What is the role of streptokinase in treating high-risk or intermediate-high risk pulmonary embolism (PE) in patients with potential contraindications to thrombolytic therapy, such as recent surgery, trauma, or bleeding disorders?

Streptokinase in Pulmonary Embolism

Direct Recommendation

Streptokinase should be administered immediately in high-risk pulmonary embolism presenting with cardiogenic shock or persistent hypotension, using the accelerated regimen of 1.5 million IU over 2 hours, and absolute contraindications that apply in other conditions (such as recent surgery within 3 weeks) become relative contraindications when facing immediately life-threatening PE. 1

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High-Risk PE: Clear Indication for Thrombolysis

When to Use Streptokinase

• High-risk PE with hemodynamic instability (shock, systolic BP <90 mmHg, or pressure drop of ≥40 mmHg for >15 minutes) represents a Class I, Level A indication for thrombolytic therapy 1
• Meta-analysis data demonstrate that thrombolysis in massive PE reduces the combined endpoint of recurrent PE or death from 19.0% to 9.4% (OR 0.45,95% CI 0.22-0.92) 1
• Mortality trends favor thrombolysis (12.7% with heparin alone vs 6.2% with thrombolysis), though this did not reach statistical significance in the meta-analysis 1
• Only one small randomized trial specifically addressed high-risk PE: all 4 patients receiving heparin died, while all 4 receiving streptokinase survived—this difference was highly significant and led to early trial termination 1

Dosing Regimens

Two approved streptokinase regimens exist 1:

• Standard regimen: 250,000 IU loading dose over 30 minutes, followed by 100,000 IU/hour over 12-24 hours
• Accelerated regimen: 1.5 million IU over 2 hours (preferred for faster hemodynamic improvement)

The accelerated 2-hour regimen produces faster hemodynamic improvement compared to longer infusions, with the most critical benefit occurring in the first hours after admission when mortality risk is highest 1

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Intermediate-Risk PE: Selective Use Only

Evidence Against Routine Use

• Do not use streptokinase routinely in hemodynamically stable patients with intermediate-risk PE (those with RV dysfunction but normal blood pressure), as bleeding risk outweighs mortality benefit 2
• The PEITHO trial showed thrombolysis reduced hemodynamic decompensation but increased major bleeding without reducing 30-day mortality in intermediate-risk patients 1
• Thrombolysis causes 65 additional major bleeding events per 1,000 patients and increases intracranial hemorrhage risk 3-4 fold (7 additional ICH per 1,000 patients) 2

When to Consider in Intermediate-Risk PE

Reserve streptokinase for intermediate-risk patients only if 1:

• Clinical deterioration occurs despite adequate anticoagulation (decreasing BP, increasing heart rate with shock signs, worsening respiratory failure, progressive RV dysfunction on repeat imaging)
• No elevated bleeding risk exists
• Thorough consideration of bleeding risk has been completed

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Contraindications: Context-Dependent Decision Making

Absolute Contraindications (Standard Settings)

The following are absolute contraindications in typical clinical scenarios 1, 3:

• Hemorrhagic stroke or stroke of unknown origin at any time
• Ischemic stroke in preceding 6 months
• Central nervous system damage or neoplasms
• Recent major trauma/surgery/head injury within preceding 3 weeks
• Gastrointestinal bleeding within the last month
• Known bleeding diathesis
• Active internal bleeding

Critical Caveat: Life-Threatening PE Changes the Calculus

In immediately life-threatening high-risk PE with cardiogenic shock, contraindications that are absolute in other conditions (such as acute MI) become relative 1. This means:

• Recent surgery within 3 weeks becomes a relative rather than absolute contraindication
• Recent trauma may be acceptable if the PE is immediately fatal without intervention
• The risk-benefit calculation fundamentally shifts when facing imminent death from massive PE

The key decision point: Is this patient likely to die within hours without thrombolysis? If yes, most contraindications become negotiable 1

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Alternative Approaches When Streptokinase is Contraindicated

Surgical Embolectomy

• First-line alternative when thrombolysis is absolutely contraindicated or has failed in high-risk PE 1
• Requires immediate availability of cardiac surgery capability
• Can be performed under normothermic cardiopulmonary bypass without cardiac arrest unless intracardiac thrombi present 1

Catheter-Based Interventions

• Catheter embolectomy or thrombus fragmentation may be considered when surgery unavailable, though safety and efficacy data are limited 1
• Local intra-arterial streptokinase (10,000-20,000 units/hour) combined with systemic heparin showed 96.4% clinical success in one study, with significantly lower mortality than systemic thrombolysis 4, 5

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Bleeding Risk and Management

Expected Bleeding Rates

• Major bleeding occurs in 21.9% of patients receiving thrombolysis vs 11.9% with heparin alone (OR 1.98,95% CI 1.00-3.92) in massive PE trials 1
• Intracranial hemorrhage rate: 1.8% across thrombolysis trials 1
• Recent studies using non-invasive imaging for PE confirmation show lower bleeding rates than historical data 1

Concurrent Anticoagulation

• Start unfractionated heparin immediately in high-risk PE before thrombolysis, as LMWH and fondaparinux have not been tested in hypotension/shock 1, 6
• Continue heparin during and after streptokinase infusion 6
• Avoid intramuscular injections, minimize arterial punctures, and use compressible sites only 3

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Timing and Monitoring

When to Initiate

• Greatest benefit occurs when treatment starts within 48 hours of symptom onset, but thrombolysis remains useful up to 6-14 days after symptoms begin 1
• Start immediately upon diagnosis in high-risk PE—do not delay for angiographic confirmation if clinical probability is high and echocardiography shows acute cor pulmonale 1

Monitoring Response

• Hemodynamic improvement typically occurs within 4 hours 5, 7
• Unsuccessful thrombolysis (persistent clinical instability and unchanged RV dysfunction at 36 hours) occurs in 8% of high-risk PE patients 1
• If thrombolysis fails, proceed immediately to surgical embolectomy 1

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Common Pitfalls to Avoid

• Do not withhold streptokinase in high-risk PE due to relative contraindications—the mortality from untreated massive PE exceeds bleeding risk 1
• Do not use RV dysfunction alone as indication for thrombolysis in stable patients—this significantly increases bleeding without proven mortality benefit 2
• Do not use LMWH or fondaparinux as initial anticoagulation in hemodynamically unstable PE—only unfractionated heparin has been studied in this setting 1, 6
• Do not delay anticoagulation while awaiting imaging if clinical suspicion is high—start heparin immediately 6