HISTORY project may have ‘profound impact’ on congenital plasminogen deficiency research
Congenital plasminogen deficiency is an extremely rare disorder characterized by development of fibrinous or woody pseudomembranes that typically accumulate on mucosal surfaces.
The most common presentation is termed ligneous conjunctivitis, which can result in corneal abrasion and visual impairment.
However, congenital plasminogen deficiency (C-PLGD) — also referred to as type plasminogen deficiency or hypoplasminogenemia — is a multisystem disease with lesions also occurring in the respiratory/gastrointestinal/genitourinary tracts, oropharynx, middle ear, skin and central nervous system.
If left untreated, C-PLGD can significantly reduce a patient’s quality of life and result in potentially life-threatening complications.
Classified as an ultra-rare disorder, C-PLGD has an estimated prevalence of 1 or 2 per 1 million people. Incidence may be higher in some areas where consanguineous marriage is more prevalent.
C-PLGD’s rarity and the fact that symptoms may be ascribed to other more common entities often results in delayed or misdiagnoses.
Data on disease burden and manifestations are limited.
No therapy has demonstrated consistent efficiency for C-PLGD treatment. Clinicians rely on anecdotal information and a small number of case studies and series to develop patient management plans.
There are large knowledge gaps in many key areas of C-PLGD. These include documenting the number of affected individuals, identifying contributing factors and triggers of disease manifestations, predicting disease course or progression over time, and collecting data related to use of potential therapeutics.
A collaborative research effort is underway to address these unmet needs and advance the first disease-specific natural history study of C-PLGD.
The HISTORY project — the acronym for which stands for “Hypoplasminogenemia: An International Retrospective and Prospective Cohort Study” — includes teams at Indiana Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Italy, and University of Milan.
State of coagulation disorder data
The European Network of Rare Bleeding Disorders (EN-RBD) and American Thrombosis and Hemostasis Network (ATHN) are among organizations that have made strides to collect data from patients living with rare coagulation disorders other than hemophilia A and B.
Although these registries have enabled an improved disease characterization — including clinical manifestations, definitions of potential severity categories and available therapeutic options — they have not collected data specific to C-PLGD.
The ATHN developed a US-based large data collection system and genetic hemophilia repository in conjunction with the CDC and pharmaceutical partners. The CDC surveillance system contains data from more than 80,000 patients with rare coagulation disorders.
The EN-RBD created the Rare Bleeding Disorders Database in 2004 to organize clinical, genetic and treatment data on rare bleeding disorders beyond classical hemophilia A and B, including fibrinogen deficiencies.
The study’s early data were collected from 592 patients from 11 European countries and resulted in the development of a new severity classification system for bleeding symptoms associated with the disorders. This database has been expanded to include prospective data collection from patients from 62 centers worldwide, with the goal of gathering sufficient data on ultra-rare diseases with a prevalence of less than 1 per 1 million people.
Known as the Prospective Rare Bleeding Disorders Database, it is designed to support more accurate assessments of the prevalence of rare bleeding disorders and provide new insights related to symptoms, disease burden and clinical management. Although these results will have important applications related to rare bleeding disorders, these systems and studies do not address C-PLGD.
The HISTORY project
The HISTORY project — an extension of the Prospective Rare Bleeding Disorders Database — is coordinated by Indiana Hemophilia and Thrombosis Center and IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan/University of Milan.
The HISTORY project collects data related to all aspects of C-PLGD, including the general health of each participant, age at diagnosis, reasons screened for C-PLGD, phenotypes and genotypes.
Pseudomembrane manifestations will be analyzed by site, frequency and duration. The types, intensities and duration of any associated treatments also will be recorded.
Researchers will evaluate local laboratory parameters, information about management of surgical procedures, obstetric data and complications associated with treatment. Participants with C-PLGD will be classified as asymptomatic, intermittently symptomatic or continuously symptomatic, and their data will be analyzed against elements such as gender, environmental factors, centralized advanced coagulation testing and genetic studies.
The collection of data from first-degree family members, including those who are heterozygous or asymptomatic, will contribute important information.
Previously undiagnosed and untested affected individuals may be identified and followed over time to provide valuable information about disease triggers. The inclusion of heterozygous family members contributes further insight into the relationship between minimal plasminogen activity levels and disease manifestations.
Participants will be observed a minimum of seven times: at baseline and then every 6 months for 3 years.
Retrospective data and laboratory assessments are collected during the baseline visit, performed at the study site. Participants then provide follow-up data via telephone contact every 6 months.
However, at times of development of a suspected clinical manifestation of pseudomembrane development or an important medical event such as pregnancy, enrolled individuals will be evaluated in person. Additionally, the last study visit is conducted in-person.
Data collected through this study may help to develop disease severity categories, identify triggers of disease manifestations and predictors of disease course, evaluate the need for structured surveillance in specific groups, and help with development of treatment algorithms and recommendations to guide disease management.
Implications for the C-PLGD community
Clinicians have little evidence and insight to predict the course of C-PLGD based on patient plasminogen activity levels, genetic analysis or symptom presentation.
The likelihood of age at presentation, symptom duration and recurrence, and development of multisystem disease manifestations cannot be predicted, and surveillance guidelines for affected individuals are largely absent.
Once a specific efficacious therapy is available, clear treatment guidelines must be developed to determine treatment duration for specific manifestations or application of treatment in a prophylactic manner to suppress symptom development.
There is no available screening coagulation test that may indicate C-PLGD diagnosis. The diagnosis must be considered followed by specific analysis of the plasminogen activity and antigen. These laboratory tests are not uniformly available.
Mutation analysis can provide further confirmation but, again, is not always available.
Researchers plan to use information collected during the study regarding methodological details of locally performed tests to evaluate their reliability and sensitivity, as well as investigate further advanced coagulation testing to determine its utility.
The HISTORY project also may have a profound impact on the future of clinical research in C-PLGD.
Clinical research in ultra-rare diseases is challenged by patient identification, phenotypic heterogeneity and recruitment. Use of small populations of affected individuals contributes to difficulty generalizing data.
For this reason, and due to the rarity of C-PLGD, the HISTORY project has been intentionally designed as an international study. Data from the HISTORY project can help with patient identification for future clinical research, and support more accurate procedures for diagnosis and assessment of disease prevalence.
Although there are no approved treatments, researchers are exploring the use of a plasminogen concentrate — derived and isolated from the plasma of healthy donors — to treat C-PLGD. This investigational therapy is under FDA review.
Plasminogen is an essential component of the fibrinolytic system and, once activated, is the main enzyme involved in the lysis of blood clots and clearance of fibrin. Plasminogen plays a central role in maintenance of mucous membranes, wound healing, cell migration, tissue remodeling, angiogenesis and embryogenesis.
Although the HISTORY study will play a role in design of future clinical research, data from the registry also is positioned to have an immediate positive impact.
New insights on both prevalence and disease burden can help improve standards of care while identifying new opportunities to build disease awareness and provide effective support for patients and families.
For more information:
Amy Shapiro, MD, can be reached at email@example.com.