Deciphering the Complex Relationships Between the Hemostasis System and Infective Endocarditis
Abstract
:1. Introduction
2. Current Understanding of Infective Endocarditis Pathogenesis
2.1. Endocardial Damage and Platelet–Fibrin Deposition
2.2. Infected Vegetation Growth
2.3. Vegetation-Borne Complications: Embolization and Septic Emboli
3. Influence of Infective Endocarditis on Hemostasis System Function
3.1. Platelet Pre-Activation in IE
3.2. Coagulation Cascade Activation and Hypercoagulability Due to IE
3.3. Hemostasis and Innate Immunity Interaction (Immunothrombosis) in IE
4. Role of Thrombophilia in Infective Endocarditis
4.1. Definition and Types of Thrombophilia: Inherited and Acquired
4.2. Specific Thrombophilic Conditions Associated with Infective Endocarditis
4.3. The Potential Role of Thrombophilia in IE: A Cause or a Consequence?
5. Diagnostic and Therapeutic Implications
5.1. Effect of Antibiotic Therapy on IE Vegetation and Embolic Risk
5.2. Effect of Prior or De Novo Antiplatelet Treatment on IE Vegetation and Embolic Risk
5.3. Effect of Prior or De Novo Anticoagulant Treatment on IE Vegetation and Embolic Risk
5.4. Future Approaches to Targeting Thrombophilia and Coagulation Abnormalities in IE
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
IE | infective endocarditis |
VWF | von Willebrand factor |
NBTE | non-bacterial thrombotic endocarditis |
ClfA | clumping factor A |
ClfB | clumping factor B |
MSCRAMMs | microbial surface components recognizing adhesive matrix molecules |
vWbp | von Willebrand factor-binding protein |
CRP | C-reactive protein |
PET/CT | Positron Emission Tomography/Computed Tomography |
GPIb | glycoprotein Ib |
GPIIb/IIIa | glycoprotein IIb/IIIa |
NETs | neutrophil extracellular traps |
TF | tissue factor |
FVL | Factor V Leiden |
FII | prothrombin |
APS | antiphospholipid syndrome |
ESC | European Society of Cardiology |
ICH | Intracranial hemorrhage |
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Hemostasis Phase | Components | Normal Function | Alterations in IE | Clinical Implications |
---|---|---|---|---|
Primary Hemostasis | Platelets, vWF (von Willebrand factor), collagen | Platelet adhesion, activation, and aggregation | Increased platelet activation, P-selectin expression | Enhanced vegetation formation, resistance to antiplatelet therapy |
Secondary Hemostasis | Coagulation factors, thrombin | Fibrin formation and clot stabilization | Pathogen-driven activation, coagulase production | Vegetation enlargement, embolic risk |
Tertiary Hemostasis | Plasmin, fibrinolytic enzymes | Clot dissolution and remodeling | Bacterial exploitation for tissue invasion | Compromised vegetation stability, septic emboli |
Microorganism | Vegetation Characteristics | Embolic Risk/Rate | Coagulopathy Effects |
---|---|---|---|
Staphylococcus aureus [17,71,72] | Large, friable vegetations rich in bacterial biofilms and fibrin | Particularly high risk of systemic embolization | Pronounced coagulopathy via secreted coagulases, associated with higher D-dimer levels |
Streptococcus spp. [65,70] | Smaller, densely adherent vegetations | Size has not been shown to influence embolic potential significantly; it follows a more indolent course | Does not activate coagulation |
Candida spp. [17,71] | Very large, friable vegetations | Low risk | Consumption coagulopathy |
Risk Factor | Risk Effect | Evidence | Comments |
---|---|---|---|
Vegetation Characteristics | |||
Size > 10 mm | OR 2.28 (95% CI 1.71–3.05) | [42,43] | Independent predictor across multiple studies; stronger association with anterior mitral leaflet vegetations |
Size > 15 mm | OR 2.80 (95% CI 1.97–3.98) | [44,67] | Higher risk threshold with stronger predictive value |
Mobile/filiform morphology | 40–60% risk | [67] | Compared to 15–20% with sessile vegetation |
Increasing vegetation size during therapy | OR 3.5 (95% CI 1.9–6.4) | [75] | Dynamic assessment is more significant than single measurement |
Mitral valve location | OR 2.1 (95% CI 1.4–3.2) | [65,68] | Especially anterior leaflet due to higher hemodynamic stress |
Aortic valve vegetation with severe regurgitation | OR 1.8 (95% CI 1.2–2.7) | [67] | Hemodynamic factors influence embolization risk |
Microcalcifications within vegetation | 89% sensitivity for embolic prediction | [67] | Detectable on cardiac CT imaging |
Microbial Factors | |||
S. aureus etiology | 35–61%; aOR 1.76 (95% CI 1.09–2.86) | [76,77] | Cumulative embolic incidence for total embolic events; embolic risk confined to pre-treatment phase, with no independent effect after antibiotic initiation |
Fungal pathogens | OR 2.9 (95% CI 1.5–5.4) | [65] | Associated with larger vegetations and delayed treatment response |
Streptococcus bovis | OR 1.7 (95% CI 1.1–2.6) | [78] | Associated with gastrointestinal malignancies |
Enterococci | OR 1.2 (95% CI 0.8–1.8) | [79,80] | Intermediate embolic risk profile |
HACEK group organisms | OR 1.8 (95% CI 1.1–2.9) | [16] | High biofilm formation capability |
Patient factors | |||
Younger age (<50 years) | Negative correlation with age | [68] | Possibly related to more vigorous immune response |
CRP > 75 mg/L + D-dimer > 2500 μg/L | 82% accuracy for prediction | [76] | Combined biomarker approach improves predictive accuracy |
Procalcitonin > 0.5 ng/mL | OR 2.0 (95% CI 1.3–3.1) | [16] | Reflects ongoing bacterial invasion and inflammation |
Thrombophilia | OR 1.8 (p = 0.08) | [81] | Trend toward higher in-hospital mortality |
First two weeks of antibiotic therapy | 10–20× higher risk | [75,82] | Temporal risk clustering during early treatment phase |
Prior embolic event | OR 2.7 (95% CI 1.9–3.8) | [43] | Strong predictor of recurrent embolism |
Pre-existing cardiovascular disease | OR 1.5 (95% CI 1.1–2.1) | [83] | Modifies protective effect of antiplatelet therapy |
Advanced Imaging Markers | |||
18F-FDG PET/CT uptake intensity | SUVmax > 3.5: OR 2.8 (95% CI 1.6–4.8) | [84] | Reflects metabolic activity of infected vegetation |
Brain MRI with acute silent infarcts | OR 2.2 (95% CI 1.3–3.6) | [85] | Indicates ongoing embolization; may warrant early surgery |
Cardiac CT detection of vegetation instability | 89% sensitivity | [67] | Complementary to echocardiography |
Risk Scoring Systems | |||
Italian SEU score ≥ 7 points | 65% risk vs. 5% if <7 points | [16] | Integrates vegetation size, etiology, and underlying conditions |
ENVELOPE score ≥3 | OR 3.5 (95% CI 2.3–5.4) | [84] | Combines echocardiographic and microbiological parameters |
Embolic Risk French Calculator | 86% accuracy | [42] | Web-based tool for clinical use |
Monaldi diagnostic score model | Low (0–2 points): 22% EE incidence Intermediate (3–5 points): 53% EE incidence High (6–8 points): 78% EE incidence | [69] | Score incorporates the following: 1. S. aureus infection (2 points) 2. CRP > 6.7 mg/dL (2 points) 3. Splenomegaly (2 points) 4. Vegetation size ≥ 14 mm (1 point) 5. D-dimer > 747 ng/mL (1 point) Model’s modest discriminative power (LR+ 1.69, LR− 0.33) limits standalone use, necessitating integration with imaging |
Type | Specific Condition | Prevalence in IE | Mechanism in IE Pathogenesis | Clinical Impact | References |
---|---|---|---|---|---|
Inherited | FVL | 6.4% (vs. 3.25% in controls) | Enhanced thrombin generation, fibrin deposition | Increased risk in device-related IE | [81] |
FII G20210A | 8.3% in prosthetic valve IE | Elevated prothrombin levels | Higher thrombotic complications | ||
Protein C/S deficiency | Limited data | Impaired anticoagulant function | Unknown | [141] | |
Acquired | APS | Variable | β2-glycoprotein-I mediated platelet activation | Increased embolic risk | [142] |
Malignancy-associated | Common in NBTE | Predisposition to sterile vegetations | Secondary infection risk | [143,144] | |
COVID-19-related | Emerging data | Endothelial damage, NETosis | Increased IE risk in critically ill | [145,146] |
Intervention | Timing | Effect on Embolic Risk | Supporting Evidence | Clinical Recommendations |
---|---|---|---|---|
Antibiotic Therapy | Early (first 2 weeks) | 10–20× higher risk during initiation | [75] | Intensive monitoring during initial therapy |
Later phases | Reduced risk with >40% vegetation size reduction | [149] | Consider early surgery if no size reduction | |
Antiplatelet Therapy | Prior chronic use (≥6 months) | 64% reduction (aOR 0.36, 95% CI 0.19–0.68) | [83] | Continue pre-existing therapy |
De novo initiation | No benefit (OR 1.62, 95% CI 0.68–3.86) | [150] | Not recommended (Class III) | |
Anticoagulant Therapy | Pre-admission | Reduced vegetation size (>10 mm) | [86] | Continue if indicated for other reasons |
De novo | No significant embolic reduction, 71% higher hemorrhagic risk | [86] | Avoid unless specifically indicated | |
Early Surgery | Within 48 h | 78% mortality reduction (HR 0.22) | [151] | Consider for mobile vegetation >10 mm |
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Wahab, M.A.; Khan, A.U.; Mercadante, S.; Cafarella, I.; Bertolino, L.; Durante-Mangoni, E. Deciphering the Complex Relationships Between the Hemostasis System and Infective Endocarditis. J. Clin. Med. 2025, 14, 3965. https://doi.org/10.3390/jcm14113965
Wahab MA, Khan AU, Mercadante S, Cafarella I, Bertolino L, Durante-Mangoni E. Deciphering the Complex Relationships Between the Hemostasis System and Infective Endocarditis. Journal of Clinical Medicine. 2025; 14(11):3965. https://doi.org/10.3390/jcm14113965
Chicago/Turabian StyleWahab, Muhammad Aamir, Atta Ullah Khan, Silvia Mercadante, Iolanda Cafarella, Lorenzo Bertolino, and Emanuele Durante-Mangoni. 2025. "Deciphering the Complex Relationships Between the Hemostasis System and Infective Endocarditis" Journal of Clinical Medicine 14, no. 11: 3965. https://doi.org/10.3390/jcm14113965
APA StyleWahab, M. A., Khan, A. U., Mercadante, S., Cafarella, I., Bertolino, L., & Durante-Mangoni, E. (2025). Deciphering the Complex Relationships Between the Hemostasis System and Infective Endocarditis. Journal of Clinical Medicine, 14(11), 3965. https://doi.org/10.3390/jcm14113965