Journal of Thrombosis and Haemostasis最新文献

Background: Computed tomography pulmonary angiography (CTPA) and ventilation-perfusion (VQ) scans are used to diagnose pulmonary embolism (PE), but there are concerns about ionizing radiation exposure from CTPA and its potential to increase cancer risk.

Objectives: This study compared early-onset cancer risk between patients diagnosed with PE who underwent CTPA or VQ imaging.

Methods: We conducted a retrospective population-based matched cohort study using linked clinical and administrative health databases in Ontario, Canada. Patients aged 18-75 years diagnosed with PE between 2004 and 2021 were included. Each patient who underwent VQ scan was matched by age and sex to a patient who underwent CTPA. Using a landmark statistical framework starting at 18-months post PE diagnosis, cancer diagnoses were identified using the Ontario Cancer Registry. Cox proportional hazards regression models assessed the association between imaging modality and cancer risk.

Results: A total of 20,476 patients were included, 10,238 in each cohort. The median follow-up was 5.26 years for patients in the CTPA group and 6.96 years for those in the VQ group. The overall cancer rate was 10.96 per 1,000 person-years (95% CI: 10.42-11.52). There was no significant difference in cancer risk between the CTPA (10.93 per 1,000 person-years, 95% CI: 10.14-11.78) and VQ scan groups (10.98 per 1,000 person-years, 95% CI: 10.26-11.75; p=0.93). Multivariable analysis demonstrated no significant association (HR 0.95; 95% CI: 0.86-1.05).

Conclusions: In this population-based cohort, cancer risk associated with exposure to CTPA was not significantly higher than that associated with VQ lung scans.

Background: Development of neutralizing anti-factor(F)VIII antibodies (inhibitors) follows recognition by CD4⁺ T cells of epitopes that are presented on the individual's HLA Class II. Limited blood volumes have presented a major challenge in mapping T-cell epitopes in FVIII, especially as these immune responses typically develop in early childhood.

Aims: To determine if CD4⁺ T cells from individuals with and without hemophilia A (HA) respond to the same T-cell epitopes.

Methods: We utilized interferon-gamma ELISPOT assays with added co-stimulation developed by Schultz et al. (PMID 28562666) to test both unmanipulated CD4⁺ T cells and in vitro expanded FVIII-specific CD4⁺ T-cell lines from non-HA donors, akin to lines generated by Meunier, et al. (PMID 29296830), to identify responses to FVIII protein and synthetic 15-mer FVIII peptides.

Results: Tests of both unmanipulated and in vitro expanded CD4⁺ T cell populations from non-HA donors identified immunodominant epitopes in FVIII. However, the protocol utilizing expanded T-cell lines produced higher background interferon-gamma secretion, which could mask responses to some FVIII epitopes. Importantly, several HLA-DRB1-restricted epitopes identified using T cells from non-HA subjects were reproducibly found using T cells from HA subjects with the same HLA-DRB1 alleles.

Conclusion: Circulating non-HA CD4⁺ T cells with self-FVIII specificity, i.e., cells that apparently escaped thymic editing, can respond to the same epitopes recognized by CD4⁺ T cells from individuals with HA. Therefore, co-stimulation-enhanced ELISPOT assays can identify clinically relevant T-cell epitopes in FVIII using blood from healthy non-HA donors, thereby overcoming blood volume limitations inherent to pediatric patient populations.

Background: Our previous animal studies suggested the critical role of type I interferons (IFNβ) and high-mobility group box 1 (HMGB1) axis in coagulation; however, the predictive value of IFNβ/HMGB1 for the clinical onset of septic disseminated intravascular coagulation (DIC) remains unknown.

Objectives: This study aims to further elaborate on the pathogenesis of sepsis-associated DIC and identify potential biomarkers suitable for the early prediction of DIC.

Methods: The plasma levels of IFNβ/HMGB1 were determined in septic patients without DIC at admission. The onset of septic DIC was assessed 48 h thereafter. We subsequently compared the leukocyte transcriptomes of non-DIC with and DIC patients. A series of gene-modified mice, including IFNα/βR1^-/-, Tlr4^-/-, Malat1^-/-, Casp1^-/-, Casp11^-/-, and Malat1^flox/flox as well as Gpx4^flox/flox in conjugation with Cdh5-, Alb-, Vav- and Lyz2-Cre, were utilized to investigate the mechanisms.

Results: The plasma level of IFNβ but not HMGB1 in septic patients shows a consistent correlation with the onset of DIC. We identified a HMGB1-bypassing signaling pathway where IFNβ stimulates macrophages to express high levels of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in response to gram-negative bacteria. Deletion of Malat1 specifically in macrophages restores GSH (glutathione) exhaustion and enhances GPX4 activity by maintaining YY1-mediated Hba-a1 expression, which dampens lipopolysaccharide (LPS) internalization and caspase-11 activation, and suppresses caspase-11/GSDMD-dependent phosphatidylserine (PS) exposure, thereby protecting against bacteria-induced coagulation.

Conclusion: Our study unveils a novel immunocoagulation pathway: MALAT1 fuels caspase-11-dependent coagulation by inhibiting GPX4 activity, which provides new insights into the coagulation mechanisms in bacterial sepsis.

Background: Reperfusion by mechanical thrombectomy (MT) is an alternative for reperfusion in acute pulmonary embolism (PE) when systemic thrombolysis (ST) is contraindicated or has failed.

Objectives: To evaluate the early experience from MT in Sweden with comparison to ST.

Methods: We included all adult patients treated with large-bore MT in Sweden from January the year the technique was introduced until December 2023 as well as patients concurrently treated with ST in the respective hospitals. The primary outcome was a composite of early death or severe bleeding.

Results: During the study period, MT was performed exclusively with the FlowTriever system (FT). Among 132 patients included in 7 hospitals, 61 patients aged 67±15 years (mean ± SD) were treated with FT only and 61 aged 68±14 years with ST only. High-risk PE was present in 32 patients in the FT group and 38 in the ST group. The other patients all had intermediate-high risk PE. There were 6 primary outcome events in the FT group and 17 in the ST group (adjusted OR 0.19; 95% CI 0.05-0.69). Five (8%) patients in the FT group and 13 (21%) in the ST group died within 30 days (OR 0.33; 95% CI 0.11-0.99). One severe bleeding occurred after FT and 7 after ST (OR 0.18; 95% CI 0.03-1.10).

Conclusion: Mechanical thrombectomy, using the FlowTriever system, in high and intermediate-high risk pulmonary embolism was effective and possibly safer than reperfusion with systemic thrombolysis.

Background: Epigenetic regulation with histone deacetylase (HDAC) inhibition by valproic acid (VPA) has been used to regulate a number of pathological conditions to date. Recently, VPA was shown to alter production and local release of tPA and PAI-1 in the blood, and to have utility in the regulation of clot formation, resolution, and stability. However, VPA is known to be associated with a rare risk of hepatotoxicity.

Objective: To improve upon VPA, a novel HDAC inhibitor, CS014, was developed with preserved HDAC inhibition and reduced hepatotoxic potential. In this study, we sought to assess the potential of CS014 to function as an anti-thrombotic drug with a safer profile compared to VPA.

Methods: CS014 and VPA were assessed for HDAC inhibitory properties, as well as 4-ene metabolite production in both in vivo and in vitro settings. In vivo clot formation and bleeding were measured in mice dosed with CS014 or VPA. Direct effects on platelet activity of CS014 and VPA were evaluated ex vivo.

Results and conclusions: CS014 maintained equivalent inhibition of HDAC compared to VPA without the formation of a key hepatotoxic metabolite, in addition to maintaining the ability to prevent thrombus formation following a vascular injury. While significant attenuation of platelet accumulation and fibrin formation was observed at the site of injury, CS014 was not observed to alter coagulation or increase bleeding time. CS014 represents a novel HDAC inhibitor with the potential for reducing hepatotoxicity while maintaining the benefit of preventing injury-induced clotting without increased bleeding diathesis.

Background: Thrombotic microangiopathy (TMA) is a common and potentially fatal complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT). Thrombotic thrombocytopenic purpura (TTP), a distinct form of TMA caused by severe deficiency of plasma ADAMTS13 activity, has been reported to be rare in the posttransplant population.

Objectives: To investigate the clinical features and outcomes of TTP after allo-HSCT.

Methods: This retrospective cohort study used a nested case‒control approach. For each patient with TTP, three patients with high-risk transplant-associated TMA (TA-TMA) were matched as controls according to the time of transplantation.

Results: A total of 26 patients with TTP were identified and included in the cohort. Compared with patients with high-risk TA-TMA, patients with TTP had greater proportions of central nervous system (50.0% vs. 19.2%, p = 0.002) and gastrointestinal tract involvement (65.4% vs. 32.1%, p = 0.003), with central nervous system dysfunction occurring later (8.0 days vs. -1.0 days since the diagnosis of TTP, p = 0.008). Patients with TTP had a significantly lower overall survival rate than those with high-risk TA-TMA did (26.9% vs. 48.7%, log rank p = 0.026). Age over 40 years at the time of TTP diagnosis was identified as an independent predictor of 60‒day overall survival.

Conclusion: TTP occurring in the setting of HSCT is rare, but can be differentiated from TA-TMA, and is associated with a worse prognosis.

The care of menstruating individuals on anticoagulation is complex and often overlooked in current clinical guidelines. Although existing recommendations address anticoagulant use broadly, they provide little guidance on managing menstrual bleeding, contraception, or reproductive transitions in this population. To address these gaps, we developed a practical clinical toolkit focused on anticoagulation stewardship for individuals who menstruate-from adolescence through menopause. This expert-driven resource outlines best practices for identifying and managing heavy menstrual bleeding (HMB), optimizing contraceptive counseling, and coordinating care during high-risk periods such as pregnancy, surgery, and perimenopause. It also offers guidance for special populations, including adolescents, transgender and gender-diverse individuals, and those with limited access to care. Key topics include medication selection, dose adjustment, screening for anemia, and referral to gynecology when appropriate. The toolkit emphasizes the role of multidisciplinary teams-including hematology, gynecology, primary care, and anticoagulation services-in delivering patient-centered, equitable care. It also highlights practical strategies for integrating menstrual health into routine anticoagulation management, promoting shared decision-making, and improving quality of life for affected individuals.

Background: Endothelial injury is the core factor of venous thrombosis. m6A plays a critical role in metabolism and cellular processes. Moreover, the balance of mitochondrial dynamics is essential in regulating cellular growth, apoptosis, and mobility. Now, The roles of m6A modification and mitochondrial dynamics in regulating venous endothelial cells remains elusive.

Methods: M6A levels were evaluated by m6A dot blot and quantification analysis. Gain- and loss-of-function and rescue assays were performed to clarify gene functions. To investigate the mitochondrial dynamics in venous endothelium, mitochondrial morphology and function analysis were performed. The target gene of ZC3H13 was identified through RNA-seq and MeRIP-seq. Mechanism of ZC3H13-mediated m6A modification was explored through MeRIP-qPCR, luciferase reporter assay, RNA stability assay, and RNA immunoprecipitation assay.

Results: Downregulated ZC3H13 expression and elevated mitochondrial fission were observed in injured venous endothelium. Functional verification has clarified ZC3H13 regulated endothelial cells by modulating mitochondrial fission. Furthermore, ZC3H13-mediated m6A modification profile was revealed and DYRK1B was identified as its target in endothelial cells. Decreased m6A modification mediated by downregulation of ZC3H13 upregulated DYRK1B mRNA expression through inhibiting DYRK1B mRNA decay in a YTHDF-2-dependent manner. Functional verification also confirmed the functions of DYRK1B in regulating endothelial cells by modulating mitochondrial fission. Moreover, endothelial-targeted ZC3H13 overexpression attenuated venous endothelial injury, which contributed to the reduced thrombotic risk observed in mice.

Conclusions: The findings of the current study showed that ZC3H13 mitigates endothelial injury by inhibiting excessive mitochondrial fission through the m6A/YTHDF2/DYRK1B axis.

Background: Failure rates of clinical decision rules (CDRs) combined with D-dimer to exclude pulmonary embolism (PE) are higher in patients with cancer compared with noncancer patients, raising concerns about their use in this patient group.

Objectives: To compare the failure rates of the Wells score, revised Geneva score, and YEARS algorithm in patients with cancer who underwent standard imaging with those in whom imaging was withheld, and report the diagnostic yield of these algorithms.

Methods: We used data from an individual-patient level meta-analysis of prospective diagnostic management studies of patients with suspected PE. The primary outcome was the 3-month incidence of venous thromboembolism, excluding PE (failure), using fixed and age-adjusted D-dimer results across different patient management categories for all investigated CDRs. The secondary outcome included the proportion of patients for whom PE could be ruled out without further imaging (diagnostic yield).

Results: A total of 2258 (7.6%) patients with cancer from 17 studies were included in the analysis. The 3-month incidence of venous thromboembolism in patients after excluding PE ranged from 0.52% (95% CI, 0.06%-4.35%) to 2.83% (95% CI, 0.96%-8.34%) and was comparable across all management categories. The highest diagnostic yield of 26% was found for the revised Geneva score, with an age-adjusted D-dimer cutoff, and the YEARS algorithm.

Conclusion: The failure rates of patients with cancer for whom PE was excluded using CDRs and withholding imaging were similar to those observed after standard imaging. Current diagnostic algorithms for suspected PE are applicable to patients with cancer.