Low LDL-Cholesterol and Hemorrhagic Risk: Mechanistic Insights and Clinical Perspectives
Abstract
1. Introduction
2. Cholesterol and Platelet Biology: From Lipid Rafts to Aggregation
3. Endothelial Integrity and LDL-C: Mechanisms of Microvascular Fragility
4. Clinical Evidence Linking Low LDL-C to Hemorrhagic Outcomes
4.1. Hemorrhagic Stroke
4.2. Gastrointestinal and Mucosal Bleeding
4.3. Meta-Analyses and Pooled Data
5. Implications for Clinical Practice and Future Research
5.1. Personalizing LDL-C Targets Based on Bleeding Risk
- A history of intracerebral hemorrhage or cerebral microbleeds on MRI;
- Advanced age (>75 years);
- Concurrent use of anticoagulants or dual antiplatelet therapy;
- A low body mass index (BMI < 20 kg/m2);
- A history of gastrointestinal bleeding or peptic ulcer disease;
5.2. Tailoring Lipid-Lowering Regimens and Co-Medications
- Discontinuing dual-antiplatelet therapy after 12 months, unless indicated as absolutely necessary;
- Co-prescribing proton pump inhibitors for gastroprotection;
- Using bleeding risk calculators (e.g., HAS-BLED, PRECISE-DAPT) to guide the intensity and duration of therapy [59].
5.3. Knowledge Gaps and Research Priorities
- What is the “threshold” LDL-C level at which bleeding risk significantly increases? While <50 mg/dL is commonly recognized as a general marker, individual susceptibility varies.
- How does the duration of exposure to very low LDL-C influence bleeding risk? Longitudinal cohort studies are needed to assess time-dependent effects.
- Are certain genetic variants associated with an increased risk of bleeding when LDL-C is low? Mendelian randomization and genome-wide association studies may offer valuable insights.
- Can we develop predictive models that integrate both ischemic and hemorrhagic risks for managing LDL-C? Such models could help personalize therapy beyond the current binary targets.
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Clinical Implications |
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Translational perspectives |
|
Study/Analysis | Population | LDL-C Target/Achieved | Type of Bleeding Observed | Key Findings | Reference |
---|---|---|---|---|---|
SPARCL | 4731 patients with stroke or TIA | Median LDL-C: ~73 mg/dL with atorvastatin 80 mg | Intracerebral hemorrhage | 66% increased risk of ICH (HR: 1.66; 95% CI: 1.08–2.55) | [47] |
Meta-analysis 2021 | >300,000 patients (16 RCTs + 14 observational studies) | LDL-C < 50 mg/dL | Major bleeding (various sites) | 1.4–1.6-fold increased risk, especially with antithrombotic therapy | [58] |
FOURIER + ODYSSEY OUTCOMES (pooled) | High CV risk patients treated with PCSK9 inhibitors | LDL-C < 30 mg/dL (achieved) | Epistaxis, GIB, retinal bleeding | Numerical increase in bleeding events, but low absolute incidence | [59] |
J-STARS (Japan) | Patients with low baseline LDL-C at stroke risk | Already low baseline LDL-C | Intracranial bleeding | Increased hemorrhagic events, particularly in those with low initial LDL-C | [50] |
JUPITER | 17,802 healthy individuals with elevated hsCRP | Median LDL-C: ~55 mg/dL with rosuvastatin 20 mg | GIB | Increased GIB (1.2% vs. 0.9%, p = 0.03) | [54] |
NHIRD (Taiwan) | >30,000 patients on statin therapy | LDL-C < 70 mg/dL | GIB | 25% increased risk of GIB, particularly with concomitant antiplatelet agents | [55] |
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Siniscalchi, C.; Basaglia, M.; Meschi, T.; Imbalzano, E.; Futura Bernardi, F.; Perrella, A.; Trama, U.; Passannanti, A.; Di Micco, P.; Schiano, C. Low LDL-Cholesterol and Hemorrhagic Risk: Mechanistic Insights and Clinical Perspectives. Int. J. Mol. Sci. 2025, 26, 5612. https://doi.org/10.3390/ijms26125612
Siniscalchi C, Basaglia M, Meschi T, Imbalzano E, Futura Bernardi F, Perrella A, Trama U, Passannanti A, Di Micco P, Schiano C. Low LDL-Cholesterol and Hemorrhagic Risk: Mechanistic Insights and Clinical Perspectives. International Journal of Molecular Sciences. 2025; 26(12):5612. https://doi.org/10.3390/ijms26125612
Chicago/Turabian StyleSiniscalchi, Carmine, Manuela Basaglia, Tiziana Meschi, Egidio Imbalzano, Francesca Futura Bernardi, Alessandro Perrella, Ugo Trama, Angelica Passannanti, Pierpaolo Di Micco, and Concetta Schiano. 2025. "Low LDL-Cholesterol and Hemorrhagic Risk: Mechanistic Insights and Clinical Perspectives" International Journal of Molecular Sciences 26, no. 12: 5612. https://doi.org/10.3390/ijms26125612
APA StyleSiniscalchi, C., Basaglia, M., Meschi, T., Imbalzano, E., Futura Bernardi, F., Perrella, A., Trama, U., Passannanti, A., Di Micco, P., & Schiano, C. (2025). Low LDL-Cholesterol and Hemorrhagic Risk: Mechanistic Insights and Clinical Perspectives. International Journal of Molecular Sciences, 26(12), 5612. https://doi.org/10.3390/ijms26125612