Central venous catheter (CVC) dysfunction is a common complication of indwelling CVCs for hospitalized children, often secondary to intraluminal thrombosis. We sought to characterize thrombolytic agent use for restoratio...Central venous catheter (CVC) dysfunction is a common complication of indwelling CVCs for hospitalized children, often secondary to intraluminal thrombosis. We sought to characterize thrombolytic agent use for restoration of CVC patency and assess its association with hospital-acquired venous thromboembolism (HA-VTE). We performed a multicenter retrospective cohort study using the Pediatric Health Information Systems database, including critically ill children < 18 years of age with a CVC in 2023 at 44 participating centers. Exclusion criteria were VTE present on admission and thrombolytic agent (i.e., alteplase or urokinase) use for systemic or catheter-directed thrombolysis or adhesiolysis. The primary outcome was HA-VTE frequency, including deep venous thrombosis and pulmonary embolism, compared by cohorts with or without exposure to thrombolytic agents. In addition to comparative analyses, adjusted logistic regression was employed to assess the association between thrombolytic agent exposure and HA-VTE. Of 9,822 children, including 10,904 CVCs, the median participating center prescribing rate of thrombolytic agents was 33.8% (interquartile range, IQR: 25-43.5%), and the median HA-VTE rate was 11.9% (IQR: 9.2-15.8%). VTE events exhibited a bimodal age distribution (i.e., greatest among infants and adolescents) without variation by CVC type. In a multivariable conditional logistic model accounting for prothrombotic risk factors, severity of illness markers, and hospital center, thrombolytic agent use for CVC dysfunction was independently associated with HA-VTE (adjusted odds: 1.89; 95% confidence interval: 1.64-2.19, < 0.001). Among critically ill children, thrombolytic agent use for CVC dysfunction was common and independently associated with HA-VTE.
Congenital factor V (FV) deficiency, affecting approximately 1 in 1 million individuals worldwide, remains among the rare bleeding disorders (RBDs) without a licensed factor-specific replacement therapy. While other RBDs...Congenital factor V (FV) deficiency, affecting approximately 1 in 1 million individuals worldwide, remains among the rare bleeding disorders (RBDs) without a licensed factor-specific replacement therapy. While other RBDs have successfully transitioned from plasma-based treatment to approved factor concentrates-exemplified by factor X deficiency's progression to US Food & Drug Administration (FDA)-approved Coagadex and two FDA-approved concentrates for factor XIII deficiency-FV deficiency treatment has remained unchanged for decades, relying solely on plasma and platelet transfusions. Two promising therapeutic candidates have emerged: a human plasma-derived FV concentrate demonstrating in vitro correction of severe deficiency, and an engineered activated FV (superFVa) showing potent hemostatic activity in preclinical models. This commentary outlines a pragmatic pathway to clinical trials, leveraging proven development strategies from other RBDs, existing registry infrastructure, and regulatory incentives for rare diseases. We propose phased trials combining pharmacodynamic endpoints with clinical outcomes, enabling feasible enrollment while generating decision-grade evidence. The time has come to extend modern therapeutic development to FV deficiency.
Lupus anticoagulant (LA) positive only (negative anticardiolipin antibodies [aCL] and anti-β2 glycoprotein I antibodies [aβ2GPI]) thrombosis represents a clinical challenge. It is often unclear whether the cause of throm...Lupus anticoagulant (LA) positive only (negative anticardiolipin antibodies [aCL] and anti-β2 glycoprotein I antibodies [aβ2GPI]) thrombosis represents a clinical challenge. It is often unclear whether the cause of thrombosis is LA or whether other clinical conditions have led to an episode of venous thromboembolism (VTE) or arterial thromboembolism (ATE). Recent antiphospholipid syndrome (APS) classification criteria assign different scores to thrombotic events based on the presence of confounding risk factors. In the presence of strong associated risk factors, patients are not classified as having APS as a score less than 3 points is assigned to the clinical domain. This study evaluated patients LA positive only included in the group of APS in the START2 Antiphospholipid Registry. The aim of the study was to determine how many of them did not meet the new APS classification criteria due to the presence of associated risk factors. Of the 488 patients enrolled in the START Antiphospholipid Registry, 86 (18%) had LA positive only and 43 had a previous thromboembolic event (33 VTE and 10 ATE). Of the 33 patients with VTE (9%), 3 had a high-risk VTE profile and 2 had a high-risk ATE profile and did not meet the new classification criteria. The updated criteria appropriately limit the inclusion of patients with high-risk thrombotic profiles in APS research studies. Although risk factors and not LA may be the cause of thrombosis, the presence of LA can complicate treatment decisions in clinical practice.
Traditionally, platelet function has been defined in the context of their role in hemostasis and thrombus formation. In recent years, however, the concept of platelet function has expanded, as emerging evidence supports...Traditionally, platelet function has been defined in the context of their role in hemostasis and thrombus formation. In recent years, however, the concept of platelet function has expanded, as emerging evidence supports that platelets-despite their small size-serve as versatile and potent modulators in a wide range of biological processes, including immune responses. In the neonatal period, the immune response is immature and particularly susceptible to dysregulation. The distinct properties of neonatal platelets, compared with those of adults, may influence both the sensitivity and the magnitude of the inflammatory response. The aim of this review is to summarize current knowledge regarding the involvement of platelets in neonatal sepsis, to highlight the immunological and molecular characteristics implicated in this process, and to identify research gaps that limit the use of platelets as diagnostic and therapeutic targets in this particularly vulnerable population.
Bleeding complications are a frequent and clinically significant problem in patients with chronic kidney disease (CKD), with prevalence increasing as kidney function declines, and in those receiving dialysis. The bleedin...Bleeding complications are a frequent and clinically significant problem in patients with chronic kidney disease (CKD), with prevalence increasing as kidney function declines, and in those receiving dialysis. The bleeding tendency in CKD is multifactorial: arising from platelet dysfunction, uremic/inflammatory states, renal anemia, and the common concurrent use of anticoagulants in this population. Together, these mechanisms all contribute to impairment in hemostasis and increased risk of both spontaneous and procedural-hemorrhages. Current bleeding risk assessment tools perform poorly in the CKD population, limiting their utility for guiding clinical decision-making. Emerging evidence suggests that albuminuria, as an independent marker for both renal dysfunction and hemorrhage risk, may improve bleeding risk stratification in this cohort. This review summarizes the pathophysiological mechanisms underlying bleeding in CKD and the impact of dialysis and declining renal function. It also highlights the unmet need for more accurate, CKD-specific bleeding risk assessment tools.
Chronic use of multiple drugs increases risk of adverse drug reactions, drug interactions and poor therapeutic adherence. In elderly or frail patients, some drugs may become ineffective or even harmful with advancing age...Chronic use of multiple drugs increases risk of adverse drug reactions, drug interactions and poor therapeutic adherence. In elderly or frail patients, some drugs may become ineffective or even harmful with advancing age and worsening clinical conditions. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been extensively used for decades and, as a class, are both often inappropriately prescribed and involved in polypharmacotherapy untoward effects. In view of the dynamic and mutual relationship between inflammation and hemostasis in various clinical scenarios, use of anti-inflammatory agents, including NSAIDs, may tip this difficult balance in patients with hemostatic disorders. Rather than on well-established actions such as the clinically relevant antiplatelet action of low-dose aspirin and gastrointestinal bleeding, this review focuses on less highlighted, emerging or sometimes overlooked NSAID efficacy and safety endpoints. For instance, preclinical studies suggest that the antiplatelet action of low-dose aspirin enhances immune system activity against cancer cells, resulting in metastasis prevention. While use of NSAIDs in patients with coagulation disorders may have an acceptable risk-to-benefit ratio in selected patients, clinical judgement is required especially in cases of renal impairment that can be worsened by NSAIDs or in cases with high bleeding risk. In the context of polypharmacotherapy, attenuation of aspirin antiplatelet action by concomitant and inaccurately timed ibuprofen treatment may undermine the clinical benefit of aspirin in cardiovascular prevention. Thus, collaborative cross-disciplinary efforts of pharmacologists and clinicians would be desirable in order to enhance appropriateness, efficacy and safety of NSAID treatment in different settings of care.
Platelets are at the nexus of virtually all physiological processes that occur within the cardiovascular system. The inordinate number and variety of platelet surface receptors allow these anucleate cells to interact wit...Platelets are at the nexus of virtually all physiological processes that occur within the cardiovascular system. The inordinate number and variety of platelet surface receptors allow these anucleate cells to interact with and respond to all the cell types in the blood, the vast vascular endothelial cell lining, the subendothelial matrix, foreign antigens/pathogens, and soluble plasma components from simple inorganic molecules, like Ca, to some of the most complex macromolecules, like von Willebrand factor. The surface receptors are but one component of the platelet's armory that regulates cardiovascular functions. Upon activation, platelets release 100s of different molecules from dense granules, α-granules, lysosomes, and from nongranule sources. The releasate contains a host of bioreactive molecules, including cytokines, chemokines, and growth factors required for normal and pathological cardiovascular functions. Also, among the released components are high concentrations of ATP along with soluble and extracellular membrane-bound protein kinases and likely protein phosphatases. The platelet is exquisitely poised to react to extracellular signals that alter intracellular pathways ("outside-in signaling") resulting in the dramatic shape change from discoid to an enlarged amorphous cell that culminates in the direct interaction with other platelets, subendothelial matrixes, and other cell types. At the same time, the released platelet components are ideally suited to support the phosphorylation of protein players involved in a myriad of extracellular pathways within the microenvironment where platelets are activated. This paper presents scenarios where ecto-phospho-/dephosphorylated-proteins are known to or could regulate physiological processes in the cardiovascular system associated with atherogenesis and cardiovascular diseases.
Evidence-based medicine (EBM) has created a revolutionary system for disseminating a scientific method. However, the scientific rigor of early EBM did not demonstrate any concern for ethics in the management of venous th...Evidence-based medicine (EBM) has created a revolutionary system for disseminating a scientific method. However, the scientific rigor of early EBM did not demonstrate any concern for ethics in the management of venous thromboembolism (VTE) and atrial fibrillation (AF). We critically reviewed whether EBM and ethical principles have always converged, focusing on the development and use of anticoagulants, by analyzing key trials in the treatment and prevention of those conditions. Moreover, we aimed to explore whether methodological rigor has sometimes overshadowed clinical ethics, particularly in the context of placebo-controlled trials. In our opinion, even if randomized clinical trials (RCTs) are considered the first step in the hierarchy of EBM, several of these appear unjustified, as observational studies had already indicated that anticoagulants (heparins and anti-vitamin K drugs [VKA]) were considered effective in the treatment and prevention of thrombotic diseases, such as VTE and AF. The use of a placebo was often unethical. This has caused unjustified mortality and morbidity to many people when a placebo has been used as a control. Even the methodology in favor of the non-inferiority margin is questionable, as it is considered satisfactory to maintain at least half of the efficacy of the current drug. In other words, a bonus for the new medicines seems to be always generous, and in the future, phenomenon is destined to be dangerous. The belief that only RCTs, even if of paramount importance, produce trustworthy results and that observational studies are misleading can lead to a disadvantage in patient care, clinical investigation, and the education of health care professionals (visual abstract).
Clinical laboratory results are inherently uncertain. Variability arises when repeating measurements of the same sample under different conditions. Measurement uncertainty (MU) is a metrological framework that quantifies...Clinical laboratory results are inherently uncertain. Variability arises when repeating measurements of the same sample under different conditions. Measurement uncertainty (MU) is a metrological framework that quantifies this variability, enabling clinical interpretation and comparison of results within and between patients. In hemostasis assays, MU describes uncertainty propagation across the entire traceability chain-from international standards to final patient results.The Guide to the Expression of Uncertainty of Measurement (GUM) offered a statistically rigorous but complex method for estimating MU, limiting its widespread adoption. A relatively recent technical specification (TS) from the International Standardization Organization (ISO; ISO/TS 20914:2019) introduced a top-down approach that balances rigor with operational feasibility, supporting ISO 15189 compliance. However, its applicability to specialist areas such as hemostasis has been questioned. Furthermore, despite improved understanding of calculation methods, international guidance recommends against reporting results, together with MU, directly to service users; instead, the laboratory is required to provide it upon request. This review explores the implementation of different approaches for MU in hemostasis laboratories.
Venous thromboembolism (VTE) remains a major cause of preventable morbidity and mortality. Prophylaxis with anticoagulation is limited by bleeding risk, contraindications, and patient-specific factors. Interest has there...Venous thromboembolism (VTE) remains a major cause of preventable morbidity and mortality. Prophylaxis with anticoagulation is limited by bleeding risk, contraindications, and patient-specific factors. Interest has therefore grown in alternative or adjunctive nonanticoagulant strategies that can mitigate thrombotic risk without increasing bleeding complications. Aspirin has demonstrated efficacy in both primary and secondary prevention of VTE. Most studies and trials have been undertaken in an orthopaedic population but with favorable safety profile. Statins have been shown to reduce VTE incidence without increased bleeding in several trials. Metformin appears to reduce prothrombotic mechanisms in type 2 diabetes. Observational studies have suggested its use to lower VTE risk. However, randomized data are lacking. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to reduce weight, improve metabolic control, and possess anti-inflammatory effects. Evidence suggests GLP-1 RAs may reduce VTE risk. However, findings are inconsistent across observational and trial-based analyses. Other emerging alternatives include hydroxychloroquine, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (post hoc analyses of cardiovascular trials suggesting lower VTE rates potentially via lipoprotein (a) reduction), sodium-glucose cotransporter-2 inhibitors (overall neutral in meta-analyses of randomized control trials with some real-world evidence vs. comparators), and renin-angiotensin-aldosterone system modulators (mixed observational data and no trial-proven benefit). Uncertainties remain regarding optimal patient selection, duration of prophylaxis, and their role in combination with standard anticoagulation across these drug classes. Further studies/trials are warranted to define the efficacy, safety, and guideline positioning of these agents in diverse patient populations.
Red light therapy is emerging as a potential non-pharmacological modulator of thrombosis and hemostasis. Photobiomodulation with red, near-infrared (NIR), and far-infrared (FIR) wavelengths has been shown to influence ni...Red light therapy is emerging as a potential non-pharmacological modulator of thrombosis and hemostasis. Photobiomodulation with red, near-infrared (NIR), and far-infrared (FIR) wavelengths has been shown to influence nitric oxide release, endothelial function, platelet activation, and vascular tone. These effects align with the components of Virchow's triad (i.e., endothelial dysfunction, stasis, and hypercoagulability), and ameliorate thromboinflammation. Experimental data indicate that photobiomodulation may be effective to reduce platelet aggregation, von Willebrand factor activity, and improve microvascular perfusion. However, controversy remains regarding whether observed benefits reflect active red/NIR effects or simply the exclusion of pro-thrombotic blue light. Limitations in tissue penetration, protocol standardization, and translational modeling pose challenges for clinical implementation. Despite these uncertainties, red light therapy offers promise in high-risk patients where conventional anticoagulation is limited by bleeding risk. Future studies must define optimal dosing parameters, clarify mechanistic pathways, and evaluate efficacy in randomized clinical trials to establish its role in contemporary thrombosis management.
Lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, is well-known for its role in triggering inflammation via innate immune receptors. However, evidence suggests that LPS can influe...Lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, is well-known for its role in triggering inflammation via innate immune receptors. However, evidence suggests that LPS can influence coagulation, in part through activation of the contact pathway. Recent studies from our group and others demonstrate that the supramolecular organization and physicochemical properties of LPS-such as aggregate size, surface charge, and chemotype-critically determine the ability of LPS to activate coagulation factor XII (FXII). While monomeric LPS can modulate FXII activity, only aggregated forms of LPS (e.g., micelles) function as a procoagulant surface, initiating contact activation. This review synthesizes current knowledge on LPS structural heterogeneity and explores how the biophysical properties of LPS govern supramolecular assembly in aqueous environments, ultimately dictating interactions with the contact activation pathway. We further discuss the possible mechanisms by which LPS-driven FXII activation contributes to thromboinflammatory disorders, including disseminated intravascular coagulation and sepsis-associated vascular leakage. Finally, we highlight novel therapeutic strategies-from FXIIa inhibitors to molecules that disrupt LPS supramolecular structures-as potential interventions to mitigate coagulation-driven pathology during bacterial infections. These insights not only reflect our growing understanding of infection-associated thrombosis but may also pave the way for targeted therapies in sepsis and other thromboinflammatory conditions.
Arterial and venous thromboembolism represent major contributors to global morbidity and mortality. Despite substantial progress in risk stratification and clinical management, a significant proportion of thromboembolic...Arterial and venous thromboembolism represent major contributors to global morbidity and mortality. Despite substantial progress in risk stratification and clinical management, a significant proportion of thromboembolic events occur in individuals not classified within traditional high-risk groups indicating the involvement of additional, non-conventional risk factors in thrombotic pathophysiology.Recent evidence has highlighted the gut microbiome as a critical determinant of human health, with increasing recognition of its role in cardiovascular and thrombotic disorders. Furthermore, the gut microbiome constitutes a modifiable risk factor, offering new horizons for therapeutic intervention and emerging evidence suggests that alterations in the microbiome may significantly impact thrombotic risk.Moreover, microbiome-derived metabolites have gathered considerable scientific attention for their potential involvement in the initiation and progression of thrombosis. These metabolites may serve as novel biomarkers, complementing conventional risk indicators in disease diagnosis, prognosis, screening, and patient monitoring. Microbiome-derived metabolites may hold dual utility, first as diagnostic and prognostic biomarkers, and, second, as potential targets for pharmacologic modulation. Collectively, these findings underscore the growing significance of the gut microbiome as an environmental factor in thromboembolic disease and justify the constantly increasing employment of the scientific community in several aspects of health and disease.