Preeclampsia is a hypertensive disorder of pregnancy associated with significant maternal and fetal complications. Its pathogenesis involves endothelial dysfunction, abnormal placentation, and coagulation abnormalities, leading to increased thrombotic and hemorrhagic risks. This narrative review provides an in-depth overview of the pathophysiological mechanisms underlying preeclampsia, with a particular focus on its thrombotic and hemorrhagic complications. Treatment strategies are explored, with emphasis on the role of low-dose aspirin in reducing early-onset preeclampsia. However, aspirin’s effectiveness varies based on dosage and timing, with higher doses showing greater benefit in preventing severe preeclampsia. Despite aspirin’s widespread use, further optimization of its therapeutic role remains necessary to enhance maternal and fetal outcomes.

Sodium–glucose co-transporter-2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP-1 RAs) are now established as cornerstone therapies for patients with type 2 diabetes mellitus (T2DM), given their cardiovascular and renal protective properties. However, their use in patients with peripheral artery disease (PAD) remains controversial due to concerns raised in early trials about potential increases in lower limb complications, particularly amputations. This narrative review examines current evidence on the association between SGLT2is and GLP-1 RAs in PAD-related outcomes, including limb events, amputation risk, and cardiovascular and renal endpoints. Drawing from randomized controlled trials, real-world cohort studies, and systematic reviews, we provide an integrated perspective on the safety and utility of SGLT2is and GLP-1 RAs in individuals with PAD, highlight patient selection considerations, and identify areas for future investigation.

Oxidative stress (OS), derived from an imbalance between reactive oxygen species (ROS) accumulation and impaired antioxidant defense, is a recognized cause of atherothrombosis, through a complex interaction between low-grade inflammation and platelet activation.

Background and Aims. Metabolic-associated steatotic liver disease (MASLD) is characterized by systemic alterations involving the liver–platelet axis. Experimental evidence has demonstrated that platelets actively contribute to NASH development and progression to hepatocellular carcinoma, particularly through GPIbα-mediated inflammatory pathways. In parallel, the liver plays a central role in regulating platelet homeostasis by controlling both thrombopoietin (TPO) production and platelet clearance, supporting a bidirectional interaction between liver function and platelet biology. Thrombopoietin (TPO) regulates platelet production through its receptor CD110, while glycocalicin (GC), generated by ADAM17-mediated cleavage of the platelet receptor GPIbα, reflects platelet clearance. In this context, alterations in the TPO–GPIbα axis may represent a link between hepatic dysfunction and platelet-driven inflammation. However, the clinical relevance of these pathways, including the role of the TPO/GC balance in MASLD severity, remains poorly defined. This study aimed to investigate the association between MASLD severity and circulating levels of TPO, GC, and the TPO/GC ratio, as well as platelet expression of CD110, GPIbα, and ADAM17.Methods. A total of 171 subjects were enrolled. They were stratified according to the presence of MASLD [without (NO) (n=42), mild MASLD (MILD) (n=64), and moderate–severe MASLD (MOD–SEV) (n=65)]. Plasma levels of TPO and GC were measured and used to calculate the TPO/GC ratio. Platelet surface expression of CD110 and GPIbα was assessed by flow cytometry, while total platelet expression of GPIbα and ADAM17 was evaluated by Western blot. Group differences were analyzed using appropriate statistical methods.Results. Plasma TPO levels were significantly increased in subjects with moderate–severe MASLD compared with those without MASLD (MOD–SEV vs NO, P = 0.030), showing a progressive increase with disease severity; a trend was also observed when comparing MOD–SEV with MILD (P = 0.093). Plasma GC levels did not differ significantly among groups. Consequently, the TPO/GC ratio was higher in patients with moderate–severe MASLD, reaching borderline statistical significance versus controls (MOD–SEV vs NO, P = 0.050), suggesting a shift of the TPO–GPIbα axis toward increased TPO availability (Figure). The percentage of platelets expressing the TPO receptor (%CD110: MOD–SEV vs NO, P = 0.070; MILD vs NO, P = 0.094) and GPIbα (MOD–SEV vs NO, P = 0.095; MILD vs NO, P = 0.003) showed a trend toward higher values in MASLD subjects compared with controls. Conversely, the mean fluorescence intensity (MFI) of both receptors was reduced in moderate–severe MASLD (MFI CD110: MOD–SEV vs MILD, P = 0.068; MFI GPIbα: MOD–SEV vs NO, P = 0.043; MOD–SEV vs MILD, P = 0.042), indicating receptor redistribution or remodeling (Figure). Platelet ADAM17 expression did not differ significantly among groups, whereas total GPIbα expression assessed by Western blot showed a trend toward increased levels in moderate–severe MASLD (MOD–SEV vs NO, P = 0.065) (Figure).Conclusions. MASLD severity is associated with progressive dysregulation of the thrombopoietin–platelet axis, characterized by increased circulating TPO. Increased platelet expression of GPIbα may contribute to the enhanced thrombopoiesis in advanced disease, supporting sustained platelet production and survival. These changes occur in the absence of significant ADAM17-mediated shedding, indicating functional platelet adaptation rather than overt activation. Overall, the TPO/CD110–GPIbα axis emerges as a candidate biomarker of disease severity and a mechanistic contributor to MASLD progression.

Background and Aims. In patients with type 2 diabetes (T2D), atherosclerotic cardiovascular disease (ASCVD) is characterized by enhanced platelet activation and increased oxidative stress, both of which contribute to thrombotic risk and disease progression. Carotid artery stenosis represents a clinically relevant manifestation of systemic atherosclerosis and is included among ASCVD conditions. However, the relative contribution of platelet activation and oxidative stress to atherosclerotic burden in patients with T2D remains incompletely defined. This study aimed at investigating urinary markers of platelet activation and oxidative stress—11-dehydro-thromboxane B₂ (11-dh-TXB₂) and 8-iso-prostaglandin F₂α (8-iso-PGF₂α)—in T2D patients with or without ASCVD, including those with carotid artery stenosis ≥50%.Methods. Urine samples were collected from 179 patients with T2D, with (n=84) or without (n=95) aspirin (ASA) therapy. Urinary levels of 11-dh-TXB₂ and 8-iso-PGF₂α were measured by enzyme immunoassay (EIA) following chromatography-based prostaglandin extraction. Patients were stratified according to the presence of ASCVD (n=98 with ASCVD) and carotid artery stenosis ≥50% (n=84 with carotid stenosis ≥50%).Results. Patients with ASCVD showed higher urinary levels of 8-iso-PGF₂α compared with those without ASCVD, both among patients not receiving ASA therapy (P = 0.058) and among those receiving ASA therapy (P = 0.013), indicating increased oxidative stress in subjects with established atherosclerotic disease. When carotid artery stenosis ≥50% was considered, 8-iso-PGF₂α levels remained significantly higher in patients not receiving ASA therapy (P = 0.048), whereas no significant difference was observed among ASA-treated patients (P = 0.140), supporting an association between oxidative stress and advanced atherosclerotic burden. Urinary 11-dh-TXB₂ levels were significantly higher in patients with ASCVD only among those not receiving ASA therapy (P = 0.006), while no significant difference was observed in patients on ASA therapy (P = 0.140). Similarly, patients with carotid artery stenosis ≥50% showed significantly higher 11-dh-TXB₂ levels only in the absence of ASA therapy (P = 0.024), with no difference among ASA-treated patients (P = 0.898). Urinary levels of 8‑iso‑PGF₂α and 11‑dh‑TXB₂ were directly correlated (rho=0.565, <0.001), further confirming the close interplay between oxidative stress and platelet activation in patients with T2D.Conclusions. In patients with T2D, oxidative stress—as reflected by increased urinary 8-iso-PGF₂α—is significantly associated with the presence of ASCVD, including carotid artery stenosis ≥50%. Aspirin therapy effectively attenuates platelet activation, as indicated by the lack of association between urinary 11-dh-TXB₂ and atherosclerotic burden in ASA-treated patients. These results highlight oxidative stress as a key mechanism underlying residual cardiovascular risk in diabetes and suggest that urinary oxidative stress markers may represent a useful tool for identifying patients with advanced atherosclerotic disease.

Background and aims. Preeclampsia (PE) is characterized by endothelial dysfunction and platelet involvement, with increasing evidence pointing to altered platelet turnover. Enhanced platelet consumption may trigger compensatory production, leading to measurable changes in circulating biomarkers. Thrombopoietin (TPO) reflects platelet production, while glycocalicin (GC) indicates platelet destruction. Thiazole orange (TO) identifies immature, reticulated platelets and provides insight into bone marrow response and platelet activity. This study aimed to investigate longitudinal changes in TPO, GC, and TO in high-risk pregnancies treated with low-dose aspirin (ASA), to better characterize platelet turnover and its relationship with PE development.Methods. This observational study included 25 high-risk pregnant women on ASA and 12 controls with uncomplicated pregnancies. Blood samples were collected at baseline (T0), 21 gestational weeks (T4), and 27 gestational weeks (T5). Platelet-related biomarkers TPO and GC, indicating platelet production and destruction, respectively; and TO were measured longitudinally.Results. Late onset PE occurred in 6/25 (24%) high-risk women and in none of the controls, while there was no case of early onset disease. Within the high-risk group, TPO and GC levels remained relatively stable in women without events, whereas in women who developed PE, TPO levels increased and were linked to disease onset (overall p=0.036), with more notable differences at T4–T5 (weeks 21 and 27); conversely, GC levels were higher at baseline (p=0.048) and decreased over time in women who developed PE. Using the latest PE risk algorithm, clinical stratification showed high sensitivity and NPV (both 1.00) but low specificity (0.39) and PPV (0.24). Adding baseline glycocalicin improved prediction, with higher thresholds (≥0.80) markedly increasing specificity (0.95) and PPV (0.80), supporting a two-step algorithm–biomarker approach.Conclusions. Preeclampsia is characterized by a dynamic imbalance in platelet turnover, with early alterations in glycocalicin and subsequent increases in TPO, suggesting temporally distinct changes in platelet destruction and production. While the current PE risk algorithm shows excellent rule-out performance, its limited specificity may be improved by incorporating platelet biomarkers. In particular, baseline glycocalicin enhances risk stratification at higher thresholds, supporting a combined algorithm–biomarker approach for identifying high-risk women despite aspirin prophylaxis.