Seminars in thrombosis and hemostasis最新文献

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.

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, biocreep 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).

Since their discovery in 2004, neutrophil extracellular traps (NETs) have been at the center of multidisciplinary attention. Although a key tool in neutrophil-mediated immunity, these filamentous, enzyme-enriched DNA-histone complexes can be detrimental to tissues and have been identified as an underlying factor in a range of pathological conditions. Building on more than 20 years of research into NETs, this review places thrombosis, the pathological formation of blood clots, in the spotlight. From this point of view, we discuss the structure and formation of NETs, as well as the interaction of their components with the hemostatic system, dissecting the pathways through which NETs exert their marked effect on formation and the dissolution of thrombi. We pay distinct attention to the latest developments in the research of a key player in NET formation, peptidyl-arginine-deiminase (PAD) enzymes: their types, sources, and potential cross-play with the hemostatic machinery. Besides these molecular details, we elaborate on the link between pathological thrombosis, NETs, and widespread conditions that represent a debilitating public health burden worldwide, such as sepsis and neoplasms. Finally, future implications on the treatment of thrombosis-related conditions will be discussed.

Acute pulmonary embolism (PE) is potentially life-threatening, with up to 15% risk of death. We compared four risk stratification models to identify outpatients at risk of mortality up to 90 days post acute PE. A retrospective cohort study included outpatients aged ≥18 years with confirmed PE from June 1, 2014 to May 31, 2019, identified via diagnostic imaging reports. Simplified Pulmonary Embolism Severity Index (sPESI) and Hestia scores were calculated as per original derivation methods. Patients were stratified by four models: sPESI alone, Hestia alone, sPESI plus right ventricular dysfunction (RVD), and Hestia plus RVD. Model accuracy and discriminatory power for 30- and 90-day mortality were assessed by area under the receiver operating curve (AUC). The study comprised 785 outpatients (mean age 65.0 years; 42.2% male). Overall mortality rates were 4.1% at 30 days and 7.8% at 90 days. sPESI identified 31.5% as low risk versus 19.1% by Hestia. All models demonstrated 100% sensitivity and negative predictive value for 30-day mortality, but modest discriminatory power (AUC range: 59.2-67.1). sPESI consistently outperformed other models in both timeframes. Including RVD with sPESI or Hestia did not enhance accuracy and slightly reduced performance. The net reclassification index indicated minor improvement in non-event classification with RVD, but no benefit for identifying deaths. sPESI remains a modest yet effective predictor of mortality risk within 90 days following acute PE, consistently outperforming sPESI + RVD, Hestia alone, and Hestia + RVD at both 30 and 90 days. Adding RVD minimally improved predictive accuracy.

Antiphospholipid syndrome (APS), a disorder characterized by the presence of antiphospholipid antibodies, is commonly associated with thrombotic events and pregnancy complications. Although cardiac involvement of APS is very common, intracardiac thrombus is rare and easily misdiagnosed. In order to reduce missed diagnosis and misdiagnosis, we investigated the clinical features of APS with intracardiac mass by summarizing 50 cases (1 newly presented case and 49 additional cases collected from PubMed from 1985 to the present). There were 10 males and 40 females, with ages ranging from 8 to 75 years (median age 35.5). Intracardiac masses were distributed in four cardiac chambers. Mass size ranged from a diameter of 0.5 to 7.1 cm. Clinical manifestations were heterogeneous, including dyspnea, fever, hemiparesis, limb ischemia, and other nonspecific symptoms. In 41 cases with available pathology results, 33 cases were confirmed as thrombus, 2 cases as myxoma, 3 cases as non-bacterial endocarditis, 2 cases as fibrous tissue, and 1 case as inflammatory necrosis. Among 41 cases, 18 cases were suspected of primary cardiac tumors preoperatively, while pathological examination revealed none was tumor. APS patients with intracardiac masses are extremely rare, mostly seen in young or middle-aged people, and they present with a variety of clinical manifestations. Most masses disappear following medical treatment. APS can be accompanied by cardiac myxomas. APS should be promptly investigated in young patients presenting with thrombotic events without any underlying risk factors.

Novel antidiabetic drugs, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have significantly transformed the management landscape for type 2 diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, owing to their well-established cardiorenal protective effects. Given the shared risk factors and comorbidities, it is relevant to consider the potential risk of venous thromboembolism (VTE) in individuals prescribed these novel antidiabetic medications. This literature review aims to summarize currently available evidence on VTE risk associated with novel antidiabetic drugs, including GLP-1 receptor agonists, dipeptidyl-peptidase IV (DPP-4) inhibitors, and SGLT2 inhibitors. Following a comprehensive search on PubMed using relevant keywords and backward reference searching, we identified 25 publications that directly reported on associations between these medications and VTE risk. Findings from these studies, including seven meta-analyses, reveal inconsistent results: some studies suggest that GLP-1 receptor agonists or DPP-4 inhibitors may be associated with increased risk of VTE, whereas SGLT2 inhibitors do not appear to be associated with VTE and may even be a protective factor. A notable limitation of the existing studies is the significant challenge posed by confounding in observational studies, while the randomized controlled trials (RCTs) often concluded with a limited number of VTE events, if it was studied. Furthermore, all identified studies focused on the risk of primary VTE, leaving an important knowledge gap regarding whether these novel antidiabetic drugs may influence the efficacy or safety of anticoagulants used for preventing VTE recurrence. Addressing these gaps presents an important avenue for future research.

Deep vein thrombosis (DVT) is a preventable yet serious complication among people living with human immunodeficiency virus (PLWH), attributed to hypercoagulability, low CD4+ counts, and antiretroviral therapy. Despite the high burden of human immunodeficiency virus (HIV), data on DVT in this population remain scarce, particularly in high-prevalence regions. This study systematically reviews the prevalence, risk factors, and outcomes of DVT in adults with HIV. Following PRISMA guidelines, we extracted data from 23 studies (180,495 participants) and conducted subgroup analyses based on country, continent, study design, and quality. Heterogeneity and publication bias were assessed statistically. The global DVT prevalence among PLWH was 14%, with Africa reporting the highest prevalence (47%) and Europe the lowest (3%). Kenya exhibited the highest country-specific prevalence (74%), whereas the Netherlands and Denmark had the lowest (2%). Cross-sectional studies reported the highest prevalence (16%). Identified risk factors included hospitalization, opportunistic infections, malignancies, and comorbidities such as hypertension and diabetes. Funnel plot asymmetry indicated potential publication bias and small-study effects. DVT poses a significant health burden among PLWH, particularly in Africa. Given the high prevalence and associated risk factors, integrating DVT prevention and management into HIV care is critical. Targeted interventions should focus on modifiable risk factors and enhanced diagnostic strategies to improve patient outcomes. Future studies should address knowledge gaps and methodological variations to guide better prevention and treatment approaches.

Functional limitations often persist in patients with venous thromboembolism (VTE). The relevance of biomarkers for these outcomes remains unexplored. Therefore, we aimed to investigate the association of hemostatic, inflammatory, and cardiovascular biomarkers with functional limitations 3 months after VTE. We conducted a prospective cohort study, including patients with acute VTE within 21 days of diagnosis. Biomarker levels (D-dimer, fibrinogen, factor VIII [FVIII], von Willebrand factor antigen [VWF], C-reactive protein [CRP], troponin T, N-terminal pro-B-type natriuretic peptide [proBNP]) were measured at inclusion and 3 months. Functional limitations at 3 months were evaluated with the post-VTE functional status (PVFS) scale (0-4, higher indicating more limitations). The association of biomarkers with functional limitations was assessed with proportional odds models adjusted for confounders. Furthermore, we evaluated the area under the receiver operating characteristic curve (AUC-ROC) for the presence of slight-to-severe functional limitations. Overall, we included 290 patients (41.4% of women) with a median age of 54.9 years (interquartile range [IQR]: 43.1-64.2). D-dimer, fibrinogen, FVIII, VWF, and CRP measured at inclusion were independently associated with functional limitations at 3 months. VWF showed the most favorable AUC-ROC (0.62, 95% CI, 0.55-0.69). In patients with pulmonary embolism, troponin T and proBNP were not associated with functional limitations. At the 3-month follow-up, D-dimer was the only biomarker independently associated with functional limitations, yielding an area under the curve (AUC) of 0.62 (95% CI, 0.55-0.69). In conclusion, we identified biomarkers independently associated with functional limitations 3 months after VTE. Our results indicate a role of these biomarkers in the early identification of patients at risk of persistent functional limitations and suggest their involvement in the underlying mechanisms.