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.

12. Bouisson, M. Ophthalmie sur-aigue avec formation de pseudomembranes a la surface de la conjonctive. Ann. Ocul. (Paris) 17: 100-104, 1847.