Platelet-targeted thromboprophylaxis with a human serum albumin fusion drug: Preventing thrombosis and reducing cardiac ischemia/reperfusion injurywithout bleeding complications.

Background: Myocardial infarction (MI) as a consequence of atherosclerosis-associated acute thrombosis is a leading cause of death and disability globally. Antiplatelet and anticoagulant drugs are standard therapies in preventing and treating MI. However, all clinically used drugs are associated with bleeding complications, which ultimately limits their use in patients with a high risk of bleeding. We have developed a new recombinant drug, targ-HSA-TAP, that combines targeting and specific inhibition of activated platelets as well as anticoagulation. This drug is designed and tested for a prolonged circulating half-life, enabling unique thromboprophylaxis without bleeding complications. Methods: Targ-HSA-TAP combines a single-chain antibody (scFv) that targets activated glycoprotein IIb/IIIa on activated platelets, human serum albumin (HSA) for prolonged circulation, and tick anticoagulant peptide (TAP) for coagulation FX inhibition. A non-binding scFv is employed as a non-targeting control (non-targ-HSA-TAP). Its efficacy was investigated in vivo using murine models of acute thrombosis and cardiac ischemia-reperfusion (I/R) injury. Results: Our experiments confirmed the targeting specificity of targ-HSA-TAP to activated platelets and demonstrated effective prevention of platelet aggregation and thrombus formation, as well as FXa inhibition in vitro. Thromboprophylactic administration of targ-HSA-TAP subcutaneously in mice prevented occlusion of the carotid artery after ferric chloride injury as compared to non-targ-HSA-TAP and PBS-control treated mice. By comparing the therapeutic outcomes between targ-TAP and targ-HSA-TAP, we demonstrate the significant improvements brought by the HSA fusion in extending the drug's half-life and enhancing its therapeutic window for up to 16 h post-administration. Importantly, tail bleeding time was not prolonged with targ-HSA-TAP in contrast to the clinically used anticoagulant enoxaparin. Furthermore, in a murine model of cardiac I/R injury, mice administered targ-HSA-TAP 10 h before injury demonstrated preserved cardiac function, with significantly higher ejection fraction and fractional shortening, as compared to the non-targ-HSA-TAP and PBS control groups. Advanced strain analysis revealed reduced myocardial deformation and histology confirmed a reduced infarct size in targ-HSA-TAP treated mice compared to control groups. Conclusion: The inclusion of HSA represents a significant advancement in the design of targeted therapeutic agents for thromboprophylaxis. Our activated platelet-targeted targ-HSA-TAP is a highly effective antithrombotic drug with both anticoagulant and antiplatelet effects while retaining normal hemostasis. The long half-life of targ-HSA-TAP provides the unique opportunity to use this antithrombotic drug for more effective, long-lasting and safer anti-thrombotic prophylaxis. In cases where MI occurs, this prophylactic strategy reduces thrombus burden and effectively reduces cardiac I/R injury.

Perioperative anticoagulation in free microvascular flaps - a comparison of different prophylactic regimes in oncologic reconstructive surgery.

OBJECTIVE: Free tissue transfer has an established place in oncologic head and neck surgery. However, the necessity and specific regimen of perioperative thromboprophylaxis remain controversial. Here, the risk of postoperative hemorrhage contrasts with vascular pedicle thrombosis and graft loss. This work compares three different heparin protocols (A-C) with regard to postoperative complications. PATIENTS AND METHODS: A retrospective analysis of our free flap transplants between 2004 and 2023 was conducted. Inclusion criteria were thromboprophylaxis with (A) 500 IU/h unfractionated heparin (UFH), (B) low-molecular-weight heparin (LMWH) once daily, and (C) LMWH once daily with additional immediate preoperative administration. Primary endpoints were the incidence of postoperative bleeding and hematoma and the appearance of flap thrombosis. RESULTS: We evaluated 355 cases, 87 in group A, 179 in group B, and in group C 89 patients. Overall, postoperative bleeding occurred in 8.7% of patients, and 83% underwent hemostasis under intubation anesthesia, with no significant difference between groups (p = 0.784). Hematoma formation requiring revision was found in 3.7% of patients (p = 0.660). We identified postoperative hematoma as a significant influencing factor for venous pedicle thrombosis (OR 3.602; p = 0.001). Venous and arterial flap thrombosis in the graft vessel showed no difference between the groups (p = 0.745 and p = 0.128). CONCLUSIONS: The three anticoagulation regimens appear to be equivalent therapy for the prevention of thrombosis without significant differences in postoperative bleeding. The use of LMWH with additional preoperative administration can, therefore, be administered in free flap reconstruction.

[Heparin-Induced Thrombocytopenia].

The extensive use of therapeutic doses of heparin to prevent thrombosis in critically ill patients with COVID-19 during the pandemic has led to an increased incidence of bleeding and heparin-induced thrombocytopenia (HIT). In addition, the introduction of the AstraZeneca and Johnson&Johnson vaccines against COVID-19 into clinical practice was associated with the development of a rare but very severe, adverse thrombotic complication, vaccine-induced immune thrombotic thrombocytopenia (VITT). Thrombotic complications of VITT turned out to be similar to HIT both clinically and pathophysiologically. HIT is a potentially fatal immune-mediated adverse drug response that results in emergence of antibodies that activate platelets in the presence of heparin. HIT is characterized by a high incidence of venous and arterial thromboses, often with fatal outcomes. Currently, there are clearly defined international guidelines for the diagnosis, treatment and prevention of HIT. In case of thrombotic complications, non-heparin anticoagulants should be used.

Effect of veno-arterial extracorporeal membrane oxygenation lower-extremity cannulation on intra-arterial flow characteristics, oxygen content, and thrombosis risk.

PURPOSE: This study aimed to investigate the effects of lower-extremity cannulation on the intra-arterial hemodynamic environment, oxygen content, blood damage, and thrombosis risk under different levels of veno-arterial (V-A) ECMO support. METHODS: Computational fluid dynamics methods were used to investigate the effects of different levels of ECMO support (ECMO flow ratios supplying oxygen-rich blood 100-40 %). Flow rates and oxygen content in each arterial branch were used to determine organ perfusion. A new thrombosis model considering platelet activation and deposition was proposed to determine the platelet activation and thrombosis risk at different levels of ECMO support. A red blood cell damage model was used to explore the risk of hemolysis. RESULTS: Our study found that partial recovery of cardiac function improved the intra-arterial hemodynamic environment, with reduced impingement of the intra-arterial flow field by high-velocity blood flow from the cannula, a flow rate per unit time into each arterial branch closer to physiological levels, and improved perfusion in the lower extremities. Partial recovery of cardiac function helps reduce intra-arterial high shear stress and residence time, thereby reducing blood damage. The overall level of hemolysis and platelet activation in the aorta decreased with the gradual recovery of cardiac contraction function. The areas at high risk of thrombosis under V-A ECMO femoral cannulation support were the aortic root and the area distal to the cannula, which moved to the descending aorta when cardiac function recovered to 40-60 %. However, with the recovery of cardiac contraction function, hypoxic blood pumped by the heart is insufficient in supplying oxygen to the front of the aortic arch, which may result in upper extremity hypoxia. CONCLUSION: We developed a thrombosis risk prediction model applicable to ECMO cannulation and validated the model accuracy using clinical data. Partial recovery of cardiac function contributed to an improvement in the aortic hemodynamic environment and a reduction in the risk of blood damage; however, there is a potential risk of insufficient perfusion of oxygen-rich blood to organs.

Palliative effects of carnosol on lung-deposited pollutant particles-induced thrombogenicity and vascular injury in mice.

The toxicity of inhaled particulate air pollution perseveres even at lower concentrations than those of the existing air quality limit. Therefore, the identification of safe and effective measures against pollutant particles-induced vascular toxicity is warranted. Carnosol is a bioactive phenolic diterpene found in rosemary herb, with anti-inflammatory and antioxidant actions. However, its possible protective effect on the thrombotic and vascular injury induced by diesel exhaust particles (DEP) has not been studied before. We assessed here the potential alleviating effect of carnosol (20 mg/kg) administered intraperitoneally 1 h before intratracheal (i.t.) instillation of DEP (20 µg/mouse). Twenty-four hours after the administration of DEP, various parameters were assessed. Carnosol administration prevented the increase in the plasma concentrations of C-reactive protein, fibrinogen, and tissue factor induced by DEP exposure. Carnosol inhibited DEP-induced prothrombotic effects in pial microvessels in vivo and platelet aggregation in vitro. The shortening of activated partial thromboplastin time and prothrombin time induced by DEP was abated by carnosol administration. Carnosol inhibited the increase in pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor α) and adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin) in aortic tissue. Moreover, it averted the effects of DEP-induced increase of thiobarbituric acid reactive substances, depletion of antioxidants and DNA damage in the aortic tissue. Likewise, carnosol prevented the decrease in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) caused by DEP. We conclude that carnosol alleviates DEP-induced thrombogenicity and vascular inflammation, oxidative damage, and DNA injury through Nrf2 and HO-1 activation.

The impact of small movements with dual lumen cannulae during venovenous extracorporeal membrane oxygenation: A computational fluid dynamics analysis.

BACKGROUND AND OBJECTIVES: Venovenous Extracorporeal Membrane Oxygenation (VV ECMO) provides respiratory support to patients with severe lung disease failing conventional medical therapy. An essential component of the ECMO circuit are the cannulas, which drain and return blood into the body. Despite being anchored to the patient to prevent accidental removal, minor cannula movements are common during ECMO. The clinical and haemodynamic consequences of these small movements are currently unclear. This study investigated the risk of thrombosis and recirculation caused by small movements of a dual lumen cannula (DLC) in an adult using computational fluid dynamics. METHODS: The 3D model of an AVALON Elite DLC (27 Fr) and a patient-specific vena cava and right atrium were generated for an adult patient on ECMO. The baseline cannula position was generated where the return jet enters the tricuspid valve. Alternative cannula positions were obtained by shifting the cannula 5 and 15 mm towards inferior (IVC) and superior (SVC) vena cava, respectively. ECMO settings of 4 L/min blood flow and pulsatile flow at SVC and IVC were applied. Recirculation was defined as a scalar value indicating the infused oxygenated blood inside the drainage lumen, while thrombosis risk was evaluated by shear stress, stagnation volume, washout, and turbulent kinetic energy. RESULTS: Recirculation for all models was less than 3.1 %. DLC movements between -5 to 15 mm increased shear stress and turbulence kinetic energy up to 24.7 % and 11.8 %, respectively, compared to the baseline cannula position leading to a higher predicted thrombosis risk. All models obtained a complete washout after nine seconds except for when the cannula migrated 15 mm into the SVC, indicating persisting stasis and circulating zones. CONCLUSION: In conclusion, small DLC movements were not associated with an increased risk of recirculation. However, they may increase the risk of thrombosis due to increased shear rate, turbulence, and slower washout of blood. Developing effective cannula securement devices may reduce this risk.

New insights and novel perspectives in bileaflet mechanical heart valve prostheses thromboresistance.

BACKGROUND: Although well-known for their thromboresistance, bileaflet mechanical heart valves (BMHV) require lifelong anti-thrombotic therapy. This must be associated with a certain level of thrombogenicity. Since both thromboresistance and thrombogenicity are explained by the blood-artificial surface or liquid-solid interactions, the aim of the present study was to explore BMHV thromboresistance from new perspectives. The wettability of BMHV pyrolytic carbon (PyC) occluders was investigated in under-liquid conditions. The submerged BMHV wettability clarifies the mechanisms involved in the thromboresistance. METHODS: The PyC occluders of a SJM Regent™ BMHV were previously laser irradiated, to create a surface hierarchical nano-texture, featuring three nano-configurations. Additionally, four PyC occluders of standard BMHV (Carbomedics, SJM Regent™, Bicarbon™, On-X®), were investigated. All occluders were evaluated in under-liquid configuration, with silicon oil used as the working droplet, while water, simulating blood, was used as the surrounding liquid. The under-liquid droplet-substrate wetting interactions were analyzed using contact angle goniometry. RESULTS: All the standard occluders showed very low contact angle, reflecting a pronounced affinity for non-polar molecules. No receding of the contact line could be observed for the untreated occluders. The smallest static contact angle of around 61° could be observed for On-X® valve (the only valve made of full PyC). The laser-treated occluders strongly repelled oil in underwater conditions. A drastic change in their wetting behaviour was observed depending on the surrounding fluid, displaying a hydrophobic behaviour in the presence of air (as the surrounding medium), and showing instead a hydrophilic nature, when surrounded by water. CONCLUSIONS: BMHV "fear" water and blood. The intrinsic affinity of BMHV for nonpolar fluids can be translated into a tendency to repel polar fluids, such as water and blood. The blood-artificial surface interaction in BMHV is minimized. The contact between blood and BMHV surface is drastically reduced by polar-nonpolar Van der Waals forces. The "hydro/bloodphobia" of BMHV is intrinsically related to their chemical composition and their surface energy, thus their material: PyC indeed. Pertaining to thromboresistance, the surface roughness does not play a significant role. Instead, the thromboresistance of BMHV lies in molecular interactions. BMHV wettability can be tuned by altering the surface interface, by means of nanotechnology.

Novel tubing connectors reduce ECMO circuit thrombosis.

BACKGROUND: Thrombosis within extracorporeal membrane oxygenation (ECMO) circuits is a common complication that dominates clinical management of patients receiving mechanical circulatory support. Prior studies have identified that over 80% of circuit thrombosis can be attributed to tubing-connector junctions. METHODS: A novel connector was designed that reduces local regions of flow stagnation at the tubing-connector junction to eliminate a primary source of ECMO circuit thrombi. To compare clotting between the novel connectors and the traditional connectors, both in vitro loops and an in vivo caprine model of long-term (48 h) ECMO were used to generate tubing-connector junction clots. RESULTS: In vitro, the traditional connectors uniformly (9/9) formed large thrombi, while novel connectors formed a small thrombus in only one of nine (p < 0.0001). In the long-term goat ECMO circuits, the traditional connectors exhibited more thrombi (p < 0.04), and these thrombi were more likely to protrude into the lumen of the tubing (p < 0.001). CONCLUSION: Both in vitro and in vivo validation experiments successfully recreated circuit thrombosis and demonstrate that the adoption of novel connectors can reduce the burden of circuit thrombosis.

Obese patients with atrial fibrillation are more efficiently protected from thrombosis under warfarin or xabans compared to non-obese patients; a systematic review and Meta-analysis of six randomized controlled trials.

INTRODUCTION: Recommendations about proper anticoagulation in obese patients, body mass index (BMI) > 30 kg/m2, are not yet clearly defined. Obese patients were included in randomized controlled trials comparing new anticoagulants (NOACs) with warfarin in patients with atrial fibrillation or thromboembolism. METHODS: We performed a medline search entering proper criteria and finally 6 post-hoc analysis of RCTs, reporting outcome according to BMI, were included in this meta-analysis. Two major outcomes were considered end points in our meta-analysis; thrombosis, including ischemic cerebral events (transient or not) and venous thrombosis (DVD) /pulmonary embolism (PE) and bleeding, including major bleeding and clinically relevant non-major bleeding. RESULTS: In the NOACs treated group, thrombosis occurred less frequently in obese vs non-obese patients; RR and 95 % CI 0,75 (0,58-0,97), p = 0,03, while low heterogeneity was observed (I2= 40 %). In the warfarin treated subgroup there was statistically significant difference with less thrombotic events occurring in the obese vs non-obese patients; RR and (95 % CI) 0,80 (0,66-0,98), p = 0,03, and heterogeneity was low (I2 = 24 %). This protective effect called the obesity paradox is limited to obese patients anticoagulated for non-valvular atrial fibrillation (NVAF); RR (95 % CI) was 0,70 (0,58-0,85) p = 0,03 and I2 = 24 %. Bleeding events were similar under both NOACs and warfarin in obese vs non-obese analysis. CONCLUSIONS: Obese patients anticoagulated for NVAF with either standard dose of xabans or INR guided warfarin are more efficiently protected against thrombosis compared to non-obese patients.

Mechanical prosthetic valve thrombosis: A literature review of treatment strategies.

Mechanical prosthetic valve thrombosis (MPVT) is a common complication of valvular implantations. This study compared the efficacy and safety of different treatments for MPVT. A systematic search of electronic databases identified studies evaluating surgical, anticoagulant, and thrombolytic therapies. Although several studies of different types have been conducted to evaluate the efficacy of these treatment strategies the lack of randomized controlled trials has resulted in the inability to make a definitive conclusion about the pros and cons of these treatments. Recent treatments, such as slow and ultraslow infusion of thrombolytics, showed comparable efficacy and lower complication rates than traditional methods. Inadequate anticoagulant use is a major risk factor for MPVT, highlighting the importance of prevention. Treatment selection should be individualized based on patient factors and available expertise. Overall, slow and ultraslow infusion of thrombolytics may be a promising treatment option for MPVT.

Comparison of apixaban versus aspirin for the prevention of latent bioprosthetic aortic valve thrombosis: study protocol for a prospective randomized trial.

BACKGROUND: The optimal antithrombotic strategy early after aortic valve replacement surgery with a biological valve remains controversial due to lack of high-quality evidence. Either oral anticoagulants or acetylsalicylic acid should be considered for the first 3 months. Hypo-attenuated leaflet thickening on cardiac computed tomography has been associated with latent bioprosthetic valve thrombosis and may be prevented with anticoagulation. We hypothesize that anticoagulation with apixaban is superior to single antiplatelet therapy with acetylsalicylic acid in reducing hypo-attenuated leaflet thickening of bioprosthetic aortic valve prostheses. METHODS: In this prospective, open-label, randomized trial, patients undergoing isolated aortic valve replacement surgery with rapid deployment bioprosthetic valves will be randomized. The treatment group will receive 5 mg of apixaban twice a day for the first 3 months and 100 mg of acetylsalicylic acid thereafter. The control group will be administered 100 mg of acetylsalicylic acid once a day, indefinitely. After the 3-month treatment period, a contrast-enhanced electrocardiogram-gated cardiac computed tomography will be performed to identify hypo-attenuated leaflet thickening of the bioprosthetic valve. The primary objective of the study is to assess the impact of apixaban on the prevention of hypo-attenuated leaflet thickening at 3 months. The secondary and exploratory endpoints will be clinical outcomes and safety profiles of the two strategies. DISCUSSION: Antithrombotic therapy after aortic valve replacement is used to prevent valve thrombosis and systemic thromboembolism. Latent bioprosthetic valve thrombosis is a precursor of clinically significant prosthetic valve dysfunction or thromboembolic events. The hallmark feature of latent bioprosthetic valve thrombosis is hypo-attenuated leaflet thickening on cardiac computed tomography. Subclinical leaflet thrombosis occurs frequently in bioprosthetic aortic valves, more commonly in transcatheter than in surgical valves. There is no evidence on the effect of direct oral anticoagulants on the incidence of hypo-attenuated leaflet thickening after surgical aortic valve replacement with rapid deployment bioprostheses. TRIAL REGISTRATION: ClinicalTrials.gov NCT06184113. Registered on December 28, 2023.

Prophylaxis of microvascular thrombosis using direct oral anticoagulants (DOAC) in microvascular free tissue transplantation - a pilot study.

INTRODUCTION: We conducted this pilot study to assess direct oral anticoagulants (DOACs) in the prevention of microvascular thrombosis. MATERIALS AND METHODS: Five patients undergoing microvascular free tissue transplantation received rivaroxaban or apixaban (depending on their home medication). We compared this group to 19 patients who received enoxaparin subcutaneously. We evaluated the rate of graft loss due to microvascular thrombosis and the number of transfusions administered intra- and postoperatively. RESULTS: There was no graft loss due to microvascular thrombosis in either of the groups. There was no significant difference in the number of intraoperative (study group mean 1.00 (SE 0.32) vs. control group mean 1.11 (SE 0.59); p = 0.876) and postoperative (study group mean 1.2 (SE 0.37) vs. control group mean 1.74 (SE 0.34); p = 0.310) red blood cell transfusions. CONCLUSION: Based on our results in this pilot study, DOACs can be used with microvascular flaps. Further studies with larger sample sizes should be performed to find an optimal medication regimen both for patients already taking DOACs and perhaps even for those not taking DOACs.

Selective binding of cationic fibrinogen-mimicking chitosan nanoparticles to activated platelets and efficient drug release for antithrombotic therapy.

Thrombosis is the main cause of catastrophic events including ischemic stroke, myocardial infarction and pulmonary embolism. Acetylsalicylic acid (ASA) therapy offers a desirable approach to antithrombosis through a reduction of platelet reactivity. However, major bleeding complications, severe off-target side effects, and resistance or nonresponse to ASA greatly attenuate its clinical outcomes. Herein, we report a cationic fibrinogen-mimicking nanoparticle, denoted as ASA-RGD-CS@TPP, to achieve activated-platelet-targeted delivery and efficient release of ASA for safer and more effective antithrombotic therapy. This biomimetic antithrombotic system was prepared by one-pot ionic gelation between cationic arginine-glycine-aspartic acid (RGD)-grafted chitosan (RGD-CS) and anionic tripolyphosphate (TPP). The platform exhibited selective binding to activated platelets, leading to efficient release of ASA and subsequent attenuation of platelet functions, including the remarkable inhibition of platelet aggregation through a potent blockage of cyclooxygenase-1 (COX-1). After intravenous administration, ASA-RGD-CS@TPP displayed significantly prolonged circulation time and successful prevention of thrombosis in a mouse model. ASA-RGD-CS@TPP was demonstrated to significantly enhance antithrombotic therapy while showing minimal coagulation and hemorrhagic risks and excellent biocompatibility in vivo as compared to free ASA. This platform provides a simple, safe, effective and targeted strategy for the development of antithrombotic nanomedicines.

Rationale and design for the randomized placebo-controlled double-blind trial studying the effect of single antiplatelet therapy (clopidogrel) versus dual antiplatelet therapy (clopidogrel/acetylsalicylic acid) on the occurrence of atherothrombotic events following lower extremity peripheral transluminal angioplasty (CLEAR-PATH).

RATIONALE: Antiplatelet therapy (APT) is the standard of care after endovascular revascularization (EVR) in patients with peripheral artery disease (PAD). APT aims to prevent both major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Nonetheless, the rates of MACE and MALE after EVR remain high. In coronary artery and cerebrovascular disease, dual APT (DAPT)compared to acetylsalicylic acid alone has been proven to reduce MACE without increasing the risk of major bleeding when applied for a restricted number of weeks. However, within the PAD population, insufficient data are available to understand the potential attributable effect of DAPT over single APT (SAPT). Therefore, prospective randomized studies in targeted study populations are warranted. TRIAL DESIGN: CLEAR-PATH is a Dutch multicenter, double-blind, placebo-controlled, randomized trial comparing SAPT (clopidogrel 75 mg plus placebo) with DAPT (clopidogrel 75 mg plus acetylsalicylic acid 80 mg) in patients with PAD undergoing EVR. CLEAR-PATH includes a time-to-event analysis with a follow-up of one year. The primary composite efficacy endpoint consists of all-cause mortality, nonfatal stroke, nonfatal myocardial infarction, severe limb ischemia, (indication for) re-intervention due to any symptomatic restenosis, re-occlusion, or due to acute limb ischemia, and major amputation. The primary safety endpoint contains major bleeding following the Thrombolysis in Myocardial Infarction classification. The enrolment started in August 2022. In total 450 primary efficacy outcome events are required which expectedly amounts to 1696 subjects. Recruitment will take approximately 36 months. CONCLUSION: CLEAR-PATH will assess the efficacy and safety of DAPT compared to SAPT following EVR in PAD patients. TRIAL REGISTRATION NUMBER: NL80009.041.21.

[New anticoagulants in 2024: Development of factor XI and XIa inhibitors]. / Les nouveaux anticoagulants en 2024 : développement des inhibiteurs du facteur XI et du XIa.

Thrombosis remains one of the leading causes of death in the world. The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Since the last decade, DOAC are widely used in clinical practice because of their ease to use, their favorable pharmacological profile and the fact that they do not require monitoring. However, despite having a better safety profile than vitamin K antagonist, their bleeding risk is not negligible. New anticoagulants targeting the contact phase of coagulation are currently being developed and could make it possible to prevent the risk of thrombosis without impairing hemostasis. Epidemiological and preclinical data on FXI deficiency make FXI a promising therapeutic target. The aim of this review is to summarize the results of the various clinical trials available that focus on FXI/FXIa inhibition, and to highlight the challenges that this new therapeutic class of anticoagulants will face.

A real-world study of different doses of rivaroxaban in patients with nonvalvular atrial fibrillation.

To explore the anticoagulant effect and safety of utilizing different doses of rivaroxaban for the treatment of patients with atrial fibrillation (AF) in the real world. A retrospective case-control analysis was performed by applying the hospital database, and 3595 patients with non-valvular atrial fibrillation (NVAF) who were hospitalized and taking rivaroxaban at Wuhan Asia Heart Hospital and Wuhan Asia General Hospital from March 2018 to December 2021 were included in the study, and were divided into the rivaroxaban 10 mg and 15 mg groups according to the daily prescribed dose, of which 443 cases were in the 10 mg group and 3152 cases were in the 15 mg group. The patients were followed up regularly, and the incidence of thrombotic events, bleeding events and all-cause deaths were recorded and compared between the 2 groups, and logistic regression was applied to analyze the influencing factors for the occurrence of adverse events. Comparison of the incidence of thrombosis, bleeding and all-cause death between the 2 groups of patients showed that the 10 mg group was higher than the 15 mg group, but the difference was not statistically significant (χ2 = 0.36, 3.26, 1.99, all P > .05); the incidence of total adverse events between the 2 groups of patients was higher in the 10 mg group than in the 15 mg group, with a statistically significant difference (χ2 = 4.53, P = .033); multifactorial logistic regression results showed that age [OR (95% CI) = 1.02 (1.00-1.04)], diabetes mellitus [OR (95% CI) = 1.69 (1.09-2.62)], D-dimer level [OR (95% CI) = 1.06 (1.00-1.11)] and persistent AF [OR (95% CI) = 1.54 (1.03-2.31)] were risk factors for adverse events (P < .05). In the real world, Asian clinicians recommend rivaroxaban 10 mg once daily for NVAF patients for a variety of reasons; however, this dose is not superior or even inferior to the 15 mg group in terms of effectiveness and safety. Advanced age, elevated D-dimer levels, history of diabetes mellitus, and persistent AF are risk factors for adverse events, and the optimal dosage of rivaroxaban or optimal anticoagulation strategy for Asian patients with nonvalvular AF requires further study.