Plasminogen Deficiency

Medications/Treatment

Several available medications have been utilized to treat clinical symptoms associated with plasminogen deficiency; agents other than specific systemic or local plasminogen replacement are inconsistently effective (see Table 1).39

Table 1
Table 1

Both topical and systemic plasminogen concentrates have been intermittently available, but when utilized, these have demonstrated efficacy.40-43 The results of treatment with systemic Lys-plasminogen in a young child with ligneous conjunctivitis were reported.  Ophthalmologic lesions improved and/or resolved when plasminogen activity levels were maintained at 40-50%; lesions were able to be surgically excised without recurrence. Withholding therapy for 48 hours resulted in early lesion recurrence, with subsequent resolution with re-initiation of systemic therapy.40 Three subsequent studies demonstrated the efficacy of topical plasminogen ophthalmologic drops in improving ligneous conjunctivitis lesions.41-43 Interestingly, one of study reported initial use of plasmin local therapy and was reported as ineffective; use of local plasminogen was subsequently effective.42 More recently, use of either systemic or topical fresh frozen plasma (FFP) has been reported with some success.33 The current lack of an available regulatory agency-approved efficacious local or systemic plasminogen replacement product represents an important therapeutic gap.

Therapies targeted to inhibit either inflammation or fibrin generation have been utilized; this approach is reasonable given the pathophysiology of lesion development with accumulation of fibrin rich tissue often stimulated by inflammation.39 Several reports discuss the benefit of topical antithrombotic agents, such as heparin or argatroban.22,34,35 Warfarin was shown in one case to improve ligneous gingivitis.38 Alternatively, immunosuppressive agents including steroids, cyclosporine, and azathioprine have been utilized topically or systemically with limited or intermittent success.1 One study reported an increase in plasminogen levels when oral hormonal therapy was instituted in two women of child-bearing age with resultant improvement in ligneous conjunctivitis lesions.36

Lesions are commonly removed surgically or with another local modality; removal often results in acute improvement with regrowth. Some lesions have been reported to spontaneously resolve.1 Currently, there is no consensus on optimal treatment of lesions, nor markers that assist in prediction of lesion response or recurrence. An important therapeutic gap is the lack of universal availability of either a local or systemic plasminogen replacement.

At this time, several options would be reasonable to consider, depending on lesion location. Conjunctival lesions often require surgical excision; however removal should be accompanied by consideration of systemic and/or topical therapy. One study utilized both systemic and topical fresh frozen plasma (FFP) with a systemic FFP dose of 20 ml/kg every 8 hours, while the topical dose was 1 drop applied every 3 hours instituted 2 days prior to excision.33 Systemic FFP was continued for one week, while the topical dose was continued for 3 days, with dosing interval extension to every 4 hours for one week, then every 6 hours for 6 months. Alternatively, the combination of heparin and corticosteroids applied topically has demonstrated some efficacy.34,35 A recent study reported the use of local heparin therapy at a concentration of 5000 IU/ml with topical dexamethasone (1mg/ml) post excision; the heparin dosing regimen utilized was two drops every hour for the first 24 hours with subsequent interval extension to every 4 hours. The dexamethasone was administered every 6 hours for 16 days. The heparin regimen was continued for over 5 years without lesion recurrence. Finally, in female patients of child bearing age, oral contraceptives may be considered in an attempt to increase baseline plasminogen levels.36

In gingival lesions, topical heparin therapy has not been effective.37 Warfarin use may be considered.38

In one case of laryngeal involvement with ligneous lesions, FFP in conjunction with surgical excision provided little benefit. The child eventually required a tracheotomy to bypass location of the lesion.25

At this time, many patients affected with plasminogen deficiency continue to suffer increased morbidity associated with lesion development including serious sequelae such as loss of vision and hearing, and infertility.