Tissue Plasminogen Activator

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Article initiated by:

Hashem Abu Serhan

All contributors:

Yara Abukhaled, Kishan Avaiya, Rishika Geda (BMSc, MSc.), Mohd Salim Harun Gigani, Hashem Abu Serhan

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Medical Therapy

Description

Tissue plasminogen activators (tPA), like Alteplase, Reteplase, and Tenecteplase, are recombinant fibrinolytic agents that promote degradation of fibrin clots via activation of plasminogen. Endogenous tPA is produced primarily by vascular endothelial cells and has been identified in multiple ocular tissues, including the conjunctiva, cornea, trabecular meshwork, lens epithelium, vitreous, and retina.

In ophthalmology, fibrin formation following intraocular surgery or inflammation can lead to significant visual obstruction and complications, making targeted fibrinolysis a valuable adjunctive therapy. Alteplase is used off-label, most commonly via intracameral injection, to lyse fibrin within the anterior chamber. It may be used therapeutically to dissolve established fibrin or clot, or prophylactically in high-risk eyes following intraocular surgery.

Patient Selection

Indications

• Postoperative anterior chamber fibrin (e.g., cataract or glaucoma surgery).
• Fibrinous pupillary membranes.
• Prophylaxis of fibrin formation, particularly in pediatric cataract surgery.
• Hyphema-associated fibrin or clot.
• Severe inflammatory fibrin (e.g., uveitis, endophthalmitis).
• Obstruction or threatened obstruction of glaucoma drainage devices by fibrin or blood.
• Subretinal/submacular hemorrhage.

Contraindications

• Active intraocular bleeding or uncontrolled hyphema.
• High risk of rebleeding following recent surgery or trauma.
• Known hypersensitivity to alteplase.
• Situations where fibrinolysis may worsen intraocular hemorrhage.

Clinical Pharmacology

Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin, a proteolytic enzyme responsible for fibrin degradation. tPA binds to fibrin within thrombi and preferentially activates fibrin-bound plasminogen, resulting in localized clot dissolution with relative preservation of circulatory coagulation factor.

tPA activity is regulated by plasminogen activator inhibitor-1 (PAI-1), which forms an inactive complex cleared by the liver. tPA has a short systemic half-life of approximately 5 minutes. However, when bound to fibrin, its fibrinolytic activity may persist for several hours.

Following intracameral administration, clinical effects are typically rapid, with fibrin dissolution occurring within minutes to hours.

Warnings/Precautions

General

The primary risk associated with intraocular tPA use is dose-dependent intraocular bleeding, including hyphema or rebleeding.

Other reported complications include:

• Hypotony
• Anterior chamber flattening
• Corneal endothelial toxicity (rare).

In a large clinical series, complications occurred in approximately 21.8% of injections, with severe complications (e.g., significant hyphema or hypotony) occurring in 10.9%. The risk of complications appears higher when tPA is administered early in the postoperative period (within the first 5-9 days).

Information for Patients

Patients should be informed that:

• Use of tPA in ophthalmology is off-label
• It is used to dissolve fibrin or clot and improve postoperative outcomes
• Effects are typically rapid (within hours to 24 hours).
• Risks include bleeding, inflammation, and rare toxicity.

Patients should seek medical attention if they experience:

• Worsening vision
• Eye pain
• New or increased intraocular bleeding

Drug Interactions

• Limited ophthalmic-specific data are available
• Based on systemic use, bleeding risk may increase with:

1. Anticoagulants
2. Antiplatelets

Carcinogenesis/Mutagenesis/Impairment of Fertility

• No ophthalmic-specific data are available.
• Systemic studies have not demonstrated clinically significant carcinogenic or mutagenic effects at therapeutic doses.

Pregnancy

• No ophthalmic-specific studies exist.
• Based on systemic data, alteplase should be used only if the potential benefit justifies the potential risk due to bleeding concerns.

Nursing Mothers

• It is unknown whether alteplase is excreted in human milk.
• Use with caution due to limited data.

Pediatric Use

Intracameral tPA has been used in pediatric ophthalmology, particularly in congenital cataract surgery.

Administration of approximately 20 µg intracamerally has been shown to:

1. Reduce early postoperative fibrin formation
2. Decrease anterior chamber inflammatory reaction

• No significant long-term differences were observed at later follow-up.
• Use should be individualized, as administration may require sedation or general anesthesia.

Adverse Reactions

Adverse reactions to intracameral and intraocular alteplase are primarily ocular and dose-dependent. In a large clinical series of eyes with valved glaucoma drainage implants, complications occurred in approximately 21.8% of injections, with severe complications in 10.9%.

Ocular adverse reactions include:

Common:

• Hyphema or rebleeding: most frequently reported complication, particularly with doses > 25 µg or early postoperative use (first 5-9 days).
• Anterior chamber flare and inflammation
• Transient intraocular pressure elevation

Less common:

• Hypotony
• Anterior chamber flattening or shallowing
• Fibrin reformation requiring repeat Injection.

Rare:

• Corneal endothelial toxicity: dose- dependent in vitro effects; minimal clinical impacts at  standard doses (25 µg/0.1 mL).
• Vitreous hemorrhage following intravitreal administration
• Retinal toxicity: reported at higher doses; doses >50 µg intravitreally should be avoided Avoided.

Route-specific considerations:

In subretinal administration for submacular hemorrhage displacement, reported adverse events include retinal pigment epithelium tears, vitreous hemorrhage, persistent subretinal fluid, retinal detachment, and failure of hemorrhage displacement displacement.

Systemic adverse reactions are exceedingly rare given minimal systemic absorption at ophthalmic doses. No systemic thromboembolic or hemorrhagic events attributable to ophthalmic alteplase use have been reported in the literature.

Overdosage

There is no established antidote for alteplase overdosage in the ophthalmic setting. Overdosage refers to the administration of doses exceeding those shown to be safe and effective, rather than systemic toxicity.

Ocular consequences of overdosage may include:

• Worsening hyphema or vitreous hemorrhage
• Corneal endothelial decompensation at supratherapeutic doses.
• Hypotony and anterior chamber collapse
• Retinal toxicity at intravitreal doses substantially above the clinical range.

Management of suspected overdosage:

• Careful slit-lamp and funduscopic examination to assess for hemorrhagic or structural complications
• Intraocular pressure monitoring
• Management of hyphema per standard protocols if rebleeding occurs
• Observation for corneal endothelial changes with repeat specular microscopy if clinically indicated

Systemic effects are not expected at ophthalmic doses. If accidental systemic administration occurs, standard monitoring per the Activase (alteplase) prescribing information should be followed if clinically indicated.

Dosage and Administration

Alteplase is used off-label in ophthalmology and is prepared from the intravenous formulation (Activase, Genentech) under sterile conditions immediately prior to use.

Preparation:

Reconstitute to 1mg/mL (1000 µg/mL), then dilute with preservative- free saline to the desired concentration. Use immediately after preparation.

Intracameral Injection (Anterior Chamber Fibrin)

Dose: 6-25 µg in 0.1 mL

●      Pediatric Prophylaxis: ~20 µg at the conclusion of surgery reduces early postoperative fibrin formation and anterior chamber inflammatory reaction.

●      Established Fibrin: 10-25 µg (Star low to reduce risk of bleeding).

●      Glaucoma drainage device obstruction: 10-25 µg; repeat dosing may be required.

Timing: Administration beyond 5-9 days postoperatively is associated with lower complication rates; earlier use should be reserved for vision-threatening fibrin.

Intravitreal/Intracameral Injection (Endophthalmitis and TASS)

Dose:  ~25 µg in 0.05-0.1 mL

●      In Endophthalmitis: Improves visualization; fibrin clears within 2-14 hours.

●      In TASS:  ~80% fibrin resolution within 24 hours.

Subretinal Injection (Submacular Hemorrhage)

Indication: Submacular hemorrhage secondary to neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, retinal arterial macroaneurysm, or trauma, when hemorrhage is large, fovea-involving, and of recent onset.

Pneumatic displacement (intravitreal, without vitrectomy): 12.5-25 µg in 0.1 mL injected intravitreally, followed by expansile gas (SF6 or C3F8) with face-down positioning for 1-3 days. Appropriate for recent-onset hemorrhage and avoids the risks of vitrectomy.

Subretinal administration during vitrectomy: 25-50 µg in 0.1-0.2 mL injected directly into the subretinal space through a 41-gauge cannula, followed by fluid-air exchange and gas tamponade. Preferred for large or thick hemorrhages.

General Administration Principles:

• Under strict sterile technique
• Use lowest effective dose
• Consider cumulative bleeding risk with repeat injections
• Monitor intraocular pressure and anterior chamber stability

Overall, intracameral tPA remains the most commonly utilized route in anterior segment pathology, while intravitreal and subretinal approaches are reserved for posterior segment indications.

How Supplied

Alteplase is supplied as a lyophilized powder for intravenous use (generally 50 mg or 100 mg). It must be compounded under sterile conditions for ophthalmic use. No ophthalmic- specific formulation or prefilled syringes are available.

Patient’s Instructions for Use

Alteplase is administered intraocularly by an ophthalmologist, and should not be self administered.

Patients should be informed of the following:

• Use in ophthalmology is off-label.
• It dissolves fibrin or clot to improve outcomes.
• Effects are typically rapid (within hours to 24 hours).
• Prescribed postoperative medications should be continued (e.g., corticosteroids, antibiotics).
• Patients should avoid eye rubbing or external pressure.
• Patients should follow up within 24-48 hours to assess fibrin resolution and monitor for complications.