Journal of Thrombosis and Thrombolysis最新文献

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease. The use of conventional anticoagulants carries potential side effects, mainly bleeding. Drugs targeting Factor XI (FXI) have been investigated in randomized controlled trials as a new option with more favorable outcomes. A comprehensive literature search was conducted to identify relevant studies comparing FXI inhibitors to placebo or standard therapy. The primary outcomes were incidence of all bleeding events, major bleeding, and thromboembolism. Secondary outcomes included incidence of all adverse events (AE), serious AE, and all-cause mortality. A total of 11 studies involving 10,536 patients were included. FXI inhibitors were associated with a trend toward reduction of bleeding events and incidence of thromboembolism compared to the control group (placebo/standard therapy). There was no statistically significant difference between both groups in terms of adverse events and all-cause mortality. When compared to enoxaparin, FXI inhibitors significantly reduced the risk of bleeding events (RR = 0.42, 95% CI: 0.23-0.76, P = 0.004) and thromboembolism (RR = 0.59, 95% CI: 0.44-0.77, P = 0.001). On the other hand, when compared to DOACs, FXI inhibitors were associated with a significant reduction in bleeding events but not thromboembolism. Whereas, compared to placebo, FXI inhibitors did not increase the risk of bleeding events, adverse events, or all-cause mortality (P > 0.05). FXI inhibitors could be a safer and more potent option for prevention of thromboembolism than conventional therapy.

Patients with atrial fibrillation (AF) commonly have associated comorbidities. The primary aim was to determine the effect of increasing numbers of comorbidity on clinical outcomes. The secondary aims were (1) the association of comorbidities with oral anticoagulants (OAC) discontinuation, and quality control, (2) the impact of holistic care based on the ABC pathway on clinical outcomes. The primary outcome was the composite of all-cause death, ischemic stroke/systemic embolism, major bleeding, and heart failure. A total of 3405 patients were enrolled; mean age 67.8 ± 11.3 years, 41.8% female. Compared to low comorbidity group [n = 897 (26.3%)], hazard ratios (HR) and 95% confidence intervals (CI) for the composite outcome in the high [n = 929 (27.3%)] and moderate comorbidity [n = 1579 (46.4%)] groups were 5.40 (4.20-6.94) and 2.54 (1.97-3.27), respectively. ABC pathway adherence was associated with reduction of the composite outcome overall (HR 0.63; 0.54-0.74). High comorbidity adversely impacted on OAC use, OAC discontinuation, and quality of warfarin control. If quality of anticoagulation control was included as part of the ABC pathway adherence, the reduction in composite outcome risk was greater (HR 0.46; 0.36-0.58). During 3-year follow-up, 33.9% changed from low- to the moderate-high comorbidity groups and 22.3% changed from moderate- to the high comorbidity group. In conclusion, comorbidity burden in AF patients is an important determinant of clinical outcomes, and changed over time. OAC use, OAC discontinuation, and quality of OAC control were impacted by comorbidity burden. ABC pathway adherence was associated with a reduced risk of adverse clinical outcomes.

Animal models of thrombosis play a critical role in research, helping us understand the mechanisms of hemostasis and thrombus formation, as well as in the screening of anti-thrombotic drugs. This study aimed to evaluate the safety profile of two anticoagulants in murine research and to assess coagulation parameters, including prothrombin time (PT) and activated partial thromboplastin time (aPTT), using the VETSCAN^® VSpro coagulation analyzer in wild-type (C57BL/6) mice following administration of anticoagulants. Two experiments were conducted involving a total of sixty wild-type mice that received two common anticoagulants. Warfarin was administered in the drinking water at varying dosages, while dabigatran was incorporated into a custom-chow diet at two dosages (10 mg/g and 15 mg/g chow). The VSpro was used to establish a reference range for PT and aPTT values in untreated wild-type mice and to monitor coagulation changes in mice undergoing anticoagulant therapy. Dabigatran was well tolerated at both concentrations (10 mg/g and 15 mg/g chow), while warfarin was safe at a concentration of 2.5 mg/L, resulting in a doubling of PT and aPTT compared to baseline levels. Although the VSpro effectively detected coagulation abnormalities in murine models, certain limitations were observed, including out-of-range measurements in cases of coagulopathy. This study provides insights into safe anticoagulant dosages for murine models, supporting the use of dabigatran at 10 mg/g and 15 mg/g chow and warfarin at 2.5 mg/L. The VSpro analyzer was able to monitor coagulation parameters under these conditions, making it a feasible tool for murine research.

The use of weight-based unfractionated heparin (UFH) infusions is the standard of care in hospital management of venous thromboembolism (VTE). Initial dosing strategies for UFH in older adults and higher body weight patients remain uncertain given differences in pharmacokinetics and concerns for over-anticoagulation. Methods: This was a single-center, retrospective, pre-post study involving older adults aged ≥ 65 years and patients weighing ≥ 100 kg with suspected or confirmed VTE to determine if the use of adjusted body weight (AdjBW)-based UFH regimens improves time to therapeutic anti-Xa levels compared to total body weight (TBW)-based regimens Patients received weight-based UFH infusions, dosed according to either TBW or AdjBW, to target a therapeutic anti-Xa level. Each cohort consisted of 40 patients, stratified by whether they met age or weight criteria to ensure equal representation of elderly and higher body weight patients between cohorts. The median time to therapeutic anti-Xa levels was shorter in the AdjBW group compared to the TBW group (13.6 h versus 20.9 h; point estimate 5.3 h (95% CI 0.2 to 9.9)). This finding was driven by those aged ≥ 65 years and those who received a bolus dose at the start of the infusion. Among older adults and higher weight adults with suspected or confirmed VTE, the use of AdjBW to guide heparin infusion initiation was associated with shorter time to therapeutic anti-Xa levels. This finding driven by the older adult sample and the subgroup analyses did not find a statistically significant difference in time to therapeutic anti-Xa levels in higher body weight patients aged less than 65 years.

Treatments with different antithrombotic agents can affect micro-rheological variables, such as red blood cell (RBC) deformability and aggregation. Since the effect of dual antiplatelet and anticoagulant (APAC) treatment on micro-rheology is unknown, we aimed to investigate the effect of different intravenous doses of APAC on hematological and micro-rheological variables in a porcine model. Two groups were formed (APAC group, Control group), and blood was collected from the animals at preset intervals. Hematological variables, RBC deformability, and aggregation were measured. We observed an improvement in the RBC deformability measured at a low shear stress range (< 3 Pa). However, after both doses, a decrease in the maximal elongation index of RBC values occurred in the APAC group. RBC aggregation increased after APAC bolus dose, while it gradually and dose-dependently decreased. Supposedly, the improvement in RBC deformability that was observed at a lower shear rate could facilitate aggregation. Administration of APAC and unfractionated heparin (UFH) caused comparable changes in hematological and hemorheological variables. Signs of thrombosis or bleeding did not occur. APAC and UFH had comparable micro-rheological effects.

Combined deficiency of coagulation factor V (FV) and factor VIII (FVIII) is a rare bleeding disease caused by variants in either lectin mannose binding 1 (LMAN1) or multiple coagulation factor deficiency 2 (MCFD2) gene. Reducing the level of FVIII by inhibiting the LMAN1-MCFD2 complex may become a new anticoagulant approach. We aimed to find a new therapeutic option for anticoagulation by RNA interference (RNAi) targeting LMAN1 and MCFD2. siRNA sequences with cross-homology between mice and humans were designed based on LMAN1 or MCFD2 transcripts in NCBI and were screened with the Dual-Luciferase reporter assay. The optimal siRNAs were chemically modified and conjugated with three N-acetylgalactosamine molecules (GalNAc-siRNA), promoting their targeted delivery to the liver. The expression of LMAN1 and MCFD2 in cell lines or mice was examined by RT-qPCR and western blotting. For the mice administered with siRNA, we assessed their coagulation function by measuring APTT and the activity of FVIII factor. After administration, siRNAs GalNAc-LMAN1 and GalNAc-MCFD2 demonstrated effective and persistent LMAN1 and MCFD2 inhibition. 7 days after injection of 3mg/kg GalNAc-LMAN1, the LMAN1 mRNA levels reduced to 19.97% ± 3.78%. MCFD2 mRNA levels reduced to 32.22% ± 13.14% with injection of 3mg/kg GalNAc-MCFD2. After repeated administration, APTT was prolonged and the FVIII activity was remarkably decreased. The tail bleeding test of mice showed that the amount of bleeding in the treated group did not significantly increase compared with the control group. Our study confirms that therapy with RNAi targeting LMAN1-MCFD2 complex is effective and can be considered a viable option for anticoagulation drugs. However, the benefits and potential risk of bleeding in thrombophilic mice model needs to be evaluated.

Factor XIIa (FXIIa) is a plasma serine protease within the contact activation pathway. Inhibiting FXIIa could offer a viable therapeutic approach for achieving effective and safer anticoagulation without the bleeding risks that accompany the use of existing anticoagulants. Therefore, we investigated the anticoagulant properties of an amidine-containing molecule (inhibitor 1) to identify a potential lead molecule for subsequent development of FXIIa inhibitors. Results indicated that inhibitor 1 primarily inhibits human FXIIa with an IC₅₀ value of ~30 µM. The inhibitor demonstrated variable selectivity against thrombin, factor IXa, factor Xa, factor XIa, and activated protein C. Michaelis-Menten kinetics indicated that the molecule is an active site inhibitor of FXIIa. Molecular modeling studies revealed that the molecule recognizes residues His57, Asp189, and Ala190 in FXIIa's active site. The inhibitor selectively and concentration-dependently prolonged the clotting time of human plasma under activated partial thromboplastin time assay conditions. The inhibitor did not exhibit significant cytotoxicity in human HEK293 cells and the in silico pharmacokinetics and toxicology data were comparable to known anticoagulants. This study introduces inhibitor 1 as a lead platform for further development as an anticoagulant to provide a more effective and safer approach to preventing and treating thromboembolic diseases.

Drugs targeting factor XI may offer an alternative to heparin for preventing blood clotting in extracorporeal circulation. We investigated the effects of abelacimab, a novel monoclonal antibody targeting factor XI. We collected whole blood samples into two bags (each 240 ml, control group: enoxaparin 1.2 mg, treatment group: enoxaparin 1.2 mg plus abelacimab 5 mg) and circulated in a hemodialysis device for up to 3 h. We performed whole blood aggregation and thromboelastometry at several time points. Time to filter clotting was the primary endpoint. We included 10 volunteers. Each volunteer's blood was split into two bags (containing enoxaparin +/- abelacimab) and used simultaneously on two hemodialysis devices. The treatment group's time to filter clotting was significantly prolonged (treatment: 180 min, IQR 180-180 vs. control: 120 min, IQR 97-147, p < 0.001), and the transmembrane pressure was significantly lower at the end of the circuit flow (treatment: 13 mmHg vs. control: 65 mmHg, p = 0.001). Fibrinogen levels and median platelet counts were preserved. Platelet aggregation was better preserved in the treatment group for ristocetin (p = 0.015), thrombin receptor activating peptide (p = 0.015), and arachidonic acid (p = 0.001). Thromboelastometry showed prolonged clotting times in the treatment group at the end of the experiment (INTEM, p < 0.001; HEPTEM, p = 0.001). Abelacimab prolonged the time to filter clotting in this ex vivo model of hemodialysis. This is an aggressive model due to the frequent re-circulation of blood and a lack of endothelial cells. These data provide support for testing abelacimab in patients on hemodialysis.