Fibrinolytic Therapy in ACS and Stroke

Fibrinolytic Mechanism

• Plasmin generation and fibrin degradation: Fibrinolytic agents (tissue plasminogen activator [tPA], streptokinase [SK], tenecteplase [TNK]) activate plasminogen to plasmin, a serine protease that degrades fibrin crosslinks and dissolves the structural matrix of thrombi. This occurs through both direct (tPA, TNK) and indirect (SK) plasminogen activation pathways. tPA is fibrin-selective with preferential activation at the thrombus surface, whereas SK is non-selective and causes systemic plasminogen depletion.

• Thrombus dissolution and reperfusion: Plasmin cleaves fibrin into fibrin degradation products (FDPs) and D-dimers, reducing clot burden and restoring microvascular and epicardial flow. In STEMI, successful thrombolysis restores TIMI Grade 3 flow (normal flow) in 50-60% of patients with SK and 85% with accelerated alteplase. In acute stroke, recanalization of the occluded vessel (typically middle cerebral artery) restores cerebral perfusion and limits infarct expansion.

• Systemic fibrinolytic state and bleeding risk: Fibrinolytic agents induce a systemic fibrinolytic state characterized by depletion of fibrinogen, platelets, and coagulation factors. This hypofibrinogenemia and consumption coagulopathy increase bleeding risk, particularly at vascular access sites, in the intracranial space (hemorrhagic transformation in stroke), and at sites of tissue trauma. The duration and intensity of this systemic effect varies by agent: SK causes maximal fibrinogen depletion (nadir 1-2 g/dL); tPA has intermediate effects; and newer agents (TNK, reteplase) demonstrate relative fibrin-selectivity with less systemic effect.

Indications for Fibrinolytic Therapy in ACS

• STEMI with delayed PCI access: ST-elevation on ECG in anatomically relevant distribution (anterior, inferior, posterior, right ventricular) with symptom onset ≤12 hours (preferably ≤3 hours for optimal benefit). Door-to-needle time should be <30 minutes. First medical contact-to-balloon time >120 minutes favors fibrinolysis over delayed PCI.

• STEMI with contraindications to PCI: Cardiogenic shock (relative contraindication to early invasive strategy), mechanical complications (free wall rupture, papillary muscle rupture, ventricular septal defect [VSD]) where surgical intervention may be delayed, and settings without interventional capability.

Indications for Fibrinolytic Therapy in Acute Ischemic Stroke

• Ischemic stroke within 4.5-hour window: Confirmed by head CT (or MRI) excluding hemorrhage, with symptom onset clearly defined. Alteplase (tPA) at 0.9 mg/kg is FDA-approved for this indication. Tenecteplase has shown non-inferiority to alteplase in the TASTE trial and is increasingly used.

• Selected cases with extended time window (4.5-9 hours): Based on perfusion imaging criteria (ECASS-4, DEFUSE-3 trials) demonstrating viable penumbra with mismatch between diffusion-weighted imaging (DWI) lesion and perfusion defect; primarily for thrombectomy but may inform thrombolytic candidacy.

Acute Coronary Syndrome (STEMI)

• Chest pain characteristics: Acute onset substernal or left-sided chest discomfort, often described as pressure, heaviness, or tightness, typically lasting >20 minutes and unresponsive to nitrates. Associated dyspnea, diaphoresis, and autonomic symptoms (nausea, syncope) may accompany inferior MI.

• Physical examination findings: Diaphoresis, pallor, and signs of acute heart failure (pulmonary crackles, elevated jugular venous pressure [JVP]). Inferior STEMI may present with bradycardia and hypotension (right ventricular involvement). Mechanical complications produce new cardiac murmurs (apical holosystolic murmur in papillary muscle rupture/VSD, early diastolic murmur in acute aortic regurgitation from aortic dissection).

• Cardiogenic shock presentation: Hypotension (systolic BP <90 mmHg), elevated JVP, cool extremities, oliguria, and altered mental status indicate shock physiology requiring urgent reperfusion and hemodynamic support.

Acute Ischemic Stroke

• Acute neurologic deficit: Sudden onset focal neurologic symptoms corresponding to arterial territory (middle cerebral artery [MCA] territory most common with contralateral hemiparesis, hemisensory loss, homonymous hemianopia, aphasia; anterior cerebral artery [ACA] with leg predominance; posterior cerebral artery [PCA] with visual field defects; vertebrobasilar with ataxia, cranial nerve signs). NIHSS (National Institutes of Health Stroke Scale) score quantifies severity.

• Time-critical presentation: Precise symptom onset time is critical; "last known well" is used if onset unwitnessed, triggering extended window consideration only with perfusion imaging evidence of viable brain. Fluctuating or transient deficits (transient ischemic attack [TIA]) do not typically warrant thrombolysis, though recent evidence supports tPA in acute TIA with high-risk features.

Acute Coronary Syndrome (STEMI)

• 12-lead electrocardiogram: Diagnostic modality for STEMI; shows ST-segment elevation ≥1 mm (2 mm in precordial leads) in ≥2 anatomically contiguous leads. Reciprocal ST depression in distant leads supports diagnosis. New left bundle branch block (LBBB) with concordant ST elevation indicates STEMI equivalency. Door-to-ECG time should be <10 minutes.

• Cardiac biomarkers: Serial troponin (troponin I, troponin T, high-sensitivity troponin) rises above the 99th percentile upper reference limit at 3-4 hours from symptom onset; myoglobin and CK-MB rise earlier but lack specificity. Troponin elevation is required for NSTEMI diagnosis but not for STEMI diagnosis (which is ECG-based and time-critical).

• Coronary angiography (gold standard): Identifies culprit lesion (thrombotic occlusion with TIMI 0-1 flow in STEMI), vessel distribution (LAD, LCx, RCA), and presence of multivessel disease. Angiography should follow successful thrombolysis (rescue PCI if failure) or occur after stabilization.

• Imaging (chest X-ray, echocardiography): Baseline chest X-ray assesses for pulmonary edema and alternative diagnoses. Transthoracic echocardiography evaluates left ventricular ejection fraction (LVEF), wall motion abnormalities (regional vs. global), mechanical complications (VSD, papillary muscle rupture, free wall rupture), and right ventricular involvement.

Acute Ischemic Stroke

• Head computed tomography (non-contrast): Mandatory before thrombolysis to exclude intracranial hemorrhage (ICH), which is an absolute contraindication. CT also detects hypodensity (early infarct signs), mass effect, and alternative diagnoses. Sensitivity for acute hemorrhage >95%; acute ischemia may not be evident in first hours.

• Magnetic resonance imaging: Diffusion-weighted imaging (DWI) shows acute ischemic lesion within minutes of symptom onset (restricted water diffusion appears hyperintense). Perfusion-weighted imaging (PWI) demonstrates tissue at risk. DWI-PWI mismatch indicates viable penumbra and guides extended-window thrombolysis decisions.

• Laboratory studies: Baseline glucose (hyperglycemia worsens outcome), coagulation studies (PT/INR, aPTT, platelets), CBC, comprehensive metabolic panel. NIHSS score quantifies neurologic severity (score ≥4 traditionally favored thrombolysis, though benefit extends to mild strokes).

• Vessel imaging: CT angiography (CTA) or MR angiography (MRA) identifies occlusion location and extent (proximal vs. distal), collateral circulation quality, and eligibility for concurrent thrombectomy.

First-Line Fibrinolytic Therapy in STEMI

• Alteplase (tPA) - accelerated regimen (preferred): Dose is 15 mg intravenous bolus, then 0.75 mg/kg (up to 50 mg) over 30 minutes, then 0.5 mg/kg (up to 35 mg) over 60 minutes. Total dose ≤100 mg. Mechanism: Recombinant tPA, fibrin-selective, directly activates plasminogen. Achieves TIMI 3 flow in 60-65% of STEMI at 90 minutes with lower intracranial hemorrhage (ICH) rate (~0.8%) compared to SK. Superior to SK in pooled analyses with 15% relative reduction in mortality and 30-minute earlier reperfusion.

• Tenecteplase (TNK) - bolus dosing (increasingly preferred): Single weight-based intravenous bolus (30-50 mg based on body weight <60 kg to ≥90 kg). Mechanism: Engineered variant of tPA with enhanced fibrin-selectivity and resistance to plasminogen activator inhibitor-1 (PAI-1); longer half-life (~20 min vs. 5-10 min for tPA) permitting bolus administration. ASSENT-2 trial demonstrated non-inferiority to accelerated alteplase with similar 30-day mortality and ICH, but simpler dosing improves prehospital administration and door-to-needle times.

• Streptokinase (SK) - in resource-limited settings: 1.5 million units IV over 60 minutes. Non-selective activator; less expensive than tPA/TNK. GUSTO-I trial showed 15% higher mortality and 55% more ICH versus accelerated alteplase; primarily used in developing countries where cost is prohibitive barrier.

First-Line Fibrinolytic Therapy in Acute Ischemic Stroke

• Alteplase (tPA) IV: 0.9 mg/kg (maximum dose 90 mg); 10% of dose as intravenous bolus over 1 minute, remainder over 60 minutes. NINDS rt-PA Stroke Study showed 30% relative improvement in favorable neurologic outcome (minimal/no disability) at 3 months despite 6.4% symptomatic ICH rate (vs. 0.6% placebo). Number needed to treat (NNT): 8 patients treated to prevent one additional disability. Earlier treatment (within 90 minutes) yields better outcomes.

• Tenecteplase in acute stroke: 0.25 mg/kg intravenous bolus (maximum 25 mg). AHA/ASA guidelines 2019 give equal recommendation as tPA based on non-inferiority data (TASTE trial, EXTEND-IA TNK trial) with advantage of single-bolus administration. Increasingly used in prehospital settings and emergency departments.

Adjunctive Antiplatelet and Anticoagulation Therapy

• Aspirin: 325 mg chewed loading dose immediately after fibrinolytic initiation (contraindicated only if allergy); reduces mortality by ~15%. Continue indefinitely for secondary prevention.

• P2Y12 inhibitors: Clopidogrel (600 mg loading dose followed by 75 mg daily), prasugrel (5-10 mg based on weight <60 kg), or ticagrelor (180 mg loading dose then 60 mg BID). Dual antiplatelet therapy (DAPT) for ≥12 months reduces stent thrombosis and recurrent ischemic events. COMMIT trial supported early clopidogrel in STEMI.

• Anticoagulation: Unfractionated heparin (UFH) 60 units/kg IV bolus (max 5000 units) followed by infusion targeted to aPTT 50-70 seconds for ≥48 hours. Alternatives: enoxaparin (30 mg IV bolus + 1 mg/kg SC BID) or fondaparinux (2.5 mg IV daily) preferred in NSTEMI. Low molecular weight heparin (LMWH) advantages: predictable kinetics, SC dosing, less HIT risk; disadvantage is renal clearance (contraindicated if CrCl <30 mL/min). UFH preferred if urgent revascularization anticipated.

Non-Pharmacological Management

• Cardiac care unit (CCU) admission with continuous telemetry, hemodynamic monitoring (arterial line in shock), serial troponins, and echocardiography. Oxygen if hypoxemic; avoid routine supplementation (increases mortality).

• Mechanical support: Intra-aortic balloon pump (IABP) for cardiogenic shock with mechanical complications; ventricular assist devices (VAD) as bridge to decision or transplant in refractory shock.

• Rescue PCI: If fibrinolysis fails (no ST resolution ≥50% at 60-90 min, hemodynamic instability, worsening symptoms), urgent coronary angiography with PCI and thrombectomy reduces mortality versus repeat fibrinolysis.

• Stroke-specific care: Neurologic ICU admission with frequent NIHSS assessments; blood pressure management (maintain <180/105 mmHg to reduce ICH risk), normoglycemia (avoid hypo- and hyperglycemia), fever control, early dysphagia screening, and DVT prophylaxis.

Monitoring Parameters

• Serial ECG: Assess for ST resolution (≥50% in fibrinolysis success), arrhythmias (reperfusion arrhythmias common, usually self-limiting), and post-MI changes.

• Troponin trajectory: Serial measurement at presentation, 3 hours, 6 hours confirms diagnosis and risk stratifies (higher peak = larger infarct).

• Coagulation profile: Baseline and repeat aPTT 6-12 hours after UFH initiation; maintain therapeutic range. Check fibrinogen (if <100 mg/dL consider transfusion).

• Neurologic examination in stroke: Serial NIHSS scores, fundoscopy for hemorrhage, and repeat head CT at 24-48 hours to detect symptomatic ICH.

Bleeding Complications

• Intracranial hemorrhage (ICH) - most feared: Occurs in 0.5-1% of STEMI patients (higher with SK, age >65 years, low body weight, female sex, hypertension, elevated INR). In acute stroke, symptomatic ICH rate 3-6% with tPA; often fatal or severely disabling. Management: Immediate reversal with fresh frozen plasma (FFP) 2-4 units or prothrombin complex concentrate (PCC), cryoprecipitate if fibrinogen <100 mg/dL; neurosurgical consultation for possible evacuation.

• Systemic bleeding: Intramuscular hematomas, retroperitoneal hemorrhage, gastrointestinal bleeding (especially peptic ulcer disease history), genitourinary bleeding. Risk increases with concurrent anticoagulation, antiplatelet therapy, and invasive procedures. Management: Apply pressure to accessible sites; transfuse packed RBCs PRN to maintain Hgb >8 g/dL; reverse anticoag

The reperfusion decision

• Fibrinolysis is a substitute for PCI only when PCI is not timely: per ACC/AHA STEMI guidance, if first medical contact–to–device time cannot be kept under about 120 minutes, give a lytic within 30 minutes of arrival (door-to-needle), then transfer for angiography — the pharmacoinvasive strategy. Primary PCI is always preferred when available promptly.
• NSTEMI/unstable angina is a contraindication, not an indication: the classic distractor. Non-occlusive platelet-rich thrombus does not respond to plasmin, and lytics increased MI/death in trials of non-ST-elevation ACS.
• New LBBB alone is not a STEMI criterion: apply Sgarbossa criteria (concordant ST elevation ≥1 mm, concordant ST depression V1–V3, or excessively discordant ST elevation) before committing to a lytic.

Absolute contraindications examiners love

• Any prior intracranial hemorrhage, ischemic stroke within 3 months, known intracranial neoplasm or AVM, active bleeding, significant closed head trauma within 3 months, and suspected aortic dissection — a "tearing" pain radiating to the back or unequal pulses means CT angiography, not tPA.
• Blood pressure must be below 185/110 mmHg before IV thrombolysis in stroke and kept under 180/105 mmHg for 24 hours afterward (AHA/ASA acute ischemic stroke guideline). Check a fingerstick glucose first — hypoglycemia is the great stroke mimic.

Post-treatment traps

• Accelerated idioventricular rhythm is a reperfusion marker, usually benign and self-limited — do not treat it with lidocaine or amiodarone.
• No antiplatelet or anticoagulant for 24 hours after IV thrombolysis in stroke, and repeat non-contrast head CT before starting them (AHA/ASA). In STEMI, by contrast, aspirin plus a P2Y12 inhibitor and heparin are given with the lytic.
• Orolingual angioedema occurs in a small minority of alteplase-treated stroke patients, especially those on ACE inhibitors — secure the airway first.
• Streptokinase is antigenic: hypotension and anaphylaxis occur, and it should not be re-administered after prior exposure.
• Failed lysis (<50% ST resolution at 60–90 minutes, ongoing pain, instability) → rescue PCI, not a second dose of lytic.
• Large-vessel occlusion still gets thrombectomy; giving a lytic never justifies withholding it.