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Plasminogen deficiency (PLGD) is a rare, multi-system disorder in which patients do not produce enough functional plasminogen. In Type I PLGD (or hypoplasminogenemia), patients do not make enough of the plasminogen protein (plasminogen antigen and activity are both low), and these patients can present with symptoms in multiple organ systems. In Type II PLGD (or dysplasminogenemia), patients make enough of the plasminogen protein, but it does not work normally (plasminogen antigen is normal, but activity is low); these patients are typically without symptoms. Most patients with diagnosed PLGD are therefore of the Type I variety.

Plasminogen is a protein that is produced in the liver, and functions throughout the body as part of the blood clotting system. Its primary role is to break down fibrin, the substance that creates blood clots. If there is not enough functional plasminogen available, fibrin can accumulate after injuries as part of the wound healing process. Interestingly, medical researchers have not observed a relationship between PLGD and the development of blood clots in affected patients. Patients with PLGD often develop excessive growth of fibrin (called fibrin membranes) on mucosal surfaces, and can have trouble with normal wound healing (see Symptoms).

Due to the rarity of PLGD, there is much that needs to be learned to improve the care of those affected. One issue is that physicians are currently unable to predict each person’s clinical course, meaning they cannot predict if and when a person might develop symptoms, how long those symptoms might last, and if they will recur. There has not been a relationship reported between the plasminogen activity levels and development of clinical symptoms, or a relationship between symptoms and the genetic changes that result in PLGD. Another issue is that, presently, there are no specifically licensed therapies to replace plasminogen which is the best method to treat this type of clotting factor deficiency. Once these therapies are available, we will need further research to understand their best use for each person with PLGD.

Image Credit: Liminal Biosciences

Symptoms of plasminogen deficiency (PLGD) are due to an accumulation of fibrin, a protein involved in the blood clotting system.  Individuals with PLGD have too little of the needed normal plasminogen activity to help regulate and dissolve fibrin once formed. Accumulations of fibrin membranes usually occur in areas that have linings called mucous membranes including the eyes, ears, nose, mouth, airways, gastrointestinal and genitourinary tracts, and less commonly, the central nervous system. These abnormal membranes are called “ligneous” because they are “wood-like” in their appearance and can affect the normal function of the involved organ.

The most commonly reported symptoms are lesions in the eyes. Eye lesions, called ligneous conjunctivitis (LC) appear as thick, whitish, hard “woody” growths inside the upper and/or lower eyelids. LC events may result in chronic tearing, photophobia, pain and corneal abrasions with vision loss. Gum lesions, called ligneous periodontitis, may result in loss of gums and eventually teeth (ref 1). Other documented symptoms included: lesions in the airways also called bronchial lesions (ref 2,3) ear complications, kidney complications, and glass-like growths on skin (colloid milium) (ref 1).

PLGD lesions often appear after minor injury or infection (pink eye, ear infection, or tooth eruption, for instance), but may also appear without injury. These lesions often re-grow quickly after they have been removed. The most severe symptoms are often observed in children but may appear at any time in a person’s life. PLGD is a lifelong disorder that appears to affect females in terms of clinical manifestations more than males. Woman with PLGD may experience painful intercourse, abnormal menses, and infertility (ref 4,5).

  1. Schuster V, Hugle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5(12): 2315-2322.
  2. Schuster V, Seregard S. Ligneous conjunctivitis. Surv Ophthalmol. 2003;48(4):369-388
  3. Ciftci E, et al. Ligneous conjunctivitis, hydrocephalus, hydrocele, and pulmonary involvement in a child with homozygous type I plasminogen deficiency. Eur J Pediatr. 2003;162(7-8):462-465.
  4. Pantanowitz L, et al. Ligneous (pseudomembranous) inflammation involving the female genital tract associated with type-1 plasminogen deficiency. Int J Gynecol Pathol. 2004;23 (3):292-295.
  5. HISTORY, an International Retrospective and Prospective Registry of Patients with Plasminogen Deficiency. Shapiro et. al. Poster Abstract ISTH2020.

Congenital plasminogen deficiency (PLGD) is inherited in an autosomal recessive fashion due to mutations on chromosome 6. Many different mutations have been identified in type I deficiency, and in affected patients mutations can be compound heterozygous or homozygous. The specific genetic mutation is not currently known to predict the development of symptoms or severity of disease (ref 1).

PLGD is very rare genetic disorder estimated to affect 1.6 per 1 million persons (ref 3,4). The true prevalence may be under-estimated because the symptoms can present in a variety of ways to many different types of healthcare providers (ophthalmologists, dentists, ENT physicians, gynecologists, etc), and may not be recognized as a symptom of plasminogen deficiency.

  1. Schuster V, Hugle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5(12): 2315-2322.
  2. Tait RC et al. Plasminogen levels in healthy volunteers–influence of age, sex, smoking and oral contraceptives. Thromb Haemost. 1992;68(5):506-510.
  3. Dykes and Polesky. Incidence of the PLG* QO allele in human populations. In: Mayr WR, ed. Advances in Forensic Haemogenetics: Springer-Verlag Berlin Heidelberg, 1988:261-264.
  4. Mehta and Shapiro. Plasminogen deficiency. Haemophilia. 2008;14(6):1261-1268.

In patients with plasminogen deficiency, blood levels of plasminogen activity are reduced (ref 1). Diagnosis therefore depends on the development of symptoms followed by blood testing to confirm a deficiency of plasminogen (performed by plasminogen activity and antigen assays). The availability of these tests is not consistent in the United States or around the world. Plasminogen activity levels below the normal range likely confirms the diagnosis; a specific plasminogen activity cut off level (for example, a plasminogen activity of less than 50%) has not yet been defined that establishes the diagnosis. Some medical researchers and practitioners recommend using a level of <40% plasminogen activity; however, it has been documented that individuals with confirmed PLGD have had levels that are above this cutoff (for example about 50%), and therefore this is currently under investigation. Genetic testing can also help establish the diagnosis despite the absence of symptoms.

The diagnosis of PLGD is challenging, for a variety of reasons. Affected individuals may present to different types of physicians including their general medical doctor, their dentist, or specialists such as an ophthalmologist, ear-nose-and throat doctor, lung doctor, etc. As PLGD is a very rare condition, it is unlikely that these physicians have personally seen someone with PLGD, or learned about this rare deficiency during their training. This often delays diagnosis and prolongs the time that affected individuals endure their symptoms. Once the cause of the symptoms has been identified, the ability of physicians to identify specialists who can help treat and guide therapy may be difficult.

  1. Tefs et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108(9):3021-3026.

In June 2021, the FDA approved Ryplazim, the first-ever treatment for patients with plasminogen deficiency. This medication is plasminogen, purified from human plasma, that is given as an infusion into the bloodstream. Ryplazim was found to be safe and effective in a clinical trial of 15 adult and pediatric patients with plasminogen deficiency (ref 4), and represents a major advancement in the treatment of this rare disorder. It should be considered the first-line treatment for patients with plasminogen deficiency. The approval of Ryplazim will dramatically change the experience of living with PLGD for the better.

Investigational plasma-derived plasminogen concentrate has also shown clinical success when formulated as ophthalmologic drops (ref 3). The patients in this study have generally shown excellent clinical progress, resolution of nearly all ophthalmologic lesions and return to normal organ function, and very low rates of side effects. The ophthalmologic concentrate is not yet commercially available, but once accessible by all patients, will be another safe and effective treatment option for PLGD patients.

Surgical removal of lesions usually results in regrowth which can be rapid without appropriate medical therapy, and can contribute to long-term scarring and organ damage. Patients should minimize any surgical procedures, including surgical membrane removal, unless lesions become life threatening. Even then, surgical procedures should be done under the guidance of a physician who is knowledgeable about plasminogen deficiency (see Patient Resources for a list of recommended PLGD treatment centers).

Prior to the approval of Ryplazim, many non-specific treatments have been reported in case studies and series; however, these treatment options have inconsistent efficacy and do not address the underlying deficiency state. Fresh frozen plasma (FFP) has been reported to have success in some cases when used systemically (injected into the veins) (ref 1) or when prepared as eye drops or given as an injection into the subconjunctival area (ref 2). FFP has a low concentration of plasminogen and often must be given repeatedly over a period of time to increase the plasminogen activity level and improve symptoms. Additional complications of FFP administered intravenously can include allergic reactions to other proteins in the FFP, or volume overload with difficulty breathing, and in rare cases, heart pumping issues.

  1. Kizilocak et. al. Treatment of plasminogen deficiency patients with fresh frozen plasma. Pediatr Blood Cancer. 2018;65(2):e26779.
  2. Tabbara. Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. Am J Ophthalmol. 2004; 138 (2):299-300.
  3. Nakar et. al. Safety & efficacy of human plasma derived plasminogen ophthalmic drops for treatment of ligneous conjunctivitis: report of phase 2/3 clinical trial. Blood. 2015;126(23):2288.
  4. Shapiro et. al. Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency. Blood. 2018;131(12):1301-1310.
Kedrion
About Kedrion Biopharma

Kedrion, and its United States subsidiary Kedrion Biopharma, is an international company based in Italy with a long history of supporting patients with blood disorders, with a focus on rare and debilitating disorders. Kedrion has long been involved with the Plasminogen Deficiency community through the development of their Plasminogen Ophthalmic Solution, an eye drop medication to treat ligneous conjunctivitis, the most common symptom of plasminogen deficiency. This product is not yet approved by the FDA or commercially available, though a study evaluating its use is ongoing. In June of 2021, Kedrion purchased the license to Ryplazim, a plasma-derived human plasminogen concentrate indicated for the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia), also known as C-PLGD.

“The most important mission at Kedrion Biopharma is to improve the lives of people with rare and serious diseases,” said Kedrion Biopharma Chief Executive Officer, Val Romberg. “As the newest addition to our growing portfolio of products, Ryplazim is an excellent example of that dedication. An ultra-orphan therapy, Ryplazim meets an urgent unmet medical need for people who face plasminogen deficiency type 1, a potentially devastating, but treatable, medical condition. We are pleased and gratified to be in a position now to help these patients.”

The Board of the Plasminogen Deficiency Foundation has had the  opportunity to work with the leadership team at Kedrion to provide the patient perspective on plasminogen deficiency, and the multitude of ways that patients need support in living with this disorder. Below are questions and answers about the launch of Ryplazim, summarized from our conversations with the leadership team at Kedrion. We look forward to continuing this relationship in support of PLGD patients everywhere.

What is Ryplazim?

Ryplazim (pronounced RIP-la-zeem) is a new treatment for patients with plasminogen deficiency type 1 (PLGD). Ryplazim is a plasma-derived human plasminogen concentrate. This means it was made from donated human blood. For most patients, this medicine can be given through a needle in a vein (also called an IV, or intravenous infusion). Some patients may need a port. A port is a small device that goes under your skin, usually on your chest. Ports are used to draw blood or to give treatments, like Ryplazim. Your doctor will talk to you about the best option for you.

Learn more about Ryplazim here.

When will Ryplazim be available?

Ryplazim will became available in the United States the first week of January, 2022. The drug will continues to be manufactured in Laval, Quebec, and packaged in Baltimore, Maryland, before being distributed to patients. There is currently a limited supply of Ryplazim, though Kedrion is working hard to increase supply. Your doctor can request access to this medication for you by emailing P.Underland@kedrion.com or  US_Medicalinfo@kedrion.com

Who can take Ryplazim?

Ryplazim was tested in clinical trials in patients aged from 4 to 42 years. The FDA approved Ryplazim for patients of all ages.

What were the most common side effects in the clinical trials?

These side effects were seen in more than 10 percent of people in clinical trials:

Stomach pain, feeling sick to your stomach, or bloating
Fatigue (feeling tired)
Pain in arms or legs
Hemorrhage (bleeding)
Constipation (hard poop that you may have trouble passing)
Dry mouth
Headache
Feeling dizzy
Joint stiffness
Back pain

I am a patient with plasminogen deficiency type 1 (PLGD) who did not participate in a clinical trial. I need Ryplazim treatment. What do I need to do to start this medicine?

At first, it may be hard to get Ryplazim. Kedrion Biopharma is making as much as they can, but the supply may be limited when it is first introduced to the public. Until there is enough for everyone who needs it, your doctor will need to apply to get Ryplazim for you. Kedrion has created a special team who will make sure that patients who need Ryplazim the most are able to get it. Kedrion is working hard to increase the supply of the drug as soon as possible so it can be available to more patients.

We encourage you to get care from your nearest Hemophilia Treatment Center (HTC), where there are doctors who understand PLGD. The doctors at an HTC can work with you and with Kedrion to get Ryplazim when it is more widely available.

To apply to get Ryplazim, your doctor should contact the team at Kedrion by email at: US_Medicalinfo@kedrion.com

Why should I get care from a Hemophilia Treatment Center (HTC)?

There are lots of reasons to get care from the closest HTC:

  • HTCs provide patients with the support you need to understand and live with your diagnosis. HTCs have a multidisciplinary team. This team includes social workers who can help you with your school and work needs.
  • HTCs have experience working with insurance companies to get approval for the care you need.
  • The doctors at an HTC are trained to look at the whole body in PLGD patients. They don’t just look at the areas where you have symptoms.
  • HTCs understand how to use clotting factor concentrates. They know when and how to adjust your dose.
  • HTCs know how what to do if you need surgery or if you develop new symptoms from your plasminogen deficiency.
  • HTCs can teach you how to give yourself your medicine, and how to keep a record of how much you use.
How do HTCs improve care for people with PLGD?

HTCs are part of a national network that collects important data on people with plasminogen deficiency. This data is used to improve your care and treatment. The data doesn’t include any personal information, so your identity is always kept safe. There are a lot of things we still don’t know about plasminogen deficiency. By working together through this national network, we can learn more.

Here are some questions that the national network is trying to answer:

Why do some people develop symptoms and others don’t?
Why do some people have symptoms for a long time and others only have symptoms for a short time?
Although Ryplazim has been studied and FDA approved, we can still learn even more about how it helps individual people. HTCs may also have other studies that you could be part of. These studies might improve how we understand and care for people with plasminogen deficiency.

Will someone teach me how to give myself this medicine? What if I can’t do it?

The nursing staff at your HTC will teach you to give yourself Ryplazim at home. The staff at your HTC will continue to teach and support you until you are able to give yourself the medication at home.

Will Ryplazim be covered by my insurance?

Kedrion Biopharma is working with insurance companies to make sure Ryplazim will be covered. We expect that most insurance companies will cover this medicine.

Will there be any support to help with the costs for the out-of-pocket expenses?

Kedrion Biopharma is working with a patient support group to help patients with their out-of-pocket expenses if needed.

TOOLKITS FOR PATIENTS:

Frequently Asked Questions Toolkit

This toolkit helps to answer some frequently asked questions about managing Plasminogen Deficiency throughout different life events. This Toolkit will be regularly updated as we learn more about how to best manage and treat PLGD.

Frequently Asked Questions Toolkit

Appendix A: Wallet Card

Appendix A: Emergency Treatment Travel Letter

Insurance Approval Toolkit

This Toolkit will help you understand and participate in the insurance approval process – also known as Prior Authorization – for medications to treat PLGD. It also contains resources for your doctor to use when submitting a prescription on your behalf, so be sure to share it with your prescribing physician!

Insurance Approval Toolkit

Appendix A: Sample Letter of Medical Necessity

Appendix B: Ryplazim Formulary Submission Dossier – This document can be provided by Kedrion directly to your insurer, when requested

Appendix C: Compiled Insurer Policies on Ryplazim

Appendix D: Co-Pay Assistance Program Enrollment Instructions

Newly Diagnosed Toolkit

Have you or a loved one been newly diagnosed with plasminogen deficiency? It can be a scary, confusing time, but you are not alone. Start with this resource.

Newly Diagnosed Toolkit

Find Care: Hemophilia Treatment Centers

Plasminogen deficiency is not the same as hemophilia; yet the same doctors, called hematologists, who treat hemophilia, are also the experts at treating PLGD. Some hematologists work in centers called Hemophilia Treatment Centers, or HTCs, where they can provide care as a team alongside pharmacists, social workers, career and school counselors, child life specialists, and insurance specialists. Choosing an HTC gives you a medical home, coordinated care, and assistance with the many life challenges that patients with PLGD will face. Find your nearest HTC here:

The physicians, nurses, and other healthcare providers who treat PLGD patients are essential to our mission of improving patients’ experiences and outcomes. This section contains information and links to help healthcare professionals most effectively treat PLGD patients. Please also consider signing up for our newsletter to stay up-to-date on the latest research, treatments, and clinical trials available for PLGD patients.

*NEW* Ryplazim CME for Healthcare Providers

Hope on the Horizon for Patients with Plasminogen Deficiency Type 1, a 1-hour CME-eligible activity, by Dr. Amy Shapiro, with funding from Postgraduate Institute for Medicine and Spire Learning, and an educational grant from Kedrion Biopharma. *CME credit will be available until Feb 8, 2024.

Diagnosis: Plasminogen Antigen/Activity and Genetic Testing

Diagnostic Checklist PDF

PLGD is diagnosed with a blood test measuring plasminogen activity and antigen levels. Not all laboratories perform plasminogen activity and antigen tests needed for an accurate diagnosis. We are aware that Esoterix as a national laboratory has the capability to perform both of these tests accurately. Other laboratories may be capable as well. We recommend that the laboratory utilized is confirmed as capable and accurate.

Currently, genetic testing is being performed primarily as part of study participation. Subjects participating in the HISTORY study (see Research) are having their genetic testing done at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.

Management: Optimize Ryplazim Dosing

WAPPS-Hemo Plasminogen pK Model

Activating the Plasminogen pK Model

Now available, a population pK model describing the pK of Ryplazim to help with dosing for individual patients

What to do with a Newly Diagnosed Patient

Ensure your patient has a medical home at a Hemophilia Treatment Center (HTC)

PLGD can manifest in many different ways, including most commonly ophthalmologic lesions and gum lesions, but it is important to remember that this is a systemic disorder, requiring whole body monitoring for lesion development. A Hemophilia Treatment Center has the resources to be a medical home for PLGD patients, with physicians who can conduct thorough physical exams, and support staff to assist patients with the many challenges this diagnosis can bring, such as assistance navigating insurance, educating patients to perform home infusions, and support for school / work disruptions or needs. And, HTCs are uniquely equipped to collect and input valuable clinical data about PLGD so that we can continue to learn the best way to manage this rare disorder. Help your patient find the nearest HTC here so they can have the most comprehensive care available.

Request Ryplazim for your plasminogen deficiency patient

Currently, the supply of Ryplazim is limited, and providers who need access to the medication for their patients should email Kedrion at US_Medicalinfo@kedrion.com where an internal team can work with you to allocate this medication for your patient.

Learn more about Ryplazim

Refer your patient to ongoing research studies

Currently, the Hypoplasminogenemia: An International RetroSpecTive and PrOspective CohoRt StudY (HISTORY) study is enrolling patients to follow them over time and learn more about the natural history of PLGD. Patients can learn more and decide if they would like to enroll by following this link.

More Information

Pharmaceutical Companies Involved in PLGD