Pharmacology · Cardiovascular

Thrombolytic Therapy and Procoagulant Agents

Thrombolytics, reversal agents, and hemostatic pharmacology at a glance

Thrombolytics convert plasminogen to plasmin, which degrades fibrin clots — the critical distinction is fibrin specificity: alteplase and tenecteplase activate plasminogen preferentially at fibrin surfaces, limiting systemic fibrinolysis, while streptokinase produces a systemic lytic state and is now rarely used; tenecteplase's 80-fold resistance to PAI-1 and single-bolus dosing make it the preferred agent for STEMI where PCI is unavailable.
Time windows govern thrombolytic eligibility: STEMI fibrinolysis is most effective within 3 hours of symptom onset and acceptable up to 12 hours if PCI cannot be performed within 120 minutes of first medical contact; acute ischemic stroke requires alteplase within 4.5 hours with blood pressure below 185/110 and CT confirmation of ischemia; massive PE with hemodynamic instability warrants alteplase 100 mg over 2 hours.
Heparin reversal uses protamine sulfate (1 mg per 100 units UFH from the last 2 to 3 hours); LMWH is only partially reversed by protamine (anti-Xa activity incompletely neutralized); fondaparinux has no specific antidote and relies on 4F-PCC off-label; warfarin reversal in life-threatening bleeding requires 4F-PCC dosed by INR plus intravenous vitamin K 10 mg to prevent INR rebound.
DOAC reversal has specific approved agents: idarucizumab (5 g IV) completely reverses dabigatran within minutes by binding it with near-irreversible affinity; andexanet alfa reverses apixaban and rivaroxaban by acting as a decoy factor Xa; edoxaban lacks an approved specific agent and relies on 4F-PCC 50 units/kg as the best available option.
Thrombolytic reversal for intracranial hemorrhage is a pharmacological emergency: stop the infusion immediately, give cryoprecipitate 10 units IV to restore fibrinogen above 150 mg/dL, and add tranexamic acid (which blocks plasminogen binding to fibrin) or epsilon-aminocaproic acid; tranexamic acid also reduces mortality in trauma hemorrhage when given within 3 hours of injury (CRASH-2).

Abbreviations: tPA = tissue-type plasminogen activator · PAI-1 = plasminogen activator inhibitor-1 · STEMI = ST-elevation myocardial infarction · AIS = acute ischemic stroke · PE = pulmonary embolism · TXA = tranexamic acid · EACA = epsilon-aminocaproic acid · 4F-PCC = four-factor prothrombin complex concentrate · INR = international normalized ratio · ICH = intracranial hemorrhage · UFH = unfractionated heparin · LMWH = low molecular weight heparin · DOAC = direct oral anticoagulant

Thrombolytic Agents

Agent	Fibrin Specificity	Half-Life	Dosing	Approved Indications
Alteplase	High (fibrin-dependent)	3–5 min	Weight-based infusion over 60–90 min	STEMI, AIS (0–4.5 h), massive PE — universal coverage
Tenecteplase	Highest; 80× PAI-1 resistant	20–24 min	Single weight-based IV bolus	STEMI (preferred); less non-cerebral bleeding vs alteplase
Reteplase	Moderate	13–16 min	Two fixed 10-unit boluses 30 min apart; no weight adjustment	STEMI and AMI only; not for stroke or PE
Streptokinase	None — systemic lytic state	Variable	1.5 million units over 60 min	STEMI only; antigenic; no repeat within 6–12 months; not for stroke

Anticoagulant Reversal Agents

Thrombolytic Reversal

Antifibrinolytics + Cryoprecipitate

Stop infusion immediately on suspected ICH
Cryoprecipitate 10 units IV: fibrinogen target ≥150 mg/dL
TXA 10–15 mg/kg IV over 10 min OR EACA 5 g load then 1 g/hr
TXA mechanism: blocks plasminogen lysine-binding sites on fibrin
TXA also reduces mortality in trauma (within 3 hours) and surgical blood loss

Heparin / Warfarin Reversal

Protamine & Vitamin K / 4F-PCC

UFH: protamine 1 mg per 100 units (last 2–3 h)
LMWH: protamine 1 mg per 1 mg enoxaparin; partial anti-Xa reversal only
Fondaparinux: no specific agent; 4F-PCC off-label
Warfarin life-threatening: 4F-PCC (INR-dosed) + IV vitamin K 10 mg
Warfarin non-urgent: oral vitamin K 2.5–5 mg

DOAC Reversal

Idarucizumab & Andexanet Alfa

Dabigatran: idarucizumab 5 g IV (two 2.5 g boluses); complete reversal in minutes
Apixaban / rivaroxaban: andexanet alfa (low or high dose per timing)
Edoxaban: 4F-PCC 50 units/kg (no approved specific agent)
All: 4F-PCC 50 units/kg is best non-specific alternative if specific agent unavailable
Resume anticoagulation when hemostasis achieved

Thrombolysis Time Windows and Selection Rules

STEMI: fibrinolysis if PCI not available within 120 min of first medical contact; benefit greatest within 3 hours; tenecteplase single bolus preferred; pharmacoinvasive strategy (coronary angiography 3 to 24 hours after) if successful lysis; rescue PCI if less than 50% ST resolution at 90 minutes. AIS: alteplase 0.9 mg/kg within 4.5 hours; confirm ischemic stroke by CT; blood pressure below 185/110 before treatment; mechanical thrombectomy for large vessel occlusion. Massive PE: alteplase 100 mg over 2 hours for hemodynamic instability; catheter-directed thrombolysis for intermediate-high risk with right ventricular dysfunction.

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