When should heparin and warfarin be started after thrombolysis with alteplase (tissue plasminogen activator)?

Timing of Heparin and Warfarin After Alteplase Thrombolysis

Heparin Initiation

Heparin should be started when the aPTT has decreased to less than twice the normal control value after completing alteplase infusion, typically without a loading dose. 1

Specific Timing Protocol

• Begin heparin infusion when aPTT falls below 2× the upper limit of normal following alteplase completion 1
• For pulmonary embolism treated with alteplase, one protocol used heparin at 1,280 IU/hour continuous infusion as soon as the aPTT was less than twice the upper limit of normal 1
• In prosthetic valve thrombosis, heparin treatment without a loading dose should begin when the aPTT has decreased to less than twice the normal control (or baseline) value 1

Heparin Dosing and Monitoring

• Target aPTT of 1.5 to 2 times normal (55 to 80 seconds) 1
• Average dosage to achieve therapeutic effect is 20,000 to 40,000 U/24 hours, with initial dosing typically around 1,300 U/hour 1
• Check aPTT four times every 6 hours and three times every 8 hours during the first 24-48 hours after stopping thrombolysis, then daily 1
• This frequent monitoring is necessary because of rapidly changing levels of fibrinogen and heparin-binding proteins in the first 24-48 hours post-thrombolysis 1

Special Considerations for Pediatric Populations

• In pediatric patients, continue heparin during alteplase administration at 10 μg·kg⁻¹·h⁻¹ 1
• After alteplase completion, increase to age-appropriate dose: ≥12 months = 20 μg·kg⁻¹·h⁻¹; <12 months = 28 μg·kg⁻¹·h⁻¹ 1

Important Caveat for Acute Ischemic Stroke

For acute ischemic stroke patients, avoid antithrombotic therapy (including heparin) for the first 24 hours after IV alteplase unless there are compelling concomitant conditions where withholding treatment poses substantial risk 1

Warfarin Initiation

Warfarin may be started as soon as the diagnosis requiring anticoagulation is confirmed, even during thrombolytic therapy. 1

Overlap Protocol

• Begin warfarin concomitantly with heparin therapy 2
• Continue full-dose heparin with warfarin overlap for 4 to 5 days until warfarin produces the desired therapeutic response as determined by PT/INR 2
• A 5-day heparin course appears as effective as a 7-10 day course 1
• Heparin should be continued until adequate maintenance anticoagulation with warfarin is achieved 1

Warfarin Monitoring During Overlap

• If both heparin and warfarin are being administered, blood for PT/INR determination should be drawn at specific intervals to avoid heparin interference 2:
  • At least 5 hours after the last IV bolus dose of heparin, OR
  • 4 hours after cessation of continuous IV heparin infusion, OR
  • 24 hours after the last subcutaneous heparin injection

Target Anticoagulation

• Target INR of 2.5 to 3.5 for most indications post-thrombolysis 1, 3
• Addition of low-dose aspirin (81 to 100 mg daily) is strongly recommended once warfarin is therapeutic 1, 3

Critical Pitfalls to Avoid

• Do not administer adjuvant anticoagulant therapy during active thrombolytic infusion (except in specific pediatric protocols or certain endovascular procedures) 1, 3
• Do not start heparin too early when aPTT is still >2× normal, as this increases bleeding risk 1
• Do not give heparin loading dose immediately post-thrombolysis; begin with continuous infusion only 1
• Monitor platelet count if heparin is continued beyond 5 days due to risk of heparin-induced thrombocytopenia with thrombosis 1
• For stroke patients specifically, the 24-hour window without antithrombotics should be respected unless exceptional circumstances exist 1