Miele C, Mennitti C, Gentile A
… +10 more, Calvanese M, Manfredi L, Ruggiero A, Randa I, Cirillo F, D'Alicandro G, Tinto N, Frisso G, Mazzaccara C, Scudiero O
Platelets play a central role in primary hemostasis and arterial thrombosis, and accumulating evidence suggests that physical exercise can modulate platelet function. Acute vigorous or exhaustive bouts commonly produce t...Platelets play a central role in primary hemostasis and arterial thrombosis, and accumulating evidence suggests that physical exercise can modulate platelet function. Acute vigorous or exhaustive bouts commonly produce transient thrombocytosis, enhanced aggregation and degranulation (e.g., P-selectin, β-TG, and PF4), increased thromboxane generation, and short-lived shifts toward hypercoagulability; these responses seem to scale with exercise intensity, adrenergic drive, and shear stress and may be amplified in untrained or high-risk individuals. By contrast, repeated training across modalities (aerobic, resistance, and high-intensity interval) generally lowers resting platelet reactivity, augments endothelial nitric oxide (NO) bioavailability, improves redox balance, and strengthens fibrinolytic capacity. These favorable adaptations may diminish with detraining, suggesting that the platelet-modulating effects of exercise are dynamic and contingent on consistent training exposure. In this review, we examine the association between platelet function and distinct exercise modalities, including aerobic, resistance, and high-intensity training, influence. We compare exercise modalities, intensities, and fitness states and consider major methodological sources of heterogeneity (assay selection, sampling timing, exercise prescription, and inter-individual variability) that complicate interpretation. Clinically, regularly performed, appropriately progressed exercise appears net favorable for hemostatic balance, whereas unaccustomed extreme exertion in high-risk individuals should be approached with preparation and caution. Better-standardized protocols and biomarker-informed trials are needed to refine exercise prescriptions for reducing thrombotic risk.
In 2025, the International Society on Thrombosis and Haemostasis (ISTH) released updated definitions and diagnostic criteria for disseminated intravascular coagulation (DIC), reflecting advances in understanding its path...In 2025, the International Society on Thrombosis and Haemostasis (ISTH) released updated definitions and diagnostic criteria for disseminated intravascular coagulation (DIC), reflecting advances in understanding its pathophysiology. DIC is now defined as an acquired, life-threatening condition involving systemic coagulation activation, impaired fibrinolysis, and endothelial injury. The revised framework emphasizes the condition's dynamic nature, progressing from preclinical abnormalities to overt clinical manifestations such as bleeding and organ dysfunction. A major innovation in the 2025 update is the phase-based classification of DIC: Pre-DIC, early-phase DIC, and overt DIC. Early-phase DIC-also referred to as subclinical or compensated DIC-is characterized by laboratory abnormalities preceding clinical symptoms. Overt DIC represents the advanced stage with clear evidence of coagulopathy and organ failure. Importantly, the new criteria are tailored to the underlying disease, such as sepsis, trauma, or malignancy. For example, the sepsis-induced coagulopathy score is now acknowledged as a tool for detecting early-phase DIC in septic patients. The overt DIC scoring system has been refined, including revised D-dimer thresholds: Levels >3× and >7 × , the upper normal limit now corresponds to 2 and 3 points, respectively. Platelet count, prothrombin time-international normalized ratio, and fibrinogen levels remain key indicators. The criteria also classify DIC into thrombotic and hemorrhagic phenotypes. Thrombotic DIC is marked by microvascular thrombosis and organ dysfunction, while hemorrhagic DIC is characterized by bleeding due to consumption of coagulation factors. By introducing clearer definitions and individualized approaches, these updates aim to enable earlier diagnosis and more effective management of DIC across clinical contexts.
Venous thromboembolism (VTE) remains a leading cause of cardiovascular morbidity and mortality, despite advances in imaging and anticoagulation. VTE arises from diverse and overlapping risk factors, such as inherited thr...Venous thromboembolism (VTE) remains a leading cause of cardiovascular morbidity and mortality, despite advances in imaging and anticoagulation. VTE arises from diverse and overlapping risk factors, such as inherited thrombophilia, immobility, malignancy, surgery or trauma, pregnancy, hormonal therapy, obesity, chronic medical conditions (e.g., heart failure, inflammatory disease), and advancing age. Clinicians, therefore, face challenges in balancing the benefits of thromboprophylaxis against the bleeding risk. Existing clinical risk scores often exhibit only modest discrimination and calibration across heterogeneous patient populations. Machine learning (ML) has emerged as a promising tool to address these limitations. In imaging, convolutional neural networks and hybrid algorithms can detect VTE on CT pulmonary angiography with areas under the curves (AUCs) of 0.85 to 0.96. In surgical cohorts, gradient-boosting models outperform traditional risk scores, achieving AUCs between 0.70 and 0.80 in predicting postoperative VTE. In cancer-associated venous thrombosis, advanced ML models demonstrate AUCs between 0.68 and 0.82. However, concerns about bias and external validation persist. Bleeding risk prediction models remain challenging in extended anticoagulation settings, often matching conventional models. Predicting recurrent VTE using neural networks showed AUCs of 0.93 to 0.99 in initial studies. However, these lack transparency and prospective validation. Most ML models suffer from limited external validation, "black box" algorithms, and integration hurdles within clinical workflows. Future efforts should focus on standardized reporting (e.g., Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis [TRIPOD]-ML), transparent model interpretation, prospective impact assessments, and seamless incorporation into electronic health records to realize the full potential of ML in VTE.
Thrombosis is the most common manifestation of antiphospholipid syndrome (APS), but concurring evidence of the mechanisms leading to a hypercoagulable state and thereby thrombosis is lacking. Existing reviews on this top...Thrombosis is the most common manifestation of antiphospholipid syndrome (APS), but concurring evidence of the mechanisms leading to a hypercoagulable state and thereby thrombosis is lacking. Existing reviews on this topic often include both animal and in vitro models. Additionally, studies with a systematic approach and stringent methodology, focusing exclusively on human studies, are lacking. Therefore, we conducted a scoping review of studies with human subjects, focusing on the mechanisms contributing to hypercoagulability in thrombotic APS (T-APS). The process was guided by the PRISMA Extension for Scoping Reviews and performed according to a preregistered protocol in Open Science Framework (https://osf.io/tjdwv). A systematic search of Ovid (EMBASE) and MEDLINE (PubMed) was performed on October 10, 2024. Records investigating mechanisms of hypercoagulability in adults (≥18 years) with T-APS, published between January 2000 and October 2024, were included. A total of 4,160 titles and abstracts were screened, 115 articles were assessed in full text, of which 35 studies fulfilled the predefined eligibility criteria for inclusion. Of the included studies, 8 focused on primary hemostasis, 10 on secondary hemostasis, 9 on fibrinolysis, 4 on neutrophil extracellular traps, 6 on endothelial cells, 3 on complement factors, 5 on monocytes, 3 on oxidized low-density lipoprotein complexes, 2 on oxidative stress, and 1 on amyloid-β1-40. No clear consensus was found regarding the underlying cause of hypercoagulability in T-APS, highlighting the need for further studies with human subjects. Nonetheless, this scoping review indicates that hypercoagulability in T-APS is possibly multifactorial, with no single mechanism being solely responsible.
Thrombocytopenia following hematopoietic stem cell transplantation (HSCT) is a common complication that is associated with a remarkable increase in morbidity and mortality. Post-HSCT thrombocytopenia is a multifactorial...Thrombocytopenia following hematopoietic stem cell transplantation (HSCT) is a common complication that is associated with a remarkable increase in morbidity and mortality. Post-HSCT thrombocytopenia is a multifactorial condition with several mechanisms, including reduced platelet production in bone marrow, immune-mediated platelet destruction, and consumptive thrombocytopenia. Graft-versus-host disease (GVHD), medications, infections, and autoimmune mechanisms are potential risk factors for post-HSCT thrombocytopenia. Management of post-HSCT thrombocytopenia primarily focuses on supportive care through platelet transfusions. Moreover, immunosuppressive agents are used to target immune-mediated mechanisms. Thrombopoietin receptor agonists and complement inhibitors are novel treatment options with promising results and fewer side effects. However, further research is essential to establish treatment protocols and improve patient care. In this review, we provide a better understanding of the pathophysiology and risk factors associated with post-HSCT thrombocytopenia for early detection and intervention, ultimately aiming to reduce complications.
Venous thromboembolism is often underestimated in transfusion-dependent thalassemia (TDT) patients, as arterial thrombotic events are more commonly observed. Although therapeutic advancements have transformed this diseas...Venous thromboembolism is often underestimated in transfusion-dependent thalassemia (TDT) patients, as arterial thrombotic events are more commonly observed. Although therapeutic advancements have transformed this disease from a once-fatal childhood disease into a manageable chronic condition, some treatments may contribute to an increased risk of thrombosis. Additionally, the prolonged life expectancy of these patients further contributes to the overall thrombotic risk. Patients with thalassemia major present multiple challenges when considering anticoagulation therapy. The decision-making process is complicated by a delicate balance between thrombotic risk-driven by disease-related and treatment-associated factors-and potential bleeding tendencies, particularly in the presence of comorbid conditions such as liver dysfunction, hypersplenism, or thrombocytopenia. Therefore, ongoing assessment of both thrombotic and bleeding risk and the implementation of appropriate preventive strategies are essential to optimize patient outcomes. This document presents a consensus statement from the Steering Committee of the Hemostasis Working Group of the Hellenic Society of Hematology, offering guidance on thromboprophylaxis and anticoagulation management in adult TDT patients.
Demonstrating the efficacy of new treatments in any condition may be a challenging endeavor, and is particularly the case in sepsis. In the early 21st century, recombinant activated protein C showed a survival benefit in...Demonstrating the efficacy of new treatments in any condition may be a challenging endeavor, and is particularly the case in sepsis. In the early 21st century, recombinant activated protein C showed a survival benefit in severe sepsis; however, subsequent studies could not replicate these results, leading to the discontinuation of this agent. Several potential reasons have been proposed for the unfavorable results of trials, including choosing an inappropriate outcome target. Concerning anticoagulant therapies, some studies have targeted sepsis with disseminated intravascular coagulation (DIC) and demonstrated clinical benefits, while other studies have focused on severe sepsis or septic shock independent of whether patients had DIC. The timing for treatment initiation, dosage, and duration of anticoagulant agents could be significant factors contributing to the limitations faced in these trials. Moreover, relying solely on 28-day mortality as the primary endpoint for sepsis trials may not be appropriate, as it can be influenced by various factors beyond anticoagulant therapies, and discernment in a shorter period might be more pertinent. Success in clinical trials is more likely if these issues are addressed and improvements are made. Recent clinical trials concentrating on anticoagulants are increasingly targeting sepsis or septic shock with coagulopathy, and adopting composite endpoints, including DIC resolution, is anticipated to overcome some of these challenges.
The coronavirus disease 2019 (COVID-19) pandemic introduced unprecedented disruptions to health care delivery, compelling rapid adaptations in anticoagulation management. Direct oral anticoagulants (DOACs), already displ...The coronavirus disease 2019 (COVID-19) pandemic introduced unprecedented disruptions to health care delivery, compelling rapid adaptations in anticoagulation management. Direct oral anticoagulants (DOACs), already displacing warfarin due to their convenience and reduced monitoring requirements, appeared well-positioned for broader adoption during pandemic-induced lockdowns. This commentary examines whether the pandemic catalyzed a meaningful shift in anticoagulant prescribing patterns from vitamin K antagonists (VKAs) to DOACs, drawing on data from the United Kingdom, Australia, the United States, Europe, and Asia. In the United Kingdom, national guidance led to an abrupt and large-scale switch to DOACs, with sustained changes postpandemic. In contrast, Australia and the United States exhibited continuity in preexisting trends, with modest, transient shifts that did not persist. Asian and European data revealed a gradual trajectory toward DOACs, likely driven by long-term policy and infrastructure rather than acute pandemic pressures. While no universal transformation occurred, the pandemic accentuated existing preferences and exposed system-level vulnerabilities in warfarin monitoring. The global experience suggests that the COVID-19 crisis served as a selective accelerant of DOACs adoption, where health care systems and policies facilitated change. As health systems prepare for future disruptions, equitable access to DOACs and investment in remote care infrastructure will be essential to ensuring continuity and safety in anticoagulation therapy.
Lupus anticoagulant-hypoprothrombinemia syndrome (LAHS) is a rare hemorrhagic disorder that should be differentiated from classical antiphospholipid syndrome. Literature review shows that LAHS may affect people at any ag...Lupus anticoagulant-hypoprothrombinemia syndrome (LAHS) is a rare hemorrhagic disorder that should be differentiated from classical antiphospholipid syndrome. Literature review shows that LAHS may affect people at any age but approximately 40% are children younger than 10 years. Autoimmune and infectious diseases are the most frequent triggering causes, and the laboratory profile is characterized by a prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) with a mild to severe reduction in factor II levels. In more than half the patients, the other coagulation factors are normal, while anti-cardiolipin and anti-β2-glycoprotein I antibodies show a high titer. Lupus anticoagulant (LA) is positive in 100% of cases, as this represents a defining feature. The majority of patients have mucocutaneous bleeding events (44%); cerebral bleeding can occur in 10% of patients and other common bleeding sites are the gastrointestinal and genitourinary tracts. There is no standard treatment for LAHS. Supportive measures, such as fresh frozen plasma, packed red blood, and platelet transfusion, are frequently administered in association with steroids alone or in combination with intravenous immunoglobulin or cyclophosphamide, azathioprine, and rituximab. Death, recurrent bleeding, and thrombosis can occur in approximately 3, 13, and 14% of patients, respectively. Our patient was an old man with a myocardial infarction and a systemic infection from . Thrombin generation and clot waveform analysis were performed before and after treatment. Thrombin generation better reflected the role of prothrombin, revealing that a factor II value of below around 15% can represent a risk for major bleeding. Treatment with methylprednisolone and three-factor human prothrombin complex concentrate allowed the patient to reach a complete recovery 1 month after initial diagnosis.
Thromboinflammation is an emerging concept which highlights the interactions between coagulation and inflammation in various disease states. Activation of coagulation and inflammation are both hallmarks of hemolytic stat...Thromboinflammation is an emerging concept which highlights the interactions between coagulation and inflammation in various disease states. Activation of coagulation and inflammation are both hallmarks of hemolytic states. However, the mechanisms by which they cause adverse outcomes in hemolytic disorders is incompletely understood. A body of literature suggests that red blood cells (RBCs) play a role in thrombosis and in immune regulation. RBCs release extracellular vesicles (RBC-EVs), with increased numbers found in the circulation of patients with hemolytic disorders. In this review, we summarize the existing literature addressing the interaction of RBC-EVs with coagulation and inflammatory pathways and . Additionally, we discuss the potential contribution of RBC-EV-induced thromboinflammation in the pathogenesis of certain complications of sickle cell disease as a model of a severe hemolytic disorder.
Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in sports, although rare, remain pressing concerns with rising global participation in athletics. Recent epidemiological analyses indicate that incidence of SCA/...Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in sports, although rare, remain pressing concerns with rising global participation in athletics. Recent epidemiological analyses indicate that incidence of SCA/SCD in athletes is low and has remained relatively stable over the past two decades. However, outcomes have improved as survival rates increase, reflecting advances in emergency response. Key risk factors are well-established, such as male athletes face a markedly higher risk than females, older master athletes have higher SCD risk rates than those under 35 years (largely due to acquired coronary artery disease), and certain high-intensity sports (e.g., basketball, American football, soccer, and endurance exercise) present higher SCA/SCD risk. In young competitive athletes, most SCDs are a consequence of undetected hereditary or congenital heart disorders. Predominant causes in this group include structural cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy, and primary electrical diseases (channelopathies like long QT syndrome, Brugada syndrome, or catecholaminergic polymorphic ventricular tachycardia). Contrarily, occult atherosclerotic coronary disease becomes the leading cause of fatal events in master athletes. Multifaceted prevention strategies have expanded in recent years. Pre-participation cardiac screening programs aim to detect at-risk individuals and have successfully prevented SCD. Equally important, widespread implementation of emergency action plans, including on-site automated external defibrillators and cardiopulmonary resuscitation training, has improved resuscitation outcomes. Heightened public awareness, prompted by high-profile on-field cardiac arrests, has catalyzed policy changes that mandate better cardiac screening and emergency preparedness. Collectively, these efforts are shaping a safer sporting environment and reducing the SCA/SCD risk in athletes.
Disseminated intravascular coagulation (DIC) in the postpartum period is a rare but potentially life-threatening complication arising from various obstetric conditions, including postpartum hemorrhage (PPH), placental ab...Disseminated intravascular coagulation (DIC) in the postpartum period is a rare but potentially life-threatening complication arising from various obstetric conditions, including postpartum hemorrhage (PPH), placental abruption, intrauterine fetal demise (IUFD), and amniotic fluid embolism. This review explores pathophysiology, risk factors, diagnostic challenges, and management strategies of postpartum DIC. The delicate balance of hemostasis during pregnancy predisposes women to thromboembolic events, which, when disrupted, may lead to rapid consumption of coagulation factors and subsequent coagulopathy. The incidence of obstetric-related DIC varies globally, with higher rates reported in low-resource settings due to delayed diagnosis and management. Diagnostic criteria, including the International Society on Thrombosis and Haemostasis (ISTH), Japanese obstetric DIC, and pregnancy-specific DIC scores, are evaluated, emphasizing their applicability and limitations in obstetric practice. Preventive strategies, primarily targeting the early identification and treatment of PPH, are discussed, with particular focus on active management of the third stage of labor, the administration of uterotonic agents, and the use of antifibrinolytic medications like tranexamic acid. Timely recognition, standardized diagnostic protocols, and multidisciplinary management are essential for improving maternal outcomes and reducing the burden of postpartum DIC.
Acute ischemic stroke leads to rapid and progressive neuronal losses. Early revascularization with thrombolytics and/or endovascular thrombectomy plays an important role in salvaging brain infarction. Currently, alteplas...Acute ischemic stroke leads to rapid and progressive neuronal losses. Early revascularization with thrombolytics and/or endovascular thrombectomy plays an important role in salvaging brain infarction. Currently, alteplase and tenecteplase are approved thrombolytics for the treatment of acute ischemic stroke, whereas favorable outcomes of reteplase have recently been reported in a phase 3 clinical trial. These thrombolytics share common and distinct pharmacological characteristics, which contribute to their efficacy and safety in patients. In this review, biological profiles of alteplase, tenecteplase, and reteplase, including their advantages versus disadvantages in acute ischemic stroke, are discussed. Tenecteplase has high fibrin specificity, increased resistance to plasminogen activator inhibitor-1 (PAI-1), wider concentration-response curve, and less off-target activities, which support its efficacy with low incidence of symptomatic intracranial hemorrhage (sICH). Reteplase greatly penetrates into the clot with prolonged retention, generating durable clot lysis. This activity might be associated with its excellent clinical outcomes in patients, although reteplase is sensitive to PAI-1. Notably, reteplase and alteplase produce off-target activities by inducing hypofibrinogenemia and hypoplasminogenemia, which may increase risk of hemorrhagic transformation. Moreover, orolingual angioedema is a life-threatening complication of all thrombolytics. Mechanistically, an increase in plasmin by thrombolytics leads to bradykinin generation. In addition, plasmin activates mast cell degranulation (e.g., histamine release). Together, these biopharmacological data of thrombolytics promote insights into their clinical outcomes, and might provide comprehensive bases for future research.
Venous thromboembolism (VTE), including deep vein thrombosis (DVT), and pulmonary embolism (PE), is a common complication in patients with ischemic stroke. Several prophylactic strategies are used to reduce the risk of V...Venous thromboembolism (VTE), including deep vein thrombosis (DVT), and pulmonary embolism (PE), is a common complication in patients with ischemic stroke. Several prophylactic strategies are used to reduce the risk of VTE. However, there is still a lack of consensus on the optimal strategy due to the lack of randomized controlled trials (RCTs) directly comparing different interventions. The objective of this study was to explore the efficacy and safety of different thromboembolic prophylaxis strategies in patients with ischemic stroke. We conducted a systematic literature review to identify all eligible RCTs, searching MEDLINE and Embase up to December 31, 2024. We considered DVT and PE as efficacy outcomes and intracranial and extracranial hemorrhage as safety outcome measures. Relevant data were extracted for network meta-analyses. A random-effects model was used for the analysis. A total of 33 RCTs were included in the analysis. Network meta-analysis revealed that low-molecular-weight heparin (LMWH) and heparinoid were associated with significantly decreased risk of DVT and PE compared with no prophylaxis, with risk ratios of 0.18 (95% confidence interval: 0.10-0.32) and 0.36 (0.20-0.63), respectively. However, LMWH and heparinoid were associated with an increased risk of extracranial hemorrhage compared with no prophylaxis, with a risk ratio of 2.03 (1.24-3.34). Our study supports the use of LMWH and heparinoid as the primary thromboembolic prophylaxis measure in patients with acute ischemic stroke. Further, high-quality RCTs are needed to strengthen the evidence base and determine the optimal prophylactic strategy in these patients.
Puerperal sepsis (PPS) is a severe postpartum infection that remains a significant maternal health concern. Recent evidence suggests a potential link between PPS and ovarian vein thrombosis (OVT), a rare but life-threate...Puerperal sepsis (PPS) is a severe postpartum infection that remains a significant maternal health concern. Recent evidence suggests a potential link between PPS and ovarian vein thrombosis (OVT), a rare but life-threatening complication occurring in 0.01 to 0.18% of pregnancies. Despite the historical significance of PPS and its well-documented consequences, its association with thrombosis remains underrecognized in obstetric practice. This narrative review explores the historical context, clinical presentation, diagnosis, and management of PPS and OVT while emphasizing the need for increased awareness and preventive strategies. Sepsis triggers a hypercoagulable state through inflammatory cytokine release, endothelial injury, and coagulation activation, contributing to thrombotic complications such as OVT. The right ovarian vein is more commonly affected due to anatomical factors, including uterine dextrorotation during pregnancy. OVT typically presents with abdominal pain and fever, requiring imaging modalities such as Doppler ultrasound and magnetic resonance imaging for diagnosis. Although anticoagulation therapy is widely used for deep vein thrombosis, its application in OVT remains inconsistent, despite comparable recurrence rates between the two conditions. The review also highlights the lack of consensus on thromboprophylaxis in septic postpartum patients. Although guidelines from major obstetric organizations are inconsistent, emerging evidence suggests that low-molecular-weight heparins may reduce thrombotic risk in PPS. In the absence of large-scale randomized trials, observational studies remain essential for guiding clinical decisions.