Thrombosis and haemostasis最新文献

This study aimed to evaluate the impact of systemic inflammation burden using high-sensitivity C-reactive protein (hsCRP) and long-term prognosis in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) stratified by bleeding risk status.Consecutive patients admitted for ACS and who received PCI between March 2016 and March 2022 were enrolled in the analysis. Elevated systemic inflammation was defined as hsCRP >2 mg/L, and high bleeding risk (HBR) was defined the Academic Research Consortium (ARC)-HBR criteria. The primary outcome was ischemic events at 12 months, composed of cardiac death, myocardial infarction, and/or stroke. The main secondary outcomes included all-cause death, and Bleeding Academic Research Consortium (BARC) types 2, 3, and 5 bleeding and types 3 and 5 bleeding.Of 15,013 patients, 4,606 (30.7%) were qualified as HBR and 8,395 (55.9%) had hsCRP >2 mg/L. Elevated hsCRP was consistently associated with higher risk of ischemic events in both HBR (adjusted hazard ratio [aHR]: 1.20; 95% confidence interval [CI]: 0.91-1.58) and non-HBR (aHR: 1.34; 95% CI: 1.01-1.78) subgroups (P _interaction = 0.755). Although the incidence of bleeding events was higher in HBR patients, an elevated hsCRP level was not associated with bleeding events regardless of HBR status. Restricted cubic spline regression represented an inverse J-shaped relation between hsCRP and non-HBR for ischemic events (P _nonlinearity <0.001) and all-cause death (P _nonlinearity = 0.003).Regardless of HBR status, high levels of hsCRP were associated with an increased risk of ischemic events and all-cause death in ACS patients following PCI, but not for bleeding.

To evaluate residual fibrinolysis resistance activity (FRA) in plasma, a detergent-modified plasma clot lysis assay time (dPCLT) was established in which α2-antiplasmin (A2AP) and plasminogen activator inhibitor type 1 (PAI-1) are inactivated without impacting protease activity. We applied this novel assay to severely injured trauma patients' plasma.Tissue-type plasminogen activator (tPA)-induced plasma clot lysis assays were conducted after detergents- (dPCLT) or vehicle- (sPCLT) treatment, and time to 50% clot lysis was measured ("transition midpoint", T _m). Residual FRA was then calculated as ([sPCLT T _m] - [dPCLT T _m]/[sPCLT T _m]) x100% = Δ T_m PCLT (%). Assay results were compared to rapid thromboelastography (TEG) LY30, tPA TEG LY30, and plasma fibrinolysis biomarkers in polytrauma patients' plasma (N=43).Δ T_m PCLT(%) in normal plasma (N=5) was 63.0 ± 8.3 whereas in A2AP-depleted plasma was -19.1 ± 1.3%, Plasmin-antiplasmin (PAP) complex increased after complete lysis of sPCLT, whereas that in dPCLT was negligible in normal plasma. In trauma plasma, significant correlations between Δ T_m PCLT and active PAI-1 (r = 0.85, p<0.0001), PAP complex (r = -0.85, p<0.0001), free A2AP (r = 0.66, p<0.0001), total A2AP levels (r = 0.52, p=0.001) and tPA TEG LY30 (r = -0.85, p<0.0001) were found. dPCLT in hyperfibrinolysis patients diagnosed by tPA TEG was significantly shorter than those with low fibrinolysis [10.2 ± 6.4 minutes versus 20.2 ± 2.1 minutes, p=0.0006].Hyperfibrinolysis after trauma is significantly related to exhaustion of FRA, and our novel assay appears to quickly assess this state and may be a useful clinical diagnostic after additional validation. · We established a new clot lysis assay to measure residual fibrinolysis resistance activity after inactivating PAI-1 and A2AP by detergents without impacting protease function.. · This novel clot lysis assay unmasked the mechanism of hyperfibrinolysis after trauma as exhaustion of fibrinolysis resistance activity, and appeared useful in quickly identifying these patients..

The criteria for diagnosing sepsis-induced coagulopathy (SIC) may overlap with those of Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC). This study determined if the diagnostic criteria of SIC overlap with JAAM DIC diagnostic criteria for identifying patients with DIC according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and whether the patients diagnosed with these criteria have the same prognosis.This multicenter retrospective study included patients with sepsis diagnosed using the JAAM and ISTH DIC and SIC criteria on days 1 and 4. The established ISTH DIC criteria was the reference standard for primary outcome that compared the characteristics of SIC and JAAM DIC. Secondary outcomes were multiple organ dysfunction syndrome (MODS), ventilator-free and intensive care unit-free days, and in-hospital mortality.A total of 1,438 patients were included in this study. On day 1, the JAAM DIC and SIC criteria diagnosed almost all patients with ISTH DIC (98 and 94%, respectively), predicting ISTH DIC (area under the receiver operating curve [AUC]: 0.740 versus 0.752, p = 0.523) and MODS (AUC: 0.686 versus 0.697, p = 0.546) on day 4 and progressing to ISTH DIC in the same proportion (28.6 versus 30.1%, p = 0.622). There were no differences in survival probabilities (p = 0.196) or secondary outcomes between patients diagnosed using JAAM DIC and SIC criteria on day 1.SIC and JAAM DIC diagnoses were equal among patients with sepsis, suggesting that SIC criteria add little to current DIC scoring systems.

The advent of angiogenesis inhibitors has expanded therapeutic options for tumors but poses challenges due to bleeding risks, especially in patients requiring anticoagulation therapy for cancer-associated hypercoagulability.This study aimed to evaluate whether combining anticoagulants with angiogenesis inhibitors increases bleeding risk in cancer patients.A network meta-analysis was conducted based on PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials to compare bleeding risks with angiogenesis inhibitors alone versus their combination with anticoagulants. Furthermore, a real-world cohort of 645 patients receiving antiangiogenic therapies between January 2010 and June 2024 was studied. Patients were separated into two groups according to whether they were receiving concomitant anticoagulants. The primary outcome was all-grade bleeding events.Of 2,644 patients from six studies included in network meta-analysis, all-grade bleeding events were found in 614 (23.2%) patients. The addition of anticoagulation to either high-dose bevacizumab (10 or 15 mg/kg) (OR 4.95, 95% CI: 2.68-9.42) or antiangiogenic tyrosine kinase inhibitors (OR 2.2, 95% CI: 1.08-4.44) significantly increased bleeding risk compared with antiangiogenic monotherapy, except for low-dose bevacizumab (5 or 7.5 mg/kg). In the cohort study, 163 patients matched in each group after propensity score matching weighting. Over a median follow-up duration of 56 days, there were 28 (17.2%) all-grade bleeding events during concurrent treatment and 16 (9.8%) all-grade bleeding events reported during antiangiogenic monotherapy.Adding anticoagulation to high-dose bevacizumab or antiangiogenic TKIs might increase bleeding risk compared with monotherapy. Conversely, anticoagulants appeared to be safe in patients receiving low-dose bevacizumab.

Acute myocardial infarction (AMI) remains a formidable challenge in cardiovascular medicine, necessitating effective antiplatelet therapy to mitigate adverse outcomes. Recent advances have underscored the pivotal role of oxidative stress and micro ribonucleic acids (miRNAs) in regulating platelet activation and modulating the efficacy of antiplatelet agents. This review comprehensively examines the current understanding of how oxidative stress influences platelet function and the regulatory mechanisms of miRNAs in this context. It discusses the dual role of oxidative stress in promoting and impairing platelet activity and its implications for miRNAs as critical modulators of platelet activation, including their potential utility as biomarkers and therapeutic targets. Furthermore, the interaction between oxidative stress, miRNA expression, and antiplatelet drugs is analyzed to elucidate their combined impact on AMI treatment. These insights provide potential pathways to optimize therapeutic strategies, ultimately improving patient outcomes in AMI management.

Cancer-associated thrombosis (CAT) is common and a leading cause of mortality in patients with cancer. In specific CAT scenarios, low-molecular-weight heparins (LMWHs), including tinzaparin, are preferred over direct oral anticoagulants. Despite the importance of understanding LMWH pharmacokinetics (PK) in cancer for optimizing CAT management, available data remain limited.To compare tinzaparin PK in cancer and non-cancer patients by developing a population PK model.This prospective, multicenter, case-: control trial enrolled patients receiving once-daily subcutaneous tinzaparin at a therapeutic dose of 175 IU·kg^-1, including matched cancer and non-cancer patients. Plasma anti-Xa activity was measured at multiple time points and analyzed using a non-linear mixed-effect modeling. A PK model was developed, and covariate effects were assessed for parameters of the model. The impact of cancer on tinzaparin PK was evaluated by incorporating cancer status as a categorical covariate.A total of 333 patients (including 46 matched cancer and non-cancer patients) were included in the analysis. A monocompartmental model with first-order absorption best described tinzaparin PK. The volume of distribution was associated with body weight, while clearance and anti-Xa activity were associated with creatinine clearance. No significant differences were observed between matched cancer and non-cancer patients in anti-Xa activity exposure at day 1 and steady state.PK profiles were comparable between cancer and non-cancer patients. Additionally, further studies should clarify the role of renal function in guiding tinzaparin dosing.

Vaccination against SARS-CoV-2 was instrumental in controlling the COVID-19 pandemic. Rare cases of vaccine-induced immune thrombocytopenia and thrombosis (VITT) emerged following vaccination with the adenovirus vector-based vaccines ChAdOx1 nCov-19-S and Ad26.COV2.S. VITT is mediated by high-titer IgG anti-platelet factor 4 (PF4) antibodies that activate platelets, leading to thrombosis and thrombocytopenia. Similar antibodies have been detected following natural adenovirus infections, suggesting a common immunological trigger. This indicates that a constituent of adenovirus is relevant. Adenovirus is a DNA virus. Virion-unbound viral DNA is present in natural adenovirus infections.To identify whether free virion-unbound DNA is present in ChAdOx1-nCoV19 vaccine and whether adenoviral DNA enhances the immune response to PF4 in mice.We assessed ChAdOx1 nCov-19-S for virion-unbound DNA and differentiated free human and free adenovirus DNA by sequencing. We immunized mice with ChAdOx1 nCov-19-S and its fractions, in which we removed proteins by proteinase K and/or DNA by DENERASE.Using ultracentrifugation and proteinase K digestion, we isolated and characterized free nucleic acids, confirming the presence of both adenoviral and host cell-derived DNA in ChAdOx1 nCov-19-S. Mice immunized with PF4 in combination with ChAdOx1 nCov-19-S or its virion-free supernatant-but not with PF4 alone-developed a strong anti-PF4 IgG response, an effect completely abolished by nuclease (DENARASE) treatment.Virion-unbound DNA in ChAdOx1 nCov-19-S contributes to anti-PF4 antibody formation. This highlights the potential of reducing virion-unbound DNA in vaccine formulations to mitigate unintended immune responses to PF4.

Heavy menstrual bleeding (HMB) is a common complication of anticoagulant therapy in menstruating women with venous thromboembolism (VTE). Direct oral anticoagulants (DOAC) used for VTE treatment may differ in their menstrual bleeding profiles. Therefore, the prospective multicenter noninterventional investigator-initiated HEMBLED registry (HE: avy M: enstrual BLE: eding in patients treated with D: OAC) was performed to analyze spontaneous menstrual bleeding in women treated with therapeutic DOAC doses.A modified pictorial blood assessment chart (PBAC) score was used to define the severity of menstrual bleeding. Patients were only included when they did not use hormonal or intrauterine contraception methods. The prospective follow-up was 4 months. The primary endpoint was the comparison of the PBAC scores between the individual DOAC groups.Overall, 73 patients with 213 monthly assessments of the PBAC scores were analyzed. Patients were on average 35 years old and were anticoagulated with apixaban (62%), rivaroxaban (26%), edoxaban (7%), or dabigatran (6%). The PBAC scores of the rivaroxaban group (mean: 145 points) were significantly increased by 54% compared with the apixaban group (mean: 93 points, p = 0.0193). HMB (PBAC score > 100 points) at least once was detected in 53% of the apixaban group compared with 79% of the rivaroxaban group (p = 0.0913). The duration of menstrual bleeding was numerically shorter in the apixaban group compared with the rivaroxaban group (p = 0.1894).DOAC differ in their influence on the intensity of spontaneous menstrual bleeding. This should be taken into account when advising young women with VTE who need an oral anticoagulant.

Ankylosing spondylitis (AnkS) has been associated with an increased risk of venous thromboembolism (VTE). Data comparing VTE events in AnkS with other immune-mediated inflammatory diseases and non-inflammatory patients are lacking. This study aimed to compare clinical outcomes between VTE patients with AnkS, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and patients without inflammatory disease.We analyzed 112,539 VTE patients enrolled in the RIETE registry. A Greedy Nearest Neighbor Matching approach was used to select a comparable non-inflammatory VTE cohort. Outcomes included recurrent VTE, mortality, and major bleeding at 1 year, and were compared using Cox regression or sub-hazard models.Among the inflammatory-disease cohort of 2,427 VTE patients (mean age ± standard deviation, 64.1 ± 16 years, 41.4% males), 6.4% had AnkS, 50.6% had RA, 10.8% had SLE, and 32.2% had IBD. The matched population without inflammatory disease comprised 7,800 VTE patients. The rate of recurrent VTE was 11.5%, all-cause mortality 5.1%, and major bleeding 1.9% in AnkS patients. Similar rates were observed in patients with RA, SLE, or IBD. Recurrent VTE was significantly higher in AnkS patients than in the non-inflammatory group (HR, 7.43, 95% CI, 2.28-24.23). AnkS patients who discontinued anticoagulation earlier than 1 year experienced higher adverse outcomes (a composite of mortality, major bleeding, recurrent VTE) compared with those who pursued extended therapy.VTE patients with AnkS have clinical outcomes comparable to other inflammatory diseases but a significantly increased risk of recurrent VTE compared with non-inflammatory patients, suggesting that extended anticoagulation strategies may be warranted.

Chronic inflammation plays a key role in the development and progression of atherosclerotic cardiovascular disease (ASCVD) and its complications. Despite the use of blood pressure-, lipid-, and glucose-lowering therapies as well as antithrombotic agents, the lifetime residual cardiovascular (CV) risk in patients with ASCVD remains high. Because chronic inflammation remains an unaddressed risk factor, anti-inflammatory therapy has the potential to further lower residual CV risk in these patients. Low-dose colchicine (0.5 mg daily) has emerged as a promising low-cost oral anti-inflammatory therapy for this indication. In patients with chronic coronary syndrome (CCS), low-dose colchicine was well-tolerated and reduced the risk of myocardial infarction, stroke, coronary revascularization, and CV death. However, trials in patients with acute coronary syndrome (ACS) yielded conflicting results, and two trials in patients with ischemic stroke did not show a benefit. In patients with peripheral artery disease (PAD), preliminary observational data suggested a potential benefit, and a randomized trial is currently underway to examine its efficacy in reducing CV and limb events. The long-term safety data for low-dose colchicine in ASCVD are reassuring. Although pooled data from trials in ASCVD show a small (0.55%) absolute increase in the risk of hospitalization for gastrointestinal events, adverse signals were not observed for serious infection, cancer, or severe myotoxicity. In this article, we review the clinical studies of colchicine that examined its risk-benefit for the prevention of CV events in patients with ASCVD, discuss clinical and research implications, and highlight knowledge gaps.