Plasminogen Deficiency: Fibrin Accumulation and Its Effects on Patients

The most common sign of PLGD1, ligneous conjunctivitis, was first described in the 19th Century, but it wasn’t until 1933 before the term was defined in reference to the wood-like consistency of the lesions. Reports of these ligneous lesions in other areas of the body followed in subsequent decades, but the first patient with plasminogen deficiency was described only in 1978.[3] In 1997, researchers definitively linked these lesions with low levels of plasminogen.[7] 

PLGD1 is considered a rare disease, with a theoretical prevalence of 1.6 per 1 million people.[8] Based on the prevalence, an estimated 500 people are affected by PLGD1 in the United States and 12,000 globally.[2] The average age of initial symptom presentation is between 9 and 10 months.[9]

However, epidemiologic estimates of hypoplasminogenemia may be too low, as patients without easily visible lesions may not seek medical care. In addition, symptoms can resemble more common conditions, may wax and wane over time, and can vary significantly—even among members of the same family with similar genetic defects.[1] For these reasons, the diagnosis, based on ligneous lesions or masses on mucus membranes throughout the body, may be easily missed, particularly when lesions are subtle or do not produce overt clinical symptoms.

PLGD1 is caused by variants of the PLG gene, which can affect the quantity of plasminogen that is produced by the body, alter its functional activity, or both. The gene is located on chromosome 6q26-q27.[10] If the gene variants inhibit plasminogen levels as well as hamper the activity of the protein, patients are considered to have plasminogen deficiency type 1 or PLGD1, and are at risk for the growth of woody or ligneous masses in body surfaces covered by mucous membrane. [1]

In the case of gene variants that do not result in abnormal plasminogen production but possibly in reduced plasminogen activity, patients will be diagnosed with type 2 plasminogen deficiency or PLGD2. Patients with plasminogen deficiency type 2 generally do not present with symptoms. [1] ​

Whereas individuals with PLGD2, may experience mild or no symptoms, patients with PLGD1 often present with a multitude of clinical issues.[1] 

The most common symptom, pseudomembranous or ligneous conjunctivitis, appears in more than 80% of patients. Removal of the fibrin accumulations in the conjunctiva, or in the upper or lower eyelid, does not prevent regrowth of these masses.[5] Ligneous conjunctivitis is frequently misdiagnosed as chronic pink eye, viral, allergic and infectious conjunctivitis with pseudomembranes and membranes formation, pyogenic granuloma, conjunctival papilloma or ocular cysts. [4]

Ligneous lesions are also commonly found in the gingival tissue and in the ears, as well as in the respiratory system, gastrointestinal tract, urinary tract, and female reproductive tract.[8] This is noteworthy, because ligneous lesions on the mucus membranes within these organs may not cause specific, identifiable symptoms, contributing to missed diagnosis.[1]  

Table 1 provides examples of some manifestations of these ligneous lesions affecting multiple organs. Symptoms that are nonspecific but associated to varying degrees with PLGD1 include abdominal pain and diarrhea,[2] pelvic inflammation and endometritis,[11] otitis media, and chronic cough. [12]

Patients with hypoplasminogenemia often have difficulty with wound healing, as the mechanism of fibrin accumulation and tissue replacement at the wound site is impaired.[8] ​

The diagnosis of PLGD1 is often delayed, as it is in many cases misdiagnosed for one of its common symptoms. It is sometimes misidentified as an independent appearance of infectious conjunctivitis, recurrent otitis media, gingivitis, asthma, or plantar warts.[12] The first symptoms often appear between 9 and 10 months of age, but the correct diagnosis may not be made for years.[5,12] 

PLGD1 is exclusively a hereditary disorder, a confirmed diagnosis in a first-degree relative will help focus on the genetic cause. 

In addition to the key signs of ligneous lesions on mucous membranes, a plasminogen functional assay indicating reduced activity levels is commonly used to confirm diagnosis of plasminogen deficiency type 1.[10] Activity levels below 45% have been cited in clinical trials and literature as a diagnostic threshold. In a registry of 51 patients with PLGD1, median endogenous plasminogen activity was 18.5% (range, 1–42%).[2] Depending on the methodology and population norms, plasminogen levels below 75% may also be considered low in some settings.[2]  A negative finding on the plasminogen activity test rules out PLGD1. In the registry study by Shapiro and colleagues,[2] the median endogenous concentration of plasminogen antigen was 3.4 mg/dL (range, 1–12 mg/dL).

Genetic testing may be helpful but is not considered diagnostically required, owing to the limited information we have today on specific genetic variants directly causing PLGD1.[2] As a result, a molecular genetic analysis revealing variants in the PLG gene may serve as confirmation of the diagnosis; roughly one-third of patients with PLGD1 demonstrate K19E mutations.[2,9] Thirty-eight individual mutations in the plasminogen gene were identified by 2008.[9] Certain identified variants (e.g., K38E) have been linked to a milder clinical course, whereas evidence for others do not present a clear prognosis.[2]

Plasminogen deficiency is a chronic, life-long disease.[2] The ligneous conjunctival lesions are often initiated by injury to the eye or by infection, and the ocular complications include corneal involvement, degraded vision, or even blindness if undiagnosed or untreated. Furthermore, about one-third will experience gingivitis and periodontal complications like tooth loss.[2]

Other complications include hydrocephalus in about 14% of patients, resulting from fibrin accumulation in the cerebroventricular system; impaired wound healing because of difficulties with fibrin metabolism; loss of hearing related to ligneous formation in the middle ear; airway obstruction; and dysmenorrhea, abnormal menses, dyspareunia, and infertility in women owing to ligneous lesion–related inflammation.[3,5,13] Interestingly, PLGD1 has not been definitively linked to venous thromboembolism, despite the prominent role of fibrin in blood-clot formation.[2] 

There has not been a definitive natural history study of PLGD1 prior to the “Hypoplasminogenemia: An International RetroSpecTive and PrOspective CohoRt StudY” (HISTORY) registry, initiated in 2020. This study has a 3-year follow-up period, and will provide a limited longitudinal picture of patients with PLGD1.[2] With this investigation of congenital plasminogen deficiency, it is hoped that categories of severity will be better understood, which will help predict disease course and allow care providers to tailor treatment plans and develop guidelines for medical professionals to improve outcomes.[1] 

Surgical removal of the ligneous lesions may offer temporary relief, but excision will not prevent regrowth.[3,5] Immunologic therapies, such as corticosteroids, cyclosporine, and azathioprine, have shown inconsistent and generally limited efficacy.[3] Similarly, topical or systemic administration of Fresh Frozen Plasma has proven to have only limited efficacy due to its low plasminogen concentration.[14] 

In June of 2021, the U.S. Food and Drug Administration approved RYPLAZIM® (plasminogen, human-tvmh) to treat patients with plasminogen deficiency type 1 (PLGD-1) by increasing the plasma level of plasminogen. Click here to learn more about the approval, and here for the full prescribing information.[15]

Although most patients will be treated by a hematologist, a multidisciplinary care team will be required, including ophthalmology, dentistry, obstetrics/gynecology, and other organ system specialists. One leading physician in the field recommends that patients receive care at hemophilia treatment centers to assure access to these multidisciplinary teams.[5]  

Young patients diagnosed with the disorder may live into adulthood. Since any organ containing mucous membranes may be open to fibrin accumulation and dysfunction, this increases patients’ risk of a wide variety of life-threatening maladies, including respiratory failure, renal failure, occlusive hydrocephalus, and impaired wound healing.[2,3]

HISTORY Natural History Trial 

NCT03797495

Plasminogen Deficiency Foundation

Plasminogen Deficiency Support Group

Plasminogen.com

1. Congenital type 1 plasminogen deficiency. National Organization for Rare Disorders. January 8, 2024. Accessed August 12, 2025. https://rarediseases.org/rare-diseases/congenital-plasminogen-deficiency/.
2. Shapiro AD, Menegatti M, Palla R, et al. An international registry of patients with plasminogen deficiency (HISTORY). Haematologica. 2020;105:554-561. https://doi.org/10.3324/haematol.2019.241158.
3. Mehta R, Shapiro AD. Plasminogen deficiency. Haemophilia. 2008;14:1261-1268. https://doi.org/10.1111/j.1365-2516.2008.01825.x.
4. Shoshany TN, Thomson A, Shapiro A, et al. Advancing understanding of ligneous conjunctivitis: Bridging pathogenesis, diagnosis, and therapy. Cornea. September 10, 2025. doi: 10.1097/ICO.0000000000003987. 
5. Shapiro AD, Nakar C. How I treat type 1 plasminogen deficiency. Blood. 2025;145:2954-2965. https://doi.org/10.1182/blood.2024026973.
6. Klammt J, Kobelt L, Aktas D, et al. Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with PLG activity. Thromb Haemost. 2011;105:454-460. https://doi.org/10.1160/TH10-04-0216.
7. Schuster V, Mingers A-M, Seidenspinner S, et al. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood. 1997;90:958-966.
8. Schuster V, Seregard S. Ligneous conjunctivitis. Surv Opthalmol. 2003;48:369-388. https://doi.org/10.1016/s0039-6257(03)00056-0.
9. Tefs K, Gueorguieva M Klammt J et al. Molecular and clinical spectrum of type I plasminogen deficiency: A series of 50 patients. Blood. 2006;108:3021-3026. https://doi.org/10.1182/blood-2006-04-017350.
10. Schuster V, Hügle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5:2315-2322. 
11. Baithun M, Freeman-Wang T, Chowdary P, et al. Ligneous cervicitis and endometritis: A gynaecological presentation of congenital plasminogen deficiency.  Haemophilia. 2018;24:359-365. https://doi.org/10.1111/hae.13418.
12. Hickman RJ. Often misdiagnosed, plasminogen deficiency has a home in hematology. ASH Clinical News. March 2025. Accessed August 21, 2025.  https://ashpublications.org/ashclinicalnews/news/8474/Often-Misdiagnosed-Plasminogen-Deficiency-Has-a. 
13. Pantanowitz L, Bauer K, Tefs K, et al. Ligneous (pseudomembranous) inflammation involving the female genital tract associated with type-1 plasminogen deficiency. Int J Gynecol Pathol. 2004;23:292-295. doi: 10.1097/01.pgp.0000130043.59593.82.
14. Everyone.org. (2025). New Plasminogen Deficiency Treatments 2025. Retrieved November 13, 2025, from https://everyone.org/explore/treatment/?id=90.
15. U.S. Food and Drug Administration. FDA approves first treatment for patients with plasminogen deficiency, a rare genetic disorder. Published June 4, 2021. Accessed November 18, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-plasminogen-deficiency-rare-genetic-disorder.