Thrombolytics

Definition and Clinical Scope

Thrombolytics, also referred to as fibrinolytic agents, are a specialized class of drugs designed to dissolve thrombi (blood clots) that have already formed within the vasculature. They act by stimulating the conversion of plasminogen to plasmin, a serine protease that digests fibrin—the main structural component of blood clots. These agents are most commonly used in acute, time-sensitive cardiovascular emergencies such as myocardial infarction (STEMI), ischemic stroke, and pulmonary embolism (PE).

Thrombolytics represent reperfusion therapy, intended to restore perfusion to ischemic tissues by clearing obstructive thrombi in critical vessels. The benefit of thrombolytic therapy is time-dependent, with maximal efficacy within a narrow window after symptom onset.

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Mechanism of Action

Thrombolytics mimic or enhance the activity of endogenous tissue plasminogen activator (tPA) by:

• Binding to fibrin within a thrombus

• Converting plasminogen to plasmin

• Plasmin then degrades fibrin, fibrinogen, and other clotting factors

• Leads to clot dissolution, improved blood flow, and tissue reperfusion

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Classification of Thrombolytics

Thrombolytic drugs are divided into non-fibrin-specific and fibrin-specific agents.

1. Non-fibrin-specific agents (first-generation)

• Activate circulating plasminogen non-selectively, leading to systemic fibrinolysis

• Higher risk of bleeding

2. Fibrin-specific agents (second- and third-generation)

• Preferentially bind to fibrin-bound plasminogen at the clot site

• Lower systemic effects, improved safety profile

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Commonly Used Thrombolytic Agents

1. Alteplase (rtPA)

• Type: Recombinant tissue plasminogen activator (fibrin-specific)

• Indications:

  • Acute ischemic stroke (within 4.5 hours)

  • STEMI (within 12 hours)

  • PE with hemodynamic instability

  • Central venous catheter occlusion (low dose)

• Dosing:

  • Stroke: 0.9 mg/kg IV (max 90 mg) over 60 minutes

  • STEMI: weight-based bolus + infusion protocol

• Brands: Activase, Actilyse

2. Tenecteplase (TNK-tPA)

• Type: Genetically modified tPA with longer half-life and bolus dosing

• Advantages: Single IV bolus, more fibrin-specific, resistant to plasminogen activator inhibitor-1

• Indications: STEMI; off-label in stroke (in some guidelines)

• Brand: TNKase

3. Reteplase (rPA)

• Type: Recombinant tPA derivative

• Indications: STEMI

• Advantages: Double bolus administration

• Brands: Retavase

4. Streptokinase

• Type: Non-enzymatic bacterial protein that indirectly activates plasminogen

• Indications: STEMI, DVT, PE

• Limitations: High antigenicity (hypersensitivity), resistance in patients with prior streptococcal exposure

• Brands: Kabikinase, Streptase

5. Urokinase

• Source: Human neonatal kidney cells

• Mechanism: Direct conversion of plasminogen to plasmin

• Indications: PE, catheter clearance, peripheral arterial occlusion

6. Anistreplase (APSAC)

• Type: Acylated streptokinase-plasminogen complex (prodrug)

• Longer half-life than streptokinase

• Use: Previously used in AMI (now rarely)

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Indications and Approved Uses

Clinical Condition	Recommended Thrombolytic Therapy
Acute ischemic stroke	Alteplase (rtPA) within 4.5 hours
STEMI	Alteplase, Tenecteplase, Reteplase, Streptokinase (within 12 hours)
Pulmonary embolism	Alteplase for massive/life-threatening PE
Deep vein thrombosis (DVT)	Catheter-directed thrombolysis in select cases
Central line occlusion	Alteplase (low-dose)
Peripheral artery occlusion	Urokinase or catheter-directed lysis

Contraindications

Absolute contraindications (varies by indication):

• Active internal bleeding

• History of intracranial hemorrhage

• Recent ischemic stroke (within 3 months except acute stroke indication)

• Known intracranial neoplasm or vascular malformation

• Recent head trauma or neurosurgery (last 3 months)

• Suspected aortic dissection

• Uncontrolled severe hypertension (>185/110 mmHg)

• Bleeding diathesis or platelet count <100,000/μL

Relative contraindications:

• Age >75 years (depending on indication)

• Recent surgery (within 2–3 weeks)

• Traumatic or prolonged CPR

• Pregnancy

• Current anticoagulant use (INR >1.7)

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Adverse Effects

1. Hemorrhage

   • Intracranial hemorrhage (most feared complication, especially in stroke)

   • Gastrointestinal or genitourinary bleeding

   • Puncture site or surgical site bleeding

2. Allergic reactions

   • Common with streptokinase (due to bacterial origin)

3. Reperfusion arrhythmias

   • Occur after sudden restoration of coronary flow (usually transient)

4. Hypotension

   • Especially with streptokinase

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Monitoring Requirements

• Baseline:

  • Complete blood count

  • PT/INR, aPTT

  • Renal function (for catheter-directed therapies)

  • CT/MRI to rule out hemorrhage (stroke protocol)

• During therapy:

  • Neurological monitoring (for stroke or bleed)

  • Hemodynamic monitoring

  • Repeat imaging (if clinical deterioration)

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Key Dosing Strategies (Examples)

Drug	STEMI Protocol	Stroke Protocol
Alteplase	15 mg IV bolus + infusion over 90 mins	0.9 mg/kg IV (max 90 mg) over 60 mins
Tenecteplase	Weight-based single IV bolus (30–50 mg)	0.25 mg/kg IV bolus (off-label)
Reteplase	10 units IV bolus ×2, 30 minutes apart	Not approved for stroke
Streptokinase	1.5 million units IV over 60 minutes	Not approved for stroke

Drug Interactions

• Antiplatelet drugs (aspirin, clopidogrel): Additive bleeding risk

• Anticoagulants (heparin, warfarin, DOACs): Significant bleeding potential; often co-administered with caution

• NSAIDs: Increased risk of gastrointestinal bleeding

• ACE inhibitors: May increase risk of angioedema with tPA

• Other thrombolytics: Should not be used in combination due to overlapping action

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Clinical Considerations

• Time is critical: Delays beyond 4.5 hours for stroke or 12 hours for STEMI significantly reduce benefit.

• In ischemic stroke, brain imaging (CT or MRI) must rule out hemorrhage prior to therapy.

• Reversal agents do not exist for thrombolytics; bleeding complications are managed with supportive care (blood products, antifibrinolytics like tranexamic acid).

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Comparative Summary

Feature	Alteplase	Tenecteplase	Reteplase	Streptokinase
Fibrin Specificity	Moderate	High	Moderate	None
Half-life	~5 min	~20 min	~15 min	~20–25 min
Administration	Bolus + infusion	Single bolus	Double bolus	Infusion
Immunogenic	No	No	No	Yes
Stroke Approved	Yes	Off-label	No	No

Future Directions and Research

• Development of next-generation thrombolytics with lower bleeding risk and longer half-life.

• Ultrasound-assisted thrombolysis for PE and DVT (e.g., EKOS system).

• Use of microbubble-enhanced thrombolysis to enhance fibrin dissolution.

• Gene therapy targeting plasminogen activator pathways in prothrombotic disorders.