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.
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.
Asterisk with author names denotes non-ASH members.