Library › Pharmacology › Fibrinolytic therapy

Fibrinolytic therapy: agents, dosing, indications, and contraindications

Fibrinolytic agents in adults from plasminogen biology and pharmacology through dosing by indication, STEMI and pulmonary embolism use, prosthetic valve thrombosis, contraindications, and the management of bleeding.

Plasminogen activation and the endogenous fibrinolytic system

Fibrinolysis is the enzymatic dissolution of fibrin. Its central enzyme is plasmin, a serine protease that cleaves fibrin and fibrinogen into soluble degradation products. Plasmin circulates as its inactive precursor, plasminogen, a glycoprotein synthesized in the liver. Plasminogen contains five kringle domains with lysine-binding sites, through which it binds to lysine residues exposed on partially degraded fibrin. The enzymes that convert plasminogen to plasmin are the plasminogen activators.

Two plasminogen activators operate in the circulation. Tissue-type plasminogen activator (tPA) is released by endothelial cells in response to thrombin, venous occlusion, exercise, and catecholamines. It is a poor activator of free plasminogen and an efficient activator of plasminogen bound to fibrin, because fibrin acts as a template that brings tPA and plasminogen together in a ternary complex. Urokinase-type plasminogen activator (uPA) is secreted as a single-chain precursor (prourokinase, scu-PA) and acts mainly in tissues and on cell surfaces through its receptor. Thrombolysis within the vascular lumen is driven chiefly by tPA.

The system is restrained at two levels. Plasminogen activator inhibitor 1 (PAI-1), secreted by endothelium and released in large amounts from activated platelets, inactivates tPA and uPA within seconds; PAI-1 is an acute-phase reactant and is elevated in acute myocardial infarction, obesity, and insulin resistance. Alpha-2-antiplasmin neutralizes free plasmin almost instantaneously, so plasmin that escapes from the fibrin surface is cleared before it can degrade circulating fibrinogen. Thrombin-activatable fibrinolysis inhibitor (TAFI) removes the carboxy-terminal lysine residues that anchor plasminogen and tPA to fibrin and slows lysis of mature clot.

These controls explain the main clinical properties of therapeutic fibrinolysis. A fresh, fibrin-rich thrombus with abundant bound plasminogen lyses readily; an older, organized, or platelet-rich thrombus cross-linked by factor XIIIa does not. Platelet-rich arterial thrombus releases PAI-1 and resists lysis, which is one reason fibrinolysis restores normal Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in only about half to two-thirds of occluded coronary arteries. Lysis also exposes clot-bound thrombin and activates platelets, so reocclusion follows unless antiplatelet and anticoagulant therapy are given with the lytic agent. Lipoprotein(a), whose apolipoprotein(a) resembles plasminogen, competes for fibrin binding sites and impairs endogenous fibrinolysis.

Fibrin specificity and the systemic lytic state

Fibrin specificity is the ratio of plasminogen activation on the fibrin surface to activation in the free circulation. A fibrin-specific agent concentrates plasmin generation in the thrombus and spares circulating fibrinogen, plasminogen, and alpha-2-antiplasmin. A nonspecific agent activates circulating plasminogen indiscriminately, depletes fibrinogen and factors V and VIII, and generates large quantities of fibrinogen degradation products that themselves inhibit fibrin polymerization and platelet aggregation. The resulting systemic lytic state is anticoagulant in its own right.

Fibrin specificity is relative. Alteplase lowers circulating fibrinogen by 16% to 36% after a 100-mg dose, and in one trial of a 3-hour regimen 11% of patients had a fibrinogen level below 100 mg/dL. Tenecteplase, the most fibrin-specific agent in clinical use, lowers fibrinogen by 4% to 15% and plasminogen by 11% to 24% after STEMI doses. Streptokinase, by contrast, depletes fibrinogen profoundly. Reteplase, a deletion mutant without the fibrin-binding finger domain, binds fibrin less avidly than alteplase but remains more fibrin-selective than streptokinase.

Fibrin specificity does not protect against intracranial hemorrhage. Plasmin generated on hemostatic plugs in cerebral vessels, recent puncture sites, or a peptic ulcer lyses those plugs regardless of fibrinogen depletion. In GUSTO-I, accelerated alteplase produced more hemorrhagic strokes than streptokinase (0.72% against 0.49% and 0.54%), even though it was more fibrin-specific and saved more lives. The clinical value of fibrin specificity lies in greater patency and fewer systemic bleeding complications. The tenecteplase label states that the clinical significance of fibrin specificity for bleeding or efficacy has not been established.

Development of fibrinolytic agents: streptokinase, urokinase, and anistreplase

Streptokinase. Streptokinase is a protein produced by group C beta-hemolytic streptococci. It has no enzymatic activity of its own. It forms a 1:1 complex with plasminogen, and the complex converts other plasminogen molecules to plasmin, in the circulation as much as on fibrin. The standard myocardial infarction dose is 1.5 million units infused over 30 to 60 minutes. In ISIS-2, which randomized 17,187 patients within 24 hours of suspected infarction, streptokinase and aspirin each reduced 5-week vascular mortality, and the combination reduced it from 13.2% to 8.0%. Streptokinase is antigenic. Prior streptococcal infection produces neutralizing antibodies in many adults, and treatment induces high titers for months to years, so a second course is ineffective and carries a risk of allergic reaction. Prior streptokinase treatment within 6 months is listed as an absolute contraindication to repeat use. Infusion-related hypotension from bradykinin release is common. Streptokinase is not marketed in the United States but remains in use in parts of the world because of its low cost.

Anistreplase. Anisoylated plasminogen-streptokinase activator complex (APSAC) was a preformed complex with an acylated active site that deacylated slowly in plasma, permitting bolus injection. It shared the antigenicity and lack of fibrin specificity of streptokinase and is no longer marketed.

Urokinase and prourokinase. Urokinase is the two-chain active form of uPA. It activates plasminogen directly, is not antigenic, and is not fibrin-specific. The US label (Kinlytic) covers acute massive pulmonary embolism, with a loading dose of 4,400 IU/kg over 10 minutes followed by 4,400 IU/kg/h for 12 hours. Its half-life for biologic activity is 12.6 ± 6.2 minutes, but decreases in fibrinogen and plasminogen and increases in degradation products persist for 12 to 24 hours after the infusion. Urokinase has also been used for intra-arterial and catheter-directed infusion in peripheral arterial occlusion. Prourokinase (saruplase) is relatively fibrin-specific but was not adopted in the United States.

Alteplase: recombinant tissue plasminogen activator

Alteplase is recombinant human tPA, a 527-amino-acid glycoprotein with five domains: a fibronectin finger domain and an epidermal growth factor domain at the amino terminus, two kringle domains, and a serine protease domain. The finger and kringle 2 domains mediate fibrin binding, and the epidermal growth factor domain mediates hepatic clearance. Alteplase is fibrin-enhanced: it produces limited conversion of plasminogen in the absence of fibrin and initiates local fibrinolysis when bound to fibrin in a thrombus.

Alteplase is cleared rapidly by the liver, with an initial plasma half-life of less than 5 minutes and plasma clearance of 380 to 570 mL/min. Its short half-life requires a bolus followed by continuous infusion to maintain therapeutic concentrations, and the infusion schedule differs by indication. Because clearance depends on hepatic blood flow, low cardiac output prolongs exposure. Fibrinolytic activity falls quickly after the infusion stops, although effects on fibrinogen and on clot integrity outlast circulating drug.

Alteplase carries US labeling for acute ischemic stroke, acute myocardial infarction (to reduce mortality and the incidence of heart failure), and acute massive pulmonary embolism. A separate low-dose product (Cathflo Activase, 2 mg reconstituted in 2 mL) is labeled for restoring function to occluded central venous access devices. The myocardial infarction label carries a limitation of use: in patients at low risk of death from cardiac causes, the risk of stroke may outweigh the benefit.

The accelerated (front-loaded) regimen for STEMI was established in GUSTO-I. It consists of a 15-mg intravenous bolus, then 0.75 mg/kg over 30 minutes (maximum 50 mg), then 0.5 mg/kg over 60 minutes (maximum 35 mg), for a total of no more than 100 mg over 90 minutes. Patients above 67 kg receive the fixed 15-50-35 mg schedule. The older 3-hour regimen remains on the label: 60 mg in the first hour, including a 6- to 10-mg bolus, then 20 mg in each of the second and third hours, or 1.25 mg/kg over 3 hours in patients below 65 kg. It has no outcome comparison with the accelerated regimen. Intracranial hemorrhage rises with dose. In the label's pooled myocardial infarction data, intracranial hemorrhage occurred in 0.4% with the 100-mg 3-hour regimen, 0.7% with the accelerated regimen, and 1.3% with 150 mg, and a dose of 150 mg or more is not used. For stroke, doses above 0.9 mg/kg may increase intracranial hemorrhage.

Tenecteplase: bioengineered for bolus administration

Tenecteplase (TNK-tPA) is a 527-amino-acid variant of tPA with three modifications. In the kringle 1 domain, threonine 103 is replaced by asparagine, which adds a glycosylation site, and asparagine 117 is replaced by glutamine, which removes a high-mannose glycosylation site; together these changes slow hepatic clearance. In the protease domain, the tetra-alanine substitution at positions 296 to 299 (replacing lysine-histidine-arginine-arginine) confers resistance to PAI-1. The engineered molecule has slower plasma clearance, greater fibrin specificity, and higher PAI-1 resistance than alteplase.

After a single intravenous bolus in STEMI, tenecteplase shows biphasic disposition with a central volume of distribution approximating plasma volume (4.2 to 5.4 L), a terminal half-life of 90 to 130 minutes, and plasma clearance of 99 to 119 mL/min across 30- to 50-mg doses. Clearance is mainly hepatic. Body weight explains only 19% of the variability in clearance, which is why dosing uses five weight bands. The slower clearance allows a single bolus over 5 seconds, which reduces dosing errors and suits prehospital administration.

Tenecteplase has carried a US indication for reducing the risk of death in STEMI since 2000 and gained an indication for acute ischemic stroke in adults in 2025. In ASSENT-2, which randomized 16,949 patients within 6 hours of onset, tenecteplase and accelerated alteplase had equivalent 30-day mortality (6.18% and 6.15%) and identical intracranial hemorrhage rates (0.93% and 0.94%). Tenecteplase caused fewer noncerebral bleeding complications (26.43% against 28.95%) and less transfusion (4.25% against 5.49%). The five-band schedule in the label keeps the dose near 0.5 mg/kg across the weight range.

Reteplase: the double-bolus deletion mutant

Reteplase is a 355-amino-acid deletion mutant of tPA that retains only the kringle 2 and protease domains. It is produced in Escherichia coli and is not glycosylated. Loss of the finger domain lowers fibrin affinity, and loss of the epidermal growth factor domain and of glycosylation slows hepatic clearance. Clearance is partly renal. The effective half-life is 13 to 16 minutes, long enough for two 10-unit boluses given 30 minutes apart.

In GUSTO-III, which randomized 15,059 patients within 6 hours of onset, double-bolus reteplase did not reduce 30-day mortality compared with accelerated alteplase (7.47% against 7.24%); stroke rates (1.64% against 1.79%) and death or nonfatal disabling stroke (7.89% against 7.91%) were similar. Reteplase is therefore an alternative to alteplase without a survival advantage. Reteplase (Retavase) has been discontinued in the United States, where its sole supplier withdrew all presentations; it remains in use in other countries.

Comparative pharmacology of fibrinolytic agents

Pharmacology of fibrinolytic agents, from the current US prescribing information for alteplase and tenecteplase, the urokinase and reteplase product literature, and the pivotal trials. PAI-1, plasminogen activator inhibitor 1.

Dosing of fibrinolytic agents by indication

Doses differ by indication even for the same molecule, and a dose correct for one indication is an overdose for another: the tenecteplase dose for stroke is half the STEMI dose, and alteplase totals 100 mg for STEMI and pulmonary embolism but no more than 90 mg for stroke. Weight is measured or estimated before the dose is drawn; an underestimated weight undertreats, and an overestimated weight raises intracranial hemorrhage risk.

Fibrinolytic dosing by indication. ACC, American College of Cardiology; AHA, American Heart Association; ASA, American Stroke Association; aPTT, activated partial thromboplastin time; TEE, transesophageal echocardiography. Catheter-directed peripheral arterial and venous regimens are protocol-specific and are described with acute limb ischemia and deep vein thrombosis.

Fibrinolytic dose calculator

The calculator applies the weight bands and per-kilogram limits of the US labels and the regimens of the trials cited above. Age determines whether the calculator shows the half-dose tenecteplase option, the age-adjusted adjunctive therapy tested in older STEMI patients, and the age caution for pulmonary embolism thrombolysis.

STEMI: tenecteplase by the five label weight bands; accelerated alteplase 15 mg + 0.75 mg/kg (maximum 50 mg) + 0.5 mg/kg (maximum 35 mg). Pulmonary embolism: alteplase 100 mg over 2 hours; the alternative is the reduced 50-mg regimen (0.5 mg/kg below 50 kg). Stroke: tenecteplase 0.25 mg/kg (maximum 25 mg); alteplase 0.9 mg/kg (maximum 90 mg) with 10% as bolus. An 82-kg patient with STEMI receives 45 mg of tenecteplase or 100 mg of accelerated alteplase.

Preparation and administration of fibrinolytic agents

Tenecteplase is supplied as a lyophilized powder with sterile water and reconstituted to 5 mg/mL; the vial is swirled gently and not shaken, and the volume in milliliters is one-fifth of the dose in milligrams (45 mg is 9 mL). The 50-mg kit serves STEMI dosing, and a 25-mg vial is available for stroke dosing. Tenecteplase precipitates in dextrose-containing solutions, so a dextrose line is flushed with normal saline before and after the bolus. Reconstituted drug is used immediately or, if refrigerated, within 8 hours.

Alteplase is reconstituted to 1 mg/mL. The bolus is drawn from the vial or given from the infusion pump, and the remainder is infused by pump; any drug in the vial beyond the calculated dose is discarded before the infusion starts, so that a weight-based dose below 100 mg is not inadvertently infused as the full vial. No other medication is added to the alteplase infusion. Extravasation causes ecchymosis or inflammation and ends the infusion at that site.

All agents are given through a peripheral line when possible. Noncompressible punctures, including internal jugular and subclavian venous access and arterial puncture outside the upper extremity, are avoided; when an arterial puncture is unavoidable, an upper-extremity vessel is used with manual pressure for at least 30 minutes. Intramuscular injections are not given. Defibrillation, antiarrhythmic drugs, and atropine are immediately available, because reperfusion arrhythmias and bradycardia are expected. Vital signs and neurologic status are monitored frequently during the infusion and for the first 24 hours, the period of greatest intracranial hemorrhage risk.

Standardized order sets with indication-specific weight tables, independent double-checks, and storage that separates agents reduce dosing errors. Alteplase vials labeled for catheter clearance and reteplase doses written in units instead of milligrams are further sources of confusion.

Mortality benefit of fibrinolysis in STEMI and the influence of time

The Fibrinolytic Therapy Trialists' (FTT) overview of nine trials with 58,600 patients established the indications that still frame practice. Among about 45,000 patients with ST elevation or bundle branch block, fibrinolysis prevented about 30 deaths per 1,000 treated within 6 hours of onset and about 20 per 1,000 treated at 7 to 12 hours. Benefit at 13 to 18 hours (about 10 per 1,000) was statistically uncertain. Proportional benefit was similar across sex, blood pressure, heart rate, prior infarction, and diabetes; in patients 75 years and older, the absolute benefit was smaller and statistically less certain. Patients with ST depression did not benefit. Fibrinolysis caused an early excess of deaths on days 0 and 1 (greater in late presenters and older patients) and about 4 extra strokes per 1,000 in the first 2 days. A larger benefit over days 2 to 35 outweighed the early hazard.

The relation between time and benefit is steep in the first hours. In a reanalysis of 22 trials with 50,246 patients, fibrinolysis saved 65 lives per 1,000 treated within the first hour, 37 at 1 to 2 hours, 26 at 2 to 3 hours, and 29 at 3 to 6 hours, and the proportional mortality reduction was 44% within 2 hours against 20% later. Early fibrinolysis acts on fresh thrombus and salvageable myocardium; with delay, the drug mostly opens an artery supplying necrotic tissue.

Trials that defined the efficacy and safety of fibrinolytic agents in STEMI.

The benefit of primary PCI over fibrinolysis in the 2003 meta-analysis came from fewer reinfarctions, fewer strokes, and lower mortality, and it narrows as the delay to PCI lengthens. Fibrinolysis therefore remains a reperfusion strategy where timely primary PCI is not available, and it is most competitive in patients presenting within 2 to 3 hours of onset.

Fibrinolysis for STEMI when timely PCI is unavailable

The 2025 ACC/AHA/ACEP/NAEMSP/SCAI acute coronary syndrome guideline recommends fibrinolytic therapy for patients with STEMI whose symptoms began within 12 hours and in whom primary PCI is anticipated to be delayed by more than 120 minutes from first medical contact, when no contraindication exists (Class 1, Level A). The target from hospital arrival to fibrinolytic administration is 30 minutes or less. In patients with ST depression alone, fibrinolysis is not given because of hemorrhagic stroke and major noncerebral bleeding without benefit (Class 3: Harm), except when true posterior STEMI is suspected. Fibrinolysis is not used in non–ST-elevation acute coronary syndromes. System delays, time targets, and the choice between primary PCI and fibrinolysis are covered in ST-elevation myocardial infarction.

Between 12 and 24 hours from onset, transfer to a PCI-capable hospital for primary PCI is reasonable (2025 guideline, Class 2a, Level B-NR). The 2025 guideline makes no graded recommendation for fibrinolysis in this window; its text supports a fibrinolytic agent when timely primary PCI is not possible and the patient has hemodynamic instability or a large area of myocardium at risk. The 2013 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) STEMI guideline rated fibrinolysis as reasonable in this window only when PCI is unavailable and there is evidence of ongoing ischemia with a large area of myocardium at risk or hemodynamic instability (Class 2a, Level C). After 24 hours, fibrinolysis has no role.

A fibrin-specific agent is preferred over streptokinase. Tenecteplase is widely used because of single-bolus administration, equivalent efficacy to alteplase, and fewer noncerebral bleeds; alteplase is the alternative. The decision to give fibrinolysis is itself a commitment to transfer: after fibrinolysis, every patient is transferred to a PCI-capable center (Class 1, Level A).

European guidance differs in how delay is measured. The 2023 European Society of Cardiology (ESC) acute coronary syndrome guideline measures delay from the time of STEMI diagnosis: primary PCI is preferred when the anticipated time from diagnosis to wire crossing is 120 minutes or less, and fibrinolysis is otherwise given within 10 minutes of diagnosis. The 2025 ACC/AHA guideline measures from first medical contact. Both recommend transfer after fibrinolysis, rescue PCI for failed reperfusion, and angiography 2 to 24 hours after successful fibrinolysis.

The diagnosis is confirmed before the drug is given. Conditions that mimic STEMI on the electrocardiogram (ECG), including pericarditis, left ventricular aneurysm, early repolarization, Takotsubo syndrome, and hyperkalemia, gain nothing from fibrinolysis and are exposed to its full bleeding risk. Aortic dissection involving a coronary ostium, most often the right coronary artery, produces true inferior ST elevation; fibrinolysis in that setting extends the dissection and causes hemorrhage into the pericardium or mediastinum. Pain maximal at onset, a pulse or blood pressure differential, a new aortic regurgitation murmur, focal neurologic signs, or a widened mediastinum prompts imaging before any lytic agent.

Prehospital fibrinolysis delivers the drug at first medical contact, typically by paramedics or emergency physicians after transmitted ECG interpretation. It shortens the time to treatment compared with in-hospital fibrinolysis, most of all in rural systems with long transport times, and the single-bolus agents make it practical. In ASSENT-3 PLUS, which randomized 1,639 patients to prehospital tenecteplase with enoxaparin or unfractionated heparin, 53% of patients received treatment within 2 hours of symptom onset. The trial also identified the hazard of full-dose enoxaparin in older patients: intracranial hemorrhage was 2.20% with enoxaparin against 0.97% with heparin, with the excess confined to patients older than 75 years, which led to the age-adjusted enoxaparin regimen used today.

Prehospital fibrinolysis is used in regions where transport times to a PCI-capable center are long, including much of rural North America, Scandinavia, and France. In the United States, most systems bypass non-PCI hospitals or transfer for primary PCI, and prehospital fibrinolysis is uncommon outside remote regions. The STREAM trials tested prehospital or early fibrinolysis as part of a pharmacoinvasive strategy.

Pharmacoinvasive strategy, facilitated PCI, and the STREAM trials

A pharmacoinvasive strategy is fibrinolysis followed by transfer for angiography: immediate rescue PCI when reperfusion fails and routine angiography with PCI as indicated 2 to 24 hours later when it succeeds. It differs from facilitated PCI, in which a full- or reduced-dose lytic is given immediately before planned primary PCI. Facilitated PCI was harmful. In ASSENT-4 PCI, full-dose tenecteplase given a median of 104 minutes before PCI increased death, heart failure, or shock at 90 days (19% against 13%), in-hospital mortality (6% against 3%), strokes (1.8% against 0%), reinfarction, and repeat target-vessel revascularization. The trial stopped early. In FINESSE, half-dose reteplase with abciximab before PCI did not improve outcomes compared with primary PCI (primary end point 9.8% against 10.7%). Fibrinolysis is therefore given only when primary PCI cannot be achieved in time, never as a bridge to PCI that is already available.

In STREAM, 1,892 patients presenting within 3 hours of onset who could not undergo primary PCI within 1 hour were randomized to prehospital or early tenecteplase with clopidogrel and enoxaparin, or to primary PCI. The fibrinolysis group underwent angiography 6 to 24 hours later, or emergency angiography for failed fibrinolysis. The 30-day composite of death, shock, heart failure, or reinfarction occurred in 12.4% and 14.3%. Intracranial hemorrhage was more frequent with fibrinolysis (1.0% against 0.2%); after the dose was halved in patients 75 years and older, the rates were 0.5% against 0.3%. About one-third of the fibrinolysis group needed emergency angiography.

STREAM-2 extended the strategy to older patients. In 604 patients 60 years and older with ST elevation of 2 mm or more in two contiguous leads who could not undergo primary PCI within 1 hour, half-dose tenecteplase followed by angiography 6 to 24 hours later produced ST resolution at least comparable to primary PCI (85.2% against 78.4% with 50% or greater resolution after the last angiogram). TIMI grade 3 flow was about 87% in both groups, and the 30-day composite was similar (12.8% against 13.3%). Six intracranial hemorrhages occurred with tenecteplase (1.5%), three of them after protocol violations (excess anticoagulation in two and uncontrolled hypertension in one), and none with primary PCI. In a pooled analysis of patients 75 years and older from both trials, half-dose and full-dose tenecteplase produced similar ST resolution (63.2% and 62.6%) with intracranial hemorrhage of 0% against 7.1%.

The US label specifies full weight-based dosing. Half-dose tenecteplase in patients 75 years and older rests on the STREAM amendment and STREAM-2 and is used in many pharmacoinvasive protocols. The practical management of transfer, timing, and the decision for rescue PCI is described in ST-elevation myocardial infarction.

Assessment of reperfusion after fibrinolysis

Reperfusion is assessed 60 to 90 minutes after the lytic is given. The standard noninvasive marker is ST-segment resolution, measured in the lead with the greatest initial elevation or as the sum of ST elevation across the involved leads, at the J point relative to the PR or TP baseline. In US guidance, resolution of 50% or more in anterior infarction and 70% or more in inferior infarction, together with relief of ischemic pain and hemodynamic and electrical stability, indicates successful reperfusion. Lesser resolution, persistent or recurrent pain, or instability indicates failed reperfusion. The REACT trial defined failure as less than 50% resolution at 90 minutes.

Complete ST resolution predicts TIMI grade 3 flow and low mortality, but ST resolution and angiographic patency diverge. Partial resolution can coexist with an open epicardial artery and microvascular obstruction, and a patent artery with impaired myocardial perfusion carries a worse prognosis than one with full tissue-level reperfusion. ST resolution is therefore a triage tool that selects patients for rescue angiography; it does not substitute for angiography, which all patients undergo.

Supporting markers include accelerated idioventricular rhythm, an early and high peak of troponin or creatine kinase from washout of the reperfused territory, and abrupt relief of pain. Accelerated idioventricular rhythm, a ventricular rhythm at 50 to 110 beats per minute that often appears within minutes of reperfusion, is specific but not sensitive; it is benign, usually self-limited, and is observed without suppression. Pain relief is unreliable after opioids, and transient hypotension with streptokinase lowers myocardial oxygen demand without reperfusion. Sustained ventricular tachycardia or fibrillation after fibrinolysis indicates ongoing ischemia and is not counted as a reperfusion marker. A prior bundle branch block or ventricular pacing prevents assessment by ST resolution, and these patients are managed by clinical criteria and early angiography.

Rescue PCI and routine angiography after fibrinolysis

When failed reperfusion is suspected, immediate angiography with rescue PCI is recommended to reduce death or recurrent infarction (Class 1, Level B-R). In REACT, 427 patients with less than 50% ST resolution at 90 minutes were randomized to repeat fibrinolysis, conservative care, or rescue PCI. Event-free survival at 6 months (free of death, reinfarction, stroke, or severe heart failure) was 84.6% with rescue PCI, 70.1% with conservative care, and 68.7% with repeat fibrinolysis. Repeat fibrinolysis gave no benefit over conservative therapy and added bleeding; it is not used. Rescue PCI increases access-site bleeding, which radial access reduces.

When fibrinolysis succeeds, early angiography with the intent to perform PCI between 2 and 24 hours after the lytic is recommended to reduce death or myocardial infarction (Class 1, Level B-R). The basis is a series of trials. In TRANSFER-AMI, routine transfer for PCI within 6 hours of fibrinolysis in high-risk patients reduced the 30-day composite of death, reinfarction, recurrent ischemia, new or worsening heart failure, or shock from 17.2% to 11.0% without more major bleeding. The 2-hour lower limit reflects the period of greatest thrombotic and bleeding risk after lysis, as shown by the harm of facilitated PCI. The 24-hour upper limit reflects the risk of reocclusion of a residual stenosis on a recently lysed, platelet-activated plaque. Reocclusion after successful fibrinolysis presents as recurrent pain with new ST elevation and leads to immediate angiography.

Patients with cardiogenic shock or acute severe heart failure after fibrinolysis undergo emergency angiography regardless of the time since the lytic.

Adjunctive antiplatelet therapy with fibrinolysis

Aspirin. In ISIS-2, aspirin 160 mg daily reduced vascular mortality by about one-quarter on its own and added to the benefit of streptokinase. Aspirin (162 to 325 mg chewed as a loading dose, then 81 mg daily) is given to every patient receiving fibrinolysis.

Clopidogrel. Clopidogrel is the P2Y12 inhibitor recommended with fibrinolysis, given concurrently to reduce death and major adverse cardiovascular events (Class 1, Level A). Patients younger than 75 years receive a 300-mg loading dose and 75 mg daily; patients 75 years and older receive 75 mg without a loading dose. In CLARITY-TIMI 28, which enrolled 3,491 patients 18 to 75 years old, clopidogrel added to aspirin and fibrinolysis reduced the composite of an occluded infarct-related artery on angiography, death, or reinfarction from 21.7% to 15.0%. It also reduced cardiovascular death, reinfarction, or recurrent ischemia leading to urgent revascularization at 30 days from 14.1% to 11.6%, without more major bleeding or intracranial hemorrhage. In COMMIT, clopidogrel 75 mg daily without a loading dose was given to 45,852 Chinese patients, about half of whom received fibrinolysis. It reduced death, reinfarction, or stroke from 10.1% to 9.2% and death from 8.1% to 7.5%, with no excess in fatal, transfused, or cerebral bleeding, including in patients older than 70 years and those given fibrinolysis.

Ticagrelor and prasugrel. Neither has been tested as a concurrent adjunct to fibrinolysis. In TREAT, 3,799 patients younger than 75 years were switched to ticagrelor or continued on clopidogrel a median of 11.4 hours after fibrinolysis (90% pretreated with clopidogrel). TIMI major bleeding at 30 days was 0.73% against 0.69%, meeting noninferiority, and intracranial bleeding was 0.42% against 0.37%. When PCI follows fibrinolysis, clopidogrel is continued; in patients younger than 75 years, ticagrelor can be used within 24 hours of the lytic; prasugrel is an option after 24 hours in patients without prior stroke or transient ischemic attack.

Glycoprotein IIb/IIIa inhibitors. Combining a reduced-dose lytic with a glycoprotein IIb/IIIa inhibitor improved early patency in angiographic studies but did not reduce mortality, and it increased bleeding, particularly in older patients. In ASSENT-3, half-dose tenecteplase with abciximab and low-dose heparin reduced the 30-day composite of death, in-hospital reinfarction, or refractory ischemia compared with full-dose tenecteplase and heparin (11.1% against 15.4%), as did full-dose tenecteplase with enoxaparin (11.4%). The abciximab regimen increased major bleeding and was not adopted. Glycoprotein IIb/IIIa inhibitors are not given with fibrinolysis; during PCI after fibrinolysis, they are reserved for bailout of large thrombus or no-reflow.

Adjunctive anticoagulation with fibrinolysis

A parenteral anticoagulant is given with fibrinolysis and continued for the hospital stay, to a maximum of 8 days, or until revascularization (Class 1, Level A). The anticoagulant prevents rethrombosis on the lysed clot, which is a strong stimulus to thrombin generation. For patients in whom no invasive approach is planned, enoxaparin is the recommended anticoagulant (Class 1, Level A), and fondaparinux is a recommended alternative (Class 1, Level B-R). In current pharmacoinvasive practice, enoxaparin or unfractionated heparin is chosen with the transfer and catheterization plan in view.

Parenteral anticoagulation with fibrinolytic therapy for STEMI, after the 2013 ACCF/AHA STEMI guideline and the 2025 ACC/AHA/ACEP/NAEMSP/SCAI acute coronary syndrome guideline.

Evidence. ExTRACT-TIMI 25 randomized 20,506 patients receiving fibrinolysis (mostly streptokinase or alteplase) to enoxaparin for the hospitalization or weight-based unfractionated heparin for at least 48 hours. Death or nonfatal reinfarction at 30 days occurred in 9.9% with enoxaparin and 12.0% with heparin. Nonfatal reinfarction fell from 4.5% to 3.0%, mortality did not differ significantly (6.9% against 7.5%), and major bleeding rose from 1.4% to 2.1%. Net clinical benefit, measured as death, nonfatal reinfarction, or nonfatal intracranial hemorrhage, favored enoxaparin (10.1% against 12.2%). The age-adjusted regimen (no bolus and 0.75 mg/kg at age 75 years and older) was designed after the intracranial hemorrhage excess in ASSENT-3 PLUS. The enoxaparin arm also benefited from a longer duration of anticoagulation, which accounts for part of the difference.

In OASIS-6, fondaparinux 2.5 mg daily for up to 8 days in 12,092 patients with STEMI reduced death or reinfarction at 30 days from 11.2% to 9.7%, with benefit in patients given fibrinolysis (hazard ratio 0.79) and those given no reperfusion therapy (hazard ratio 0.80), and no benefit in those undergoing primary PCI. Most fibrinolysis in OASIS-6 used streptokinase. Fondaparinux is not used alone during PCI because guiding-catheter thrombosis occurred in the trial.

Heparin during alteplase for pulmonary embolism. The pulmonary embolism protocol differs from the STEMI protocol. Parenteral anticoagulation is withheld during the 2-hour alteplase infusion and started near the end of or immediately after it, when the aPTT or thrombin time returns to twice normal or less. After thrombolytic therapy, low-molecular-weight heparin is preferred over unfractionated heparin for initial parenteral anticoagulation (2026 AHA/ACC guideline, Class 1, Level B-NR).

Fibrinolysis in cardiogenic shock, cardiac arrest, and right ventricular infarction

Fibrinolysis is less effective in cardiogenic shock: low perfusion pressure limits delivery of the drug into the thrombus, and the patency rate falls. In the SHOCK trial, early revascularization improved long-term survival compared with initial medical stabilization, which included fibrinolysis in most patients. Emergency revascularization is the strategy for STEMI with cardiogenic shock regardless of time from onset (Class 1). When transfer for PCI is not possible within a reasonable time, fibrinolysis is given to patients in shock without contraindications, with transfer to a PCI-capable center that offers mechanical circulatory support.

In undifferentiated out-of-hospital cardiac arrest, routine fibrinolysis during resuscitation did not help. TROICA randomized 1,050 patients with witnessed arrest of presumed cardiac origin to tenecteplase or placebo during cardiopulmonary resuscitation. Survival at 30 days was 14.7% against 17.0%, return of spontaneous circulation and neurologic outcome did not differ, and intracranial hemorrhage was more frequent with tenecteplase. Fibrinolysis during cardiac arrest is reserved for confirmed or strongly suspected pulmonary embolism, in which it is reasonable as one of several reperfusion options (2026 AHA/ACC pulmonary embolism guideline, Class 2a for category E). After return of circulation in STEMI, emergency angiography is preferred; prolonged or traumatic resuscitation, with rib fractures or pulmonary contusion, is a relative contraindication to fibrinolysis that is weighed against the available alternative.

Right ventricular infarction complicating inferior STEMI has higher in-hospital mortality. The indication for fibrinolysis is unchanged when PCI is not available in time. Management addresses preload, atrioventricular synchrony, and the hypotension and bradycardia that accompany reperfusion of the right coronary artery.

Systemic thrombolysis for high-risk pulmonary embolism

Thrombolysis in pulmonary embolism lowers pulmonary artery pressure and right ventricular afterload within hours, whereas anticoagulation alone prevents clot extension and relies on endogenous fibrinolysis over days to weeks. The 2026 AHA/ACC multisociety pulmonary embolism guideline grades patients in clinical categories A to E and assigns the reperfusion options by category. Systemic thrombolysis is reasonable in category E (cardiopulmonary failure, including cardiogenic shock and cardiac arrest; Class 2a), may be considered in categories C3 and D (Class 2b), and is harmful in lower categories (Class 3: Harm). Category definitions, the role of the pulmonary embolism response team, and the choice among systemic, catheter-directed, mechanical, and surgical therapy are covered in Pulmonary embolism.

The US-labeled regimen is alteplase 100 mg infused over 2 hours for acute massive pulmonary embolism, defined in the label as emboli obstructing blood flow to a lobe or multiple segments, or emboli with unstable hemodynamics. An accelerated regimen of 0.6 mg/kg (maximum 50 mg) over 15 minutes is used in cardiac arrest or imminent arrest. Tenecteplase in the STEMI weight bands was the agent in PEITHO and is used off label. Urokinase and streptokinase regimens are labeled or historical alternatives. Thrombolysis is most effective when given within 48 hours of symptom onset but has benefit in patients with symptoms for up to 14 days. The 2019 ESC guideline recommends systemic thrombolysis for high-risk (hemodynamically unstable) embolism and rescue thrombolysis for intermediate-risk patients who deteriorate on anticoagulation.

In PEITHO, 1,005 normotensive patients with right ventricular dysfunction and a positive troponin were randomized to tenecteplase or placebo with heparin. Death or hemodynamic decompensation within 7 days fell from 5.6% to 2.6%, driven by fewer decompensations, but mortality did not differ at 7 days (1.2% against 1.8%) or 30 days (2.4% against 3.2%). Major extracranial bleeding occurred in 6.3% against 1.2% and stroke in 2.4% against 0.2%, with 10 of the 12 strokes in the tenecteplase group hemorrhagic. In a meta-analysis of 16 trials, thrombolysis lowered all-cause mortality (odds ratio 0.53) at the cost of major bleeding (9.24% against 3.42%) and intracranial hemorrhage (1.46% against 0.19%), with the bleeding excess concentrated in patients older than 65 years. These data underlie the practice of reserving systemic thrombolysis for patients with hemodynamic compromise, or for normotensive patients who deteriorate, and of using it with caution in older patients.

The pulmonary embolism label adds two cautions. Thrombolysis does not treat the underlying deep vein thrombosis, and re-embolization from lysed venous thrombus is possible. In patients with a left heart thrombus, as in mitral stenosis or atrial fibrillation, lysis may cause systemic embolism. Thrombus in transit in the right heart and a straddling thrombus across a patent foramen ovale are treated by a multidisciplinary team, with systemic thrombolysis or surgical embolectomy as options.

Reduced-dose and catheter-directed thrombolysis

Reduced-dose systemic thrombolysis. Reduced-dose regimens aim to preserve hemodynamic benefit with less bleeding. MOPETT was a small open-label trial. In it, 121 patients with "moderate" pulmonary embolism received 50 mg of alteplase (0.5 mg/kg below 50 kg; a 10-mg bolus followed by the remainder over 2 hours) with reduced-dose heparin or anticoagulation alone. Pulmonary hypertension at follow-up was less frequent with thrombolysis, and no major bleeding occurred. The 2026 AHA/ACC guideline states that reduced-dose regimens may be considered to reduce bleeding (Class 2b). PEITHO-3 (NCT04430569) is testing reduced-dose alteplase against placebo for clinical outcomes in normotensive patients at elevated risk.

Catheter-directed thrombolysis. Catheter-directed thrombolysis delivers a small dose of alteplase, typically 5 to 10 mg per pulmonary artery over hours, through multi–side-hole catheters in one or both pulmonary arteries, with or without ultrasound to disperse fibrin. The total dose is a fraction of the systemic dose, and the aim is to reduce bleeding. In ULTIMA, ultrasound-assisted infusion of 10 to 20 mg over 15 hours reduced the right ventricular to left ventricular diameter ratio at 24 hours more than heparin alone (0.30 against 0.03) without major bleeding. In SEATTLE II, a single-arm study of 150 patients, 24 mg over 12 to 24 hours lowered the ratio from 1.55 to 1.13 and pulmonary artery systolic pressure from 51 to 37 mm Hg, with 10% moderate or severe bleeding and no intracranial hemorrhage.

In HI-PEITHO, 544 patients with intermediate-high-risk embolism and at least two markers of cardiorespiratory distress were randomized to ultrasound-facilitated catheter-directed thrombolysis with anticoagulation or anticoagulation alone. Pulmonary embolism–related death, cardiorespiratory decompensation, or recurrence at 7 days occurred in 4.0% against 10.3%, major bleeding at 30 days in 4.1% against 3.0%, and no intracranial hemorrhage occurred.

Doses below 5 mg per artery are not recommended over 5 to 10 mg (Class 3: No Benefit). During catheter-directed thrombolysis, therapeutic low-molecular-weight or unfractionated heparin, or subtherapeutic unfractionated heparin, is recommended over no anticoagulation (Class 1). Mechanical thrombectomy, which removes clot without a lytic, and its comparison with catheter-directed thrombolysis are described in Pulmonary embolism.

Other catheter-directed uses. Catheter-directed thrombolysis for acute limb ischemia, with alteplase or urokinase infused into the thrombus, is an option for viable or marginally threatened limbs with recent occlusion; patient selection, regimens, and comparison with surgery are covered with acute limb ischemia and arterial embolism. For proximal deep vein thrombosis, the ATTRACT trial randomized 692 patients to pharmacomechanical catheter-directed thrombolysis with anticoagulation or anticoagulation alone. Post-thrombotic syndrome at 6 to 24 months did not differ (47% against 48%), major bleeding within 10 days was higher (1.7% against 0.3%), and moderate-to-severe post-thrombotic syndrome was less frequent (18% against 24%). Catheter-directed venous thrombolysis is therefore reserved for selected patients with extensive iliofemoral thrombosis, severe symptoms, or limb threat.

Thrombolysis for prosthetic valve thrombosis

Obstructive thrombosis of a mechanical valve presents with dyspnea, heart failure, embolism, or shock, with muffled closing clicks, a rising gradient, and restricted leaflet motion on fluoroscopy or echocardiography. For a thrombosed left-sided mechanical valve with symptoms of obstruction, the 2020 ACC/AHA valvular heart disease guideline recommends urgent initial treatment with either slow-infusion, low-dose fibrinolytic therapy or emergency surgery (Class 1), chosen by the heart valve team with the patient. Factors favoring fibrinolysis include high surgical risk or no surgical expertise, a first episode, New York Heart Association (NYHA) class I to III, a small thrombus (0.8 cm² or less), no left atrial thrombus, and a thrombus visualized without pannus. Factors favoring surgery include low surgical risk, a contraindication to fibrinolysis, recurrent thrombosis, NYHA class IV, a large thrombus, left atrial thrombus, concomitant coronary or valve disease requiring surgery, and possible pannus. In pregnancy, slow-infusion, low-dose fibrinolysis is reasonable for hemodynamically stable obstructive left-sided mechanical valve thrombosis (Class 2a).

Contemporary regimens use alteplase without a bolus at low dose and slow rate under serial transesophageal echocardiographic guidance. In the TROIA series, 25 mg was infused over 6 hours and repeated as needed. In PROMETEE, 25 mg infused over 25 hours and repeated when needed achieved success in 90% of 120 episodes in 114 patients, with an overall complication rate of 6.7% (3.3% nonfatal major, 2.5% minor, and 0.8% death). Higher NYHA class was the only independent predictor of failure. Echocardiography-guided, low-dose protocols have achieved hemodynamic success above 90% with embolic and major bleeding rates each below 2%, results better than those of earlier high-dose, rapid regimens. Heparin is withheld during the infusion and resumed after it, and warfarin is restarted with a review of the anticoagulation target and adherence. Bioprosthetic valve thrombosis is treated first with a vitamin K antagonist in stable patients. Pannus does not respond to fibrinolysis. Diagnosis of thrombus versus pannus, imaging, and surgical options are covered in Prosthetic heart valves.

Right-sided mechanical valve thrombosis, in the tricuspid or pulmonary position, carries a lower systemic embolic consequence, and fibrinolysis is the usual initial treatment in place of reoperation.

Fibrinolysis in acute ischemic stroke: agents, dosing, and eligibility

Cardiologists encounter thrombolysis for stroke in patients with atrial fibrillation, after cardiac procedures, with prosthetic valves, and with recent myocardial infarction. The 2026 AHA/ASA guideline for the early management of acute ischemic stroke endorses tenecteplase 0.25 mg/kg (maximum 25 mg) or alteplase 0.9 mg/kg (maximum 90 mg) for disabling stroke within 4.5 hours of onset or last known well, with the two agents given equal standing (Class 1). Tenecteplase 0.4 mg/kg is not recommended. Patients 4.5 to 9 hours from last known well, or who wake with symptoms within 9 hours of the midpoint of sleep, who have salvageable penumbra on automated perfusion imaging and are not candidates for thrombectomy also benefit from thrombolysis (Class 2a). Thrombolysis is not given for mild, nondisabling deficits.

In AcT, 1,600 patients within 4.5 hours of onset were randomized to tenecteplase 0.25 mg/kg or alteplase; an excellent outcome (modified Rankin Scale 0 to 1 at 90 to 120 days) occurred in 36.9% against 34.8%, meeting noninferiority, and symptomatic intracranial hemorrhage occurred in 3.4% against 3.2%. In the pivotal alteplase stroke trials, symptomatic intracranial hemorrhage within 36 hours occurred in 6.4% against 0.6% with placebo, with no increase in 90-day mortality. Blood pressure is lowered to 185/110 mm Hg or lower before treatment and kept below 180/105 mm Hg for 24 hours afterward.

The stroke eligibility criteria differ from those for STEMI. Coagulation results are not awaited in patients without recent anticoagulant use; treatment is not given (or the alteplase infusion is stopped) if the international normalized ratio exceeds 1.7 or the aPTT is elevated. Recent direct oral anticoagulant use is a contraindication unless drug-specific testing or timing excludes a clinically relevant effect. Antiplatelet and anticoagulant drugs are generally withheld for 24 hours after stroke thrombolysis, in contrast to their mandatory use with STEMI fibrinolysis.

Conditions of cardiac origin call for particular caution. Stroke from infective endocarditis carries a high risk of hemorrhagic transformation and mycotic aneurysm rupture, and thrombolysis is avoided. Stroke with acute aortic dissection, in which carotid malperfusion mimics embolic stroke, is a contraindication. A mechanical heart valve does not by itself exclude stroke thrombolysis; eligibility follows the anticoagulant status, so a therapeutic international normalized ratio excludes it.

Absolute and relative contraindications to fibrinolysis

Contraindications are graded by the risk of intracranial or fatal bleeding. An absolute contraindication means fibrinolysis is not given, and for STEMI the patient is transferred for primary PCI regardless of the delay. A relative contraindication is weighed against the expected benefit, which is largest with a large anterior infarction presenting early, with shock or cardiac arrest from pulmonary embolism, and with obstructive mechanical valve thrombosis and high surgical risk.

Contraindications to fibrinolytic therapy in STEMI, after the 2013 ACCF/AHA STEMI guideline (Table 6) and the 2025 ACC/AHA/ACEP/NAEMSP/SCAI acute coronary syndrome guideline (Table 14), which omits the streptokinase item and defines severe uncontrolled hypertension as systolic pressure above 180 mm Hg or diastolic pressure above 110 mm Hg unresponsive to therapy. The tenecteplase label also lists current severe uncontrolled hypertension, a known bleeding diathesis, intracranial or intraspinal surgery or trauma within 2 months, and intracranial neoplasm, arteriovenous malformation, or aneurysm as contraindications.

Hypertension that falls below 180/110 mm Hg with treatment converts an absolute concern into a relative one, but the excess intracranial hemorrhage risk associated with presenting hypertension persists. "Recent" internal bleeding covers gastrointestinal and genitourinary bleeding within 2 to 4 weeks. Menstruation is not a contraindication. The alteplase and tenecteplase labels add conditions in which bleeding risk is increased and weighed against benefit: recent major surgery or procedure (including coronary bypass grafting, obstetric delivery, and organ biopsy), cerebrovascular disease, recent gastrointestinal or genitourinary bleeding, recent trauma, systolic pressure above 175 mm Hg or diastolic pressure above 110 mm Hg, acute pericarditis, subacute bacterial endocarditis, hemostatic defects including those of severe hepatic or renal disease, significant hepatic dysfunction, pregnancy, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis, advanced age, and current anticoagulant therapy. Pericarditis presenting as ST elevation is a diagnosis to exclude before fibrinolysis, because hemorrhagic pericardial effusion and tamponade follow.

Absolute and relative contraindications after the 2013 ACCF/AHA STEMI guideline (Table 6) and the 2011 AHA scientific statement on pulmonary embolism. Age above 75 years is listed as a relative contraindication for pulmonary embolism thrombolysis; in STEMI it is a determinant of dose and adjunctive therapy. The checklist does not cover acute ischemic stroke, which has its own eligibility criteria.

Differences in contraindications by indication

The same agent carries different contraindication lists for different indications because the alternatives and the stakes differ. For STEMI, the alternative is primary PCI, so even relative contraindications usually favor transfer. For pulmonary embolism with cardiac arrest, the alternative may be death, so absolute contraindications are weighed against the risk of death. For stroke, the brain is both the target organ and the site of potential hemorrhage, so criteria are stricter on blood pressure, anticoagulation, glucose, and imaging.

Indication-specific differences, after the 2013 ACCF/AHA STEMI guideline, the 2025 ACC/AHA acute coronary syndrome guideline, the 2026 AHA/ACC pulmonary embolism guideline, the 2011 AHA scientific statement on pulmonary embolism, the 2026 AHA/ASA acute ischemic stroke guideline, and the US labels. INR, international normalized ratio.

Intracranial hemorrhage after fibrinolysis: incidence and risk factors

Intracranial hemorrhage occurs in about 0.5% to 1% of patients treated with fibrinolysis for STEMI in trials (0.93% with tenecteplase and 0.94% with alteplase in ASSENT-2) and in more than 1% of older patients in practice. Most hemorrhages are intraparenchymal and occur within the first 24 hours, many within hours of the drug. Most patients with intracranial hemorrhage after fibrinolysis die or are left disabled.

In a Medicare cohort of 31,732 patients 65 years and older treated with fibrinolysis for myocardial infarction, intracranial hemorrhage occurred in 1.43%. Independent predictors were age 75 years or older, female sex, Black race, prior stroke, systolic blood pressure of 160 mm Hg or higher, alteplase (against other agents), excessive anticoagulation (international normalized ratio of 4 or more or prothrombin time of 24 seconds or more), and below-median body weight (65 kg or less for women, 80 kg or less for men). The rate rose from 0.69% with none or one factor to 1.02% with two, 1.63% with three, 2.49% with four, and 4.11% with five or more.

Intracranial hemorrhage after fibrinolysis by setting. Rates are not comparable across rows because definitions, imaging, and populations differ.

The modifiable risk factors are dose (weight-based dosing and half-dose tenecteplase in older STEMI patients), blood pressure (control before and after the lytic), concurrent anticoagulant intensity (age-adjusted enoxaparin and weight-based heparin without overshoot), and patient selection. Three of the six intracranial hemorrhages in STREAM-2 followed protocol violations, which shows how much of the residual risk lies in adjunctive therapy.

Management of intracranial hemorrhage after fibrinolysis

Any acute neurologic change during or within 24 hours of fibrinolysis, including headache, vomiting, confusion, a fall in consciousness, or a new focal deficit, is managed as intracranial hemorrhage until emergency noncontrast computed tomography (CT) excludes it. Management is based on expert consensus and small series; no randomized trial has tested reversal strategies.

Management of symptomatic intracranial hemorrhage after fibrinolysis, after the 2017 AHA/ASA scientific statement on hemorrhagic transformation after alteplase and the 2026 AHA/ASA acute ischemic stroke guideline. The 2017 statement and earlier guidance used a fibrinogen threshold of 200 mg/dL for repeat cryoprecipitate.

Fibrinogen is the central target because fibrinolysis consumes it and fibrin degradation products impair clot formation. Cryoprecipitate provides fibrinogen and factor VIII. Fibrinogen concentrate is used where available as an alternative source. Fresh frozen plasma corrects factor deficiencies but supplies fibrinogen inefficiently. Antifibrinolytic agents inhibit the binding of plasminogen to fibrin and halt ongoing lysis, but they also stop lysis of the original coronary or pulmonary thrombus, which is accepted in a life-threatening bleed. When intracranial hemorrhage occurs after STEMI fibrinolysis, aspirin, the P2Y12 inhibitor, and anticoagulation are all withheld, and the coronary artery is managed with these restrictions in view.

Major extracranial bleeding after fibrinolysis

Most bleeding after fibrinolysis is extracranial. Access sites, the gastrointestinal tract, the genitourinary tract, the retroperitoneum, and recent surgical or traumatic wounds are the usual sources. In ASSENT-2, noncerebral bleeding complications of any severity occurred in 26% to 29% of patients and transfusion in 4% to 5%. Major bleeding with enoxaparin in ExTRACT-TIMI 25 was 2.1%, and major extracranial bleeding with tenecteplase in PEITHO was 6.3%. Bleeding risk rises with rescue or routine PCI after lysis, especially through femoral access.

Minor bleeding at puncture sites is controlled with manual pressure and does not require stopping therapy. Moderate or major bleeding leads to discontinuation of the lytic infusion and of heparin and to assessment of hemoglobin, platelets, fibrinogen, and coagulation tests. Transfusion follows standard thresholds and hemodynamic status. Cryoprecipitate is given for a low fibrinogen, antifibrinolytic therapy for persistent bleeding, and protamine for recent unfractionated heparin. Endoscopic, radiologic, or surgical control is applied to a localized source. Retroperitoneal hemorrhage, suspected with hypotension, back or flank pain, or a falling hemoglobin after femoral access, is confirmed by CT. Because tenecteplase has a terminal half-life of 90 to 130 minutes and alteplase effects persist beyond the infusion, bleeding risk does not end when the drug is stopped. Hemorrhage can also occur 1 or more days after administration while anticoagulant therapy continues.

Hypersensitivity, hypotension, embolization, reperfusion arrhythmias, and myocardial rupture

Hypersensitivity and angioedema. Allergic reactions to streptokinase range from fever and rash to anaphylaxis, and repeat exposure is avoided. Hypersensitivity, including anaphylaxis, laryngeal edema, rash, and urticaria, is reported with alteplase and tenecteplase. Orolingual angioedema occurs during and up to 2 hours after alteplase infusion, more often in patients taking angiotensin-converting enzyme inhibitors and in stroke patients; it occurred in 1.0% with tenecteplase and 1.4% with alteplase among patients treated within 3 hours in AcT. The infusion is stopped, the airway is assessed, and antihistamine and corticosteroid therapy are given; bradykinin-directed therapy (icatibant or C1-esterase inhibitor) has been used in refractory cases.

Hypotension. Streptokinase causes hypotension through plasmin-mediated bradykinin generation, most often during rapid infusion. It is treated by slowing or pausing the infusion, elevating the legs, and giving fluid; it does not indicate an allergic reaction. Hypotension with fibrin-specific agents raises suspicion of bleeding, right ventricular infarction, or a mechanical complication.

Embolization. Lysis of a left atrial or left ventricular thrombus can release fragments into the systemic circulation. Lysis of venous thrombus in patients with pulmonary embolism can produce re-embolization. Cholesterol embolization, with livedo reticularis, "purple toe," acute kidney injury, or bowel ischemia, is reported rarely after fibrinolysis, usually in association with invasive vascular procedures.

Reperfusion arrhythmias. Accelerated idioventricular rhythm, ventricular premature beats, and sinus bradycardia with hypotension (from the Bezold-Jarisch reflex, typically with reperfusion of the inferior wall) accompany reperfusion. They are generally benign. Ventricular fibrillation within the first hours reflects ischemia or reperfusion injury and is treated by defibrillation. Antiarrhythmic prophylaxis is not given.

Myocardial rupture. Fibrinolysis given late, beyond 12 hours, has been associated with earlier free-wall rupture. Rupture is one proposed contributor to the early excess of deaths on days 0 and 1 in the FTT overview, and the association is one reason fibrinolysis is not extended beyond 12 to 24 hours.

Laboratory effects of fibrinolytic therapy

Fibrinolysis produces predictable changes in coagulation tests. Fibrinogen falls (4% to 15% with tenecteplase, 16% to 36% with alteplase, and much more with streptokinase), while degradation products of fibrinogen and fibrin, including D-dimer, rise sharply. The aPTT and thrombin time are prolonged by fibrinogen depletion and by degradation products as well as by heparin, which complicates heparin titration in the first hours. Plasminogen and alpha-2-antiplasmin fall in proportion to the systemic lytic effect.

Laboratory samples drawn during therapy can mislead. Fibrinolytic agents remain active in the collection tube and continue to degrade fibrinogen in vitro, so fibrinogen measured in a sample drawn during therapy can be falsely low unless specific precautions against in vitro lysis are taken. A fibrinogen level drawn after a serious bleed is nonetheless used to guide replacement. No laboratory test predicts intracranial hemorrhage or verifies reperfusion. Routine monitoring of fibrinogen after STEMI fibrinolysis is not required; monitoring is used in prosthetic valve thrombolysis and in prolonged catheter-directed infusions, where serial fibrinogen levels guide the rate.

Special populations: older adults, women, pregnancy, anticoagulated patients, and kidney disease

Older adults. Absolute mortality reduction with fibrinolysis is preserved in older patients because their baseline risk is high, but the intracranial hemorrhage risk is higher. Patients 75 years and older receive clopidogrel without a loading dose, enoxaparin at 0.75 mg/kg without an intravenous bolus, and, under pharmacoinvasive protocols informed by STREAM and STREAM-2, half-dose tenecteplase. Primary PCI is preferred when timely. In pulmonary embolism, the bleeding excess with thrombolysis is concentrated in patients older than 65 years, and age above 75 years is a relative contraindication.

Women and low body weight. Female sex and low body weight are independent predictors of intracranial hemorrhage, largely through excess dose per kilogram with fixed-dose anticoagulants. Weight-based dosing of the lytic and heparin limits this excess.

Pregnancy. Pregnancy and the first postpartum week are relative contraindications. Case series of thrombolysis in pregnancy describe maternal bleeding, placental abruption, and fetal loss, and the label risk summary notes that limited data have not identified an increased risk of major birth defects. For STEMI in pregnancy, primary PCI is preferred, and spontaneous coronary artery dissection, a frequent cause of pregnancy-associated infarction, is not an indication for fibrinolysis. For life-threatening pulmonary embolism and for obstructive mechanical valve thrombosis in pregnancy, thrombolysis is used when the maternal risk of death exceeds the bleeding risk.

Patients taking oral anticoagulants. Current oral anticoagulation is a relative contraindication for STEMI and pulmonary embolism, and an international normalized ratio of 4 or more was an independent predictor of intracranial hemorrhage in the Medicare cohort. Patients with STEMI taking warfarin or a direct oral anticoagulant are transferred for primary PCI whenever possible.

Kidney and liver disease. Tenecteplase and alteplase are cleared by the liver and need no adjustment for kidney function. Enoxaparin is given once daily when creatinine clearance is below 30 mL/min, and fondaparinux is avoided below 30 mL/min. Significant hepatic dysfunction impairs synthesis of clotting factors and is a listed warning. Severe kidney disease increases bleeding through platelet dysfunction.

Prior coronary artery bypass grafting. Fibrinolysis is less effective for occluded saphenous vein grafts, which contain large thrombus burdens, and primary PCI is preferred when available.

Sources of error in fibrinolytic therapy

• Giving fibrinolysis when timely primary PCI is available: the drug adds intracranial hemorrhage risk without benefit over PCI, and facilitated PCI increased death, shock, and stroke in ASSENT-4 PCI.
• Treating a STEMI mimic or aortic dissection: pericarditis, left ventricular aneurysm, Takotsubo syndrome, and dissection involving a coronary ostium produce ST elevation without a lysable coronary thrombus.
• Using the stroke dose of tenecteplase for STEMI or the STEMI dose for stroke: the two indications use different weight tables, and the 50-mg kit and 25-mg vial are not interchangeable.
• Omitting the weight: an estimated weight that is too high increases the dose per kilogram, the mechanism behind excess intracranial hemorrhage in low-weight patients and women.
• Withholding clopidogrel or anticoagulation after STEMI fibrinolysis: reocclusion follows. Conversely, full-dose enoxaparin with a bolus in a patient older than 75 years more than doubled intracranial hemorrhage in ASSENT-3 PLUS.
• Continuing a heparin infusion during the 2-hour alteplase infusion for pulmonary embolism: the label protocol withholds heparin during the infusion.
• Accepting partial ST resolution with ongoing pain as success: failed reperfusion leads to immediate angiography, and repeat fibrinolysis gave no benefit in REACT.
• Leaving a patient with successful fibrinolysis at a non-PCI hospital: angiography within 2 to 24 hours is a Class 1 recommendation, and reocclusion occurs in a minority of patients without warning.
• Drawing coagulation samples during active therapy without precautions against in vitro lysis: fibrinogen degrades in the tube and appears falsely low.
• Repeating streptokinase within months of a prior course: neutralizing antibodies inactivate the drug and allergic reactions occur.
• Attributing new confusion or headache within 24 hours to opioids or sedation: any neurologic change is intracranial hemorrhage until CT excludes it.

References

1. Rao SV, O’Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2025;151:e771–e862 (corrections: Circulation. 2025;151:e865; Circulation. 2025;151:e1098; Circulation. 2025;152:e402). doi:10.1161/CIR.0000000000001309
2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78–e140. doi:10.1016/j.jacc.2012.11.019
3. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44:3720–3826. doi:10.1093/eurheartj/ehad191
4. Creager MA, Barnes GD, Giri J, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN guideline for the evaluation and management of acute pulmonary embolism in adults: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026;153:e977–e1051 (correction: Circulation. 2026;154:e24). doi:10.1161/CIR.0000000000001415
5. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41:543–603. doi:10.1093/eurheartj/ehz405
6. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788–1830. doi:10.1161/CIR.0b013e318214914f
7. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143:e72–e227. doi:10.1161/CIR.0000000000000923
8. Prabhakaran S, Gonzalez NR, Zachrison KS, et al. 2026 guideline for the early management of patients with acute ischemic stroke: a guideline from the American Heart Association/American Stroke Association. Stroke. 2026;57:e316–e436 (correction: Stroke. 2026;57:e461–e467). doi:10.1161/STR.0000000000000513
9. Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48:e343–e361. doi:10.1161/STR.0000000000000152
10. Genentech, Inc. TNKase (tenecteplase) for injection, for intravenous use: prescribing information. South San Francisco, CA; revised 2025. DailyMed set ID e647640d-c395-4b4b-a0be-1162f9c21d84.
11. Genentech, Inc. Activase (alteplase) for injection, for intravenous use: prescribing information. South San Francisco, CA; revised 2022. DailyMed set ID c669f77c-fa48-478b-a14b-80b20a0139c2.
12. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994;343:311–322. doi:10.1016/S0140-6736(94)91161-4
13. Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996;348:771–775. doi:10.1016/S0140-6736(96)02514-7
14. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349–360. doi:10.1016/S0140-6736(88)92833-4
15. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–682. doi:10.1056/NEJM199309023291001
16. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997;337:1118–1123. doi:10.1056/NEJM199710163371603
17. Van de Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354:716–722. doi:10.1016/S0140-6736(99)07403-6
18. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13–20. doi:10.1016/S0140-6736(03)12113-7
19. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet. 2001;358:605–613. doi:10.1016/S0140-6736(01)05775-0
20. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the ASSENT-3 PLUS randomized trial in acute myocardial infarction. Circulation. 2003;108:135–142. doi:10.1161/01.CIR.0000081659.72985.A8
21. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) Investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet. 2006;367:569–578. doi:10.1016/S0140-6736(06)68147-6
22. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction (FINESSE). N Engl J Med. 2008;358:2205–2217. doi:10.1056/NEJMoa0706816
23. Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction (STREAM). N Engl J Med. 2013;368:1379–1387. doi:10.1056/NEJMoa1301092
24. Van de Werf F, Ristić AD, Averkov OV, et al. STREAM-2: half-dose tenecteplase or primary percutaneous coronary intervention in older patients with ST-segment-elevation myocardial infarction: a randomized, open-label trial. Circulation. 2023;148:753–764. doi:10.1161/CIRCULATIONAHA.123.064521
25. Bainey KR, Welsh RC, Zheng Y, et al. Pharmaco-invasive strategy with half-dose tenecteplase in patients with STEMI: prespecified pooled analysis of patients aged ≥75 years in STREAM-1 and 2. Circ Cardiovasc Interv. 2024;17:e014251. doi:10.1161/CIRCINTERVENTIONS.124.014251
26. Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction (REACT). N Engl J Med. 2005;353:2758–2768. doi:10.1056/NEJMoa050849
27. Cantor WJ, Fitchett D, Borgundvaag B, et al. Routine early angioplasty after fibrinolysis for acute myocardial infarction (TRANSFER-AMI). N Engl J Med. 2009;360:2705–2718. doi:10.1056/NEJMoa0808276
28. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation (CLARITY-TIMI 28). N Engl J Med. 2005;352:1179–1189. doi:10.1056/NEJMoa050522
29. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial (COMMIT). Lancet. 2005;366:1607–1621. doi:10.1016/S0140-6736(05)67660-X
30. Berwanger O, Nicolau JC, Carvalho AC, et al. Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a randomized clinical trial (TREAT). JAMA Cardiol. 2018;3:391–399. doi:10.1001/jamacardio.2018.0612
31. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction (ExTRACT-TIMI 25). N Engl J Med. 2006;354:1477–1488. doi:10.1056/NEJMoa060898
32. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:1519–1530. doi:10.1001/jama.295.13.joc60038
33. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock (SHOCK). N Engl J Med. 1999;341:625–634. doi:10.1056/NEJM199908263410901
34. Böttiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest (TROICA). N Engl J Med. 2008;359:2651–2662. doi:10.1056/NEJMoa070570
35. Brass LM, Lichtman JH, Wang Y, et al. Intracranial hemorrhage associated with thrombolytic therapy for elderly patients with acute myocardial infarction: results from the Cooperative Cardiovascular Project. Stroke. 2000;31:1802–1811. doi:10.1161/01.STR.31.8.1802
36. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism (PEITHO). N Engl J Med. 2014;370:1402–1411. doi:10.1056/NEJMoa1302097
37. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311:2414–2421. doi:10.1001/jama.2014.5990
38. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111:273–277. doi:10.1016/j.amjcard.2012.09.027
39. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism (ULTIMA). Circulation. 2014;129:479–486. doi:10.1161/CIRCULATIONAHA.113.005544
40. Piazza G, Hohlfelder B, Jaff MR, et al. A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the SEATTLE II study. JACC Cardiovasc Interv. 2015;8:1382–1392. doi:10.1016/j.jcin.2015.04.020
41. Rosenfield K, Klok FA, Piazza G, et al. Ultrasound-facilitated, catheter-directed fibrinolysis for acute pulmonary embolism (HI-PEITHO). N Engl J Med. 2026;394:1979–1990. doi:10.1056/NEJMoa2516567
42. Özkan M, Gündüz S, Gürsoy OM, et al. Ultraslow thrombolytic therapy: a novel strategy in the management of PROsthetic MEchanical valve Thrombosis and the prEdictors of outcomE: the Ultra-slow PROMETEE trial. Am Heart J. 2015;170:409–418. doi:10.1016/j.ahj.2015.04.025
43. Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400:161–169. doi:10.1016/S0140-6736(22)01054-6
44. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis (ATTRACT). N Engl J Med. 2017;377:2240–2252. doi:10.1056/NEJMoa1615066