Thrombolytic Agents (Fibrinolytic Agents)

Overview

Figure: Alteplase and tenecteplase activate plasminogen → plasmin, which degrades fibrin into fibrin degradation products (Lippincott Illustrated Reviews Pharmacology)

Classification

1. Non-Fibrin-Specific (Systemic Fibrinolytics)

• Streptokinase
• Anistreplase (APSAC)

2. Fibrin-Specific Agents

• 1st generation: Streptokinase (non-selective)
• 2nd generation: Alteplase (tPA)
• 3rd generation: Reteplase, Tenecteplase

Individual Agents

Streptokinase (1st Generation)

Anistreplase / APSAC (1st Generation)

Alteplase / tPA (2nd Generation)

Reteplase (3rd Generation)

Tenecteplase / TNK-tPA (3rd Generation)

Mechanism Summary Table

Therapeutic Indications

1. Acute STEMI - All agents used; primary PCI preferred if available within 2 hours; fibrinolysis remains important when PCI is not accessible. Early thrombolysis (<2 hrs) reduces 30-day mortality (5.5% vs 9% when given >4 hrs after symptom onset).
2. Acute Ischemic Stroke - Alteplase is standard of care within 4.5 hours of symptom onset. Tenecteplase (0.25 mg/kg) is an alternative in some guidelines (AHA-ASA IIb recommendation). Mechanical thrombectomy should still be considered even after thrombolysis.
3. Massive Pulmonary Embolism - Indicated in hemodynamic instability. Meta-analysis shows systemic thrombolysis reduces composite end point of death and recurrent thromboembolism (9.4% vs 19%; OR 0.45).
4. Deep Vein Thrombosis - Selected cases
5. Arterial Thromboembolism
6. Thrombosis of cardiac valve prosthesis
7. Catheter/shunt occlusion - Restore patency

Adverse Effects

1. Hemorrhage - Major adverse effect. Thrombolytics cannot distinguish between pathological thrombus fibrin and normal hemostatic plug fibrin. Previously occult lesions (e.g., gastric ulcer) may bleed.
2. Intracranial hemorrhage - Most feared complication, especially in stroke treatment
3. Angioedema - Alteplase (risk increased with ACE inhibitors)
4. Allergic/anaphylactic reactions - Streptokinase, anistreplase
5. Secondary thrombosis - As the clot dissolves, platelet aggregation may paradoxically increase; co-administration of aspirin or heparin is used to mitigate this

Contraindications

Key Pharmacological Points

• Clot age matters: Older clots are more resistant to lysis. Therapy must be initiated early.
• Fibrin-selective agents (alteplase, reteplase, tenecteplase) cause less systemic fibrinogenolysis than streptokinase, but clinical bleeding profiles are comparable.
• Streptokinase re-treatment: Do not re-administer within 6 months of previous use, or within 12 months of a streptococcal infection.
• Heparin timing: Delayed after streptokinase (due to prolonged fibrinolytic state); given shortly after alteplase infusion completion.
• Pregnancy: Recombinant tPA does not cross the placenta. Streptokinase and alteplase have been used in life-threatening situations; no teratogenic effects reported in humans, but maternal/fetal hemorrhage is a risk.

Contraindications to Thrombolytic Therapy - Harrison's Principles of Internal Medicine (22nd ed., 2025)

• PE should be treated with fibrinolytic agents if massive, and in some cases if submassive
• Fibrinolytic contraindications exist and surgical alternatives should be used when present (but the specific list is not in the indexed sections)

Context: Standard Contraindications Referenced Across Major Textbooks

Note: Harrison's 22nd edition (2025) was searched exhaustively. The specific contraindication list for thrombolytics was not found as a discrete table in the indexed blocks of this edition. If your exam or course material references a Harrison table specifically, the STEMI (ST-Elevation MI) chapter - Chapter 270 or thereabouts in Harrison's 22e - would be the location to verify, as it typically contains the fibrinolytic contraindications table within the "Reperfusion Therapy" section.

• Harrison's Principles of Internal Medicine 22E (2025), p. 2176 - Interventions for Pulmonary Embolism
• Miller's Anesthesia 10e, Table 46.2
• Rosen's Emergency Medicine, Chapter 64

Thrombolytic Contraindications: Cross-Textbook Comparison

Note on Harrison's 22E: After exhaustive searching across all 56 blocks of Harrison's Principles of Internal Medicine 22E (2025), a dedicated standalone contraindications table for thrombolytics was not found in the indexed content. The STEMI chapter content was not accessible in the block structure of this edition (blocks are organized by page ranges that did not capture it). Harrison's is therefore listed as "Not Found in indexed content" in the table below, with a note on what the text does state.

Absolute Contraindications

Relative Contraindications

Key Differences & Notable Points by Source

Tintinalli (Table 239-10) - Most Inclusive / Stringent

• Only source to list aortic dissection/pericarditis and thrombocytopenia (<100,000) as absolute contraindications
• Classifies pregnancy and anticoagulation with lab evidence as absolute (most conservative stance)
• Specifies 14-day cutoff for recent internal bleeding
• Adds advanced renal/hepatic disease and noncompressible vessel puncture as relative CIs (unique to this source)
• Notes: "concurrent menses is NOT a contraindication"

Rosen's Emergency Medicine (STEMI + Stroke, Table 87.5)

• Most context-specific - provides separate criteria for STEMI vs. acute ischemic stroke
• For STEMI: Uses AHA/ACCF guideline thresholds - intracranial surgery within 2 months, head trauma within 3 months
• For stroke (AHA/ASA 2019): Detailed eligibility/exclusion table distinguishing 0-3h vs. 3-4.5h windows
• Age alone is NOT a contraindication (explicitly stated) though >75 years carries ↑ ICH risk
• Only source explicitly stating BP >200/120 mmHg is the absolute threshold (STEMI context)
• Proliferative diabetic retinopathy = "strong" relative CI (simple background retinopathy is NOT a CI)

Miller's Anesthesia (Table 46.2) - Most Concise

• Most condensed table - 6 absolute, 6 relative
• Uses SBP >185/DBP >110 mmHg as absolute threshold (aligns with alteplase stroke guidelines)
• "Vascular lesions" and "Brain tumor" listed separately (vs. combined in others)
• Surgery <3 weeks and CPR <3 weeks (slightly longer window than Tintinalli's 2-week cutoff for surgery)
• Does not mention aortic dissection, thrombocytopenia, or renal/hepatic disease

Harrison's 22E (2025) - Table Not Found

• The indexed blocks of this edition did not yield a standalone thrombolytic contraindications table
• What Harrison's does state: Surgical embolectomy is reserved for "patients who have contraindications for systemic fibrinolysis or those in whom it has failed" (PE chapter, p.2176)
• The STEMI reperfusion chapter was not accessible in the block structure indexed by the library database

• Tintinalli's Emergency Medicine, Table 239-10 (General Contraindications to Fibrinolytic Therapy)
• Rosen's Emergency Medicine, Ch.64 (STEMI/Fibrinolytic Therapy) + Ch.87 Table 87.5 (AHA/ASA Stroke Guidelines for Alteplase)
• Miller's Anesthesia 10e, Table 46.2 (Absolute and Relative Contraindications for Thrombolytics)
• Harrison's Principles of Internal Medicine 22E (2025) - table not found in indexed content

Neuroprotection in Stroke

The Ischemic Penumbra - The Target

• Infarct core - neurons irreversibly damaged; CBF typically <10-15 mL/100g/min
• Ischemic penumbra - surrounding zone of oligemia with cellular dysfunction but potentially salvageable tissue; this is the primary target of all neuroprotective strategies

The Ischemic Cascade - What Neuroprotection Targets

1. Energy failure - ATP depletion → failure of Na⁺/K⁺-ATPase pumps → cellular depolarization
2. Excitotoxicity - depolarization triggers massive release of excitatory amino acids (EAAs), primarily glutamate → overstimulation of NMDA and non-NMDA receptors → massive Ca²⁺ influx
3. Calcium overload - activates destructive enzymes: calpains, phospholipases, endonucleases, nitric oxide synthase
4. Free radical production - lipid peroxidation, oxidative stress; CNS is particularly susceptible
5. Inflammation - leukocyte adhesion via ICAMs, neutrophil infiltration → capillary obstruction + cytotoxic products
6. Apoptosis - delayed neuronal death via programmed pathways

Pharmacological Neuroprotection - Agents Studied

Status: Despite >120 Controlled Clinical Trials Involving >21,000 Subjects - No Agent Has FDA Approval for Acute Ischemic Stroke

1. Glutamate / NMDA Receptor Antagonists

2. Calcium Channel Blockers

3. Free Radical Scavengers / Antioxidants

4. Anti-Inflammatory / Leukocyte Adhesion Inhibitors

5. Calpain Inhibitors

6. Neurotrophic Factors

7. Statins (High-dose)

• Proposed neuroprotective mechanisms: pleiotropic anti-inflammatory effects, improved endothelial function, reduced oxidative stress
• Proposed as neuroprotective agents but clinical evidence for acute stroke neuroprotection remains limited
• Pre-stroke statin use is associated with better outcomes (possibly confounded)

8. Agents That Have Proven Ineffective (Established Negative Trials)

• Gangliosides
• Barbiturates
• Prostacyclin
• Opiate antagonists
• Aminophylline
• β-adrenergic receptor blockers
• Naloxone
• Naftidrofuryl
• Lubeluzole
• Basic fibroblast growth factor
• Choline
• Coenzyme Q10
• Creatine (in neurodegeneration trials)

9. Emerging / Under Investigation

Non-Pharmacological Neuroprotection

Therapeutic Hypothermia

• Well-established for anoxic encephalopathy post-cardiac arrest and perinatal asphyxia
• Fever in stroke patients is associated with poor outcomes - aggressive fever management is indicated in ALL acute stroke patients
• Several small clinical trials investigated induced hypothermia in acute ischemic stroke (including caffeineol + hypothermia with IV alteplase)
• Induced hypothermia has no proven benefit for acute ischemic stroke outcome to date
• Multiple trials ongoing

Blood Pressure Management

• In acute ischemic stroke, permissive hypertension is adopted - elevated BP is temporarily tolerated to maintain cerebral perfusion pressure to the penumbra
• Antihypertensives are withheld unless BP exceeds thrombolysis thresholds (>185/110 mmHg) or there are other compelling indications
• After neurological stability is achieved, gradual BP reduction may be introduced

Decompressive Hemicraniectomy

• Not a neuroprotective drug strategy, but is the only effective intervention for malignant MCA infarction with life-threatening cerebral edema (>2/3 MCA territory)

Glucose Management

• Hyperglycemia worsens ischemic injury; euglycemia is targeted
• IV alteplase is recommended when glucose >50 mg/dL (Rosen's)

Why Neuroprotection Has Failed in Humans - Key Reasons

1. Time window - Very few clinical trials included patients within the first 4-6 hours of ischemia when the penumbra is still viable; by the time of enrollment, irreversible injury had often occurred
2. Animal model translation - Results in rodent focal ischemia models have consistently failed to translate to humans (different anatomy, collateral circulation, comorbidities)
3. Single-target vs. multi-target approach - The ischemic cascade involves multiple simultaneous pathways; blocking one does not prevent injury from others
4. Dose and delivery - Many agents may not achieve adequate CNS concentrations
5. Heterogeneity of stroke - Cardioembolic, atherothrombotic, and lacunar strokes have different pathophysiologies

Summary

The central message from all neurology textbooks remains unchanged: reperfusion is the most effective neuroprotective strategy currently available. All pharmacological neuroprotection remains investigational.

Stroke Guidelines - 2026 AHA/ASA Update

Most current guideline: The 2026 AHA/ASA Guideline for the Early Management of Patients With Acute Ischemic Stroke (published January 2026, PMID: 41582814) replaces the 2018 guidelines and 2019 update. Key updates include new evidence on thrombolytic choice, endovascular thrombectomy eligibility, hyperglycemia management, and modified contraindication approach.

• 2024 AHA/ASA Guideline for Primary Prevention of Stroke (PMID: 39429201) - replaces 2014 guidelines; incorporates Life's Essential 8 and new sex-specific recommendations
• 2021 AHA/ASA Guideline for Secondary Prevention (stroke/TIA)

I. PREHOSPITAL AND INITIAL EVALUATION

• Cincinnati/FAST tool: Face drooping, Arm weakness, Speech difficulty, Time to call emergency services - enables rapid pre-hospital recognition
• Immediate non-contrast CT brain on arrival to exclude hemorrhage
• CT angiography (CTA) or MR angiography to identify large vessel occlusion (LVO)
• CT/MR perfusion imaging to assess ischemic penumbra - core/penumbra mismatch guides late-window treatment
• Target: Door-to-needle time ≤60 min; door-to-groin puncture ≤90 min
• Blood glucose checked immediately (hypoglycemia mimics stroke)

II. IV THROMBOLYSIS (Reperfusion Therapy)

Agents

• Multiple RCTs (EXTEND-IA TNK, NOR-TEST, AcT) show equivalent functional outcomes, symptomatic ICH, and mortality at 90 days
• Tenecteplase associated with higher reperfusion rates and better functional outcome when used before endovascular thrombectomy (EXTEND-IA TNK)
• Single bolus dosing is simpler and reduces medication errors
• Meta-analyses confirm equivalence in bridging therapy for LVO stroke (PMID: 41267970, 2025)
• 2026 guidelines now recognize tenecteplase as a preferred alternative, especially pre-thrombectomy

Time Window for IV Thrombolysis

Blood Pressure Before and After tPA

III. ENDOVASCULAR THROMBECTOMY (EVT / Mechanical Thrombectomy)

0-6 Hours - Standard Criteria (AHA/ASA, based on MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, THRACE trials)

1. Pre-stroke mRS ≤1 (no significant disability)
2. Occlusion of the ICA or M1 segment of MCA
3. NIHSS ≥6
4. ASPECTS ≥6 (Alberta Stroke Program Early CT Score - marker of infarct volume)
5. Within 6 hours of last known well

Extended Window: 6-16 Hours (DAWN / DEFUSE 3 Criteria)

• Patients with anterior circulation LVO within 6-16 hours who meet DAWN or DEFUSE 3 eligibility criteria → thrombectomy recommended
• DAWN trial: Used NIHSS + CT/MRI perfusion mismatch
• DEFUSE 3: Ischemic core <70 mL + mismatch ratio >1.8

Extended Window: 16-24 Hours

• Selected patients within 6-24 hours of last known normal - thrombectomy may be beneficial in those meeting DAWN eligibility criteria
• Overall: up to 24 hours in selected patients with favorable imaging profile

Uncertain Benefit

• Pre-stroke mRS >1
• NIHSS <6 (mild stroke)
• ASPECTS <6 (large core)
• M2/M3 occlusions (distal MCA)
• Posterior circulation (basilar, vertebral, PCA) - benefit uncertain, under investigation
• Age ≥90 years - small numbers in trials; individualize

Intra-arterial Tenecteplase Post-Thrombectomy

• Emerging strategy - meta-analysis (2026) showed potential benefit of adjunctive intra-arterial tenecteplase after successful EVT for improved perfusion and functional outcomes (PMID: 41106193)

IV. BLOOD PRESSURE MANAGEMENT IN ACUTE STROKE

• Up to 80% of acute stroke patients present with elevated BP (AHA 2025)
• Cerebral autoregulation in the ischemic penumbra is severely impaired - BP is the main driver of perfusion pressure
• Rapid BP reduction can worsen ischemia (U-shaped relationship between admission BP and outcomes)

V. GENERAL ACUTE MANAGEMENT

VI. SECONDARY PREVENTION

Antiplatelet Therapy (Non-cardioembolic stroke/TIA)

Anticoagulation (Cardioembolic stroke - Atrial Fibrillation)

Blood Pressure (Secondary Prevention)

• Target BP <130/80 mmHg for most stroke/TIA patients
• All antihypertensive classes effective; combination therapy often required

Lipid Management

• High-intensity statin therapy (atorvastatin 40-80 mg, rosuvastatin 20-40 mg) for all ischemic stroke/TIA patients with atherosclerotic disease
• Target LDL-C reduction ≥50% or LDL-C <70 mg/dL in high-risk patients
• Add ezetimibe or PCSK9 inhibitor if target not achieved

Lifestyle (Life's Essential 8 - 2024 Primary Prevention Guideline)

1. Healthy diet
2. Physical activity (150 min/week moderate or 75 min vigorous)
3. Avoid smoking / tobacco
4. Healthy weight (BMI target)
5. Healthy sleep (7-9 hours)
6. BP control (<120/80 ideal)
7. Blood glucose control (HbA1c targets)
8. Lipid management

VII. PATENT FORAMEN OVALE (PFO)

• ESO 2024 Guidelines (PMID: 38752755): PFO closure recommended in selected patients with cryptogenic stroke aged <60 years with high-risk PFO features (large shunt, atrial septal aneurysm)
• Antiplatelet preferred over anticoagulation in PFO-related stroke unless other indications exist

VIII. INTRACEREBRAL HEMORRHAGE (Brief)

• Reverse anticoagulation immediately
• BP target: SBP <140 mmHg within 1 hour (INTERACT2/ATACH-2)
• Cerebellar ICH with neurological deterioration → urgent surgical evacuation
• Supratentorial ICH: open craniotomy has no proven benefit; minimally invasive surgery (MISTIE III, ENRICH) is promising
• Ventriculostomy for hydrocephalus from IVH

• 2026 AHA/ASA Guideline for Early Management of AIS (PMID: 41582814), Stroke, January 2026
• 2024 AHA/ASA Guideline for Primary Prevention of Stroke (PMID: 39429201)
• Rosen's Emergency Medicine - Chapter 87, Table 87.5 (AHA/ASA 2019 Stroke Guidelines for Alteplase)
• Bradley and Daroff's Neurology in Clinical Practice - Antiplatelet therapy section
• Fuster and Hurst's The Heart, 15th Ed. - Ischemic penumbra and acute stroke