Page 41 - Haematologica March 2020

HISTORY, a plasminogen deficiency registry
geneity affect recruitment, interpretation of data and applicability of conclusions to the larger real-world popu- lation of patients; in many cases it may not be possible to design a clinical trial accurately because of insufficient knowledge of the disease.2 Instead clinicians have often relied on personal experience, case studies/series and patient registries to understand the natural history of these diseases and to collect data on therapeutic interven- tions and patient outcomes. Patient registries may be national, regional or international, each with its own advantages and disadvantages. The value of international patient registries in rare diseases has long been recog- nized; however, given the large number of rare diseases and the small number of affected patients, funding oppor- tunities are frequently limited, particularly for long-term maintenance.1
Some diseases are so rare that many clinicians may never see a case; for example, plasminogen deficiency (PLGD) is an ultra-rare disease with an estimated preva- lence of approximately 1.6 per million population. Most commonly it presents as ligneous conjunctivitis, an extravascular accumulation of fibrin-rich, woody (lig- neous) pseudomembranes on the mucous membrane of the eye; it can also manifest on other mucous mem- branes, and as a life-long, systemic disease impacting multiple systems either intermittently or continuously. No specific therapies are approved by the Food and Drug Administration or European Medicines Agency and non- specific treatments are inadequate.
Current knowledge of PLGD stems from case reports and small series; systematic prospective data collection coupled with serial biological samples collected from per- sons with PLGD and first-degree family members has not been performed. Knowledge gaps include identification of contributing factors to and triggers of disease manifes- tations, inability to predict disease course, and insuffi- cient real-world data for individualized use of potential new therapeutics. To address unmet needs, a retrospec- tive and prospective data collection system of a large cohort of people with PLGD and their family members has been developed to define the natural history of PLGD and is entitled Hypoplasminogenemia: An International RetroSpecTive and PrOspective CohoRt StudY (HISTORY). HISTORY addresses key gaps in the knowledge about the natural history of PLGD and builds on the productivity/infrastructure of the established collabora- tive efforts of research teams at the Indiana Hemophilia and Thrombosis Center (IHTC), the Fondazione Angelo Bianchi Bonomi, IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (IRCCS) and the University of Milan (UNIMI). Phenotypic data combined with genetic and advanced laboratory testing will be used to investigate disease course predictors and evaluate/elucidate pheno- typic relationships. A specimen biorepository will serve as a resource for further analyses. Overarching study goals are to analyze phenotypic heterogeneity, to identify markers to predict disease course, and to develop improved methods to utilize new therapeutics.
Plasminogen deficiency
Congenital PLGD is an autosomal recessive disorder caused by mutations in PLG that result in functionally defi- cient and/or reduced levels of circulating plasminogen.3 An
epidemiological study performed in the UK observed a 0.26% prevalence of asymptomatic heterozygous PLGD;4-6 similar prevalences of heterozygous PLGD have been reported in other countries.7-9 The UK data suggest that the prevalence of individuals with symptomatic PLGD (homozygous/compound heterozygous) is 1.6 per million population;10,11 there are estimated to be 500 symptomatic people with PLGD in the USA and 12,000 worldwide. Based on experience with other rare bleeding disorders, a higher prevalence of PLGD is likely to occur in regions where consanguineous marriages are more common;11,12 for this reason, a national study would likely misstate the true prevalence and phenotypic diversity of the disease. An increased number of females are reported to be sympto- matic compared to males (ratio of 1.27-1.88:1).12,13
People with PLGD may exhibit a multi-organ systemic
disease that commonly manifests as the extravascular
accumulation of fibrin-rich, woody (ligneous)
pseudomembranes on mucous membranes. PLGD is a
lifelong disease, although the most severe symptoms are
observed in infants and children.3,14 Ligneous conjunctivi-
tis is the most common disease symptom (81% preva-
lence);3 pseudomembrane growth may be triggered by a
local infection or injury and can result in impairment or
loss of vision if untreated and/or persistent.3,11
Approximately one-third of people with PLGD have
corneal involvement with potential for blindness,11,12 and
30% present with ligneous gingivitis resulting in peri-
odontal destruction and tooth loss.3,12,13 Other common
symptom locations include the respiratory tract (20%),
ears (14%), female genitourinary tract (9%), and kidneys (4%).3,11,15-18
Lesions are often inflamed and painful and can compro- mise organ function, resulting in life-threatening condi- tions including renal and respiratory failure (e.g., tracheo- bronchial lesions).11,18 Central nervous system complica- tions have been noted, including Dandy-Walker malfor- mation and occlusive hydrocephalus12 in 14% of children due to fibrin deposition in the cerebral ventricular system; shunts used to drain cerebrospinal fluid are prone to occlusion or poor peritoneal absorption, leading some neurosurgeons to recommend ventriculocholecystic shunts.19 In women, dysmenorrhea, abnormal menses, dyspareunia, and infertility have been reported.15 Wound healing may be severely impaired.20 Lesions in the middle ear may result in hearing loss.11 Although the initial case of PLGD was documented in a patient with recurrent venous thromboembolism, an association between PLGD and increased thrombotic risk has not been demonstrat- ed.10,21 Patients may suffer substantial morbidity and mor- tality and experience reduced quality of life and educa- tion/work potential.14
Surgical removal of lesions often results in accelerated pseudomembrane regrowth compounding clinical mor- bidity.22 Case reports describing use of topical or systemic heparin, corticosteroids, cyclosporine, azathioprine, hyaluronidase, α-chymotrypsin, oral contraceptives, war- farin, and amniotic membrane placement have been pub- lished; these approaches show inconsistent success (examples of therapies utilized are shown Table 1).13,23-29 Fresh-frozen plasma has been reported to be successful in some cases when eye drops, subconjunctival injection and/or intravenous infusions are utilized;30,31 however, as fresh-frozen plasma contains low concentrations of plas- minogen, volume overload may occur when the intra-
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