Journal of Thrombosis and Haemostasis最新文献

Recent advances in cancer treatment have improved outcomes for patients across a wide variety of cancers. However, despite the introduction of more targeted therapies, including those that harness the body's natural immune system, cancer-associated thrombosis, particularly during therapy, is a significant clinical problem associated with poorer outcomes. Although venous thromboembolism is more common, arterial events cause significant morbidity and are frequently fatal. In addition to the well-established chemotherapeutic regimens, multiple therapies are now used in the first-line setting, including antibody-based treatments, immunotherapy, and hormone receptor modulators. Many cancers are now being managed as chronic diseases with long-term maintenance therapies in an increasingly older patient population with significant comorbidities. With this change in the treatment landscape, predictive biomarkers are needed to effectively identify patients and treatments associated with the highest risk of thrombosis in the current cancer population. Although cancer-associated thrombosis has been extensively studied, the specific mechanisms by which cancer therapy causes thrombosis remain poorly understood. The pathogenesis of immunothrombosis associated with cancer treatments in particular is poorly defined. Focusing on solid tumors, the aim of this narrative review is to explore our current understanding of the pathogenesis of thrombotic effects of systemic cancer treatment. These include coagulation activation, vascular endothelial damage, procoagulant effects of material from dead and dying tumor cells, as well as the role of inflammatory mediators. Greater understanding of pathogenesis of treatment-related cancer-associated thrombosis will lead to the identification of more effective biomarkers to guide thromboprophylaxis.

Background: Activated protein C (APC) is a serine protease known for its anticoagulant, anti-inflammatory, and cytoprotective properties. Although clinical evidence links protein C (PC) deficiency to various retinal pathologies, the physiological role of APC in the retina remains unexplored.

Objectives: To determine whether PC and APC are synthesized locally in the healthy retina or are transported systemically across the blood-retina barrier (BRB) and to evaluate the contribution of the endothelial protein C receptor (EPCR) to APC transport and the therapeutic potential of APC in the retina following systemic administration.

Methods: We utilized a unique and viable severe protein C deficiency murine model developed in our laboratory. Reverse transcription polymerase chain reaction, immunostaining, and coagulation-based activity assays were used to determine the presence and distribution of PC, APC, and EPCR in the retina and after APC injection via the tail vein. EPCR blockage was performed using an EPCR-neutralizing antibody. The anti-inflammatory activity of the APC analog, 3K3A-APC, was assessed in a murine model of retinal pathologies.

Results: APC is not synthesized locally in the retina but originates from the systemic circulation, crosses the BRB, and accumulates in the retina. EPCR mediates the translocation of APC across the BRB. Systemically administered 3K3A-APC crosses the BRB and induces cytoprotective and anti-inflammatory effects in the retina comparable with intraocular treatment.

Conclusions: Our findings establish a fundamental step in investigating the concept of PC as a physiologically relevant, naturally protective protein in the eye. Our results support the feasibility of developing noninvasive, systemic APC-based therapies for retinal diseases.

Background: The Hokusai Venous Thromboembolism (VTE) Cancer trial demonstrated that edoxaban was noninferior to dalteparin for the treatment of cancer-associated venous VTE.

Objectives: We reanalyzed the trial using the win ratio, an approach that evaluates a composite of outcomes in a hierarchical order.

Methods: Forty-nine thrombosis experts ranked 10 outcomes in order of clinical importance from all-cause death (most important) to clinically relevant nonmajor bleeding (least important). We performed unmatched pairwise comparisons between participants on edoxaban and those on dalteparin at 6- and 12-month follow-up. Within each pair, edoxaban was assigned a win, loss, or tie according to the hierarchy of outcomes. We calculated the win ratio (total wins divided by total losses among edoxaban patients), with more wins than losses indicating the benefit of edoxaban, and the win difference (total wins minus total losses).

Results: Among 273 528 pairs (522 × 524 participants), edoxaban was associated with a win in 34.9%, a loss in 38.5%, and a tie in 26.6%. The win ratio was 0.91 (95% CI, 0.76-1.08), with a win difference of -3.55% (95% CI, -9.9% to 2.9%) at 12 months. The win ratio remained unchanged at 6 months (0.91; 95% CI, 0.75-1.11). The findings were consistent with a hierarchy of only death, recurrent VTE, and major bleeding (win ratio, 0.92; 95% CI, 0.76-1.11), or when replacing all-cause death with VTE-related death or fatal bleeding (win ratio, 0.83; 95% CI, 0.65-1.06).

Conclusion: We observed no significant difference between edoxaban and dalteparin for the treatment of cancer-associated VTE when using the win ratio approach with a hierarchy of 10 prioritized outcomes.

Background: Sepsis is characterized by the simultaneous activation of inflammation and coagulation in response to systemic infection, leading to microvascular dysfunction and consequential multiorgan failure. Previous studies have revealed that TMEM16F is involved in blood coagulation and inflammatory response. However, its detailed regulatory molecular mechanisms and functions in sepsis remain unknown.

Objectives: In this study, we aim to investigate the regulatory effects and the underlying mechanism of TMEM16F in sepsis-induced microvascular thrombosis and inflammation.

Methods: We used septic patients, lipopolysaccharide (LPS)-induced septic mouse models, and in vitro cellular experiments with LPS-stimulated endothelial cells. Bioinformatical analysis and molecular biological techniques were performed to identify the target genes of TMEM16F.

Results and conclusions: We found that TMEM16F was highly expressed in vivo and in vitro septic model, and its deletion decreased mortality, inflammation, and the microthrombi formations in LPS-induced septic mice. Additionally, silencing NRF2 not only inhibited TMEM16F expression but also improved LPS-induced thrombosis, inflammation, and organ injury, which could be reversed by inhibition of miR-17-5p. By bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments, we revealed that the transcription factor NRF2 drove TMEM16F transcription through promoter binding while suppressing miR-17-5p, thereby increasing TMEM16F expression in endothelial cells. Furthermore, plasma concentrations of TMEM16F and miR-17-5p were correlated with coagulation activation, inflammation, and disseminated intravascular coagulation scores in septic patients. Overall, these findings identify the NRF2/miR-17-5p/TMEM16F axis may be a potential therapeutic target for sepsis.

As global burden of venous thromboembolism (VTE) increases, clinicians are managing more patients across diverse and often fragmented care settings. VTE care transitions are more frequent and complex than those seen in stable anticoagulation conditions like atrial fibrillation. Each transition presents opportunity for optimizing antithrombotic therapies and mitigating associated risks. In this review, we use case-based scenarios to highlight common care transition challenges and offer evidence-based, stewardship-guided strategies to optimize antithrombotic use and outcomes throughout the VTE continuum.

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.

Background: Endothelial injury is the core factor of venous thrombosis. N6-methyladenosine (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. However, the roles of m6A modification and mitochondrial dynamics in regulating venous endothelial cells remains elusive.

Methods: Levels of m6A 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 zinc finger CCCH-type containing 13 (ZC3H13) was identified through RNA-sequencing and methylated RNA immunoprecipitation sequencing. Mechanism of ZC3H13-mediated m6A modification was explored through methylated RNA immunoprecipitation quantitative polymerase chain reaction (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 messenger RNA expression through inhibiting DYRK1B messenger RNA decay in an 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.

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

Background: Patients with a mechanical heart valve (MHV) require vitamin K antagonist (VKA) treatment to prevent thromboembolism.

Objectives: To examine the quality of VKA treatment and clinical outcomes, including all-cause mortality, bleeding, and thromboembolism, by sex and age in patients with an MHV.

Methods: Data from 17 Dutch anticoagulation clinics were linked to Statistics Netherlands. Patients with an MHV receiving VKAs between 2013 and 2019 were included and followed from the first MHV hospitalization discharge until death, VKA discontinuation, or December 31, 2019. Quality of treatment was assessed by the time in therapeutic range (TTR) and international normalized ratio variability (variance growth rate). Clinical outcomes were identified by first in-hospital diagnoses and primary causes of death and expressed as incidence rates (IR) per 100 person-years, stratified by sex and age.

Results: In total, 3527 MHV patients (38% women, median age 67 years) had a median follow-up of 3.0 years. Women <55 years (n = 228) had lower TTR compared with the other sex and age groups. All-cause mortality rates were similar across the sexes in both age groups. Women aged <55 years had a higher IR (95% CI) of both bleeding (2.52 [1.49-3.98] vs 1.03 [0.51-1.84]) and thromboembolism (2.83 [1.73-4.38] vs 1.70 [1.01-2.69]) than similarly aged men (n = 395). However, treatment quality and IR were similar for women and men aged ≥55 years.

Conclusion: Women with MHVs aged <55 years exhibited poorer quality of VKA treatment and higher rates of complications than similarly aged men. These findings highlight the need for tailored anticoagulation strategies in younger female MHV patients.