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Plasminogen deficiency: a plain-language guide

Gradient title card reading Plasminogen Deficiency, the header image for the trialport plain-language guide.
Keith

Plasminogen deficiency type 1 is a very rare inherited condition in which the body cannot clear away a protein called fibrin properly, so thick woody growths build up on the moist linings of the body such as the inside of the eyelids [1,2].

This page provides general information. It does not replace advice from a doctor or another qualified healthcare professional.

Key facts

  • This condition is filed under blood conditions, yet it is not a bleeding disorder. Plasminogen’s job is to break fibrin down, not to help form clots, so the problem is material that does not clear away rather than blood that will not stop [2,3].
  • Type 1 plasminogen deficiency, also called hypoplasminogenemia, is the form that causes illness. Type 2, called dysplasminogenemia, usually causes no symptoms at all [1,2].
  • Woody growths on the inside of the eyelids, known as ligneous conjunctivitis, are the most common first sign, reported in around 80 percent of people, which is why many are first seen by an eye specialist [4,5,13].
  • Growths can also form in the gums, nose, sinuses, middle ear, airway, gut, kidneys and female genital tract, and a small number of children have fluid build-up in the brain [1,3,5].
  • Cutting the growths out usually makes them grow back, often faster than before, so surgery alone is not a solution [3,5].
  • Plasminogen, human-intravenous, sold as Ryplazim, was approved by the United States Food and Drug Administration on 4 June 2021 for type 1 plasminogen deficiency. It is not authorized in the European Union [6,7,15].

On this page

What is plasminogen deficiency?

Plasminogen is the body’s clean-up material. When tissue is injured, the body lays down a mesh of a protein called fibrin to hold the repair together, and once healing is under way the fibrin has to be cleared. The body turns plasminogen into an enzyme called plasmin to cut it apart [1,2].

In type 1 plasminogen deficiency there is too little plasminogen, so fibrin is not cleared. It piles up on the mucous membranes, the moist linings inside the eyelids, the mouth and the airway, then becomes inflamed and hardens into growths that look and feel like wood. Doctors call these ligneous lesions [1,2,3].

The condition sits under blood conditions because plasminogen is a blood protein and blood specialists lead the care. It is not a bleeding disorder, and low plasminogen does not make blood clot inside vessels either. Specialist reviewers state plainly that type 1 is not a risk factor for clotting [1,3,26].

Telling the two types apart matters more than anything else here. Type 1, hypoplasminogenemia, also called congenital plasminogen deficiency or PLGD-1, means both the amount of plasminogen and how well it works are low, and it causes the growths. Type 2, dysplasminogenemia, means the amount is near normal while activity is reduced, and people with type 2 usually have no symptoms [1,2,3].

How common is it?

Type 1 plasminogen deficiency is ultra-rare. The figure quoted most often is about 1.6 people per million, repeated by specialist sources including a 2025 review in the journal Blood [4,5]. Orphanet, the European rare disease database, gives roughly 1 in 625,000 [3].

Treat these as rough. The 1.6 per million figure traces back to screening and referral data rather than a count of a whole population, so it is not a population rate [5]. Mild cases very likely never reach a specialist, and growths in one part of the body are often not recognized as belonging to a condition that affects many parts, so the real number is probably higher [2].

Regional figures are patchy. European regulators estimated in 2015 that about 0.02 in every 10,000 people in the European Union were affected, roughly 1,000 people [15]. One published estimate puts the number with symptoms at about 500 in the United States and around 12,000 worldwide [5]. Comparable figures for Asia, Africa, the Middle East, South America and Australasia were not found. Rates are expected to be higher where marriage between close relatives is common [3]. Published series report more affected females than males [1,5].

What causes it?

Genes are instructions inside cells for building proteins. Type 1 plasminogen deficiency is caused by changes, called variants, in a gene named PLG, which carries the instructions for plasminogen [2,17]. Many PLG variants have been described, and several stop the protein being released from cells [13,25].

Inheritance is autosomal recessive. A person has two copies of PLG, one from each parent, and symptoms develop only when both copies carry a change. Parents each carry one changed copy and one working copy. They are called carriers, and they are almost always well [1,2]. Where both parents are carriers, each pregnancy carries a one in four chance the child inherits two changed copies. Brothers and sisters of an affected child carry the same one in four chance, so families are usually offered genetic counseling [1,3].

One honest limit is worth stating. Having two changed copies does not reliably predict whether symptoms will appear or how severe they will be, and relatives with identical variants and identical plasminogen levels can still differ a great deal [1,3].

What are the symptoms?

Symptoms depend on where the growths form. They often begin in babies or young children, can start at any age, and may come and go. Growths may appear for no clear reason, or after an infection or an injury [1,3].

The most common sign by a wide margin is ligneous conjunctivitis: redness of the lining of the eye that progresses to yellow, white or red growths with a woody texture, usually on the inside of the eyelid [14]. Around 80 percent of people with the condition have it, and in roughly a third the growth spreads onto the cornea, the clear window at the front of the eye, and can scar it and lead to loss of sight [1,2,5,13].

Ligneous gingivitis, growths on the gums, comes next, in about a third of people. It is often painless yet can destroy gum tissue and cost teeth, and a dentist is sometimes the first to spot it [5,19]. Growths in the middle ear can look like repeated ear infections and cause hearing loss, and are also reported in the nose, sinuses, throat, voice box, gut and kidneys. In girls and women they can cause painful periods, pain during sex and difficulty becoming pregnant [1,3,5]. A few children are born with blocked drainage of the fluid around the brain [1,2,23].

When to seek urgent help. Growths in the windpipe and breathing tubes can narrow the airway, which can be life-threatening, particularly in small children. Get urgent help for noisy or difficult breathing, a worsening cough or wheeze, a change or loss of voice, coughing up blood, or a child struggling to breathe. Say that the condition is plasminogen deficiency, since many clinicians will not have met it [1,3,11].

How is it diagnosed?

Diagnosis is often slow. Symptoms are usually blamed on more common things first: ordinary conjunctivitis, repeated ear infections, gum disease or bowel problems. Which specialist a person sees depends on which part of the body is affected, so no one clinic sees the whole picture [4].

Two blood tests settle the question. One measures plasminogen activity, meaning how well the protein works. The other measures the plasminogen antigen level, meaning how much of it is there. In type 1 both are low. In type 2 the amount is near normal while activity is low. Most hospital clotting laboratories can run these tests [1].

Genetic testing of the PLG gene confirms the diagnosis and is usually done at a specialist laboratory, and a sample of tissue may also be examined [1,3,19]. Once one person in a family is diagnosed, relatives are usually offered testing, since people without symptoms do turn up this way [1,5]. Prenatal testing is possible where both variants in a family are known [3].

How is it treated?

There is no cure. Treatment aims to shrink existing growths, stop new ones forming and protect sight, hearing, breathing and kidney function.

The main specific treatment is plasminogen replacement: purified human plasminogen given as a drip into a vein. In the United States, plasminogen, human-tvmh, sold as Ryplazim, was approved on 4 June 2021 for type 1 plasminogen deficiency, at 6.6 mg per kilogram every two to four days [6,7]. In the study supporting approval, every participant with measurable growths improved by at least half, most within eight weeks [8,9]. A follow-on study of 12 people found no new or returning growths while treatment was taken as prescribed, and growths returning during interruptions settled once regular dosing resumed [10,24].

Known risks include bleeding at the site of a growth, and tissue sloughing, meaning a growth breaking away as it dissolves, which can block or bleed into the airway, gut or urinary system. Treatment is therefore started somewhere equipped to manage the airway, and people are watched for four hours after each infusion [7].

Availability differs sharply by country. Supply in the United States improved after regulators approved expanded manufacturing, and the distribution network was widened in March 2025 [16]. In Europe the medicine holds orphan designation, which supports development and is not permission to sell, so it is not authorized in the European Union [15]. Where concentrate is unavailable, fresh frozen plasma has been used, and it contains little plasminogen, so large repeated volumes are needed [1,3]. Plasminogen eye drops have been studied and are not a licensed product [3,12]. Steroids, heparin, immune-suppressing medicines and hormone treatments have also been tried, with inconsistent results [1,5].

Surgery deserves a plain warning: cutting growths out on its own usually leads to rapid regrowth, sometimes worse than before, so it is generally combined with plasminogen replacement [3,5].

Living with plasminogen deficiency

Care works best from one knowledgeable base. In the United States that is usually a hemophilia treatment center, able to coordinate eye, dental, ear nose and throat, lung and kidney specialists around one plan [1,4].

Practical things that help: carrying information naming the condition, the treatment and the treating center, since few clinicians will recognize the diagnosis in an emergency; telling any surgeon or dentist in advance, since procedures and even minor injury can trigger new growths; regular eye and dental checks; and reporting new breathing, hearing, vision or urinary symptoms quickly [3,4,19].

Growths in the female genital tract can affect periods, sex and fertility, so these are worth raising directly, and anyone planning a pregnancy can ask for genetic counseling [1,3]. Regular treatment can mean frequent infusions, sometimes at home, which takes planning around school and work [10]. Patient organizations help with the costs of care and travel [18].

Thinking about a clinical trial?

Clinical trials are research studies that test whether a treatment works and is safe. Plasminogen deficiency is ultra-rare, so studies are few, usually small, and often run at a handful of specialist centers. Looking into one is a personal choice, and it helps to take it in steps.

1. Understand what the study is asking

Get clear on what a study actually involves:

  • what the researchers are trying to learn
  • what treatment is being studied, and what it is being compared with
  • how long the study lasts
  • what visits, tests or procedures are involved, and how often
  • whether travel to a study site is needed, and how far
  • the possible benefits, and the known and unknown risks
  • what happens when the study ends, including whether treatment continues

2. Consider possible medical suitability

Every study has rules about who can take part. These are called eligibility criteria. Some describe who can join, others describe who cannot. For a plasminogen deficiency study the criteria might include a confirmed diagnosis of type 1 rather than type 2, measured plasminogen activity and antigen levels below set figures, a confirmed PLG genetic result, a particular age range, growths in specific places such as the eye or the airway, and whether a person is already on plasminogen replacement.

trialport’s medifit helps people consider information related to possible medical suitability. It does not diagnose a condition, confirm eligibility or replace formal screening by the study team.

Explore plasminogen deficiency clinical trials through trialport

3. Consider whether participation fits your life

A study can look like a good match on paper and still be hard in practice. Worth thinking through:

  • the time each visit takes, and how many visits there are
  • travel and distance, which can be considerable for an ultra-rare condition
  • work, school or caring commitments
  • support from family and friends
  • how you feel about infusions, blood draws and eye examinations
  • whether you understand the study well enough to decide
  • for parents, how a child feels about taking part, not only the adults

trialport’s readifit helps people reflect on their understanding, motivation, time, routines, support, emotions and practical arrangements.

4. Ask questions before deciding

Useful questions to put to a research team:

  • Why is this study being carried out, and what is already known?
  • What exactly would I or my child need to do, and for how long?
  • What are the known risks, and what is still unknown?
  • Could I receive a placebo? A placebo is a dummy treatment with no active medicine in it, used so researchers can compare results fairly.
  • Would I have to stop or change my current treatment to take part?
  • What happens if a growth appears or gets worse during the study?
  • Can I leave the study after joining, and what happens if I do?
  • Who provides my usual medical care, and who do I contact if I feel unwell?
  • Are travel and other costs covered?
  • What happens after the study ends, and could I keep receiving the treatment?

Taking part is voluntary. A person can ask questions, speak with people they trust and choose not to participate.

Search for clinical trials at app.trialport.com.

Current research

The rarity of the condition shapes the research: most of it is small studies, case series and long-term follow-up. Three areas stand out. First, long-term use of intravenous plasminogen replacement, including how often it needs to be given and whether the interval can be stretched once growths are controlled [10,24]. Second, plasminogen given as eye drops, studied in a small trial reported in the journal Ophthalmology, and not a licensed product [3,12]. Third, an international observational study called HISTORY, collecting information from people with the condition and their close relatives to describe how it behaves and to build severity groupings [1,5].

No gene therapy for plasminogen deficiency was found in any reliable source. Study status checked: 3 August 2026. Research moves and what is being studied changes, so this section will date. For current information, search at app.trialport.com.

Support and further information

The Plasminogen Deficiency Foundation is the best starting point anywhere: run for and with affected families, it publishes plain-language toolkits and runs a fund that helps with care and travel costs [18]. The Rare Coagulation Disorders Resource Room, from a specialist United States center, is the clearest free clinical explanation available [17]. In the United States, NORD publishes a detailed expert-reviewed report [1], and MedlinePlus Genetics is reliable on the genetics [2]. In Europe, Orphanet lists expert centers country by country [3], ERN EuroBloodNet is the European reference network for rare blood conditions [27], and EURORDIS links national rare disease alliances [28]. In the United Kingdom, Rare Disease UK covers rare conditions generally rather than this one [29], and in Australia Rare Voices Australia plays a similar role [30]. No condition-specific organization was found for Asia, Africa, the Middle East or South America.

Questions people often ask

Is plasminogen deficiency a bleeding disorder?
No. It is grouped with blood conditions because plasminogen is a blood protein. The problem is fibrin that is not cleared away, not blood that will not clot [2,3].

Does it cause blood clots?
Type 1 does not, and specialist reviewers say so plainly. A few reports have linked type 2 to clots, and that is not settled [1,3,26].

What is the difference between type 1 and type 2?
In type 1 both the amount of plasminogen and its activity are low, and this is the type that causes woody growths. In type 2 the amount is near normal while activity is low, and people usually have no symptoms. A variant causing type 2 is common in some East Asian populations without causing illness [1,2,21,22].

If growths keep coming back, should they be cut out?
That is for the specialist team to judge. Removing growths on their own usually leads to rapid regrowth, so surgery is generally combined with plasminogen replacement [3,5].

Can adults be diagnosed for the first time?
Yes. One published case describes ligneous conjunctivitis appearing for the first time in a man in his seventies after eye surgery [3,20].

Can it be passed on to my children?
It can. A child needs a changed copy of PLG from each parent, so where both parents are carriers each pregnancy carries a one in four chance [1,3].

Is there a treatment available where I live?
It depends on the country. Plasminogen replacement is approved in the United States and not authorized in the European Union, where fresh frozen plasma may be used instead [6,15,16].

Sources

  1. National Organization for Rare Disorders. Congenital Type 1 Plasminogen Deficiency. Report reviewed by Amy D. Shapiro MD and Gioconda Alyea MD MS; last updated 19 March 2026. https://rarediseases.org/rare-diseases/congenital-plasminogen-deficiency/ Accessed 3 August 2026.
  2. MedlinePlus Genetics, National Library of Medicine. Congenital plasminogen deficiency. Last updated 1 August 2012. https://medlineplus.gov/genetics/condition/congenital-plasminogen-deficiency/ Accessed 3 August 2026.
  3. Orphanet. Hypoplasminogenemia (ORPHA:722). Expert reviewers Dr Rebecca Bialas and Dr Amy Shapiro; last update September 2021. https://www.orpha.net/en/disease/detail/722 Accessed 3 August 2026.
  4. Shapiro AD, Nakar C. How I treat type 1 plasminogen deficiency. Blood. 2025;145(25):2954-2965. DOI 10.1182/blood.2024026973. https://doi.org/10.1182/blood.2024026973 Accessed 3 August 2026.
  5. Shapiro AD, Menegatti M, Palla R, et al. An international registry of patients with plasminogen deficiency (HISTORY). Haematologica. 2020;105(3):554-561. DOI 10.3324/haematol.2019.241158. https://haematologica.org/article/view/9275 Accessed 3 August 2026.
  6. US Food and Drug Administration. RYPLAZIM (plasminogen, human-tvmh). STN 125659. Content current as of 16 May 2022. https://www.fda.gov/vaccines-blood-biologics/ryplazim Accessed 3 August 2026.
  7. US Food and Drug Administration. RYPLAZIM (plasminogen, human-tvmh) full prescribing information. Revised November 2021. https://www.fda.gov/media/149806/download Accessed 3 August 2026.
  8. Shapiro AD, Nakar C, Parker JM, et al. Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency. Blood. 2018;131(12):1301-1310. DOI 10.1182/blood-2017-09-806729. https://doi.org/10.1182/blood-2017-09-806729 Accessed 3 August 2026.
  9. Shapiro AD, Nakar C, Parker JM, Thibaudeau K, Crea R, Sandset PM. Plasminogen, human-tvmh for the treatment of children and adults with plasminogen deficiency type 1. Haemophilia. 2023;29(6):1556-1564. DOI 10.1111/hae.14849. https://doi.org/10.1111/hae.14849 Accessed 3 August 2026.
  10. Shapiro AD, McDaniel H, Decker RW, et al. Safety and efficacy of long-term treatment of type 1 plasminogen deficient patients with intravenous plasminogen replacement therapy. Haemophilia. 2025;31(3):477-484. DOI 10.1111/hae.70019. https://doi.org/10.1111/hae.70019 Accessed 3 August 2026.
  11. Nakar C, McDaniel H, Parker JM, Thibaudeau K, Thukral N, Shapiro AD. Case report: respiratory lesions successfully treated with intravenous plasminogen, human-tvmh, replacement therapy in four patients with plasminogen deficiency type 1. Frontiers in Pediatrics. 2024;12:1465166. DOI 10.3389/fped.2024.1465166. https://doi.org/10.3389/fped.2024.1465166 Accessed 3 August 2026.
  12. Caputo R, Shapiro AD, Sartori MT, et al. Treatment of ligneous conjunctivitis with plasminogen eyedrops. Ophthalmology. 2022;129(8):955-957. DOI 10.1016/j.ophtha.2022.03.019. https://doi.org/10.1016/j.ophtha.2022.03.019 Accessed 3 August 2026.
  13. Tefs K, Gueorguieva M, Klammt J, et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108(9):3021-3026. DOI 10.1182/blood-2006-04-017350. https://doi.org/10.1182/blood-2006-04-017350 Accessed 3 August 2026.
  14. Schuster V, Seregard S. Ligneous conjunctivitis. Survey of Ophthalmology. 2003;48(4):369-388. DOI 10.1016/S0039-6257(03)00056-0. https://doi.org/10.1016/S0039-6257(03)00056-0 Accessed 3 August 2026.
  15. European Medicines Agency. EU/3/15/1511: orphan designation for the treatment of plasminogen deficiency. Designation granted 28 July 2015; sponsor Kedrion S.p.A. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-15-1511 Accessed 3 August 2026.
  16. Kedrion Biopharma. Kedrion expands Ryplazim distribution network for PLGD-1 patients. Press release, 21 March 2025. https://www.prnewswire.com/news-releases/kedrion-expands-ryplazim-distribution-network-for-plgd-1-patients-302408132.html Accessed 3 August 2026.
  17. Indiana Hemophilia and Thrombosis Center. Plasminogen deficiency. Rare Coagulation Disorders Resource Room. https://rarecoagulationdisorders.org/disorder/plasminogen-deficiency/ Accessed 3 August 2026.
  18. Plasminogen Deficiency Foundation. https://www.plasminogendeficiency.org/ Accessed 3 August 2026.
  19. Sarioglu A, Ugurlu K, Karaman M, Karakaya T, Kirtiloglu T, Zengin AZ. Ligneous periodontitis: a molecularly confirmed case of type I plasminogen deficiency. Journal of Clinical and Experimental Dentistry. 2025;17(6):e752-e755. DOI 10.4317/jced.62773. https://doi.org/10.4317/jced.62773 Accessed 3 August 2026.
  20. Godfrey AA, Pekmezci M, Seitzman GD, de Alba Campomanes AG. Ligneous conjunctivitis presenting after strabismus surgery in the eighth decade of life. American Journal of Ophthalmology Case Reports. 2026;42:102567. DOI 10.1016/j.ajoc.2026.102567. https://doi.org/10.1016/j.ajoc.2026.102567 Accessed 3 August 2026.
  21. Lee B, Kim S, Lee JJ, et al. Severe dysplasminogenemia due to homozygous PLG Ala620Thr variant in a Korean woman without a history of venous thromboembolism: a case report and literature review. Medicine. 2022;101(6):e29013. DOI 10.1097/MD.0000000000029013. https://doi.org/10.1097/MD.0000000000029013 Accessed 3 August 2026.
  22. Miyata T, Uchida Y, Yoshida Y, et al. No association between dysplasminogenemia with p.Ala620Thr mutation and atypical hemolytic uremic syndrome. International Journal of Hematology. 2016;104(2):223-227. DOI 10.1007/s12185-016-2021-3. https://doi.org/10.1007/s12185-016-2021-3 Accessed 3 August 2026.
  23. Antonakopoulos N, Perdikaris P, Styliara I, Tzela P, Adonakis G. Congenital holoprocencephaly, hydrocephalus, and Dandy-Walker malformation due to plasminogen deficiency. Cureus. 2025;17(10):e94020. DOI 10.7759/cureus.94020. https://doi.org/10.7759/cureus.94020 Accessed 3 August 2026.
  24. Shapiro AD, McDaniel H, Decker RW, et al. Plain language summary: how safe and effective is long-term treatment with intravenous plasminogen concentrate for people with type 1 plasminogen deficiency? Therapeutic Advances in Hematology. 2026;17:20406207261463031. DOI 10.1177/20406207261463031. https://doi.org/10.1177/20406207261463031 Accessed 3 August 2026.
  25. Klammt J, Kobelt L, Aktas D, et al. Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity. Thrombosis and Haemostasis. 2011;105(3):454-460. DOI 10.1160/TH10-04-0216. https://doi.org/10.1160/TH10-04-0216 Accessed 3 August 2026.
  26. Schuster V, Hugle B, Tefs K. Plasminogen deficiency. Journal of Thrombosis and Haemostasis. 2007;5(12):2315-2322. DOI 10.1111/j.1538-7836.2007.02776.x. https://doi.org/10.1111/j.1538-7836.2007.02776.x Accessed 3 August 2026.
  27. European Reference Network on Rare Haematological Diseases (ERN EuroBloodNet). https://eurobloodnet.eu/ Accessed 3 August 2026.
  28. EURORDIS-Rare Diseases Europe. https://www.eurordis.org/ Accessed 3 August 2026.
  29. Genetic Alliance UK. Rare Disease UK. https://geneticalliance.org.uk/campaigns-and-research/rare-disease-uk/ Accessed 3 August 2026.
  30. Rare Voices Australia. https://rarevoices.org.au/ Accessed 3 August 2026.

Review information

Written by: trialport editorial team
Reviewed by: Keith Berelowitz, Founder and CEO, trialport
Reviewed on: 3 August 2026
Next review due: 3 August 2027
References last checked: 3 August 2026