Thrombosis and haemostasis最新文献

A direct oral anticoagulant (DOAC) concentration threshold above which an impact on surgical hemostasis starts to occur is unknown. Thrombin generation assays (TGAs) provide a measure of the coagulation phenotype. This study aimed to determine whether preoperative TGA parameters are associated with postoperative bleeding, and whether this is partly due to residual DOAC levels.We conducted a nested case-control study using samples from apixaban/rivaroxaban-treated patients with atrial fibrillation from the PAUSE (Perioperative Anticoagulation Use for Surgery Evaluation) perioperative study. Cases were participants with postoperative major or clinically relevant nonmajor bleeding; controls were participants without bleeding. DOAC levels were measured using a chromogenic anti-Xa assay (BIOPHEN DiXaI; rivaroxaban/apixaban calibrators). TGA parameters were measured using calibrated automated thrombography.Generalized linear mixed models and causal mediation analyses were used to evaluate the relationship between DOAC levels, TGA parameters, and bleeding.Forty eight cases were matched to 474 controls. Residual DOAC levels were higher in cases than controls (p = 0.03) and each TGA parameter was correlated with residual DOAC levels (p<0.05). A longer lag time (LT; odds ratio [OR] = 1.319 per minute [95% confidence interval [CI]: 1.077-1.617]) and time-to-peak (TTP; OR = 1.154 per minute [95% CI: 1.028-1.296]) were associated with an increased odds of bleeding; higher peak (OR = 0.994 per nM [95% CI: 0.989-0.998]) and mean velocity rate index (mVRI; OR = 0.986 per nM/min [95% CI: 0.976-0.996]) were associated with a lower odds of bleeding. The effect of apixaban/rivaroxaban levels on bleeding was mediated by altered TGA parameters (LT, TTP, peak, mVRI).These findings support a measurable effect from low residual DOAC levels on thrombin generation and suggest a causal contribution of both toward bleeding.

We previously identified a factor (F)VIII molecular defect associated with an R2159C mutation in the C1 domain (named "FVIII-Ise") together with undetectable FVIII antigen (FVIII:Ag) levels measured by two-site sandwich ELISA using an anti-C2 domain alloantibody (alloAb). The patient had clinically mild hemophilia A, and his reduced FVIII:C correlated with FVIII:Ag measured by ELISA using monoclonal antibodies (mAbs) with A2 and A2/B domain epitopes, suggesting that the R2159C mutation modified C2 domain antigenicity.To investigate functional and structural characteristics of the FVIII-R2159C mutant.ELISAs using a previous anti-C2 domain alloAb confirmed that the antigen level of recombinant FVIII-R2159C mutant prepared in BHK cells was 56% lower relative to wild-type (WT), consistent with our earlier reports. This anti-C2 domain alloAb competitively inhibited FVIII and anti-C1 domain mAb binding, indicating the involvement of specificity for C1 and C2 epitopes. The K _m for FVIII-R2159C with FIXa or FX in the tenase complex was similar to that of FVIII-WT. Thrombin- and FXa-catalyzed cleavage reactions of FVIII-R2159C were similar to those of WT. The K _d for FVIII-R2159C binding to phospholipids was moderately greater than for FVIII-WT, however, while there were no significant differences in von Willebrand factor binding. In silico molecular dynamic simulation analyses revealed subtle differences between FVIII-WT and FVIII-R2159C.The FVIII-R2159C mutation was not different from FVIII-WT in interactions with FIXa, FX, and thrombin, but reduced binding potential to phospholipids and to an anti-C1/C2 domain alloAb was evident apparently due to subtle changes in conformational structure.

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.