Congenital plasminogen deficiency (C-PLGD), also known as hypoplasminogenemia or type I plasminogen deficiency, is an ultra-rare genetic disorder that is characterized by genetic mutations in the PLG gene that lead to decreased production of the fibrinolytic zymogen plasminogen and ultimately results in a decreased ability to break down fibrin once formed. Plasminogen is an important component of the clotting system that plays a role in a range of physiological functions, including blood clotting and wound healing.
Patients often develop fibrinous lesions known as pseudomembranes on mucous membranes throughout their bodies. Lesions most commonly occur in the eye and cause a risk of permanent corneal damage that can result in blindness, but they can also present in the respiratory, genitourinary, and gastrointestinal tracts, oropharynx, gingiva, 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.
C-PLGD's exact incidence or prevalence is unknown, but prevalence is currently estimated at 1-2 per 1 million in general population. As C-PLGD is so rare, presenting symptoms may be difficult to recognize and be ascribed to other diseases. Patients are often misdiagnosed and experience delayed diagnosis. In addition, their treatment journeys can vary widely. Patients who experience lesions on their eyelids may first visit an ophthalmologist. Others may seek treatment from a dentist, a primary care provider, or a specialist including OB-GYNs. Eventually, hematology-oncology specialists often play a central role in confirming the diagnosis and to managing care.
There has been insufficient coordinated national or international effort to establish a data registry that could document the number of affected individuals and range of symptoms experienced over time. As a result, quantifiable information about the patient experience and the burden of disease is limited. This lack of information has required clinicians to rely on personal experience, anecdotal information, and access to a small number of case studies when trying to understand the disorder and develop management plans.
The identification of contributing factors or triggers of disease manifestations, prediction of disease progression, and data related to the use of potential therapeutics are among the most significant gaps in knowledge surrounding C-PLGD. 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) aim to address these gaps and build broader awareness of PLGD by initiating a collaborative natural history research effort titled Hypoplasminogenemia: An International RetroSpecTive and PrOspective CohorRt StudY, also known as HISTORY.
Rare Bleeding Disorder Database Efforts
Efforts to collect data from patients living with rare coagulation disorders have primarily been led by the American Thrombosis and Hemostasis Network (ATHN) and the European Network of Rare Bleeding Disorders (EN-RBD). While their work has made great contributions to the rare coagulation disease community as a whole, some factors have limited their ability to be applied to C-PLGD research.
The world's largest genetic hemophilia repository was created by the ATHN in conjunction with the Centers for Disease Control and Prevention and pharmaceutical partners. While more than 80,000 patients have participated in this largely successful effort, the study collected data only from patients in the United States. Because of this limitation, conclusions drawn from the data collected during this study may not be applicable to patients from other countries who belong to different populations and have access to different medical resources.
In 2004, the EN-RBD founded the Rare Bleeding Disorders Database to collect and organize clinical, genetic and treatment data on rare bleeding disorders beyond classical hemophilia A and B. The study's early data included information from 592 participants from 11 European countries and allowed for development of a new severity classification system for bleeding symptoms associated with the disorders involved.
The database was then expanded to include prospective data collection from patients from 62 study centers around the world and renamed the Prospective Rare Bleeding Disorders Database (PRO-RBDD). While PRO-RBDD supports more accurate assessments of the prevalence of rare bleeding disorders and provides valuable insight related to symptoms, burden, and clinical management of these diseases, the study does not address C-PLGD.
The HISTORY Project
The IHTC and IRCCS/UNIMI created the HISTORY project as an extension of PRO-RBDD with the hope of applying the study's findings to develop a system ultimately to categorize C-PLGD disease severity, more accurately predict disease progression, assess the need for disease surveillance in certain subpopulations, and develop new treatment algorithms to provide improved guidance for disease management. The development of a more successful treatment management system in this rare chronic disease, coupled with the development of new investigational therapies, would support efforts for hematology-oncologists who often play a central role in overseeing these patients.
The HISTORY project is the first international study that aims to assess and define the natural history of C-PLGD. Researchers hope that by collecting and analyzing this information they will be able to provide valuable insight that can help hematologist-oncologists and other clinicians who may be involved in diagnosing or treating C-PLGD patients develop more effective treatment plans.
As part of this effort, researchers plan to collect data from up to 100 C-PLGD patients and approximately 400 of their first-degree family members over the course of 4 years. Participants will provide 1 year of retrospective data beginning with a baseline in-person study center visit followed by 3 years of prospective data collection that is obtained via telephone calls. If enrolled individuals experience a suspected clinical manifestation indicating pseudomembrane development or other medical event such as pregnancy, then an in-person local study site visit is conducted.
Researchers will collect information relating to a variety of factors, including participants' overall health, age of diagnosis, reasons they were originally screened for PLGD, phenotypes, and genotypes. Patients will be classified as asymptomatic, intermittently symptomatic, or continuously symptomatic as their data is considered alongside factors including their gender, environmental influences, and genetic information. Patients' lesions will be observed based on their types, sites, and frequency in addition to the duration of treatments utilized. The study will also evaluate laboratory parameters, information relating to the management of surgical procedures, obstetric data, and any complications associated with treatments.
Asymptomatic first-degree family members of PLGD patients will contribute data that is critical to the success of this study. At this time, asymptomatic patients are not screened for the disease. Identification of affected asymptomatic individuals will make a significant contribution researching the progression of PLGD prior to symptom onset. Heterozygous family members' data will provide insight into the relationship between minimal plasminogen activity levels and the natural history of the disease.
PLGD Research & Standard of Care
Researchers hope that the data and samples collected and analyzed during the HISTORY project can improve the standard of care in C-PLGD provided by hematologist-oncologists. The study also provides centralized plasminogen levels, genetic evaluation, and advanced coagulation testing.
For instance, there is currently no data available to assess the likelihood that patients will develop potentially life-threatening lesions in other organ systems after they present with symptoms such as ligneous conjunctivitis, a common disease presentation. Data is also lacking to assist in providing insight for what surveillance methods may be most effective, how frequently they should be employed, and the duration of effective treatment once available.
When a patient's hematologist-oncologist has access to this level of insight into their case(s) of C-PLGD, they will have greater insight into the care and other specialists required to improve the patient's quality of life. The IHTC and IRCCS/UNIMI also hope that the data they collect will contribute towards the development and confirmation of disease severity categories, a more accurate prediction of the disease's course, the effective identification of specific surveillance needs in certain subpopulations. It is hoped that ultimately the creation of treatment algorithms and more comprehensive recommendations with best practices to guide disease management will be developed.
The HISTORY project also has the potential to assist in guiding future clinical research in PLGD through the development of a biorepository and the use of advanced coagulation testing. In addition, the data collected during the study can be used to evaluate the use of locally performed tests-most patients are diagnosed through analyzing their blood plasminogen activity and antigen levels relative to the normal range.
Mutation analysis can provide further confirmation of the diagnosis, but is not always available. An effective screening test would allow for assistance in diagnosis and prediction of disease course, enabling earlier intervention and the establishment of a more accurate disease prevalence rate.
Scientists researching PLDG face a variety of challenges including patient identification and phenotypic heterogeneity. As is the case with many ultra-rare diseases, a small population of affected individuals makes it difficult to interpret data to develop conclusions that are applicable to the real-world patient population. The HISTORY project's data may aid in identifying patients for clinical trial eligibility and mitigate some of these challenges.
While there are currently no approved treatments available, researchers are exploring the use of plasminogen concentrate, derived and isolated from the blood of healthy donors, to treat PLGD. The investigational therapy is currently under review by the FDA. Plasminogen is a key zymogen that plays a fundamental role as the precursor of plasmin, the main enzyme involved in the lysis of blood clots, and clearance of extravascular fibrin, as well as playing a central role in wound healing, cell migration, tissue remodeling, angiogenesis, and embryogenesis.
Perhaps the most important goal of the HISTORY project is to increase awareness of PLGD among hematologist-oncologists and other medical specialists who should play a central role in patient care. Providing hematologist-oncologists with new levels of insight and quantifiable information regarding PLGD has the potential to improve the diagnostic process and provide access to more well-rounded and appropriate patient care plans.
For more information about the HISTORY project, visit the study website (http://www.plgdeficiency.com) or http://ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT037974)
AMY SHAPIRO, MD, is the CEO and Co-Medical Director at the Indiana Hemophilia & Thrombosis Center, Inc. She is also Adjunct Senior Investigator of the Blood Center of Wisconsin and Adjunct Professor of Pediatrics at Michigan State University.