Heparin Infusion After Thrombolysis in Pulmonary Embolism
After thrombolytic therapy for pulmonary embolism, initiate unfractionated heparin at 1,280 IU/hour (approximately 18 U/kg/hour) as a continuous infusion once the aPTT falls below twice the upper limit of normal, targeting an aPTT of 1.5-2.3 times control (46-70 seconds). 1, 2
Timing of Heparin Initiation Post-Thrombolysis
The critical decision point is when to start heparin after thrombolytic administration:
- Wait until aPTT is less than twice the upper limit of normal before initiating heparin infusion 1
- This typically occurs several hours after completion of thrombolysis, as the thrombolytic agent's effect on coagulation parameters wanes 1
- Do not start heparin immediately after thrombolysis completion, as this increases bleeding risk without additional benefit 1
The British Thoracic Society guidelines specifically state that after rtPA administration, heparin should be given at 1,280 IU/hour as continuous infusion "as soon as the APTT was less than twice the upper limit of normal" 1. This approach balances the need for continued anticoagulation against bleeding risk.
Dosing Protocol
Once the aPTT threshold is met, use the following weight-based regimen:
- Initial infusion rate: 18 U/kg/hour (approximately 1,280 IU/hour for a 70 kg patient) 2
- No bolus dose is given when transitioning from thrombolysis to heparin 1
- Target aPTT: 1.5-2.3 times control (46-70 seconds) 1, 2
Dose Adjustment Algorithm
Check aPTT 4-6 hours after starting heparin, then adjust according to this nomogram 2:
| aPTT Result | Action |
|---|---|
| <35 seconds (<1.2× control) | Give 80 U/kg bolus; increase infusion by 4 U/kg/h [2] |
| 35-45 seconds (1.2-1.5× control) | Give 40 U/kg bolus; increase infusion by 2 U/kg/h [2] |
| 46-70 seconds (1.5-2.3× control) | No change - therapeutic range [2] |
| 71-90 seconds (2.3-3.0× control) | Decrease infusion by 2 U/kg/h [2] |
| >90 seconds (>3.0× control) | Stop infusion for 1 hour, then decrease by 3 U/kg/h [2] |
Duration and Transition to Oral Anticoagulation
- Continue heparin for at least 5 days AND until INR ≥2.0 for at least 24 hours on two consecutive measurements 1, 2
- Start warfarin simultaneously with heparin initiation (not waiting until after heparin is stopped) at 5-10 mg daily 1, 3, 2
- Target INR: 2.0-3.0 throughout treatment 1, 3, 2
The European Society of Cardiology guidelines emphasize that parenteral anticoagulants should be stopped only when INR is between 2.0 and 3.0 for at least 2 consecutive days 1.
Special Considerations for High-Risk PE
For patients with hemodynamic instability (shock or hypotension) who received thrombolysis:
- Intravenous unfractionated heparin is mandatory - do not use LMWH or fondaparinux in this setting 1
- These agents have not been tested in hemodynamically unstable patients 1
- The predictable pharmacokinetics of IV heparin allow for rapid reversal if bleeding occurs 1
Common Pitfalls to Avoid
Critical timing error: Starting heparin too early after thrombolysis (before aPTT normalizes to <2× upper limit) significantly increases major bleeding risk 1. The British Thoracic Society data showed that waiting for aPTT normalization was safe and effective across multiple studies 1.
Inadequate monitoring: Check aPTT at 4-6 hours after starting heparin, not later 2, 4. Delayed monitoring allows subtherapeutic anticoagulation to persist, which increases recurrent PE risk 5.
Premature heparin discontinuation: Never stop heparin before INR is therapeutic (2.0-3.0) for at least 24 hours 1, 2. This creates a dangerous anticoagulation gap, as warfarin takes several days to achieve full effect 1.
Fixed-dose error: Avoid using fixed doses like "1,000 U/hour" without weight adjustment 2. Weight-based dosing (18 U/kg/hour) achieves therapeutic anticoagulation faster and more reliably 2.
Monitoring for Complications
Throughout heparin therapy:
- Monitor platelet count every 2-3 days for heparin-induced thrombocytopenia 1
- Check hematocrit and occult blood in stool periodically 4
- Major bleeding occurs in approximately 2% of appropriately anticoagulated patients but increases to 10% in high-risk patients (recent surgery, GI bleeding history, platelet count <150 × 10⁹/L) 1
The meta-analysis by the European Society of Cardiology showed that in patients with massive PE who received thrombolysis, major bleeding occurred in 21.9% versus 11.9% with heparin alone, but this was offset by a significant reduction in death or recurrent PE (9.4% vs 19.0%) 1.