Understanding PLGD

Learn About Plasminogen Deficiency (PLGD)

In all patients with plasminogen deficiency, plasma plasminogen levels are markedly reduced.1 Plasminogen is a naturally occurring protein that is synthesized by the liver and circulates in the blood.

Activated plasminogen, known as plasmin, is an enzymatic component of the fibrinolytic system and the main enzyme involved in the lysis of clots and clearance of extravasated fibrin.2 Activated plasminogen is also involved in wound healing, cell migration, tissue remodeling, angiogenesis, and embryogenesis.3

Plasminogen deficiency has been classified as hypoplasminogenemia, or true type I plasminogen deficiency, and as dysplasminogenemia, or type II plasminogen deficiency. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries.4

Type I plasminogen deficiency is a rare autosomal recessive disorder that leads to severe clinical manifestations primarily related to the formation of fibrous depositions on mucous membranes throughout the body.5 The prevalence of type I plasminogen deficiency has been theoretically estimated at 1.6 cases per million population.1 There is no effective therapy currently available for this disease.

For additional information about therapies in clinical trial, click here.click here.

Plasminogen Background

Native PLG is produced in two main forms, Glu-PLG and Lys-PLG, named for the N-terminal amino acid of either glutamic acid or lysine. Glu-PLG is composed of the entire amino acid sequence designated by the gene sequence (excluding the activation peptide), while Lys-PLG is the result of a cleavage of the Glu-PLG between Lys-77 and Lys-78. The circulating half-life of Lys-PLG is considerably shorter than Glu-PLG (2-2.5 days for Glu-PLG, 0.8 days for Lys-PLG). Glu-PLG is the dominant form of PLG present in plasma with very little Lys- PLG detected in circulation (Violand, 1978; Collen, 1975).2, 6

PLG is a zymogen of plasmin (Figure 1). It contains 791 amino acids with a molecular weight of about 90 kD and a pI (isoelectric point) of approximately 7.0, although differential glycosylation and/or removal of the N-terminal activation peptide can result in a pI range of 6.2 to 8.0. It is a single-chain protein with 24 intra-chain disulfide bridges, 5 kringle domains (involved in the binding to fibrin and to the inhibitor α2-antiplasmin), a serine protease domain (P), and an activation peptide (AP) consisting of the first 77 amino acids.

There is one N-linked glycosylation site and one O-linked site, although a second O-linked site has been identified (Goldberg, 2006).7 Approximately 70% of the PLG in circulation contains only O-linked glycosylation while the rest contains both N- and O-linked sugars.

PLG is synthesized in the liver and secreted into plasma. PLG is distributed throughout the body, and when conditions are present for activation, the PLG pro-enzyme is converted to the active enzyme, plasmin, by tissue-type plasminogen activator (t-PA) or by urokinase plasminogen activator (u-PA). Plasmin then degrades fibrin and converts latent matrix metalloproteinases (pro-MMPs) into active MMPs, which in turn further degrade extracellular matrix (ECM) as part of the tissue healing/remodeling process. PLG activation mediated by t-PA is primarily involved in fibrin homeostasis, while plasmin generation via u-PA, forming a complex with its receptor u-PAR, plays a role in tissue remodeling.

Figure 1: Schematic of the kringle domains of plasminogen
Schematic of the kringle domains of plasminogen

References:

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. Collen D, Ong EB, Johnson AJ. Human plasminogen in vitro and in vivo evidence for the biological integrity of NH2-terminal glutamic acid plasminogen. hromb Res. 1975;7(4):515-529.

3. Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005;93(4):647-654.

4. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

5. Schott D, Dempfle C-E, 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.

6. Violand BN, Byrne R, Castellino FJ. The effect of a-w-amino acids on human plasminogen structure and activation. J Biol Chem. 1978;253(15):5395-5401.

7. Goldberg HJ, Whiteside CI, Hart GW, Fantus IG. Posttranslational, reversible O-glycosylation is stimulated by high glucose and mediates plasminogen activator inhibitor-1 gene expression and Sp1 transcriptional activity in glomerular mesangial cells. Endocrinology. 2006;147(1):222-231.

Prevalence of Type 1 Plasminogen Deficiency

Prevalence of Plasminogen Deficiency

Type I plasminogen deficiency is a very rare condition, with 1 to 2 cases per million, where patients present with no or very little plasminogen. The number of patients with some plasminogen, although still lower than normal, is presumed to be somewhat higher.1

The incidence rate of (heterozygous) hypoplasminogenemia has roughly been estimated in different geographic regions:

  • Minnesota (only white subjects), 0.35%
  • Southern Germany, 0.13%
  • Scotland, 0.26%
  • Japan, 0.42%.2

The median age of first clinical manifestation of ligneous conjunctivitis and/or other complications is typically in the pediatric population, but a range of 3 days to 61 years has been reported.1

References:

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. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

Recognize the Signs and Symptoms

The most common clinical manifestations include

ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations, such as involvement of the respiratory tract (16%), the ears (14%), ligneous vaginitis (8%), or the gastrointestinal tract (2%).1

More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus.2

There is extensive heterogeneity in type I plasminogen deficiency; patients may experience different types of fibrous lesions (location, size, and various organ system involvement).1 These fibrous lesions are often quite painful and can compromise organ function, creating emergencies, such as a collapsed lung, kidney failure, or impaired vision. As a result of this condition, patients may suffer substantial morbidity, and in some cases complications can be fatal.

Lesions tend to occur throughout life and, in the absence of replacement therapy, tend to recur after surgical excision, hence may lead to permanent disability, such as loss of eyesight or bronchial or ureteric obstruction. Patients may be subjected to dozens or even more surgical procedures.1 The frequency of recurrence of fibrous growths in the eye following surgery is unknown, although anecdotally, some patients have required more than 20 operations.

Congenital occlusive hydrocephalus and Dandy-Walker (malformation of the cerebellum) have also been reported in type I plasminogen deficiency.1

Symptoms of Plasminogen Deficiency (PGLD)

In patients with plasminogen deficiency, wound-healing capability is markedly diminished and is most pronounced in mucous membranes. Lesions in these areas are typically rich in fibrin due to lack of proteolytic capacity. As fibrin degradation is limited, the process halts at the stage of granulation tissue formation.2

Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth pharynx, duodenum, upper and lower respiratory tracts, and female genital tract).2

Impaired secretion of mutant plasminogen proteins is a common molecular pathomechanism in type I plasminogen deficiency.1

Patients are subject to lifelong medical problems, which currently have no effective treatment.

References:

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. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

Genetics

Multiple distinct mutations in the plasminogen deficiency gene have been identified. The most common genetic alteration appears to be a K19E mutation found in 34% of patients.1

Besides this K19E mutation, a variety of other genetic abnormalities have been identified in the plasminogen gene in subjects with heterozygous, homozygous, and compound-heterozygous hypoplasminogenemia.2

Although type I plasminogen deficiency shows autosomal-recessive inheritance, a female-to-male ratio of 1.27:1 has been observed.1

There are many mutations found: missense mutations, nonsense mutations, frame shift mutations, splice site mutations, an amino acid deletion mutation and an amino acid insertion mutation.2

Plasminogen is converted to plasmin by cleavage of the Arg561–Val562 peptide bond by either tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator.2

References:

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. Shoseyov D. Congenital plasminogen deificiency with respiratory complication. PowerPoint presentation at Hadassah Medical Center Jerusalem: Jerusalem, Israel.

Plasminogen Deficiency (PLGD) Clinical Trials

ProMetic Life Sciences is developing a novel protein replacement therapy for plasminogen deficiency – a rare disorder for which there is no effective therapy currently available.

ProMetic’s Plasminogen (Human), intravenous formulation, was granted Orphan Drug Designation by in the FDA on March 5, 2013, and received ODD by the European Commission on August 3, 2015 for the treatment of hypoplasminogenemia or type I plasminogen deficiency.

ProMetic is currently completing its single ascending dose Phase Ib clinical trial to demonstrate the safety, tolerability and pharmacokinetics of ProMetic’s plasma-derived plasminogen in patients with plasminogen deficiency. The clinical program will then cross-over to the phase II-III trial where the same plasminogen deficient patients will be administered multiple

doses to define the optimal treatment regimen to achieve the targeted blood concentration of plasminogen. The FDA has agreed to an accelerated regulatory approval pathway given the rarity of the condition and the unmet medical need. To secure an accelerated pathway approval, a drug must treat a serious condition, provide a meaningful advantage over available therapies and demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

Clinical trials are ongoing, and healthcare providers and patients may contact ProMetic or clinicaltrials.gov for further information.

If you are interested in participating (or know of a patient who may be interested) in the clinical trial, please register, and a representative from ProMetic will contact you.
Enroll Now

Diagnosis

A variety of conditions, resulting from the deficiency of plasminogen, necessitate multi-disciplinary, coordinated care for these patients.

Patients’ wound-healing capability is severely reduced and is often obvious in mucous membranes (e.g., conjunctivae) where plasminogen plays a crucial role in intravascular and extravascular fibrinolysis.1

Ligneous conjunctivitis, characterized by thick, woody (ligneous) growths on the conjunctiva of the eye (Figure 2), is the main manifestation (80% of cases) of hypoplasminogenemia (type I). It first appears with erythema of the conjunctivae and chronic tearing followed by the formation of pseudomembranes (yellow-white or thick red masses with a wood-like consistency) on the palpebral surfaces. Pseudomembrane development is often the result of mechanical injury to the conjunctival mucosa relating to infection, trauma, or surgery. If left untreated,

ligneous conjunctivitis can lead to blindness. Most affected cases are infants and children with plasminogen deficiency showing their first clinical manifestation at a median age of approximately 10 months.2, 3

Figure 2: Ligneous Conjunctivitis
Ligneous Conjunctivitis

The mucosa of mouth, ears, gastrointestinal tract, respiratory tract, and female genital tract may also be involved, leading to local complications.4

References:

1. Mehta R, Shapiro AD. Plasminogen activator inhibitor type I deficiency. Haemophilia. 2008;14:1255-1260.

2. Shuster V, Hügle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5(12):2315-2322.

3. Bateman J B, Pettit T H, Isenberg S J, Simons KB. Ligneous conjunctivitis: an autosomal recessive disorder. J Pediatr Ophthalmol Strabismus. 1986;23:137-140.

4. 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;170:1333-1336.

If you are interested in participating (or know of a patient who may be interested) in the clinical trial, please register, and a representative from ProMetic will contact you.

Testing

In patients with lesions suspected to be ligneous, a plasminogen antigen and activity level should be obtained.

As the majority of clinical lesions have been associated with type I deficiency, it is important to evaluate both assays to demonstrate a decreased plasminogen activity with concordant decrease in protein level. Plasminogen activity is measured with a chromogenic assay with a general normal range of 70-130%, while antigenic testing is commonly performed via immunologic assays with a normal reported range of approximately 6-25mg/dL.1 By the age of 1 year, plasminogen levels have reached a stable level, and do not vary with age.1

References:

1. Mehta R, Shapiro AD. Plasminogen deficiency laboratory evaluation. Rare Coagulation Disorders.www.rarecoagulationdisorders.org/diseases/plasminogen-deficiency/laboratory-evaluation Accessed October 30, 2015.

Prognosis

The prognosis of hypoplasminogenemia is variable depending on the extent, location(s), length, and site of the lesions.

A number of patients have died or have loss of affected organ function, such as sight and dentition, as a result of hypoplasminogenemia.1 The one clearly documented effective therapy that leads to resolution and halts re-formation of ophthalmologic lesions is systemic or topical PLG concentrates.2, 3, 4, 5

A systemic PLG replacement therapy using GLU-Plasminogen is currently under clinical investigation with patients receiving infusions twice weekly.

References:

1. Mehta R, Shapiro AD. Plasminogen activator inhibitor type I deficiency. Haemophilia. 2008;14:1255-1260.

2. Heidemann DG, Williams GA, Hartzer M, Ohanian A, Citron ME. Treatment of ligneous conjunctivitis with topical plasmin and topical plasminogen. Cornea. 2003;22:760–762.

3. Watts P, Suresh P, Mezer E, et al. Effective treatment of ligneous conjunctivitis with topical plasminogen. Am J Ophthalmol. 2002;133:451–455.

4. 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;170:1333-1336.

5. Tabarra KF. Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. Am J Ophthalmol. 2004;138(2):299-300.

Treatment

 

There is no formal standard of care or established protocol in the management of type I plasminogen deficiency.

This stems from a lack of supply or source of purified plasminogen protein that is required by these deficient patients (GMP-grade plasminogen has not previously been available) and a dearth of patients as an ultra-orphan condition, which means that clinical care has been case-specific and repeatable treatment may have been based on literature publications and successful case reports. Per case reports in medical literature, systemic and topical plasminogen concentrates have been effective in leading to a resolution and halting the reformation of ophthalmologic lesions.1, 2, 3, 4

Attempted treatments for ligneous conjunctivitis lesions include

  • Surgical Removal
  • High-Dose Intravenous Corticosteroid Treatment
  • Topical Treatment with Heparin, Corticosteroids and Alpha-Chymotrypsin, or Cyclosporine
  • Azathioprine
  • Hyaluronidase

These treatments are not consistently or completely successful in either the treatment or the prevention of lesion regrowth.5, 6, 7, 8

 

After treatment, including surgical removal, the lesions will usually recur. Local administration of fresh frozen plasma (which contains PLG) and other PLG-containing eye drops, however, has shown some effectiveness in treating eye lesions associated with ligneous conjunctivitis.1 Continued topical administration of PLG-containing eye drops can treat the lesion and prevent re-growth.

Currently, there is no replacement product approved for the treatment of plasminogen deficiency, however clinical trials with Glu-PLG are in progress. Historical research of Lys-PLG has shown that systemic administration of a Lys-PLG concentrate results in partial resolution of the lesions.9, 10 In addition, therapy of a 6-month-old child with Lys-PLG preparation as a continuous infusion and later as daily bolus injections led to complete regression of ligneous conjunctivitis within 4 weeks and normalized hyperviscous secretions in the respiratory tract as well as skin wound healing.9

Schneppenheim et al.11 treated a severe case of congenital hypoplasminogenemia with purified GLU-plasminogen therapy. A male child with serum activity plasminogen level less than 2% of normal was suffering from exophytic lesions in both the left and right main bronch at 18 months of age. Initial management involved repeated bronchoscopies with laser removal of the lesions, followed by fresh frozen plasma cover. Two months later, CXR showed atelectasis of the left lung and right lower lobe with the patient requiring ventilatory and circulatory support in ICU. Purified plasminogen therapy was administered at 4mg/kg, increasing to 6.5mg/kg every 48 hours. Dissolution of lung membranes, exophytic lesions and ligneous lesions was remarkable shortly after treatment commenced. The regimen of 6.5mg/kg plasminogen replacement therapy, given every two days, was well tolerated and maintained. After six weeks, lesions were significantly reduced. Treating physicians noted that prophylactic therapy may be warranted in patients with congenital hypoplasminogenemia.

 

There is no formal standard of care or established protocol in the management of type I plasminogen deficiency.

This stems from a lack of supply or source of purified plasminogen protein that is required by these deficient patients (GMP-grade plasminogen has not previously been available) and a dearth of patients as an ultra-orphan condition, which means that clinical care has been case-specific and repeatable treatment may have been based on literature publications and successful case reports. Per case reports in medical literature, systemic and topical plasminogen concentrates have been effective in leading to a resolution and halting the reformation of ophthalmologic lesions.1, 2, 3, 4

Plasminogen Replacement Therapy

ProMetic Life Sciences has developed a purified plasminogen replacement therapy (Glu-PLG) and is currently conducting clinical trials in the United States. Additional study centers in Europe may begin recruiting patients in 2016.

ProMetic’s novel therapeutic formulation of plasminogen is intended for the treatment of hypoplasminogenemia, as evidenced by an abnormally low plasminogen activity level regardless of antigen level.

Orphan Drug status has been granted by the FDA and EMA.

If you are interested in participating (or know of a patient who may be interested) in the clinical trial, please register, and a representative from ProMetic will contact you.
Enroll Now

References:

1. Heidemann DG, Williams GA, Hartzer M, Ohanian A, Citron ME. Treatment of ligneous conjunctivitis with topical plasmin and topical plasminogen. Cornea. 2003;22:760–762.

2. Watts P, Suresh P, Mezer E, et al. Effective treatment of ligneous conjunctivitis with topical plasminogen. Am J Ophthalmol. 2002;133:451–455.

3. 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;170:1333-1336.

4. Tabarra KF. Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. Am J Ophthalmol. 2004;138(2):299-300.

5. Shuster V, Hügle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5(12):2315-2322.

6. De Cock R, Ficker LA, Dart JG, Garner A, Wright P. Topical heparin in the treatment of ligneous conjunctivitis. Ophthalmology. 1995;102:1654.

7. Silva GB, Bariani C, Mendonca EF, Batista AC. Clinical manifestations due to severe plasminogen deficiency: a case report. J Dent Child. 2006;73(3):179-82.

8. 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.

9. Schott D, Dempfle C-E, 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.

10. Kraft J, Lieb W, Zeitler P, Schuster V. Ligneous conjunctivitis in a girl with severe type I plasminogen deficiency. Graefes Arch Clin Exp Ophthalmol. 2000;238:797–800.

11. Schneppenheim R, Moran J, Hassenpflug W, Schrum J, Schneppenheim S, Müller-Stöver S. Pending publication in peer-reviewed journal.