Ischemic stroke in young adults often occurs in the absence of advanced atherosclerosis, suggesting the involvement of nonatherosclerotic prothrombotic mechanisms. Factor VIII (FVIII) and von Willebrand factor (VWF) link...Ischemic stroke in young adults often occurs in the absence of advanced atherosclerosis, suggesting the involvement of nonatherosclerotic prothrombotic mechanisms. Factor VIII (FVIII) and von Willebrand factor (VWF) link endothelial activation, platelet adhesion, and coagulation; however, their integrated clinical and molecular relevance in early-onset stroke remains incompletely defined. We conducted a retrospective case-control study including 25 young adults with ischemic stroke and 26 age-matched controls. Plasma FVIII activity and VWF antigen levels were measured and analyzed using multivariable logistic regression and receiver operating characteristic curve analysis. To provide mechanistic context, FVIII-VWF pathway activity was assessed in three independent ischemic stroke transcriptomic datasets (GSE16561, GSE202518, and GSE22255; total = 119) using single-sample gene set enrichment analysis and random effects meta-analysis. FVIII and VWF levels were significantly higher in patients with stroke than in controls, independently of age and sex, with expected modulation by ABO blood group. FVIII, but not VWF, remained independently associated with ischemic stroke (adjusted odds ratio: 1.05, 95% confidence interval: 1.01-1.09) and showed strong discriminatory performance (area under the curve: 0.86). Transcriptomic analyses revealed heterogeneous gene-level changes but consistent upregulation of the FVIII-VWF prothrombotic pathway across datasets. Meta-analysis confirmed a significant and homogeneous pooled effect for FVIII-VWF UP scores (Hedges' g = 0.76, < 0.0001), whereas activation of the regulatory pathway was variable and nonsignificant. These findings provide complementary clinical and transcriptomic evidence supporting a central role for FVIII-driven FVIII-VWF axis activation in the prothrombotic milieu of early-onset ischemic stroke.
Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), remains a leading cause of morbidity and mortality worldwide. Emerging evidence implicates the gut microbiota as a signif...Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), remains a leading cause of morbidity and mortality worldwide. Emerging evidence implicates the gut microbiota as a significant contributor to systemic diseases, including thrombotic disorders. This mini-review synthesizes current knowledge on the role of gut microbiota in VTE pathogenesis. Dysbiosis, a disruption in microbial composition, has been associated with systemic inflammation, endothelial dysfunction, and heightened platelet activation, all of which contribute to a prothrombotic state. Although causal relationships are still being elucidated, accumulating data suggest that the gut microbiota modulates coagulation and venous thrombosis, potentially representing a modifiable target for VTE risk reduction.
Combined thrombosis and bleeding disorders pose significant challenges in neonates, critically ill children, and patients with inherited or acquired coagulopathies, such as disseminated intravascular coagulation or liver...Combined thrombosis and bleeding disorders pose significant challenges in neonates, critically ill children, and patients with inherited or acquired coagulopathies, such as disseminated intravascular coagulation or liver dysfunction. These coexisting conditions are common in neonatal intensive care units (NICUs), where critically ill infants face environmental and medical interventions that may exacerbate both the risk of arterial and venous thromboembolism (VTE) or promote hemorrhagic risks. VTE affects up to 2% to 3% of NICU patients, and is primarily linked to sepsis and catheter-related events, while intracranial hemorrhage remains one of the leading causes of mortality and morbidity in preterm neonates. In the context of developmental immaturity, neonatal hemostasis predisposes these patients to an intersection of bleeding and thrombosis risks. This narrative review aims to navigate pathophysiology, clinical presentations, diagnostic dilemmas, and treatment strategies in neonates with thrombosis and bleeding disorders. We further explore emerging research and potential advances to improve outcomes in this vulnerable population.
Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality in oncology, reflecting the convergence of tumor-driven hypercoagulability, endothelial dysfunction, and venous stasis. While current...Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality in oncology, reflecting the convergence of tumor-driven hypercoagulability, endothelial dysfunction, and venous stasis. While current models of CAT pathogenesis emphasize tumor-derived procoagulant factors, platelets, and leukocytes, the contribution of red blood cell (RBC) biomechanics has received comparatively limited attention. Emerging evidence indicates that both malignancy and cancer-related therapies impair RBC deformability and increase RBC aggregation; alterations that are known to influence blood viscosity, platelet margination, microvascular flow, and clot contraction. Hence, these alterations have been hypothesized to promote thrombosis, supported by evidence of increased thrombosis risk in diseases that primarily affect RBC biomechanics. While cancer-induced alterations in RBC biomechanics and their role in thrombosis are well-described in non-cancerous conditions, the relationship between altered RBC biomechanics and thrombosis in the setting of cancer has not been thoroughly investigated. Accordingly, this review synthesizes the mechanistic and clinical data linking altered RBC biomechanics to thrombus initiation, propagation, and stability, with particular emphasis on their relationship with established cancer-related prothrombotic pathways such as extracellular vesicle release, neutrophil extracellular trap formation, stasis, and oxidative stress. Finally, we critically assess current CAT risk assessment models (RAMs) and discuss the potential role of RBC biomechanical parameters as dynamic, integrative biomarkers to improve thrombosis risk stratification in cancer patients. Advances in automated and standardized rheological technologies may facilitate the clinical translation of RBC biomechanics, offering new opportunities to refine risk prediction and deepen mechanistic understanding of CAT.
Cancer-associated thrombosis (CAT) remains a major cause of morbidity and mortality in patients with malignancy. Direct oral anticoagulants (DOACs) have expanded the therapeutic armamentarium for CAT and are now widely u...Cancer-associated thrombosis (CAT) remains a major cause of morbidity and mortality in patients with malignancy. Direct oral anticoagulants (DOACs) have expanded the therapeutic armamentarium for CAT and are now widely used as alternatives to low molecular weight heparins (LMWHs). However, the increasing complexity of contemporary oncologic care has heightened concerns regarding clinically relevant drug-drug interactions (DDIs). All DOACs are substrates of P-glycoprotein, and some undergo partial metabolism via cytochrome P4503A4, rendering them more susceptible to pharmacokinetic (PK) modulation by anticancer agents. Moreover, several antineoplastic drugs exert intrinsic prothrombotic or hemorrhagic effects, thereby introducing pharmacodynamic interactions that may further destabilize the already dysregulated hemostatic system in cancer. Despite these theoretical concerns, evidence from randomized trials and real-world studies remains limited and largely derived from subgroup analyses, PK investigations in healthy volunteers, or retrospective registries. Consequently, the true clinical magnitude of DDIs in CAT remains incompletely defined. This review critically appraises the pharmacological basis, clinical evidence, and translational implications of DDIs between DOACs and anticancer therapies. We propose that DDIs in CAT should not be viewed solely as PK phenomena, but also as potential biological amplifiers of cancer-associated coagulopathy. Until prospective, dedicated studies become available, a structured/individualized approach-integrating thrombotic/bleeding risk, interacting medications, and patient-specific factors-is warranted.
Antiphospholipid syndrome (APS) is an autoimmune disease defined by thrombotic or obstetrical clinical manifestations and the persistent presence of antiphospholipid antibodies, including lupus anticoagulant, anticardiol...Antiphospholipid syndrome (APS) is an autoimmune disease defined by thrombotic or obstetrical clinical manifestations and the persistent presence of antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin antibodies, and anti-2-glycoprotein I antibodies. Obstetric APS (OAPS) is associated with pregnancy morbidity, including early recurrent pregnancy loss (RPL), preeclampsia, premature birth, and stillbirth. Treatment regimens for women with OAPS are designed to optimize pregnancy outcomes. It is still debated which intervention results in the most optimal pregnancy outcome. This scoping review examines treatment options for women with OAPS presenting with RPL based solely on randomized controlled trials (RCTs) reporting pregnancy outcomes. A systematic search identified 1,234 studies published up to January 2026, from which 14 RCTs met the inclusion criteria: pregnant women with APS defined as persistent aPL positivity and RPL (≥2) receiving therapeutic intervention with live birth as the primary outcome. These RCTs, published between 1992 and 2017, included 1,878 participants. Secondary outcomes, including birth weight, preeclampsia, preterm delivery, and bleeding, were also analyzed. Different treatment options such as low-dose aspirin (LDA), unfractionated heparin, low molecular weight heparin (LMWH), corticosteroids, and intravenous immunoglobulin were used in the clinical trials. Antithrombotic therapy (LDA + LMWH) was associated with higher live birth rates compared with the other evaluated strategies. However, this finding is based on a small number of heterogeneous RCTs and is disproportionately driven by a single large trial. Consequently, substantial uncertainty remains. High-quality, adequately powered RCTs are urgently needed to provide robust evidence for optimal OAPS management.
Low-load blood flow restriction (LLBFR) training has gained traction as a rehabilitation and performance tool, offering muscle strength and hypertrophy adaptations comparable to high-load resistance training while minimi...Low-load blood flow restriction (LLBFR) training has gained traction as a rehabilitation and performance tool, offering muscle strength and hypertrophy adaptations comparable to high-load resistance training while minimizing joint and tissue stress. However, its application in athletes at risk for venous thromboembolism, post-thrombotic syndrome (PTS), inherited thrombophilia, and special populations (pregnant competitive female athletes and paralympic athletes with spinal cord injury) raises safety concerns. This narrative review synthesizes evidence on LLBFR's hemodynamic and endothelial effects, highlighting pressure-dependent basal lamina thickening, impaired flow-mediated dilation, and transient elevations in peripheral venous pressure. It emphasizes the importance of pre-exercise risk stratification, genetic screening for factor V Leiden and prothrombin mutations, and assessment of cardiovascular and coagulation markers. For athletes with confirmed deep vein thrombosis, PTS, or multiple risk factors, LLBFR should be contraindicated. In paralympic athletes with spinal cord injury, stringent exclusion criteria (e.g., severe autonomic dysreflexia, pressure ulcers) are essential, whereas female athletes may require individualized monitoring of coagulation changes during oral contraceptive use and pregnancy. Although LLBFR shows promise for preserving muscle function when traditional loading is impractical, robust, large-scale studies measuring thrombogenesis and fibrinolysis markers are urgently needed. Tailored protocols that balance musculoskeletal benefits against thrombotic risks will ensure safe, effective implementation across diverse athlete populations.
Extracorporeal membrane oxygenation (ECMO) has increasingly been used in patients with refractory severe cardiorespiratory failure in recent years. The use of ECMO necessitates anticoagulation as blood passes through an...Extracorporeal membrane oxygenation (ECMO) has increasingly been used in patients with refractory severe cardiorespiratory failure in recent years. The use of ECMO necessitates anticoagulation as blood passes through an extracorporeal circuit that has a membrane lung and a centrifugal pump. Although heparin is the most common anticoagulant used during ECMO runs, other anticoagulants like direct thrombin inhibitors and Factor X inhibitors have also been implemented in special circumstances. Bleeding is a well-known and severe complication while receiving ECMO, and balancing this against circuit thrombosis is a clinical challenge. While standard laboratory tests, such as activated partial thromboplastin time and point-of-care tests such as activated clotting time, help monitor anticoagulation on ECMO, they have their drawbacks. The use of viscoelastic assays (VEAs) in aiding anticoagulation management on ECMO has shown some benefits in reducing bleeding and thrombotic complications, though these assays are not widely used at present. This article explores the challenges of monitoring anticoagulation on ECMO and reviews the available evidence regarding VEAs in adult and pediatric ECMO.
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF). Diagnosis is challenging and requires integrating bleeding histor...Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF). Diagnosis is challenging and requires integrating bleeding history, VWF antigen and activity measurements, FVIII assays, and specialized phenotyping. Genetic testing is increasingly recognized as a key component. Here, we review current concepts in VWD diagnostics and highlight the Spanish Clinical and Molecular Profile of von Willebrand Disease (PCM-EVW-ES) project as a model for genomics-enabled precision medicine. PCM-EVW-ES is a multicenter initiative involving 48 hospitals, centralized phenotypic testing, and next-generation sequencing of the coding region, enabling definitive classification in 730 individuals with VWD to date. Harmonized recruitment criteria and standardized workflows improve subtype assignment, uncover complex genotypes, refine genotype-phenotype correlations, and facilitate the identification of asymptomatic carriers. The PCM-EVW-ES variant spectrum highlights recurrent disease-causing variants in Spain and underscores the value of coordinated national registries for variant curation. Building on these data, we propose a diagnostic algorithm in which bleeding assessment and first-line VWF/FVIII assays, combined with, early molecular testing increases diagnostic accuracy and guides targeted second-line investigations to confirm and refine VWD subtype classification. We also outline persisting challenges, including the interpretation of variants of uncertain significance and patients without identifiable pathogenic variants, and future directions integrating third-generation sequencing, expanded gene panels, functional studies, and artificial-intelligence-driven multiomic approaches. Together, these advances illustrate how robust multicenter studies can bridge the gap between complex diagnostics and clinical practice in VWD.
Hemophilia is a rare inherited bleeding disorder caused by a deficiency of factor VIII or IX, leading to insufficient thrombin generation and impaired clot formation. While advances in replacement and nonfactor therapies...Hemophilia is a rare inherited bleeding disorder caused by a deficiency of factor VIII or IX, leading to insufficient thrombin generation and impaired clot formation. While advances in replacement and nonfactor therapies have improved patient outcomes, challenges such as inhibitor development, joint disease, and breakthrough bleeding persist. Extracellular vesicles (EVs) are small membrane-bound particles released from all kinds of cells and have emerged as key mediators of coagulation, vascular integrity, and immune responses. In hemophilia, EVs provide procoagulant surfaces, carry tissue factor and phosphatidylserine, and may stabilize clot structure, partially compensating for deficient coagulation. Clinical studies further suggest that EV levels and composition are altered by factor replacement or bypassing agents, indicating their role as biomarkers of treatment response. Beyond their diagnostic potential, engineered EVs are being explored as innovative therapeutic tools capable of delivering clotting factors and modulating joint inflammation. This review outlines current knowledge on circulating EVs in hemophilia, emphasizing their mechanistic roles, clinical evidence, and therapeutic potential.
Acquired haemophilia A (AHA) is an autoimmune bleeding disorder mediated by the production of autoantibody inhibitors against factor VIII (FVIII), resulting in a bleeding phenotype. The standard treatment of AHA includes...Acquired haemophilia A (AHA) is an autoimmune bleeding disorder mediated by the production of autoantibody inhibitors against factor VIII (FVIII), resulting in a bleeding phenotype. The standard treatment of AHA includes immunosuppressive therapy for inhibitor eradication, haemostatic treatment with FVIII bypassing agents and treatment of underlying causes. Emicizumab is a bispecific monoclonal antibody that restores the function of missing activated FVIII by bridging FIXa and FX. Emicizumab is successfully used for prophylaxis of bleeding in congenital haemophilia A patients with or without FVIII inhibitors; however, it is not licensed for AHA treatment in the United Kingdom. We summarise our single-centre experience of the use of emicizumab for the treatment of AHA in 10 patients in the United Kingdom. Emicizumab was started at a dose of 3 mg/kg weekly with a change to fortnightly after the fourth dose. Eight patients received a combination of corticosteroids, emicizumab and rituximab; the remaining two, emicizumab and corticosteroids. In seven patients, emicizumab was stopped after achievement of an FVIII response and haemostasis following a median of 7 doses (3-53). In one patient, the treatment with emicizumab was complicated by the development of microangiopathic haemolytic anaemia. Three patients died, and in two of them, the death was associated with bleeding.
Sepsis disrupts the physiological balance between coagulation and fibrinolysis, resulting in a state in which fibrin formation exceeds fibrin removal and drives microvascular thrombosis, organ failure, and mortality. Alt...Sepsis disrupts the physiological balance between coagulation and fibrinolysis, resulting in a state in which fibrin formation exceeds fibrin removal and drives microvascular thrombosis, organ failure, and mortality. Although an early burst of endothelial tissue-type plasminogen activator (t-PA) may transiently increase plasmin generation, this phase is rapidly eclipsed by sustained upregulation of plasminogen activator inhibitor-1 (PAI-1), dysregulated activation of thrombin-activatable fibrinolysis inhibitor, depletion of endogenous anticoagulants, and progressive endotheliopathy. Beyond inhibitor excess, emerging evidence indicates that a quantitative defect in plasminogen is a central contributor to fibrinolytic insufficiency. Neutrophil extracellular traps (NETs) contain elastase, which cleaves plasminogen into inactive fragments, reducing functional plasminogen availability and impairing fibrin-bound plasmin generation. When functional plasminogen falls below rate-limiting levels, fibrin surfaces cannot efficiently support plasmin formation, resulting in persistent microvascular fibrin deposition despite elevated D-dimer concentrations. This NET-plasminogen axis links immunothrombosis to the "fibrinolytic insufficiency phenotype observed in sepsis-induced coagulopathy and overt disseminated intravascular coagulation (DIC)." Clinically, hypofibrinolysis is characterized by high D-dimers, elevated PAI-1, reduced plasmin generation, and low fibrinolytic activity on viscoelastic testing. Multimodal assessment integrating biomarker panels and viscoelastic assays, including t-PA- or urokinase-challenged protocols, may improve risk stratification. Therapeutic strategies largely targeted coagulation; however, persistent hypofibrinolysis limits their effectiveness. Translational data demonstrate that plasminogen supplementation restores functional plasminogen levels and normalizes plasmin generation in septic patients and in experimental DIC, providing proof of concept for fibrinolysis-directed therapy. Future progress requires standardized definitions, functional fibrinolytic phenotyping, and phenotype-guided clinical trials to restore the coagulo-fibrinolytic balance in sepsis.
Miele C, Caputo C, Calcaterra IL
… +14 more, Conca P, Cimino E, Romeo M, Chiarelli G, Russo R, D'Errico G, De Luca C, Aversano M, Mazzone M, Franco E, Valletta LJ, Mazzaccara C, Di Minno M, Tufano A
Patients with liver disease exhibit complex changes in the hemostatic system that are often presumed to drive bleeding and thrombosis. Historically, liver disease was considered a bleeding disorder based on thrombocytope...Patients with liver disease exhibit complex changes in the hemostatic system that are often presumed to drive bleeding and thrombosis. Historically, liver disease was considered a bleeding disorder based on thrombocytopenia, prolonged routine coagulation tests, and reports of fulminant bleeding. Present evidence, however, indicates that antihemostatic changes are compensated for by simultaneous prohemostatic changes, resulting in a rebalanced hemostatic system. Further hemostatic changes may be induced by liver disease progression and extrahepatic factors, such as systemic inflammation, acute kidney injury and cardiometabolic diseases. Despite extensive hemostatic changes in liver disease, current evidence does not consistently show that they increase bleeding risk, although this has been suggested repeatedly in published literature. Indeed, hemostatic changes appear largely unrelated to most bleeding complications, and specific thrombotic complications also appear unrelated to hemostatic changes. Major bleeding is common but predominantly reflects portal hypertension-related acute variceal bleeding and mechanical injury-related procedural bleeding. A proportion of bleedings, however, may be hemostasis-related, but the vast majority of such events do not require prohemostatic intervention. In contrast, a large proportion of thrombotic complications, including venous thromboembolism, portal vein thrombosis, and intrahepatic thrombosis, may in part be related to prohemostatic changes, although the role of hypercoagulability in portal vein thrombosis is increasingly questioned. Despite greater attention for thrombotic complications in liver disease, robust studies on optimal anticoagulant strategies are currently lacking. Studies evaluating the pharmacokinetics, pharmacodynamics, and efficacy for prevention of thrombosis and liver decompensation, of direct oral anticoagulants and factor XIa inhibitors are therefore urgently needed.
OBJECTIVE: Red blood cells (RBCs) must be highly deformable to pass through capillaries narrower than their own diameter for delivering oxygen to the tissues. Ion channels are central regulators of RBC deformability and...OBJECTIVE: Red blood cells (RBCs) must be highly deformable to pass through capillaries narrower than their own diameter for delivering oxygen to the tissues. Ion channels are central regulators of RBC deformability and volume. Gain-of-function mutations in , as seen in hereditary xerocytosis, cause RBC dehydration and have been associated with an increased risk of thromboembolism. Here we investigated how pharmacological RBC-Piezo1 activation affects RBC membrane potential, RBC ion content, RBC deformability, coagulation dynamics, and clot structure. STUDY DESIGN: Blood samples were collected from healthy donors. RBCs were isolated and incubated with Yoda1, a drug known to activate Piezo1. Membrane potential was measured using the Macey-Bennekou-Egée method. Intracellular Na/K content was determined by flame photometry. RBC deformability was measured by ektacytometry. Coagulation dynamics were investigated by rotational thromboelastometry, and clot structure was observed by electron microscopy. RESULTS: Yoda1 treatment led to RBC membrane hyperpolarization, reduced cell volume, a decrease in intracellular K, an increase in Na, and a reduction in RBC deformability. ROTEM analysis showed shorter clotting and lysis times in Yoda1-treated samples compared with samples treated with the vehicle (control condition), independently of RBC phosphatidylserine exposure. Electron microscopy revealed structural alterations in Yoda1-treated samples, with less compacted RBCs. CONCLUSION: Altogether, these findings indicate that Piezo1 activation disrupted RBC ion balance and membrane potential, leading to dehydration and decreased deformability. These alterations contributed to accelerated coagulation and compromised clot structure, suggesting a potential role of Piezo1 in modulating thrombotic risk in RBC-related disorders.