NORD gratefully acknowledges Amy D. Shapiro, MD, Medical Director, Indiana Hemophilia & Thrombosis Center, for assistance in the preparation of this report.
Congenital type 1 plasminogen deficiency is a rare genetic disorder. Affected individuals develop thick growths, sometimes referred to as woody lesions or pseudomembranes, on the mucous membranes of the body. The mucous membranes are a moist layer of tissue that serves as a protective barrier that keeps these surfaces of the body from drying out. The mucous membranes most often affected in this disorder are those lining the inside of the eyelids and the front of the eye (called the conjunctiva) and the inside of the mouth. Other mucous membranes can be affected, including those lining the nose, middle ear, stomach and intestines (gastrointestinal tract), respiratory tract and the female genital tract. The disorder can also affect the kidneys and the brain. Without treatment, the abnormal growths that form on these surfaces can cause significant complications and they usually recur if they are removed without replacement of plasminogen. The overall severity of the disorder can vary greatly from one person to another and depends on the location and duration of lesions. The disorder is caused by alterations in the PLG gene, which leads to a deficiency of the plasminogen enzyme.
Two types of plasminogen deficiency are described in the medical literature. Congenital type 1 plasminogen deficiency is a quantitative disorder with parallel reductions in both the level of immunoreactive and functional plasminogen; type1 plasminogen deficiency is also called hypoplasminogenemia, and is a severe disorder and the condition primarily discussed in this report. Congenital type II plasminogen deficiency is a qualitative deficiency with a normal or near normal plasminogen immunoreactive plasminogen level with decreased activity and is also called dysplasminogenemia; type II plasminogen deficiency is not associated with the development of pseudomembranes and is therefore not discussed.
The signs and symptoms of type 1 plasminogen deficiency can vary from one person to another, even among members of the same family with the same genetic variants and levels. Oftentimes, initial signs present in infants or young children. Symptoms may be persistent and lifelong, may wax and wane or be intermittent or may not appear until later in life. Some individuals appear to remain asymptomatic and may be diagnosed based upon testing of clinically apparent family members. Lesions may develop spontaneously or be ‘triggered’ by infection, trauma or injury and may be localized to one area of the body or affect multiple body systems.
The most common and well recognized symptom is ligneous conjunctivitis. Conjunctivitis refers to inflammation of the conjunctiva, the membrane that lines the eyes. Ligneous is a term that means ‘resembling wood’. People with ligneous conjunctivitis have growths or lesions on the conjunctiva that are yellow, white or red and have a texture that resembles wood. These growths most often appear on the inside of the eyelid and may be preceded by redness of the conjunctiva. Sometimes, the cornea (the thin, transparent membrane that covers the front of the eye) may become be damaged by the lesions and cause scarring. Ultimately, a loss of vision can occur.
The second most common symptom is ligneous gingivitis, where ligneous growths appear on the gums and cause inflammation. They are usually not painful but can lead to a loss tissue and ultimately of teeth.
Growths can also form in the mucous membranes of the middle ear, nose, throat, vocal cords, larynx, respiratory tract, gastrointestinal tract and the female genital tract. Growths in the middle ear can lead to what appears as chronic middle ear infection (otitis media) and hearing loss. Growths in the gastrointestinal tract may result in ulcers or what appears as an inflammatory bowel disease. Growths in the respiratory tract can lead to serious complications, including recurrent pneumonia and obstruction of the airways, which can be life-threatening, especially in small children. Growths can occur in the renal tubules of the kidney and lead to obstruction and poor kidney function. When growths occur in the female genital tract, they can lead to pain with menses, intercourse and infertility.
When growths affect the skin, the condition is called juvenile colloid milium and is characterized by small, translucent, yellow-brown bumps (papules). These growths usually occur on areas of the skin that are most exposed to the sun.
Some children with congenital type I plasminogen deficiency can develop a condition called occlusive hydrocephalus when lesions obstruct the flow of cerebral spinal fluid (CSF) in the central nervous system. This results in the accumulation of CSF in the skull because the fluid cannot drain properly. This causes pressure on the tissues of the brain.
In earlier reports in the medical literature, physicians speculated that affected individuals were at risk for the development of blood clots (thrombosis). However, most evidence suggests that congenital type I plasminogen deficiency does not increase the risk of developing a blood clot.
Type I congenital plasminogen deficiency is life-long disorder that without adequate therapy can be associated with significant morbidity and disability and in some cases may be life threatening.
Type I congenital plasminogen deficiency is an autosomal recessive genetic disorder caused by alterations in the plasminogen (PLG) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic genetic variant of a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The PLG gene contains instructions for creating the protein plasminogen. Alterations in the PLG gene may result in a quantitative deficiency of plasminogen (type I plasminogen deficiency). Plasminogen is activated by other enzymes into plasmin, the main enzyme involved in fibrinolysis. Plasmin has several functions in the body. For example, plasmin breaks down another protein called fibrin through the process known as fibrinolysis. Fibrin is an important protein in blood clotting and wound healing. Because of the lack of plasminogen, fibrin abnormally accumulates in the body, causing local inflammation and the development of ligneous growths that characterize type I congenital plasminogen deficiency.
A variety of pathogenic variants in the PLG gene can lead to type I congenital plasminogen deficiency. Research is underway to develop severity levels that may help predict clinical course. This in turn will help determine the best treatment approaches. At this time, the specific PLG mutations do not predict clinical course; however the K38E variant appears to be associated with a more mild disease course.
Type I congenital plasminogen deficiency is inherited in an autosomal recessive pattern. Recessive disorders occur when an individual inherits two copies of a pathogenic gene variant for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Affected individuals may have two copies of the same pathogenic variant (homozygous) or two different pathogenic variants in the gene (compound heterozygous).
Type 1 congenital plasminogen deficiency is a rare disorder that occurs worldwide. Slightly more females have been identified than males. The exact incidence or prevalence of the disorder is not completely established, but the current best estimate places the incidence at 1.6 people per 1,000,000 in the general population. Incidence is the rate of new or newly diagnosed people with a disorder. Prevalence is the overall number of people who have the disorder at a given time. People with no symptoms or a mild case with localized symptoms may remain undiagnosed.
A diagnosis of congenital plasminogen deficiency is based upon identification of characteristic symptoms, family medical history, detailed patient history and a thorough clinical evaluation. Some affected individuals may be identified due to another family member’s diagnosis even if they are without symptoms. Diagnosis is confirmed by specific laboratory tests that measure the activity and immunoreactive level (also called the antigen level) of plasminogen; the activity level is decreased while the immunoreactive level is normal or near normal. These tests are available in most clinical coagulation laboratories.
Molecular genetic testing can confirm the diagnosis. Molecular genetic testing can detect alterations in the PLG gene known to cause the disorder but is available as a diagnostic service only at specialized laboratories.
In 2021, the U.S. Food and Drug Administration (FDA) approved Ryplazim (generic name plasminogen, human-tvmh), the first treatment for patients with type I plasminogen deficiency. Ryplazim is a plasminogen concentrate purified from human plasma and administered as an IV infusion. Treatment with Ryplazim increases the plasma level of plasminogen, temporarily correcting the deficiency and reducing or resolving lesions. It has been found to be effective in patients who haven’t responded to other treatments.
Various other therapies have been tried to treat individuals with type I congenital plasminogen deficiency. Surgical removal of the growths may be beneficial initially, but the growths usually recur if the patient is not treated with some form of plasminogen. Several medications have been tried, including high-dose intravenous corticosteroid treatment, heparin, cyclosporine, azathioprine, hyaluronidase and α-chymotrypsin. There is a report of oral contraceptives leading to an increase of plasminogen level in one woman. These therapies have shown no or only limited benefit, or have been reported to be beneficial in only single cases.
Fresh frozen plasma has also been used as a treatment for plasminogen deficiency. Plasma is a component of blood that’s been separated from red and white blood cells and contains water, salt, proteins and enzymes, including plasminogen. It has been administered as an IV infusion when multiple body systems are affected or as eye drops and eye injections for ligneous conjunctivitis. When administered intravenously, fluid overload, or too much water in the body, may become a concern. Fluid overload (hypervolemia) can affect the lungs and heart, making breathing difficult and damaging heart muscles. In addition, some people develop reactions to fresh frozen plasma, usually to some other protein component of the plasma that also may make infusions difficult. Treatment with plasminogen concentrate is a better treatment option.
Some children with hydrocephalus may require surgical implantation of a shunt to drain away excess cerebrospinal fluid. Treatment should be coordinated by a hematologist who is knowledgeable about the disorder. There is a network of hemophilia treatment centers in the United States that is skilled in the treatment of coagulation factor deficiencies and the use of replacement therapies. In addition, these physicians will coordinate efforts of a team of needed specialists depending upon the specific organ system involved. For example, pediatricians, ophthalmologists, dental specialists, lung specialists (pulmonologists) and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
The Indiana Hemophilia and Thrombosis Center and the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center are working together on the first international observational study of patients and their first degree family members with type I plasminogen deficiency known as Hypoplasminogenemia: An International Retrospective and Prospective Cohort Study (HISTORY), or the International Plasminogen Deficiency Study. Researchers are collecting data on patients with plasminogen deficiency to better classify the disorder according to severity and provide better treatment guidelines to medical professionals for better patient outcomes. More information can be found at https://www.plgdeficiency.com.
Topical plasminogen concentrates in the form of eye drops are under clinical investigation for treating congenital plasminogen deficiency patients with ligneous conjunctivitis.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
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For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Caputo R, Sartori M, Leonardi A, et al. Plasminogen eye drops are effective in preventing recurrence of pseudomembranes in ligneous conjunctivitis: results from the phase 2/3 KB046 trial. Blood. 2020 Nov 5;136(Supplement 1):24-25. https://ashpublications.org/blood/article/136/Supplement%201/24/471664/Plasminogen-Eye-Drops-Are-Effective-in-Preventing
Shapiro A, Menegatti M, Palla R, et al. An international registry of patients with plasminogen deficiency (HISTORY). Haematologica. 2020 Mar;105(3):554-561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049368
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Food and Drug Administration. Ryplazim. June 25, 2021. Available at: https://www.fda.gov/vaccines-blood-biologics/ryplazim-plasminogen-human-tvmh. Accessed September 19, 2021.
Medline Plus. Congenital plasminogen deficiency. August 18, 2020. Available at: https://medlineplus.gov/genetics/condition/congenital-plasminogen-deficiency. Accessed September 19, 2021.
Nakar C, Hardesty B, Mehta R, Shapiro A. Plasminogen Deficiency. Rare Coagulation Disorders Resource Room. Available at: http://www.rarecoagulationdisorders.org/diseases/plasminogen-deficiency/disease-overview. Accessed September 19, 2021.
Schuster V. Hypoplasminogenemia. Orphanet. Sept 2021. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=722 Accessed September 20, 2021.
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