What is plasminogen deficiency (PLGD)?
PLGD is a rare condition that occurs when plasminogen (PLG)—a protein made in the liver—is reduced or almost absent.1
How did I get PLDG?
PLGD is an inherited disorder. It is passed on from generation to generation. You were born with two mutated genes, one from each of your parents. This is commonly referred to as an autosomal recessive pattern.1
What is autosomal recessive?
Autosomal recessive is one of several ways that a trait, disorder, or disease can be passed down through families. In an autosomal recessive disorder, two copies of an abnormal gene must be present for the trait or disorder to develop. There is a 25% chance of inheriting both normal genes, a 25% chance of inheriting both abnormal genes, and a 50% chance of inheriting one abnormal gene and being a carrier, like the parents.1,2
What is plasminogen (PLG)?
PLG is a protein that is made by the liver. It circulates in the blood. PLG activators convert the protein into plasmin. Plasmin breaks down fibrin, the main protein that clots blood, so normal tissue can grow back. When PLG is reduced, there is less plasmin to break down fibrin, leading to an abnormally high buildup of fibrin. These fibrin deposits cause swelling in the tissue, resulting in lesions that are characteristic of congenital PLGD.3
What other roles does PLG play in the body?
PLG contributes to normal functioning and many important physiological processes. It helps cells move throughout the body, allowing new blood vessels to form. It aids in the development of fertilized eggs during a woman’s pregnancy.4
What is fibrin?
Fibrin is a protein essential to clotting of the blood. It forms a fibrous net that impedes the flow of blood. When there is no plasmin to break down fibrin, tissues swell and lesions can form.3
Who gets PLGD?
PLGD is a rare disorder that affects a small population—just one or two people out of a million. It occurs in patients whose bodies make little or no plasminogen (PLG). The rate of PLGD occurrence in different parts of the world (estimated): Minnesota: 0.35%, Southern Germany: 0.13%, Scotland: 0.26%, and Japan: 0.42%.5
Does PLGD affect both men and women?
Yes, although a slightly increased female-to-male ratio has been observed (1.27-to-1). The reason for this difference is unknown.1
What is congenital PLGD?
Patients classified as having congenital PLGD (also known as type I PLGD or hypoplasminogenemia) tend to be highly deficient in PLG with abnormally low or almost no, levels of the protein present in the blood. Others may produce some plasminogen protein, but a significant portion of it is not active or performing normally. People with moderate levels of PLG, whereby the levels are slightly or measurably below normal but not drastically so, may not experience symptoms at all.5
When do symptoms occur with congenital PLGD?
Symptoms have occurred in infants as early as 3 days of age and in adults as old as 61 years of age.1
What are ligneous lesions?
Ligneous lesions are coarse, woody-like lesions on the mucous membranes (thin layers) of the skin and organs throughout the body. These swollen lesions differ by their size and the organ system that is involved.1 Common areas where these lesions can appear include the eyes, ears, gums, respiratory tract, and urinary tract.5,6 The lesions form because there is not enough plasmin to break down fibrin, resulting in excess fibrin deposits that cause the tissue to swell.3
Are ligneous lesions painful?
Ligneous lesions may cause pain or discomfort and can affect normal organ functioning (how a person’s organs work). Emergencies, such as a collapsed lung, kidney failure, and blindness may occur if these lesions are left untreated. In some cases, complications can be fatal.6
What is ligneous conjunctivitis?
Ligneous conjunctivitis, the most common symptom found in patients with congenital PLGD, usually appears in infants and children. It is characterized by thick, yellow, white, or red lesions on the inside of the eyelids.7,8 In about one-third of the cases, these lesions form over the white outer layer of the eyeball. They also may grow on the cornea, the clear layer that protects the iris and pupil. If left untreated, these lesions can tear the cornea, cause scarring, and can lead to vision loss or blindness.1,9
What is ligneous cervicitis?
Female patients may be affected by ligneous cervicitis, whereby lesions form in and around the cervical area. Painful menstrual cramps are the most common symptom in adolescents and adult women. Lesions may also form in the vagina (ligneous vaginitis), fallopian tubes, ovaries, and the lining of the uterus.6 Because of these lesions, becoming pregnant may be difficult.7
What is juvenile colloid milium?
A skin condition in children, called juvenile colloid milium, is also associated with congenital PLGD. The lesions appear as small, yellow-brown, pimple-like swellings, typically located where the skin is exposed to the sun.6
What is congenital occlusive hydrocephalus?
Congenital occlusive hydrocephalus is a rare medical condition that occurs when the fluid that surrounds and protects the brain and spinal cord (the cerebrospinal fluid or CSF) is blocked and unable to drain properly. The extra fluid in the baby’s brain can cause brain damage, as well as mental and physical problems. Surgery is usually needed to help relieve the obstruction.6
What is Dandy-Walker Syndrome?
A deformity of the brain’s cerebellum and the spaces around it, known as Dandy-Walker Syndrome, also occurs in children with type I PLGD.1 A key feature of this syndrome is the complete absence of the part of the brain located between the two cerebellar hemispheres.10
How is congenital PLGD diagnosed?
Congenital PLGD may be diagnosed at a very early age. However, those individuals who don’t show the characteristic fibrous lesions associated with the condition may not be diagnosed accurately until they experience physical problems much later in life.6 The condition is often underdiagnosed, because the lesions found in one area are often not recognized as being part of a condition that can affect multiple body systems.3 Both clinical and laboratory findings are used to help identify if you or a loved one has congenital PLGD.6
Diagnosing congenital PLGD typically begins very early because of the appearance of its hallmark symptom: ligneous conjunctivitis. This is the most common of the identifiable symptoms, occurring in four out of five cases of congenital PLGD.1, 6 Since multiple body systems can be affected, examining the ears, throat, respiratory tract, and female genital tract should also be done to see if the lesions occur in other areas. In addition, examining a child’s sun-exposed skin may show juvenile colloid milium, a rare skin condition associated with type I PLGD.6 Congenital PLGD is an inherited condition, so family history also can help support the diagnosis, especially when other affected siblings or members of the family are tested. To confirm or rule out the doctor’s suspicion, a variety of tests are available, which can also help determine the extent and severity of the condition.6
What’s the prognosis for congenital PLGD?
The probable course of congenital PLGD can vary, depending on a variety of factors. These include the extent, location, length, and site of the lesions. Many affected individuals live through adulthood. However, in the absence of effective therapy, their quality of life is diminished. Surgical removal of the growths may provide temporary relief, but these lesions often reappear.
What about surgical removal of lesions?
Patients may be subjected to dozens or even more surgical procedures. In fact, some patients with recurring ligneous conjunctivitis have required more than 20 operations. These lesions are often quite painful and can compromise organ function, creating emergencies, such as a collapsed lung, kidney failure, or blindness. In some cases, complications can be fatal.6
Is there a cure?
While there is no cure, the promise of PLG replacement therapy, currently in clinical trials, offers new hope and relief for many sufferers.11,12,13
What types of treatment are available?
Currently, there is no effective therapy commercially available for this condition. A variety of treatments have been tried in recent years with PLG replacement being the most promising.9,14,15,16
• When lesions form in the eye (ligneous conjunctivitis), surgery has been the primary approach to treatment, but relief is temporary, and the lesions usually return 9
• High doses of intravenous corticosteroids have also had limited success in treating the lesions 9 • Topical treatment applied directly on the lesions did not completely or consistently treat them or prevent them from reforming. 7,17,18,19 Among those explored were hyaluronidase (an enzyme), heparin (a blood thinner or “anticoagulant”) used in combination with corticosteroids or alpha-chymotrypsin, and immunosuppressants (drugs that suppress the immune system), such as cyclosporine and azathioprine.7,17,18,19
• PLG concentrates—given locally (specific to one area) and systemically (circulating throughout the body)—have been shown to effectively prevent lesions from reforming.9,14,15,16
What is lysine-conjugated PLG (Lys-PLG)?Lys-PLG is one of two main forms of replacement plasminogen that offers hope for people with PLGD. When it was continuously infused and then injected daily in a 6-month-old infant with ligneous conjunctivitis, the lesions completely resolved within 4 weeks, and respiratory tract and wound healing functions returned to normal.12 Lys-PLG is no longer manufactured and not available for commercial sale.
What is glutamic-conjugated PLG (Glu-PLG)?
Glu-PLG is another form of replacement PLG. When given to a child on a ventilator with lesions in the lungs, remarkable reductions were observed after only 6 weeks.12 GLU-PLG is being developed by Prometic Life Sciences.
Where can I learn about participating in a clinical trial?
While there is no replacement product approved for the treatment of PLGD, a clinical trials with Glu-PLG are is in progress.6, 11
Prometic Life Sciences is developing a medicine that contains purified PLG (Glu-PLG) extracted from human blood and is currently conducting a trial in the United States and Europe.20 When given by injection to patients who lack working PLG of their own, it is expected to replace the missing protein in their blood and correct the symptoms of the condition.21 This new, PLG replacement therapy is currently in clinical a trial (Phase 2/3) to confirm its effectiveness and further demonstrate safety and tolerability in patients with congenital PLGD.
Given the rarity and urgency of this condition, the FDA has agreed to speed its approval process. This only happens in serious conditions where there is a meaningful advantage over other available therapies.20 A study center in Europe has begun recruiting patients in the second half of 2016. This novel therapeutic formulation of PLG is intended for the treatment of congenital PLGD.21
More information about this clinical trials is available at ClinicalTrials.gov.
To learn more about the ongoing clinical trials or receive information on PLGD, please register here.
Who manages my care?
The initial point of care within the health system may vary substantially from case to case. PLDG may require multiple specialists from a range of disciplines, involving different areas of expertise. This is because of the broad age range when the condition can arise and the variety of symptoms and side effects that can result from this condition.22 Coordinated care is needed from healthcare professionals in various disciplines.7,8
In addition to family doctors, pediatricians, ophthalmologists, or dentists who may recognize the first signs of the disorder, the clinical treatment team involved in caring and seeing patients may include pediatric hematologists, adult hematologists, otolaryngologists, oral surgeons, pulmonologists, and other specialty groups.5,20,22 Geneticists may also be involved in the testing and counseling of patients.3 If you are pregnant and think you could be a carrier or if you already have a child diagnosed with congenital PLGD, it is also important to alert your obstetrician.
Join the Plasminogen Deficiency Community
Are you concerned about this rare disease?
We’re here to help.
Subscribe to the community to receive periodic information on plasminogen deficiency.
You are not alone!
1. 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.
2. Mayo Clinic. Mayo Foundation for Medical Education and Research. Autosomal recessive inheritance pattern. http://www.mayoclinic.org/autosomal-recessive-inheritance-pattern/img-20007457. Accessed May 14, 2016.
3. National Institutes of Health, US National Library of Medicine, 2012. Genetics Home Reference: Congenital plasminogen deficiency. http://ghr.nlm.nih.gov/condition/congenital-plasminogen-deficiency. Accessed May 14, 2016.
4. Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005;93(4):647-654.
5. Shoseyov D. Congenital plasminogen deficiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.
6. Mehta R, Shapiro AD. Plasminogen activator inhibitor type I deficiency. Haemophilia. 2008;14(6):1255-1260.
7. Schuster V, Hügle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5(12):2315-2322.
8. Bateman JB, Pettit TH, Isenberg SJ, Simons KB. Ligneous conjunctivitis: an autosomal recessive disorder. J Pediatr Ophthalmol Strabismus. 1986;23:137-140.
9. Pergantou H, Likaki D, Fotopoulou M, Katsarou O, Xafaki P, Platokouki H. Management of ligneous conjunctivitis in a child with plasminogen deficiency. Eur J Pediatr. 2011;170(10):1333-1336.
10. National Institute of Neurological Disorders and Stroke (NINDS). NINDS Dandy-Walker Syndrome Information Page. 2016. http://www.ninds.nih.gov/disorders/dandywalker/dandywalker.htm. Accessed May 14, 2016.
11. Schneppenheim R, Moran J, Hassenpflug W, Schrum J, Schneppenheim S, Müller-Stöver S. Pending publication in peer-reviewed journal.
12. Schott D, Dempfle CE, Beck P, et al. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med. 1998;339(23):1679-1686.
13. Kraft J, Lieb W, Zeitler P, Schuster V. Ligneous conjunctivitis in a girl with severe type I plasminogen deficiency [PMID abstract 11045349]. See comment in PubMed Commons below Graefes Arch Clin Exp Ophthalmol. 2000;238(9):797-800.
14. Heidemann DG, Williams GA, Hartzer M, Ohanian A, Citron ME. Treatment of ligneous conjunctivitis with topical plasmin and topical plasminogen. Cornea. 2003;22(8):760-762.
15. Watts P, Suresh P, Mezer E, et al. Effective treatment of ligneous conjunctivitis with topical plasminogen. Am J Ophthalmol. 2002;133(4):451-455.
16. Tabbara KF. Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. Am J Ophthalmol. 2004;138(2):299-300.
17. De Cock R, Ficker LA, Dart JG, Garner A, Wright P. Topical heparin in the treatment of ligneous conjunctivitis. Ophthalmology. 1995;102(11):1654-1659.
18. Silva GB, Bariani C, Mendonca EF, Batista AC. Clinical manifestations due to severe plasminogen deficiency: a case report. J Dent Child. 2006;73(3):179-182.
19. Rubin EM, Krauss RM, Spangler EA, Verstuyft JG, Clift SM. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991;353(6341):265-267.
20. Data on file. Prometic Life Sciences Inc.
21. European Medicines Agency (EMA). EU/3/15/1511 Orphan designation granted by the European Commission to Prometic BioTherapeutics Ltd, United Kingdom, for human plasminogen for the treatment of plasminogen deficiency. Published August, 18, 2015. Published here. Accessed May 14, 2016.
22. National Center for Biotechnology Information, US National Library of Medicine, 2015. Genetic Testing Registry: Plasminogen deficiency type I. http://www.ncbi.nlm.nih.gov/gtr/tests/527642/overview. Accessed May 14, 2016.