The influence of newer glucose-lowering agents on venous thromboembolism (VTE) risk has important therapeutic implications. This meta-analysis compared sodium-glucose cotransporter-2 inhibitors (SGLT2—i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) with dipeptidyl peptidase-4 inhibitors (DPP-4i) and evaluated head-to-head SGLT2i versus GLP1-RA comparisons. Eligible studies enrolled adults with diabetes and reported adjusted relative risks for VTE, pulmonary embolism (PE), or deep vein thrombosis (DVT) using new-user cohort, target-trial emulation, nested case–control, or randomized controlled designs. Pooled estimates were derived using inverse-variance meta-analysis on the log scale, with random-effects sensitivity analyses. Six studies met inclusion criteria, all of moderate risk of bias. Compared with DPP-4i, both SGLT2—i (HR 0.72; 95 In a meta-analysis of six observational studies, both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of venous thromboembolism compared with DPP-4 inhibitors, while no significant difference was observed between SGLT2 inhibitors and GLP-1 receptor agonists in head-to-head comparisons.

Background Rheumatoid arthritis (RA) is associated with inflammation-driven hypercoagulability and increased venous thromboembolic risk. Post hoc analyses of safety trials have raised concerns regarding a potential differential thrombotic risk with Janus kinase inhibitors (JAKi) compared with tumour necrosis factor inhibitors (TNFi). Objectives To compare viscoelastic coagulation profiles and platelet reactivity in patients with RA treated with JAKi or TNFi, and in healthy controls (HC). Methods In this single-centre observational study, patients with RA with stable JAKi or TNFi therapy (>3 months) underwent whole-blood rotational thromboelastometry (ROTEM) and impedance aggregometry (MULTIPLATE). The primary outcomes were evaluation of: (a) whole-blood thrombogenic potential and (b) platelet reactivity. Multivariable linear regression adjusted for age, body mass index, ln-transformed Simple Disease Activity Index, treatment group and ln-transformed prednisone dose. Results Sixty-one patients with RA (30 JAKi, 31 TNFi) and 34 HC were included. Compared with HC, patients with RA exhibited significantly higher maximum clot firmness (MCF) across all ROTEM assays (INTEM 63.4±4.0 vs 57.2±4.1 mm; EXTEM 66.2±4.1 vs 55.9±4.7 mm; FIBTEM 15.7±3.6 vs 12.4±3.7 mm; all p<0.001) and enhanced platelet aggregation (all p<0.001). In multivariable analyses, JAKi therapy (vs TNFi) was independently associated with higher EXTEM MCF (β=2.32, 95% CI 0.42 to 4.23; p=0.018) and FIBTEM MCF (β=1.72, 95% CI 0.07 to 3.37; p=0.041). Prednisone dose independently predicted INTEM and EXTEM MCF, while SDAI independently predicted ADP-induced aggregation (β=11.34, 95% CI 4.31 to 18.37; p=0.002). Conclusions RA is characterised by enhanced clot firmness and platelet reactivity. JAKi therapy was independently associated with higher viscoelastic clot strength compared with TNFi, while inflammatory burden and glucocorticoid exposure were key determinants of prothrombotic signatures.

PURPOSE:To study COVID-19-associated coagulopathy and the clinical outcomes across different COVID-19 pandemic waves. METHODS:We retrospectively analyzed n 344 patients hospitalized for acute COVID-19 to Padova University Hospital between March 2020-March 2023, grouped by variants: Wild-type (G1, n 155; March 2020-January 2021), Alpha (G2, n 79; February-May 2021), Delta (G3, n 50; May-December 2021), and Omicron (G4, n 60; December 2021-March 2023). We compared traditional coagulation tests, thromboelastometry and impedance aggregometry. Clinical outcomes were also considered. RESULTS:Factor VIII decreased progressively from G1 (195%, IQR 149-227) to G4 (156%, IQR 128-197; p < 0.05), as did von Willebrand factor (343%, IQR 244-407 to 235%, IQR 216-247; p < 0.05). Thromboelastometry showed a significantly and progressively: i) prolonged INTEM and EXTEM clot formation time (p < 0.05 in all comparisons); ii) reduced INTEM, EXTEM and FIBTEM maximum clot firmness (p < 0.05 in all comparisons). Platelet aggregation significantly decreased from G1 to G4 (p < 0.05 in all comparisons). VTE occurred in 18.1% of G1 and 19.0% of G2 patients vs. 6.0% and 6.7% in G3 and G4, respectively (p < 0.05 in all comparisons). The 28-day mortality was 15.5% in G1 and 15.2% in G2 vs. 4.0% and 1.7% in G3 and G4, respectively (p < 0.05 in all comparisons). CONCLUSIONS:We observed a significant and progressive decrease in hypercoagulability across the four COVID-19 variants. A parallel decline in VTE incidence and 28-day mortality was also observed. Larger studies are needed to ascertain the pathophysiological mechanisms underlying the changes in coagulative profiles and their clinical implications.

BACKGROUND:Rotational thromboelastometry (ROTEM) provides comprehensive hemostasis assessment in cirrhosis but relies on exogenous activators, potentially limiting its reflection of in vivo conditions. The Viscoelastic Coagulation Monitor (VCM) is a new, activator-free device to assess whole-blood coagulation dynamics. OBJECTIVES:To investigate the concordance between VCM and ROTEM and to explore their association with clinical outcomes in cirrhosis. METHODS:We prospectively included 110 patients with cirrhosis admitted to our service. VCM and ROTEM were performed at hospitalization. All patients were followed up for bleeding, thrombosis, hepatic decompensation and liver-related mortality. RESULTS:Patients were mostly male (68.2%) with a median age of 61 years (53-68). Alcohol-related liver disease was the most common etiology (44.5%). 16.4% of patients were Child-Pugh A, 39.1% B, and 32.7% C. Inter-test analysis showed that parameters of VCM and ROTEM had moderate to strong correlation (ρ = 0.37-0.84, p < 0.0001). We observed progressive, significant alterations of VCM in parallel with disease severity (Child-Pugh C > B > A). In contrast, ROTEM was comparable between Child-Pugh A and B patients, being altered only in Child-Pugh C cirrhosis. The median follow-up was 11 months (7-13). No patient experienced bleeding or thrombosis. Incidence of hepatic decompensation and liver-related death was 27.2% and 14.5%, respectively. No VCM parameter was associated with decompensation/death. CONCLUSIONS:In a prospective cohort of hospitalized cirrhosis patients, VCM showed more gradual hemostatic changes across disease severity stages than ROTEM. However, neither test predicted decompensation or liver-related death, indicating that viscoelastic assessment alone is insufficient for prognosis. Further studies are needed to define VCM's role in cirrhosis management.

Hereditary thrombophilia encompasses a spectrum of genetic conditions predisposing to venous thromboembolism (VTE). Traditionally, it has been attributed to a limited number of well-defined defects, including deficiencies of natural anticoagulants—antithrombin, protein C, and protein S—and two common gain-of-function mutations, Factor V Leiden and prothrombin G20210A. These classical abnormalities remain clinically relevant but explain only a minority of early-onset, recurrent, or familial cases. Advances in molecular genetics have uncovered a broader landscape of inherited susceptibility. Next-generation sequencing, whole-exome sequencing, and genome-wide association studies have identified rare and population-specific variants in genes such as SERPINC1, PROS1, F2, and F5, as well as regulatory and intronic changes influencing coagulation pathways. Additional contributors include elevated factor VIII, IX, or XI levels, fibrinogen structural variants, and abnormalities in fibrinolytic regulators such as TAFI and PAI-1. Beyond single-gene defects, evidence supports a polygenic model in which multiple low-effect alleles and modifier genes act synergistically with environmental triggers to determine thrombotic risk. This expanding genetic and functional complexity challenges the traditional binary concept of thrombophilia. Integrating genomic tools into clinical evaluation—while avoiding indiscriminate testing—may improve risk stratification in selected patients, particularly those with strong family history or unusual thrombotic phenotypes. Hereditary thrombophilia should therefore be regarded as a continuum of genetic predisposition rather than a categorical disorder, calling for a refined, personalized approach to prevention and management of VTE in the genomic era.

Lipoprotein(a) [Lp(a)] is a causal and independent cardiovascular risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis, with elevated levels observed in approximately 20% of the general population. Plasma Lp(a) concentrations are predominantly determined by genetic factors, particularly polymorphisms of the LPA gene, which modulate apolipoprotein(a) [apo(a)] size and influence its hepatic synthesis. Structurally, Lp(a) consists of an LDL-like particle containing apolipoprotein B100, covalently bound to apo(a), conferring markedly enhanced atherogenic, pro-inflammatory, and prothrombotic properties compared with an LDL particle. In the absence of therapies specifically approved for Lp(a) reduction, current clinical management relies on an intensive approach to global cardiovascular risk reduction. ESC/EAS guidelines recommend aggressive lowering of LDL cholesterol, particularly through high-intensity statin therapy and, in patients at high or very high risk, the addition of ezetimibe and PCSK9 inhibitors, in order to mitigate the residual risk associated with elevated Lp(a) levels. Lipoprotein apheresis represents the only intervention capable of producing a substantial and immediate reduction in Lp(a); however, its use is limited to selected patients due to its invasive nature and limited availability. In parallel, innovative therapies targeting LPA gene silencing-such as antisense oligonucleotides and small interfering RNA-as well as oral agents inhibiting Lp(a) assembly, are in advanced stages of development. These approaches have demonstrated Lp(a) reductions of up to 80-90%, offering concrete prospects for a causal therapeutic strategy, pending the results of cardiovascular outcome trials.

Background: PSVD is a rare liver vascular disease causing intrahepatic vascular injury and portal hypertension (PH). Although its pathophysiology is not fully understood, PSVD is marked by damage of the intrahepatic portal microvasculature. In this context, large extracellular vesicles (lEVs) can play a key role. Aim: This study quantifies circulating lEVs from endothelial cells, platelets, and monocytes in PSVD with and without PH. Methods: The study included 29 patients with PSVD: 6 without PH but histologically defined, and 23 with PH. Ten healthy individuals served as controls. Platelet-poor plasma was prepared per ISTH/ISEV guidelines. lEVs (0.2–0.9 μm) were isolated by high-speed centrifugation and analyzed via flow cytometry. LEVs were stained with calcein and AnnexinV, and further characterized by immunophenotyping for endothelial markers (CD62E/CD105/CD147/TF), platelet markers (CD41/CD62P), and monocyte/macrophage markers (CD45/CD14). Results: The PSVD cohort mainly consisted of male patients (69.0%), with a median age of 58 years (40-69). An identifiable associated condition occurred in 58.2%, mainly myeloproliferative disease (24.1%). Specific lesions appeared in 79.3%, notably obliterative portal venopathy (55.2%, n=16). Among those with PH, 34.8% experienced PH-related complications.PSVD patients showed increased endothelial and platelet markers compared to controls. Specifically, endothelial lEV subtypes, including Annexin⁺CD62E⁺ (1020.93 [814.88-1361.84] vs 61.76 [29.7-76.67], AnnexinV⁺CD147⁺ (1862.77 [1588.91-2355.04] vs 365.39 [302.24-446.54]), and AnnexinV⁺CD105⁺ (1004.20 [902.13-1004.21] vs 668.38 [464.52–711.17]), were all significantly increased (p≤0.006). Platelet lEVs also showed significant elevations: AnnexinV⁺CD41⁺ (1862.77 [1588.91-2355.04] vs 933.69 [725.83-1356.24]) and AnnexinV⁺CD41⁺CD62P⁺ (80.04 [66.02-120.75] vs 25.49 [18.49-35.43]; p≤0.009). Endothelial and platelet lEVs were significantly higher in myeloproliferative-PSVD (p=0.046; p=0.032). In contrast, monocyte/macrophage lEVs were significantly reduced, as shown for Calcein⁺AnnexinV⁺CD45⁺CD14⁺ lEVs (169.42 [109.62-215.83] vs 413.72 [325.44-510.82]; p≤0.001). PSVD patients without PH also showed significantly increased endothelial (p<0.03) and platelet lEVs (p<0.029), and lower monocyte/macrophage lEVs (p<0.005). No significant differences emerged between PSVD with and without PH, although monocyte/macrophage lEVs tended to be lower in patients with PH. There were no notable differences between patients with complicated versus non-complicated PH. Conclusions: Our data reveal a distinctive endothelial-platelet lEV signature in PSVD. This pattern occurs regardless of PH presence, indicating it reflects core disease biology rather than differences in hemodynamic severity. These findings support an integrated model where endothelial injury and platelet activation interact with immune pathways to promote microvascular remodeling in PSVD.

Lipoprotein(a) [Lp(a)] is a well-established genetic risk factor for atherosclerotic cardiovascular disease, though its role as a prothrombotic risk factor remains only partially understood. We report the case of a 64-year-old woman with markedly elevated Lp(a) levels (925 nmol/L, reference range < 105 nmol/L) and a history of recurrent major cardiovascular events, despite optimal lipid-lowering and antiplatelet therapies. We confirmed a hypercoagulable profile via comprehensive functional assessment of hemostasis: enhanced thrombin generation, reduced sensitivity to thrombomodulin, platelet hyperreactivity, and increased clot firmness at thromboelastometry — with residual platelet activity despite antiplatelet treatment. This case suggests a possible association between markedly elevated plasma Lp(a) levels and a hypercoagulable profile, which may enhance atherogenesis. Global coagulation and platelet function assays may help identify high-risk patients with elevated Lp(a) levels who may benefit from tailored antithrombotic strategies.

Il metabolismo osseo e il sistema coagulativo, finora considerati come due sistemi separati, sono in realtà connessi da una complessa e articolata interazione bidirezionale. Diversi fattori coinvolti nell’emostasi influenzano l’attività delle cellule ossee, mentre fattori regolatori del metabolismo minerale agiscono sulle vie che modulano l’emostasi e il sistema vascolare. Questa interazione assume particolare rilevanza clinica con l’aumentare dell’incidenza, spesso concomitante, di patologie scheletriche e tromboemboliche, e con l’impiego prolungato di terapie che agiscono su entrambi i sistemi. In questa rassegna vengono sintetizzati i principali meccanismi molecolari e cellulari alla base di questo crosstalk, discutendo anche alcune potenziali implicazioni cliniche.

Background: Pro- and anti-coagulant factors are significantly altered in liver cirrhosis resulting in an increased bleeding and thrombosis risk. The thrombin generation (TG) test often seems unaltered in cirrhosis, indicating that a new hemostatic balance is reached. TG is determined by prothrombin conversion and thrombin inactivation, as quantified by thrombin dynamics (TD) analysis.Aim: We prospectively investigated changes in TG and TD in cirrhosis to explore its predictive potential for bleeding and thrombosis. Material and methods: TG and TD were determined in 42 CP-A, 42 CP-B and 41 CP-C cirrhosis patients and 20 healthy controls. TG peak height and velocity index were higher in patients than controls (+20%, p=0.039 and +70%, p=0.002), and time-to-peak was shorter (-18%, p<0.0001). The amount of prothrombin converted (PCtot) was significantly reduced in patients (-43%,p<0.0001), and the magnitude of the reduction was associated with disease severity. The thrombin decay capacity (TDC) was significantly lower in patients (-44%,p<0.0001). Four patients experienced bleeding and 7 experienced thrombosis during follow-up. Lower thrombin-α2Macroglobulin (T-α2M) complex formation was significantly associated with thrombosis during follow-up, and patients in the lowest quintile of T-α2M had a hazard ratio of 6.6 (1.47-29.9,p=0.014) for thrombosis. Low maximum prothrombin conversion rates (PCmax) were associated with an increased hazard of bleeding, and patients in the lowest 20% of PCmax had a 12.9-fold higher bleeding hazard (CI:1.34-124.31,p=0.027) (Figure).Conclusion: We conclude that reduced prothrombin conversion and thrombin inactivation result in rebalanced TG in cirrhosis patients. Our results demonstrate the potential clinical usefulness of TD parameters for the stratification of bleeding and thrombotic risk in cirrhosis patients.