Luca Spiezia

Background and Aims. Obstructive sleep apnea (OSA) is a common and clinically significant disorder characterized by recurrent episodes of upper airway obstruction during sleep, leading to intermittent hypoxia and sleep fragmentation. Increasing evidence suggests that OSA may promote a prothrombotic state through several interconnected mechanisms, including oxidative stress, endothelial dysfunction, platelet activation, and alterations in coagulation and fibrinolysis pathways. These changes may contribute to an elevated risk of cardiovascular and thrombotic complications in affected individuals. Methods. We conducted an observational study involving adult patients (≥18 years) diagnosed with untreated moderate-to-severe OSA, defined by an apnea–hypopnea index (AHI) greater than 15 events per hour. Patients were excluded if they had experienced recent cardiovascular events, had known coagulation disorders, active prothrombotic conditions, or were receiving anticoagulant therapy. For each participant, demographic and clinical characteristics, including body mass index (BMI), were collected. Both routine coagulation tests and more specific hemostatic markers were assessed through blood sampling. Participants were prospectively followed for a period of six months to document the occurrence of thrombotic events. The study group consisted of 41 patients with OSA, who were compared with 41 healthy controls matched for age and sex. Results. Standard coagulation parameters, including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), as well as fibrinogen, antithrombin, plasminogen, and plasminogen activator inhibitor-1 (PAI-1), showed no significant differences between OSA patients and controls. In contrast, specific procoagulant factors were significantly elevated in the OSA group, including factor VIII (P = .011), factor XI (P < .001), and the factor VIIa–antithrombin complex (P = .009). No significant differences in these markers were observed between patients with moderate versus severe OSA, and no correlation was found between AHI values and the levels of these coagulation factors. During the six-month follow-up period, 17% of patients experienced thrombotic events. These events were associated with higher baseline levels of the identified procoagulant factors. Conclusions. Moderate-to-severe OSA is associated with a selective increase in specific procoagulant factors, despite largely normal findings in routine coagulation tests. This pattern suggests the presence of a hypercoagulable state that may contribute to an increased risk of thrombotic events. Notably, these hemostatic alterations appear to be independent of OSA severity, indicating that prothrombotic mechanisms are already active even in moderate forms of the disease.

Background and Aims. Patients with inflammatory bowel disease (IBD) are at increased risk of thromboembolic events, though the link between inflammation and hypercoagulability is not fully understood, as standard coagulation tests fail to capture the dynamic changes in hemostasis. Prothrombotic mechanisms are multifactorial, involving elevated procoagulant factors, increased platelet reactivity, and endothelial activation driven by systemic cytokines. This study aimed to characterize the hemostatic profile of patients with moderate-to-severe ulcerative colitis (UC) compared to healthy controls using standard assays, viscoelastic testing, and impedance aggregometry, and to evaluate associations with systemic and mucosal inflammation.Methods. A prospective, single-center case–control study was conducted. Twenty-three patients with confirmed moderate-to-severe ulcerative colitis (UC), defined by a Mayo endoscopic subscore ≥2, and 23 age- and sex-matched healthy controls were enrolled. All patients had failed at least one prior line of therapy and were awaiting initiation of anti-JAK treatment. Standard coagulation assays were performed alongside rotational thromboelastometry and whole-blood impedance aggregometry. Disease activity in UC patients was assessed using the Mayo endoscopic subscore, as well as total and partial Mayo scores; systemic and mucosal inflammation were evaluated by C-reactive protein (CRP) and fecal calprotectin, respectively. Spearman’s correlation analysis was used to assess the relationships between hemostatic parameters and inflammatory markers.Results. Standard assays demonstrated significantly higher activities of Factor VIII (175 ± 43% vs 143 ± 21%, p=0.003) and Factor X (120 ± 26% vs 98 ± 12%, p<0.001). Rotational thromboelastometry showed a shortened clot formation time (CFT) in the extrinsic pathway (76 ± 22 s vs 101 ± 27 s, p=0.001). In addition, maximum clot firmness (MCF) was significantly increased in the extrinsic (67 ± 5 mm vs 57 ± 4 mm, p<0.001), intrinsic (65 ± 6 mm vs 57 ± 3 mm, p<0.001), and fibrinogen-specific (23 ± 8 mm vs 12 ± 3 mm, p<0.001) assays. Whole-blood impedance aggregometry revealed enhanced platelet aggregation in response to adenosine diphosphate (ADP test) (75 ± 21 vs 55 ± 11 U, p<0.001) and arachidonic acid (ASPI test) (94 ± 30 vs 45 ± 14 U, p<0.001). Regarding disease activity, systemic inflammation, as reflected by CRP levels, showed positive correlations with several procoagulant factors, including Factor VIII (p=0.013) and fibrinogen (p<0.001), as well as fibrinogen-specific MCF (p=0.006). In contrast, markers of localized intestinal inflammation, including fecal calprotectin, and clinical disease severity assessed by Mayo endoscopic subscore, total Mayo score, and partial Mayo score, were not significantly associated with either standard or viscoelastic hemostatic parameters.Conclusions. Patients with moderate-to-severe ulcerative colitis show a marked hypercoagulable state and increased platelet reactivity versus healthy controls, mainly driven by systemic inflammation rather than local disease activity, underscoring the role of systemic markers in thromboembolic risk assessment; larger prospective studies are needed to confirm mechanisms and guide clinical strategies.

Background and Aims. Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized not only by joint involvement but also by systemic manifestations, including a prothrombotic state driven by persistent inflammation. This condition is associated with increased activation of the coagulation cascade, impaired fibrinolysis, and heightened platelet activation, ultimately contributing to an elevated risk of venous thromboembolism. In recent years, post hoc analyses of randomized clinical trials and real-world safety data have raised concerns about a potentially different thrombotic risk profile between patients treated with Janus kinase inhibitors (JAKi) and those receiving tumor necrosis factor inhibitors (TNFi). Nevertheless, the precise effects of these therapeutic strategies on global coagulation dynamics in whole blood, as well as on platelet function, remain incompletely understood and warrant further investigation. The aim of this study was to compare viscoelastic coagulation properties and platelet reactivity among RA patients treated with JAK inhibitors or TNF inhibitors and to evaluate differences relative to healthy control subjects (HC) in order to better characterize treatment-related prothrombotic profiles.Methods. This was a single-center observational study including RA patients receiving stable treatment with either JAKi or TNFi for at least three months. All participants underwent assessment of coagulation and platelet function using whole-blood rotational thromboelastometry (ROTEM®) and impedance aggregometry (MULTIPLATE®). The primary endpoints were the evaluation of: (a) whole-blood thrombogenic potential, assessed through viscoelastic clot parameters, and (b) platelet reactivity in response to specific agonists. Multivariable linear regression models were applied to adjust for potential confounders, including age, body mass index (BMI), natural logarithm-transformed Simplified Disease Activity Index (SDAI), treatment group, and ln-transformed prednisone dose.Results. A total of 61 RA patients (30 receiving JAKi and 31 receiving TNFi) and 34 healthy controls were included in the analysis. Compared with healthy individuals, RA patients demonstrated significantly increased maximum clot firmness (MCF) across all ROTEM assays, including INTEM (63.4±4.0 vs 57.2±4.1 mm), EXTEM (66.2±4.1 vs 55.9±4.7 mm), and FIBTEM (15.7±3.6 vs 12.4±3.7 mm), with all comparisons reaching statistical significance (p<0.001). In addition, platelet aggregation responses were significantly enhanced in RA patients across all tested pathways (p<0.001). In multivariable analyses, treatment with JAK inhibitors, compared with TNF inhibitors, was independently associated with higher EXTEM MCF (β=2.32, 95% CI 0.42–4.23; p=0.018) and FIBTEM MCF (β=1.72, 95% CI 0.07–3.37; p=0.041). Furthermore, prednisone dose emerged as an independent predictor of increased INTEM and EXTEM MCF, while disease activity, as measured by SDAI, was independently associated with enhanced ADP-induced platelet aggregation (β=11.34, 95% CI 4.31–18.37; p=0.002).Conclusions. RA is associated with a prothrombotic phenotype characterized by increased clot firmness and heightened platelet reactivity. Treatment with JAK inhibitors appears to be independently associated with greater viscoelastic clot strength compared with TNF inhibitors. Additionally, systemic inflammation and glucocorticoid exposure represent key determinants of coagulation activation and platelet hyperreactivity, underscoring their central role in shaping thrombotic risk in this patient population.

Background and Aims. Thromboembolic events are frequently observed in wild-type transthyretin amyloidosis (ATTRwt), with a reported prevalence ranging from 6% to 28%. The main mechanisms contributing to thrombosis include atrial fibrillation (AF), mechanical atrial dysfunction, and myocardial involvement leading to myopathy. However, thromboembolic complications have also been described in patients who are in sinus rhythm or receiving apparently adequate anticoagulant therapy, suggesting that additional, not yet fully understood, pathophysiological factors may be involved. This study aimed to assess whether hyperactivation of the coagulation system can be detected through thrombin generation (TG) testing in patients with transthyretin amyloidosis. Methods. A total of 24 patients with ATTRwt (median age 80 years; 17 males and 7 females), all without AF and not receiving anticoagulant therapy, were enrolled. Their results were compared with those of 50 healthy controls matched for age (± 3 years) and sex. Thrombin generation was measured in platelet-poor plasma (PPP) samples, both in the presence and absence of thrombomodulin, using the automated and standardized ST Genesia analyzer (Stago, Asnières-sur-Seine, France) and the STG-ThromboScreen kit, in accordance with the manufacturer’s instructions. Results. Thrombin generation parameters are reported in Table 1. No statistically significant differences were observed between patients and controls across all evaluated parameters. Specifically, lag time (min), endogenous thrombin potential (ETP, nmol/L·min), peak height (nM), time to peak (min), velocity index (nM/min), and start tail (min) were comparable between the two groups, both in assays performed with and without thrombomodulin. Conclusions. Thrombin generation profiles in patients with ATTRwt appear to be similar to those observed in healthy individuals. These findings suggest that, under the conditions examined, there is no clear evidence of coagulation system hyperactivation detectable by TG. Further studies are warranted to better elucidate the molecular mechanisms underlying potential hypercoagulability and to determine whether TG may serve as a predictive marker of a prothrombotic clinical phenotype.

Background and Aims. Bernard–Soulier Syndrome (BSS) is a rare autosomal recessive platelet disorder caused by defects of the GPIb-IX-V complex and characterized by a bleeding phenotype that does not always correlate with conventional laboratory findings. The ISTH-BAT provides a standardized method for assessing bleeding; however, its relationship with platelet function in patients with BSS, particularly when evaluated using whole-blood assays, is still not well defined. This study aims to investigate the association between bleeding severity, as measured by the ISTH-BAT score, and platelet function in a cohort of patients with BSS, including individuals with both bleeding and non-bleeding phenotypes.Methods. Eighteen patients from seven unrelated families with clinical and genetic diagnosis of BSS underwent comprehensive laboratory evaluation. Bleeding tendency was assessed using the ISTH-BAT score. Data on platelet count, size, morphology were acquired. In addition, surface markers expression (CD41A, CD42A, CD42B, CD49B, PAC1, CD62P activated by ADP) were evaluated by platelet immunophenotyping on flow cytometer. Platelet function was assessed in platelet-rich plasma by light transmission aggregometry and in whole blood by using impedance aggregometry (Multiplate®). Whole-blood coagulation was additionally evaluated by rotational thromboelastometry (ROTEM®). Genetic variants were identified by Sanger sequencing.Results. All patients with BSS (mean age 45 ± 20 years; 9M/9F) had low platelet averaging at 87 ± 45 ×10⁹/L. 13/18 patients manifested haemorrhagic episodes (bleeders group) while 5/18 not having haemorrhagic events were defined as non-bleeders. The ISTH-BAT score was 0 in non-bleeders and >1 in bleeders, with overall values ranging from 0 to 8 and a mean of 3 among bleeders. A significant difference in LTA aggregation between bleeders and non-bleeders was observed in response to collagen (64±24 vs. 81±7%, respectively; p = 0.04) and to Ristocetin (48±28 vs. 73±13%, respectively; p = 0.03). No association was found between the ISTH-BAT score and aggregation assessed by Multiplate®, nor with ROTEM® profiles. Multiplate® and ROTEM® parameters were in the normal range in both groups, except ASPI test, that was reduced in bleeders and non-bleeders (see Table 1). In the PFA-200 test, closure time was prolonged in both COL/EPI and COL/ADP cartridges in both groups; the increase was less pronounced in non-bleeders, although this difference did not reach statistical significance.Conclusions. Platelet aggregation responses to collagen and Ristocetin are associated with bleeding severity in BSS, whereas platelet count is not. These findings support the variability of laboratory phenotypes in BSS and suggest that platelet function testing may better reflect bleeding risk than platelet count alone. Larger studies are needed to confirm these preliminary observations.

Background and Aims: Bleeding risk in cirrhotic patients undergoing invasive procedures is traditionally assessed using conventional coagulation tests, which poorly reflect the rebalanced haemostatic state of cirrhosis and often lead to unnecessary transfusions. Viscoelastic testing (VET) provides a global assessment of coagulation and may enable more rational transfusion strategies. We performed a systematic review and meta‐analysis of randomised controlled trials (RCTs) to evaluate the efficacy and safety of VET‐guided transfusion strategies in this setting. Methods: We systematically searched PubMed, Embase and Scopus from inception to 10 April 2026. RCTs comparing VET‐guided versus standard‐of‐care transfusion strategies in cirrhotic patients undergoing invasive procedures were included. Primary outcome was procedure‐related bleeding; secondary outcomes included transfusion requirements. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using the Mantel–Haenszel method. Results: Six RCTs including 296 patients were analysed. Procedure‐related bleeding was rare and did not differ between groups (RR 0.74, 95% CI 0.24–2.31; I ² = 0%). In contrast, VET‐guided strategies significantly reduced transfusion requirements, including any blood product transfusion (RR 0.33, 95% CI 0.26–0.44; I ² = 56%), platelet transfusion (RR 0.20, 95% CI 0.13–0.32; I ² = 40%), any fresh frozen plasma (FFP) exposure (RR 0.40, 95% CI 0.28–0.57; I ² = 63%) and FFP‐only transfusion (RR 0.22, 95% CI 0.10–0.46; I ² = 81%). Conclusions: VET‐guided transfusion strategies significantly reduce blood product utilisation without increasing bleeding risk in cirrhotic patients undergoing invasive procedures. These findings support a shift towards a physiology‐based approach to haemostasis, with potential benefits for patient safety and resource optimisation. Trial Registration: ClinicalTrials.gov identifier: CRD420261382437.

Background and Aims: Cirrhosis is characterized by progressive immune dysregulation, endothelial dysfunction, and haemostatic imbalance. Circulating extracellular vesicles (EVs) have emerged as potential biomarkers reflecting these pathophysiological processes. We aimed to determine whether EVs mirror disease severity and predict liver‐related outcomes in cirrhosis. Methods: In this prospective single‐centre study, patients with compensated, stable decompensated, or acutely decompensated cirrhosis were enrolled. EVs were isolated from platelet‐poor plasma and quantified by flow cytometry to characterize platelet‐, endothelial‐, immune‐, and CK18 ⁺ EVs, EVs expressing markers associated with endothelial anticoagulant pathways and tissue remodelling. Primary endpoints were first hepatic decompensation in compensated cirrhosis and a composite of further decompensation, acute‐on‐chronic liver failure, or liver‐related mortality in acutely decompensated cirrhosis. Associations were analysed using Fine‐Grey competing‐risk models. Results: We included 228 patients, including 75 compensated, 44 stable decompensated, and 109 acutely decompensated. Median follow‐up was 418 days. EV profiling showed progressive increases in total, platelet‐derived, endothelial‐, immune‐derived, and tissue remodelling‐associated EVs across Child–Pugh stages, suggestive of increasing thrombo‐inflammatory and endothelial perturbation. First hepatic decompensation occurred in 7 patients with compensated cirrhosis and was associated with higher MELD and Child–Pugh scores, alcohol‐related aetiology, and lower platelet count. In univariate competing‐risk analyses, higher levels of several EV subpopulations were associated with first decompensation, but these associations disappeared after adjustment for MELD. Among patients with decompensated cirrhosis, 65 developed further decompensation, ACLF, or liver‐related death; higher CRP levels were associated with these events, whereas no EV subpopulation was associated with the composite outcome. Conclusions: Circulating EVs reflect cirrhosis severity and are suggestive of progressive thrombo‐inflammatory, endothelial, and tissue‐remodelling changes. However, EVs were not independently associated with clinical outcomes.

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.

This editorial introduces a curated collection of articles published in Frontiers in Cardiovascular Medicine: Case Reports in Thrombosis: 2025. The manuscripts included in this Research Topic cover a broad and diverse range of subjects, spanning from genetic predispositions to venous thromboembolism to the clinical management of rare, complex, and potentially life-threatening comorbid conditions. Together, these contributions highlight recent advances, clinical challenges, and emerging perspectives in the field of thrombosis, offering valuable insights for both researchers and clinicians. We hope that readers will find this collection informative and practically relevant, supporting and enhancing decision-making in daily clinical practice. We would like to express our sincere gratitude to all the reviewers for their careful evaluations and constructive feedback, as well as to the Editorial Office staff for their continuous support and dedication throughout the publication process. Their contributions have been essential to the success and quality of this Research Topic. Below, we present the articles included in Frontiers in Cardiovascular Medicine: Case Reports in Thrombosis: 2025.Lower extremity deep vein thrombosis associated with transplanted renal vein thrombosis is a rare and severe post-surgical complication. This condition is characterized by venous obstruction, parenchymal edema, and a high risk of transplant failure. The authors describe a 41-year-old man and a 47-year-old man who had received an allogeneic kidney transplantation 15 and four years prior, respectively. Both patients presented with lower extremity pain and swelling. Color Doppler ultrasound in both cases showed thrombosis of the common femoral, iliac and transplanted kidney veins. The patients were treated with implantation of an inferior vena cava filter followed by mechanical thrombectomy using an AngioJet thrombus aspiration catheter. Residual stenosis in the common iliac vein required dilation with an ATLAS balloon. This report highlights that the AngioJet system is a safe and effective option in these patients to promptly remove the thrombus, restore blood flow and improve renal function without complications or recurrence. Furthermore, the authors underscore the importance or regular assessments of vascular patency in transplanted renal arteries and veins.Superior vena cava syndrome (SVCS) and non-traumatic subdural hemorrhage (SDH) are rare albeit life-threatening complications in hemodialysis patients. This case describes a 73-year-old hemodialysis male patient with end-stage renal disease who developed SVCS due to venous occlusion, later complicated by SDH. Interventional treatment with angioplasty and stent placement in the left brachiocephalic vein and SVC successfully resolved both conditions. The case suggests a pathophysiological link between venous congestion and SDH, as increased intracranial venous pressure may contribute to bleeding. Anticoagulation and hemodynamic fluctuations during dialysis may also worsen the condition. This report highlights that early treatment to relieve venous hypertension in SVCS is crucial to restore flow and prevent serious neurological complications in hemodialysis patients.Totally implantable venous access ports (TIVAPs) are widely used for chemotherapy and long-term infusions (1). Thrombosis associated with TIVAPs is uncommon and rarely leads to severe complications. This case describes a 58-year-old man with atrial fibrillation (AF) and patent foramen ovale (PFO) who developed paradoxical embolism and right atrial thrombosis 28 months after TIVAP implantation. The patient presented with dizziness and left lower extremity weakness. Imaging showed right temporal lobe infarction and a right atrial mass; he was treated with surgery and anticoagulation. This case highlights TIVAP risks and the importance of proper management, anticoagulation, and PFO screening in patients with AF and central venous catheter accesses.Venous thromboembolism (VTE) may arise from genetic or acquired risk factors, including protein S deficiency (2). This report describes a 32-year-old man with mesenteric venous thrombosis and pulmonary embolism. He presented with pleuritic chest pain and mild fever 15 days after a confirmed COVID-19 diagnosis. Genetic testing revealed a PROS1 gene missense mutation. The patient had a previous episode of mesenteric thrombosis and several acquired risk factors such as obesity, physical inactivity, and inflammation; protein S activity was reduced. Despite initially receiving glucocorticoids and macrolide, symptoms worsened and D-dimer levels increased. A CT angiography confirmed acute pulmonary embolism. The patient initiated low-molecular-weight heparin and rivaroxaban; there was no recurrent VTE or bleeding events at one year. This case highlights the importance of effective therapeutic management in patients with inherited or acquired thrombophilias.Prolonged retention of inferior vena cava filters (IVCF) significantly increases the risk of complications such as thrombosis, migration, and vessel wall perforation (3). This case describes a patient who discontinued anticoagulation six years after IVCF implantation, and soon thereafter developed acute thrombosis of the IVC and iliac veins. Imaging revealed fibrotic adhesion, wall embedding, and filter strut perforation. Standard retrieval methods proved unsuccessful and more advanced techniques were necessary, including a loop snare approach to free the embedded hook which initially failed as the filter was firmly incorporated into the vessel wall. Ultimately, successful removal was achieved using a retrograde femoral approach with a large vascular sheath. This case highlights advanced retrieval strategies for long-term IVCFs causing life-threatening complications.Acute stent thrombosis (AST) is a rare but severe complication that may occur within 24h of percutaneous coronary intervention (PCI), usually...