Thrombolytics & Antithrombotics in Stroke

Stroke pharmacology runs on a single organizing question: are you trying to open a vessel that is acutely occluded, or are you trying to prevent the next clot from forming? The first job belongs to the thrombolytics — the clot-busters given in the emergency department in the first hours after symptom onset. The second job belongs to two families of antithrombotic drugs that you choose between based on why the stroke happened: antiplatelets for atherosclerotic and small-vessel disease, and anticoagulants for cardioembolic sources such as atrial fibrillation. Get the mechanism-to-indication match right and you have most of stroke pharmacology in hand; get it wrong and you either fail to protect the patient or hand them a dangerous bleed. This page walks through all three families, their reversal agents, and the decision rule that ties them together.

Thrombolytics: the clot-busters

Thrombolytics dissolve an established thrombus by converting plasminogen into plasmin, the enzyme that degrades fibrin. They are the only acute drug therapy that actually reopens an occluded vessel, and their benefit is profoundly time-dependent — the longer the brain sits ischemic, the less salvageable tissue remains. This is the origin of the mantra "time is brain."

• Alteplase (recombinant tPA): a fibrin-specific plasminogen activator, given intravenously for acute ischemic stroke. The approved window is within 3 hours of symptom onset, extended to 4.5 hours in eligible patients. It is administered as a bolus followed by a one-hour infusion, only after a non-contrast head CT has excluded hemorrhage. Its efficacy in this window was established by the NINDS trial.
• Tenecteplase (TNK): a bioengineered variant of alteplase that is more fibrin-specific and resistant to inactivation, allowing it to be given as a single IV bolus rather than an infusion. The 2026 AHA/ASA acute ischemic stroke guideline endorses either alteplase (0.9 mg/kg) or tenecteplase (0.25 mg/kg) for eligible adults within the 4.5-hour thrombolysis window; TNK's single-bolus dosing is also operationally useful when a patient is being transferred for thrombectomy.
• The main hazard: symptomatic intracerebral hemorrhage (sICH) — bleeding into the brain that worsens the deficit. This is the dose-limiting, life-threatening risk of every thrombolytic.
• Contraindications are numerous and exist to keep sICH risk acceptable: recent intracranial hemorrhage, recent major surgery or serious trauma, active internal bleeding, known coagulopathy or therapeutic anticoagulation, very high uncontrolled blood pressure, and others. Careful screening is as important as the drug itself.

Antiplatelets: for non-cardioembolic stroke and TIA

Platelet-rich (white) thrombi form on ruptured atherosclerotic plaque and in small-vessel disease, so the drugs that blunt platelet activation are the mainstay of secondary prevention for non-cardioembolic ischemic stroke and TIA. Each agent disables a different step of platelet activation.

• Aspirin: irreversibly inhibits cyclooxygenase-1 (COX-1), blocking thromboxane A2 production for the lifespan of the platelet. It is the standard early antiplatelet for most acute ischemic stroke, usually started within 24–48 hours and delayed until 24 hours after IV thrombolysis; selected patients with minor noncardioembolic stroke or high-risk TIA may receive short-term dual antiplatelet therapy (aspirin + clopidogrel) started early.
• Clopidogrel: blocks the platelet P2Y12 ADP receptor. It is a prodrug that must be activated by the hepatic enzyme CYP2C19 — so poor metabolizers (and certain interacting drugs) get reduced antiplatelet effect.
• Ticagrelor: a P2Y12 inhibitor that is reversible and, unlike clopidogrel, is not a prodrug, so its effect does not depend on CYP2C19 activation.
• Dipyridamole: inhibits platelet aggregation through phosphodiesterase/adenosine pathways; used as extended-release dipyridamole combined with aspirin.
• Short-term DUAL antiplatelet therapy (DAPT): aspirin plus clopidogrel started early after a minor stroke or high-risk TIA reduces early recurrent stroke (shown by the CHANCE and POINT trials). Crucially this is time-limited — roughly 21 to 90 days — because the benefit is front-loaded while the bleeding risk keeps accumulating with continued dual therapy. After the short course, patients step down to a single antiplatelet.

Anticoagulants: for cardioembolic stroke

Strokes driven by clot formed in stagnant blood — most importantly in the fibrillating left atrium of atrial fibrillation — are cardioembolic, and these fibrin-rich (red) clots are best prevented with anticoagulants rather than antiplatelets.

• Warfarin: a vitamin K antagonist that depletes the vitamin-K-dependent clotting factors (II, VII, IX, X). It is effective but requires routine INR monitoring, has many food and drug interactions, and has a narrow therapeutic window.
• Direct oral anticoagulants (DOACs): generally preferred over warfarin in nonvalvular AF for comparable or better efficacy with greater safety and convenience (no routine monitoring). They split into two mechanistic groups:
  • Dabigatran — a direct thrombin (factor IIa) inhibitor.
  • Apixaban, rivaroxaban, edoxaban — direct factor Xa inhibitors.
• Heparin / LMWH: parenteral anticoagulants reserved for selected acute uses; routine full-dose anticoagulation of acute ischemic stroke is not recommended because the bleeding risk outweighs benefit in most cases.

Reversal agents (high-yield)

Many anticoagulants have specific or protocolized reversal strategies, but availability and indication vary by drug and country — knowing the matches is classic board material and real bedside knowledge when a patient on a blood thinner presents with hemorrhage.

• Warfarin → vitamin K (slower) plus 4-factor prothrombin complex concentrate (4F-PCC) for rapid reversal of serious bleeding.
• Dabigatran (direct thrombin inhibitor) → idarucizumab, a monoclonal antibody fragment.
• Factor Xa inhibitors → for apixaban- or rivaroxaban-associated life-threatening or uncontrolled bleeding, andexanet alfa (a recombinant decoy factor Xa) was the specific reversal agent, but it is no longer commercially manufactured or sold in the US after December 22, 2025 (per the FDA Andexxa safety communication); follow current institutional protocol — often four-factor prothrombin complex concentrate (4F-PCC) where a specific agent is unavailable or not indicated.
• Heparin → protamine sulfate.

The decision rule: match the drug to the mechanism

The single most important concept in stroke secondary prevention is matching the antithrombotic to the stroke's cause:

• Cardioembolic source (e.g., atrial fibrillation) → anticoagulation (a DOAC in nonvalvular AF, or warfarin).
• Non-cardioembolic — atherosclerotic or lacunar/small-vessel stroke → antiplatelet therapy.
• Don't cross the streams. Anticoagulation is not superior to antiplatelet therapy for routine non-cardioembolic stroke, and it adds bleeding risk without added benefit — so anticoagulating an atherosclerotic stroke "to be safe" is the wrong move.

Quick reference table