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Fibrinolytics (Thrombolytic Drugs)

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The Fibrinolytic System

• PAI-1 (Plasminogen Activator Inhibitor-1) - inhibits tPA and uPA (upstream control)
• α₂-antiplasmin - directly inhibits plasmin (downstream control)

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Classification of Fibrinolytic Drugs

Generation-wise Classification (KD Tripathi style):

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Mechanism of Action (General)

• Non-fibrin specific agents (Streptokinase, Urokinase, Anistreplase): Activate both fibrin-bound AND circulating plasminogen → produce a systemic lytic state (deplete fibrinogen, factors V and VIII)
• Fibrin-specific agents (Alteplase, Reteplase, Tenecteplase): Preferentially activate plasminogen bound to fibrin → more "clot-selective"

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Individual Drugs

1. Streptokinase (SK)

• Source: Beta-haemolytic streptococci
• Nature: Not an enzyme itself; acts indirectly
• Mechanism: Forms a 1:1 stoichiometric complex with plasminogen → conformational change exposes the active site → this SK-plasminogen complex then activates additional plasminogen molecules to plasmin

• Fibrin selectivity: None (non-specific); produces systemic lytic state
• Dose: 1.5 million units IV over 30-60 minutes (for AMI)
• Half-life: ~23 minutes
• Adverse effects:
  • Allergic reactions (~5%) - rash, fever, chills, rigors, rarely anaphylaxis
  • Transient hypotension (due to plasmin-mediated bradykinin release)
  • Hemorrhage (major risk)
• Important: Antigenic - prior streptococcal infection or prior SK use produces antibodies that reduce efficacy. Should NOT be re-administered after 5 days (relative contraindication).

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2. Urokinase (UK)

• Source: Originally from fetal kidney cells; later recombinant DNA technology
• Nature: Two-chain serine protease (MW 34,000)
• Mechanism: Directly converts plasminogen to plasmin (no intermediate complex needed)
• Fibrin selectivity: None (non-specific); produces systemic lytic state
• Antigenic: No (not immunogenic; allergic reactions rare)
• Use: Mainly catheter-directed lysis of DVT and peripheral arterial thrombi
• Note: No longer available in some countries due to production problems

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3. Anistreplase (APSAC - Acylated Plasminogen Streptokinase Activator Complex)

• How made: Streptokinase + equimolar Lys-plasminogen, with active site blocked by an anisoyl group
• Mechanism: After IV infusion, the anisoyl group is removed by deacylation, exposing the active site
• Half-life: ~100 minutes (longer than SK - allows single bolus administration)
• Advantage over SK: Convenient single bolus IV administration
• Disadvantage: Like SK, no fibrin selectivity; produces systemic lytic state; same allergic reactions and hypotension as SK
• Status: Largely replaced by alteplase; offers no major clinical advantage

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4. Alteplase (rt-PA, Tissue Plasminogen Activator)

• Nature: Recombinant single-chain t-PA; serine protease (MW 68,000)
• Mechanism:
  • Poor plasminogen activator in the absence of fibrin
  • When bound to fibrin, activates fibrin-bound plasminogen several hundred-fold more rapidly
  • Physiological t-PA: 5-10 ng/mL (no systemic effect)
  • Therapeutic dose: 300-3000 ng/mL (can produce systemic fibrinogen degradation)
• Fibrin selectivity: Yes (fibrin-specific, though not absolute)
• Half-life: ~5 minutes (very short; cleared by hepatic metabolism)
• Domains: Finger (F), EGF, two Kringles (K1, K2), Protease (P) - fibrin binding via finger domain and K2 domain
• Dose (AMI): 15 mg IV bolus → 0.75 mg/kg over 30 min (max 50 mg) → 0.5 mg/kg over 60 min (max 35 mg)
• Uses: Acute MI (STEMI), Acute Ischaemic Stroke, Massive Pulmonary Embolism
• Advantage over SK: Higher reperfusion rates; not antigenic; no allergic reactions; no hypotension

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5. Reteplase (r-PA)

• Type: Recombinant variant of t-PA (deletion mutant - lacks finger, EGF, and K1 domains)
• Mechanism: Same as alteplase (fibrin-specific)
• Half-life: Longer than alteplase (~18 min) → allows double-bolus dosing (10 U + 10 U, 30 minutes apart)
• Advantage: More convenient administration than alteplase (bolus vs infusion)
• Efficacy/Toxicity: Similar to alteplase

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6. Tenecteplase (TNK-tPA)

• Type: Recombinant t-PA variant with 3 substitutions (T→N at position 103, N→Q at 117, KHRR→AAAA at 296-299)
• Key advantages over alteplase:
  • Longer half-life (18-20 min) → single IV bolus administration
  • Relatively resistant to PAI-1 inhibition (due to KHRR substitution)
  • Higher fibrin specificity than alteplase
• Dose: Single weight-based IV bolus (30-50 mg)
• Efficacy/Toxicity: Similar to alteplase despite structural advantages

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Indications for Fibrinolytic Therapy

Fibrinolytic therapy saves >30 lives per 1000 patients in the first 3 hours of AMI; benefit decreases by ~1.6 lives/1000 patients per hour of delay.

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Contraindications

Absolute Contraindications

• Prior intracranial haemorrhage
• Known structural cerebrovascular lesion (AVM, aneurysm)
• Known malignant intracranial neoplasm
• Ischaemic stroke within 3 months
• Suspected aortic dissection
• Active bleeding or bleeding diathesis (excluding menses)
• Significant closed-head trauma within 3 months

Relative Contraindications

• Uncontrolled hypertension (BP >180/110 mmHg)
• Major surgery or traumatic CPR within 3 weeks
• Internal bleeding within 2-4 weeks
• Noncompressible vascular punctures
• Streptokinase: Prior exposure >5 days ago or prior allergic reaction
• Pregnancy
• Active peptic ulcer
• Current warfarin use with INR >1.7

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Adverse Effects

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Inhibitors of Fibrinolysis (Antifibrinolytics)

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Comparison of Key Fibrinolytics (KD Tripathi Table Style)

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