiene una prevalencia de 1.6 individuos por millón de habitantes y si bien puede diagnosticarse en edad adulta, los síntomas más graves se observan en lactantes y niños. La forma de inicio más común es la denominada conjuntivitis leñosa, caracterizada por membranas de fibrina que se depositan en los parpados desde la infancia, provocando lesiones exofíticas que afectan la visión. También puede afectar otras mucosas como la gingival, respiratoria, orofaríngea, digestiva y genital entre otros. Presentamos un raro caso de deficiencia grave de plasminógeno con conjuntivitis y cervicitis leñosa que ingresó con un cuadro de abdomen agudo clínico, asociado a una masa tumoral por depósito de pseudomembranas en el colon ascendente que simuló una enfermedad inflamatoria intestinal y que se resolvió espontáneamente.

Long-term follow-up in a pediatric patient with Ligneous Conjunctivitis due to PLG gene mutation in topical plasminogen treatment after successful use of ocular prosthesis for aesthetic rehabilitation: a case report.

BACKGROUND: Ligneous Conjunctivitis (LC) is the most common clinical manifestation of Type I Plasminogen deficiency (T1PD; OMIM# 217090), and it is characterized by the formation of pseudomembranes (due to deposition of fibrin) on the conjunctivae leading to progressive vision loss. In past times, patients with LC were treated with surgery, topical anti-inflammatory, cytostatic agents, and systemic immunosuppressive drugs with limited results (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022, Surv Ophthalmol 48:369-388, 2003, Blood 131:1301-1310, 2018). The surgery can also trigger the development of membranes, as observed in patients needing ocular prosthesis (Surv Ophthalmol 48:369-388, 2003). Treatment with topical purified plasminogen is used to prevent pseudomembranes formation (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022). CASE PRESENTATION: We present the case of a sixteen-year-old girl with LC with severe left eye involvement. We reported the clinical conditions of the patient before and after the use of topical plasminogen eye drops and described the treatment schedule allowing the surgical procedure for the pseudomembranes debulking and the subsequent use of ocular prosthesis for aesthetic rehabilitation. CONCLUSIONS: The patient showed a progressive response to the topical plasminogen, with a complete absence of pseudomembrane formation at a twelve-year follow-up, despite using an ocular prosthesis.

Recurrent Meningitis and Its Rare Association With Ligneous Conjunctivitis and Congenital Plasminogen Deficiency.

This case report explores the rare association of recurrent meningitis, hydrocephalus, ligneous conjunctivitis, and congenital plasminogen deficiency in a term baby boy. Born at 39 weeks with a history of hydrocephalus, the neonate later developed ligneous conjunctivitis and a serious bout of meningitis. Genetic analyses confirmed a homozygous mutation in the PLG gene, indicative of congenital plasminogen deficiency. Despite intensive treatment, including a ventriculoperitoneal shunt for hydrocephalus and intravenous antibiotics for meningitis, the child succumbed to upper airway obstruction before reaching one year of age. This report underscores the medical complexity and severity of these interconnected conditions and advocates for further research to understand the interplay between them. Although this study is limited by its single-case nature and is not generalizable, it emphasizes the necessity for early recognition and a multidisciplinary treatment approach for better patient outcomes.

Combined medical and surgical approach in the management of ligneous conjunctivitis in a pediatric patient: A case report.

INTRODUCTION: Ligneous conjunctivitis (LC), a rare chronic conjunctivitis linked to plasminogen deficiency, poses challenges in research and management due to its complexity. This case report details the combined medical and surgical approach in managing LC in a 1.5-year-old female with congenital hydrocephalus, plasminogen deficiency, and glaucoma. CASE PRESENTATION: The patient's LC required a comprehensive treatment plan involving systemic and topical therapies, surgical intervention, and fresh frozen plasma (FFP) infusions via a central line. DISCUSSION: Managing LC necessitates a comprehensive, individualized approach due to its rarity and lack of standardized treatments. Various therapies have shown promise, but their availability, cost, and potential side effects vary. FFP infusions played a crucial role in managing plasminogen deficiency, but the potential complications associated with central lines must be considered. Ongoing clinical trials aim to improve LC treatment, but until results are available, clinicians must rely on existing evidence and clinical judgment. CONCLUSION: This case underscores the complexity of managing LC and the significance of adopting an individualized treatment strategy. Regular follow-ups are crucial for flexibility and adaptability in treatment plans to address potential recurrences. Further research is necessary to validate these findings and assess the long-term effectiveness of the combined approach.

The first Moroccan case of severe type II congenital plasminogen deficiency with ligneous conjunctivitis.

Ligneous conjunctivitis (LC) is a rare form of pseudomembranous chronic conjunctivitis caused by a deficiency in plasminogen activity. Due to its rarity, little is known about this disorder. We hereby report a case of ligneous conjunctivitis, describing the clinical findings, the biological diagnosis and the treatment of this rare disease.

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.

Ligneous conjunctivitis exacerbated by Pseudomonas aeruginosa - Diagnostic and therapeutic approach.

Ligneous conjunctivitis is a rare disease in which pseudomembranes develop on the mucosal surfaces of the eye. Only a handful of cases have been reported in the past 100 years. Although plasminogen deficiency is largely implicated in the pathogenesis of this condition, infectious agents are also thought to play a role in worsening the disease. Treatment is usually challenging. We present a case of 3-year-old female in whom a multidrug-resistant Pseudomonas aeruginosa was isolated from the culture of the pseudomembranes. To the best of our knowledge, this is the first time P. aeruginosa has been implicated as an exacerbation factor. Furthermore, we have given merit to the triple regimen of corticosteroids, heparin, and cyclosporine as being effective. We also added antibiotics to target the infectious organism.

[Pharmaceutical supply of human plasminogen replacement therapy for the treatment of ligneous conjunctivitis: Logistics for a university hospital]. / 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.

Diagnosis of a case of ligneous gingivitis in a patient with moderate plasminogen deficiency.

Plasminogen deficiency is a rare congenital condition that leads to pseudomembraneous lesions, such as ligneous conjunctivitis and ligneous gingivitis. Because of its rarity, ligneous gingivitis is not a pathology one may easily suspect from its clinical symptoms. We report the case of a 35-year-old Caucasian woman who experienced gum masses with white spots, but no pain. Based on the clinical picture, one could refute a diagnosis of necrotizing ulcerative periodontitis. Several biopsies were taken. The last ones showed an amorphous eosinophilic substance that could be fibrin. Plasmatic dosage of plasminogen (activity level 44%) confirmed the hypothesis of ligneous gingivitis. This report appears to be a very rare diagnosis of a ligneous gingivitis without major conjunctivitis, associated with a moderate plasminogen deficiency.