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A.D. Shapiro et al.
venous route of administration is used. Infusion reac- tions, time required for administration and need for repeated infusions may also limit intravenous use of fresh-frozen plasma.
Several case studies have reported on topical ophthal- mological application of plasminogen for the treatment of ligneous conjunctivitis. Watts et al. noted that following surgical removal of pseudomembranes, plasminogen eye drops administered every 2 h prevented regrowth; a maintenance dose every 6 h prevented symptoms for over 1 year.32 Similarly, Pons et al. reported resolution of ligneous conjunctivitis with administration of plasmino- gen eye drops; in this patient, multisystem manifestations subsequently developed that could not be treated.33 An interim analysis of a phase II/III clinical trial studying ophthalmological plasminogen (2 drops, 4-12 times daily) was reported by Nakar et al.34 Ten out of 11 subjects (91%) experienced full regression of ophthalmological lesions and/or absence of recurrence following surgical excision (the 11th subject was withdrawn because of non- compliance). This clinical trial (NCT01554956) is ongo- ing.
Shapiro et al. have reported results from a phase II/III clinical trial (NCT02690714) investigating the use of an intravenous plasma-derived plasminogen concentrate (6.6 mg/kg iv, every 2-4 days depending on individual phar- macokinetic profile).14 All 14 subjects achieved trough plasminogen levels at least 10% above baseline; all preex- isting clinical manifestations of PLGD (including lesions on the conjunctiva, gingiva, nasopharynx, bronchus, colon, kidney, cervix, and vagina) resolved or improved. An amended biologics license application is expected to be filed with the Food and Drug Administration for this product in the first half of 2020.
The rarity of PLGD results in frequent mis- and delayed diagnoses by professionals lacking specialist knowledge. Difficulty with diagnosis and disease rarity have con- tributed to an inability to document the natural history, develop clinical guidelines, and optimize treatment regi- mens. An exclusively USA-based registry would be of limited value as this would restrict recruitment and might fail to identify the full spectrum of the disorder. Therefore, an international effort has been undertaken to gain unique and broad insights into the disease, its pro- gression and optimal treatment.
Registries in rare coagulation disorders
Hemophilia A and B are two of the more common rare coagulation disorders; they affect approximately 1:5,000 and 1:30,000 persons, respectively. Our current under- standing of hemophilia and the wide availability of spe- cialized care and therapeutic options are a result of the many clinical trials and patient registries that have been developed over the years.
Patient registries in hemophilia may be national, regional or international. O’Mahony et al. noted that 27/35 European countries had their own national hemo- philia patient registry and some countries have multiple national registries operated by different organizations with little consideration given to interoperability.35,36 This lack of interoperability and the variability in inclusion/exclusion criteria for enrolled subjects, defini- tions utilized, data collected, and different goals of these
Table 1. Examples of published therapies for the most common mani- festations of plasminogen deficiency, ligneous conjunctivitis and lig- neous gingivitis.
Therapy*
Fresh-frozen plasma
Plasminogen concentrate
LC LG [reference] [reference]
[31] [22]
[14,34] [14]
Anticoagulants
Heparin [23]
Warfarin [28] Argatroban [33]
Immunosuppressants
Corticosteroids
Azathioprine [11]
[23] [10]
Cyclosporine A
[24,25]
Oral contraceptives [27]
Thrombolytic
Anistreplase [10] Hyaluronidase [26] Alpha chymotrypsin [26] Mast cell stabilizer
Cromoglicic acid [11]
Anti-proliferative agent
Mitomycin C [11]
LC: ligneous conjunctivitis; LG: ligneous gingivitis. *Not all reported therapeutic results have been shown to be reproducible.
national registries all limit the pooling of data to the detri- ment of all stakeholders. One example of the issues asso- ciated with multiple registries pursuing similar goals may be observed in those that examined the determinants of hemophilic inhibitor development and predictors of immune tolerance induction success: different registries reported different conclusions based on the patients enrolled and the data collected.37 Ideally, collaboration between registries and harmonization of data collection are necessary to achieve minimal datasets for advance- ment of shared clinical goals in these rare disorders.38,39
Advantages and disadvantages of national, regional and international registries are highlighted in the following examples.
The American Thrombosis and Hemostasis Network
The American Thrombosis and Hemostasis Network (ATHN) collects data on patients in the USA with rare coagulation disorders. The centralized database and stan- dardized definitions for data entry enhance research and clinical goals; these include the generation of the largest genetic hemophilia repository (My Life, Our Future) and the surveillance of over 80,000 persons with rare coagula- tion disorders (Community Counts).40,41 Despite these successes, Gupta et al. noted limitations in data collection; for example, of the known 3,626 patients with an ultra- rare coagulation disorder, less than 11% had been includ- ed in the Community Counts registry.39 Furthermore, the strictly USA-centric dataset may limit wider applicability of results to other countries with different medical resources and population diversity. These limitations highlight why efforts to create a comprehensive ultra-rare coagulation disorder registry in a single country may be less successful than desired.
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