G6PD Deficiency and Aspirin Therapy
Low-dose aspirin (75–100 mg daily) is safe for antiplatelet therapy in patients with G6PD deficiency, and higher doses should be avoided due to theoretical hemolysis risk, though even this risk appears minimal with standard cardiovascular dosing.
Safety Profile of Low-Dose Aspirin in G6PD Deficiency
Evidence from Clinical Studies
Multiple case series and cohort studies demonstrate that low-dose aspirin (81–100 mg daily) does not cause clinically significant hemolysis in G6PD-deficient patients. A prospective study of 44 Mediterranean-type G6PD-deficient patients receiving long-term low-dose aspirin showed normal complete blood counts, reticulocyte counts, and serum bilirubin over three months of monitoring 1.
Dual antiplatelet therapy (aspirin plus P2Y12 inhibitor) has been successfully used in G6PD-deficient patients undergoing percutaneous coronary intervention with drug-eluting stents without hemolytic complications. A case series of five patients with G6PD deficiency receiving PCI and DAPT containing low-dose aspirin reported no clinical complications 2.
Class II G6PD-deficient patients with acute coronary syndromes have been safely treated with aspirin plus ticagrelor and PCI. Two reported cases demonstrated safe and effective management with this combination despite G6PD deficiency 3.
Contradictory Evidence Requiring Caution
One large prospective cohort study (1,121 ischemic stroke patients) found increased bleeding and mortality risk in G6PD-deficient patients taking aspirin. Among 81 G6PD-deficient patients receiving 100 mg aspirin daily for three months, moderate-to-severe bleeding occurred in 2.5% versus 0.3% in G6PD-normal patients (p=0.045), and all-cause death was 6.2% versus 1.4% (p=0.008) 4.
Acute hemolysis was rare but documented: one case of acute hemolysis occurred among 81 G6PD-deficient patients versus none among 991 G6PD-normal patients (p=0.876). This suggests hemolysis is uncommon but possible 4.
G6PD deficiency was independently associated with increased risk of moderate-to-severe bleeding (adjusted p=0.048) and all-cause death (adjusted p=0.008) during aspirin use in multivariate analysis. This represents the strongest evidence of potential harm 4.
Recommended Dosing Strategy
Standard Cardiovascular Dosing
The optimal aspirin dose for antiplatelet therapy is 75–100 mg daily (81 mg in the United States), which provides maximal cardiovascular protection while minimizing bleeding risk. This applies to both G6PD-normal and G6PD-deficient patients 5.
Daily aspirin doses as low as 30–50 mg inactivate platelet cyclo-oxygenase-1 enzyme and inhibit thromboxane production, making higher doses unnecessary. Studies comparing 75–150 mg with higher doses show comparable ischemic event rates with lower bleeding risk 5.
Avoiding Higher Doses
Higher aspirin doses (≥300 mg daily) increase bleeding risk without improving efficacy and should be avoided in all patients, particularly those with G6PD deficiency. Large overviews of nearly 200,000 persons show doses ≤100 mg daily cause less major and total bleeding than higher doses 5.
The theoretical mechanism of aspirin-induced hemolysis in G6PD deficiency involves oxidative stress, which would be dose-dependent. While low doses appear safe, higher doses (>325 mg) carry greater theoretical risk and lack additional cardiovascular benefit 6.
Clinical Decision Algorithm
When to Use Aspirin in G6PD-Deficient Patients
For secondary prevention (established cardiovascular disease):
- Aspirin 75–162 mg daily is strongly recommended for G6PD-deficient patients with prior myocardial infarction, stroke, TIA, peripheral vascular disease, or coronary revascularization. The cardiovascular benefit outweighs the minimal hemolysis risk 5.
For primary prevention:
Consider aspirin only in G6PD-deficient patients aged 50–70 years with additional major cardiovascular risk factors (hypertension, dyslipidemia, smoking, family history, albuminuria) after shared decision-making. The bleeding risk documented in the stroke cohort study warrants extra caution 4, 7.
Do not use aspirin for primary prevention in G6PD-deficient patients over age 70 or under age 50 without multiple risk factors. The bleeding risk appears higher in G6PD deficiency and outweighs potential benefit 4, 7.
Absolute Contraindications (Apply to All Patients)
- Do not prescribe aspirin to patients with aspirin allergy, active bleeding tendency, concurrent anticoagulant therapy, recent gastrointestinal bleeding, or clinically active hepatic disease. These contraindications supersede G6PD considerations 5.
Monitoring Recommendations
Baseline Assessment
Before initiating aspirin in G6PD-deficient patients, obtain baseline complete blood count, reticulocyte count, and serum bilirubin. This establishes a reference for detecting hemolysis 1.
Document G6PD enzyme activity level if available, as Class II (Mediterranean-type) deficiency has been specifically studied with aspirin. More severe variants may carry higher risk 3.
Follow-Up Monitoring
Recheck complete blood count, reticulocyte count, and bilirubin at 2–4 weeks after starting aspirin, then every 3 months for the first year. This detects subclinical hemolysis early 1.
Educate patients to report symptoms of hemolysis (dark urine, jaundice, fatigue, dyspnea) or bleeding (melena, hematemesis, unusual bruising) immediately. Early recognition allows prompt intervention 4.
Monitor more closely in patients with additional bleeding risk factors: age >70 years, concurrent NSAIDs, history of peptic ulcer disease, or chronic kidney disease. The stroke cohort data suggest G6PD deficiency compounds these risks 4.
Proton Pump Inhibitor Co-Therapy
Prescribe a proton pump inhibitor in G6PD-deficient patients with history of gastrointestinal bleeding who require aspirin (Class I recommendation). This mitigates the elevated bleeding risk documented in G6PD deficiency 5.
Consider PPI co-therapy in G6PD-deficient patients with increased bleeding risk factors (advanced age, concurrent warfarin, steroids, or NSAIDs) even without prior bleeding history (Class IIa recommendation). The 2.5% bleeding rate in G6PD-deficient stroke patients justifies this precaution 5, 4.
Critical Pitfalls to Avoid
Methylene Blue Interaction
Never administer methylene blue to G6PD-deficient patients receiving aspirin, as methylene blue itself causes severe hemolysis in G6PD deficiency. Methylene blue may induce Heinz body hemolytic anemia and paradoxically worsen methemoglobinemia in G6PD-deficient patients 5.
If methemoglobinemia develops in a G6PD-deficient patient on aspirin, use ascorbic acid (0.5–10 g IV) or exchange transfusion instead of methylene blue. Ascorbic acid is the treatment of choice when methylene blue is contraindicated 5.
Dual Antiplatelet Therapy Considerations
When dual antiplatelet therapy is required after PCI, use clopidogrel or ticagrelor as the P2Y12 inhibitor with low-dose aspirin (81 mg). Both have been safely used in G6PD-deficient patients 2, 3.
Continue DAPT for at least 12 months after drug-eluting stent placement in acute coronary syndrome, even in G6PD-deficient patients, unless severe bleeding occurs. The ischemic risk of premature discontinuation exceeds the bleeding risk 5.
Avoiding Overtreatment
Do not prescribe aspirin to G6PD-deficient patients solely based on diabetes without additional cardiovascular risk factors or established disease. Primary prevention evidence is weak even in G6PD-normal diabetic patients 7.
Prioritize statin therapy, ACE inhibitors/ARBs, optimal glycemic control, and blood pressure management over aspirin for cardiovascular risk reduction in G6PD-deficient patients without established disease. These interventions have stronger evidence and no hemolysis risk 7.