What precautions and management should be taken for a patient with pathogenic PLG (plasminogen) gene variants causing plasminogen deficiency?

Precautions for Patients with PLG Gene Pathogenic Variants

Patients with PLG gene pathogenic variants causing plasminogen deficiency require lifelong multidisciplinary monitoring for fibrin-rich pseudomembranous lesions on mucous membranes, with prompt initiation of plasminogen replacement therapy when lesions develop, as this is the only FDA-approved specific treatment that achieves rapid resolution. 1, 2, 3

Diagnostic Confirmation and Initial Assessment

• Confirm diagnosis through laboratory testing: Measure both immunoreactive and functional plasminogen levels, as type 1 plasminogen deficiency shows decreased levels of both 2
• Genetic testing: Sequence the PLG gene to identify specific pathogenic variants (homozygous or compound heterozygous mutations confirm diagnosis) 4
• Comprehensive baseline evaluation: Systematically examine all mucous membrane surfaces including conjunctiva, gingiva, nasopharynx, bronchus, gastrointestinal tract, genitourinary tract, and female genital tract for existing pseudomembranous lesions 1, 4, 3
• Screen for hydrocephalus: Obtain neuroimaging in all newly diagnosed patients, as more than 12% develop congenital occlusive hydrocephalus 5

Critical Monitoring Strategy

Regular Surveillance Schedule

• Ophthalmologic examination: Every 3-6 months, as ligneous conjunctivitis is the most common manifestation (occurring in the majority of patients) 1, 5, 4
• Dental evaluation: Every 3-6 months for ligneous periodontitis, which shows higher prevalence in recent case series 4
• Otolaryngologic assessment: Every 6 months for middle ear, pharyngeal, and respiratory tract involvement 5, 4
• Gynecologic examination: Every 6-12 months in female patients for cervical and vaginal lesions 5, 4
• Respiratory monitoring: Assess for upper and lower respiratory tract lesions, which can be life-threatening 5, 2

Systems Requiring Vigilance

• Wound healing: Any surgical procedure or trauma carries risk of pseudomembrane formation due to compromised extracellular fibrin clearance 5, 3
• Gastrointestinal tract: Monitor for duodenal and colonic involvement, though less common in some populations 4, 3
• Urogenital system: Assess for kidney and bladder lesions 3

Treatment Precautions and Management

First-Line Therapy

• IV plasminogen concentrate (human Glu-plasminogen): Administer at 6.6 mg/kg every 2-4 days for active lesions, as this is the only FDA-approved specific treatment with demonstrated efficacy 2, 3
• Rapid therapeutic effect: Expect lesion resolution or improvement within 4 weeks in most cases, with all patients achieving clinical success (≥50% improvement) by 12 weeks 3
• Prophylactic vs. intermittent treatment: Tailor approach based on disease severity—continuous prophylaxis for severe/recurrent disease, intermittent treatment for milder cases 2

Alternative and Adjunctive Therapies (When IV Plasminogen Unavailable)

• Fresh frozen plasma (FFP): Can be used topically or intravenously, though efficacy is modest and transient compared to plasminogen concentrate 4, 6
• Topical plasminogen eye drops: For mild ligneous conjunctivitis only 4
• Topical heparin: Limited efficacy for conjunctival lesions 4
• Surgical excision: Generally provides only temporary relief, as lesions typically recur without addressing underlying deficiency 4
• Hormonal therapy: Oral sex hormones showed success in two female patients with ligneous conjunctivitis, but evidence is extremely limited 5

Critical Safety Precautions

Surgical and Procedural Considerations

• Pre-procedure plasminogen replacement: Administer IV plasminogen concentrate before any surgical intervention to prevent pseudomembrane formation at surgical sites 2, 3
• Wound monitoring: Closely observe all wounds for abnormal fibrin accumulation during healing 5, 3
• Avoid unnecessary procedures: Minimize invasive interventions when possible, as each creates risk for lesion development 2

Life-Threatening Complications to Prevent

• Respiratory tract involvement: This can be fatal; maintain high index of suspicion for upper and lower airway lesions 5, 2
• Hydrocephalus: Monitor for signs of increased intracranial pressure, particularly in children 5, 4
• Multi-organ involvement: Severe cases with simultaneous involvement of multiple systems require aggressive treatment 5, 2

Important Clinical Pitfalls to Avoid

• Delayed diagnosis: Symptoms are frequently misattributed to common conditions (conjunctivitis, recurrent otitis media, reactive airway disease), leading to diagnostic delays 2
• Inadequate treatment: Topical therapies and surgical excision alone are insufficient for moderate-to-severe disease; plasminogen replacement is required 2, 4, 3
• Thrombosis misconception: Neither severe hypoplasminogenemia nor dysplasminogenemia causes venous thrombosis—do not anticoagulate based on plasminogen deficiency alone 5
• Assuming asymptomatic patients are safe: Even initially asymptomatic individuals require consistent monitoring, as lesions can develop at any time 2

Specialized Care Coordination

• Establish medical home: Refer to specialized facilities such as hemophilia treatment centers that offer multidisciplinary care for ultrarare bleeding/clotting disorders 2
• Coordinate subspecialists: Ensure access to ophthalmology, otolaryngology, pulmonology, gynecology, dentistry, and neurosurgery as needed 2, 4
• Registry enrollment: Consider enrolling patients in the Plasminogen Deficiency Registry to contribute to understanding of disease prevalence and treatment outcomes 4

Genetic Counseling Considerations

• Autosomal recessive inheritance: Counsel families that siblings have 25% risk of being affected, 50% risk of being carriers 5, 4
• Consanguinity: Higher prevalence in populations with consanguineous marriages, particularly in Turkey and Middle East 4
• Family screening: Test first-degree relatives for carrier status and plasminogen levels 6