Factor Xa Research Articles

Fixed vs Weight-Based Dosing of Four-Factor Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Patients With a Non-Neurologic Hemorrhage.

Background: There is a growing body of evidence to support that utilizing fixed dose vs weight-based dosing of Four-Factor prothrombin complex concentrate (4F-PCC) for Factor Xa inhibitor (FXaI) reversal is safe and efficacious. Objectives: The primary objective of this study was the rate of hemostatic efficacy of weight-based (50 units/kg) vs fixed dose (2000 units) 4F-PCC for FXaI reversal in patients presenting with a non-neurologic hemorrhage. Methods: This was a multi-center, retrospective chart review from January 21, 2020, to January 21, 2022. Patients were included if they were greater than or equal to 18years of age and received one dose of 4F-PCC for FXaI reversal for a non-neurologic bleed. Hemostatic efficacy for this study was defined as the absence of hemorrhagic progression confirmed with imaging, >2g/dl decrease in Hgb within 6hours of 4F-PCC administration, reports of further significant bleeding in chart note documentation within 48hours and a maintained or increased anti-factor Xa level from baseline. Results: Fifty-nine patients were included in this study (29 in the weight-based group and 30 in the fixed dose group). Rate of hemostatic efficacy was similar between fixed and weight-based dosing (93.3% vs 93.1% P = 1). Conclusions: This study adds to current evidence suggesting that a fixed dose 4F-PCC is both safe and efficacious for FXaI reversal in non-neurologic bleeds.

Correction of the effect of direct oral and parenteral anticoagulants in hemorrhagic stroke

Hemorrhagic stroke is associated with high risk of adverse outcome and follows intake of anticoagulants and antiplatelet agents in 25% of cases. The latest clinical guidelines of the Neurocritical Care Society for correction (reversal) of the effect of anticoagulants and antiplatelet agents in hemorrhagic stroke were published in 2016. In accordance with PRISMA recommendations, we reviewed the PubMed, eLibrary and UpToDate databases to a depth of 5 years and selected 48 articles. Direct oral anticoagulants are currently common. To reverse their effect, one can use specific antidotes (idarucizumab is recommended for dabigatran, andexanet alfa (not yet registered In Russia) for factor Xa inhibitors (rivaroxaban, apixaban)) and combination of prothrombin complex concentrate and tranexamic acid. Protamine sulfate is antidote for unfractionated and low molecular weight heparins. Protamine sulfate completely inactivates unfractionated heparin, but it is less effective against low molecular weight heparin. It is characterized by high probability of anaphylactic reactions, especially after repeated administrations. The effectiveness of andexanet alpha and activated factor VII for reversing the effect of low molecular weight heparin is being studied. Fondaparinux sodium is used for heparin-induced thrombocytopenia. Protamine sulfate is ineffective for reversing the effect of fondaparinux. One can use prothrombin complex concentrate and andexanet alpha, but their effectiveness is unclear. Ciraparantag is being studied in clinical trials. Apparently, ciraparantag is highly effective as an antidote for various anticoagulants. Early hemostatic therapy and reversal of anticoagulant effects in patients with hemorrhagic stroke significantly reduce the risk of adverse outcomes. This problem is being studied. Regular literature review with creation of updated clinical guidelines is needed.

Perioperative Factor Xa Inhibitor Discontinuation for Patients Undergoing Procedures With Minimal or Low Bleeding Risk

Discontinuation of oral anticoagulant treatment is common in clinical practice due to concerns about bleeding, even for procedures with minimal to low bleeding risk. To explore whether perioperative discontinuation of factor Xa inhibitors is associated with major bleeding and thromboembolic events in patients with atrial fibrillation (AF) undergoing procedures with minimal to low bleeding risk. This prospective, multicenter, single-arm cohort study conducted in Korea included patients with AF who planned to undergo a procedure with minimal to low bleeding risk between September 25, 2020, and April 5, 2024. The PERIXa (Perioperative Factor Xa Inhibitor Discontinuation in Patients With Atrial Fibrillation Undergoing Minimal to Low Bleed Risk Procedures) protocol recommending giving the last dose of factor Xa inhibitor (ie, apixaban, edoxaban, or rivaroxaban) 24 hours before the procedure (ie, endoscopy, dental procedure, or ocular surgery) and restarting treatment with the inhibitor the next day. The primary outcome was major bleeding, and the secondary outcome included a composite of thromboembolic events 30 days after the index procedure with minimal to low bleeding risk. In total, 1902 patients were included in the modified intention-to-treat analysis set encompassing all patients who underwent the intended procedure (mean [SD] age, 70.4 [8.8] years; 1135 [59.7%] male; mean [SD] CHA2DS2-VASc [congestive heart failure, hypertension, age 75 years or older, diabetes, stroke, vascular disease, age 65-74 years, and female sex; range, 0-9, with higher scores indicating higher risk of stroke] score, 2.8 [1.3]; mean [SD] HAS-BLED [hypertension, kidney or liver disease, stroke history, prior bleeding, unstable international normalized ratio, age >65 years, and drug or alcohol use; range, 0-9, with higher scores indicating higher risk of bleeding] score, 1.6 [0.7]). Among them, 921 (48.4%) were receiving apixaban, 616 (32.4%) were receiving edoxaban, and 365 (19.2%) were receiving rivaroxaban. Of the total procedures, 948 (49.8%) were endoscopy, 820 (43.1%) were dental procedures, and 120 (6.3%) were ocular surgery. The 30-day event rate of major bleeding was 0.1% (n = 2), and there were no composite thromboembolic events. The results were consistent in the per-protocol analysis, and no differences were observed by procedure category or factor Xa inhibitor type. In this cohort study, patients with AF receiving a factor Xa inhibitor and undergoing a procedure with minimal to low bleeding risk had low rates of major bleeding and thromboembolism when following the standardized PERIXa protocol for perioperative management of oral anticoagulant treatment, suggesting that this may be a safe and reasonable option for this patient population.

Production of recombinant masu salmon insulin-like growth factor binding protein-2b1 and its action on pituitary cells.

Insulin-like growth factor binding protein (Igfbp)-2b is believed to be a major carrier of circulating Igf-1 in salmonids. We cloned cDNAs of two paralogs of igfbp-2b from the liver of masu salmon and produced recombinant Igfbp-2b1 corresponding to the circulating form using a bacterial expression system. The deduced amino acid sequence of masu salmon igfbp-2b1 had a 75.2% sequence identity with that of masu salmon igfbp-2b2, and 88.7% and 96.5% with those of Atlantic salmon and rainbow trout igfbp-2b1, respectively. The coding region of masu salmon igfbp-2b1 cDNA was subcloned into the pET-16b or pET-32a vector and expressed using either a histidine (His)-tag or a thioredoxin (Trx) and His-tag. Recombinant masu salmon (rs) Igfbp-2b1 with the fusion partner was fractionated in the precipitate, solubilized, and isolated using Ni-affinity chromatography. His.rsIgfbp-2b1 and Trx.His.rsIgfbp-2b1 were treated with Factor Xa and enterokinase K, respectively, to remove the fusion partner; only the digestion with enterokinase was successful. After enzymatic digestion, rsIgfbp-2b1 was purified employing reversed-phase high-performance liquid chromatography. The purified rsIgfbp-2b1 was added to a primary culture of masu salmon pituitary cells with or without human (h) IGF-1 to assess its effect on the release of growth hormone (Gh). Although addition of hIGF-1 alone had no effect on Gh release, co-incubation with varying amounts of rsIgfbp-2b1 increased Gh release in a dose-dependent manner. In addition, rsIgfbp-2b1 in the absence of hIGF-1 showed a positive effect on Gh release from salmon pituitary cells. These results suggest that rsIgfbp-2b1 may either have Igf-1-independent action on Gh release or inhibits the suppressive effect of local pituitary Igf-1 on Gh release.

Safety and efficacy of oral direct factor Xa inhibitors in patients with nephrotic syndrome: results from a national retrospective study.

Safety and efficacy of oral direct factor Xa inhibitors in patients with nephrotic syndrome: results from a national retrospective study.

Dielectric blood coagulometry to evaluate coagulation activity in patients prescribed factor Xa inhibitors undergoing elective surgery: A prospective observational study

Dielectric blood coagulometry to evaluate coagulation activity in patients prescribed factor Xa inhibitors undergoing elective surgery: A prospective observational study

Factor Xa inhibitor-related AEs in paediatric patients

Factor Xa inhibitor-related AEs in paediatric patients

Impact of Varying Velocities and Solvation Boxes on Alchemical Free-Energy Simulations.

Alchemical free-energy perturbation (FEP) is an accurate and thermodynamically stringent way to estimate relative energies for the binding of small ligands to biological macromolecules. It has repeatedly been pointed out that a single simulation normally stays near the starting point in phase space and therefore underestimates the uncertainty of the results. Therefore, it is better to run an ensemble of independent simulations. Traditionally, such an ensemble has been generated by using different starting velocities. We argue that it is better to use also other random choices made during the setup of the simulations, in particular the solvation of the solute. We show here that such solvent-induced independent simulations (SIS) sometimes give a larger standard deviation and slightly different results for the binding of 42 ligands to five different proteins, viz. human N-terminal bromodomain 4, the Leu99Ala mutant of T4 lysozyme, dihydrofolate reductase, blood-clotting factor Xa, and ferritin. SIS does not involve any increase in the time consumption. Therefore, we strongly recommend the use of SIS (in addition to different velocities) to start independent simulations. Other random or uncertain choices in the setup of the simulated systems, e.g., the selection of residues with alternative conformations or positions of added protons, may also be used to enhance the variation in independent simulations.

Changes in Coagulation Factor XI Activity Levels in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary PCI.

Background - Although Factor XI (FXI) inhibitors are currently tested for the prevention of thrombotic events, their early treatment could prevent thrombus consolidation in ST-segment elevation myocardial infarction (STEMI). This study aims to characterize coagulation FXI levels and their variations in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Methods - Patients with STEMI were prospectively enrolled between December 2023 and May 2024. FXI activity (FXIa) levels were measured at admission and after PCI (i.e., before discharge). Variations in FXIa levels were evaluated. Differences in indicators of thrombotic risk between groups with high and low FXIa variability were analyzed, and predictors of high FXIa variability were identified. Results - After screening, 54 patients with STEMI were included. The median FXIa level was 0.865 IU/mL (interquartile range [IQR] 0.554-0.978) at admission and 1.161 IU/mL (IQR 0.982-1.317) before discharge, with a median difference of +34.2% (p-value < 0.001). No significant differences were found in indicators of thrombotic risk between groups at high and low FXIa variability, except for the days intercurred between the essays (p-value = 0.016). Neither this nor other variables emerged as independent predictors of high FXIa variability. Conclusions - This study firstly reported an increase in FXIa levels from admission to discharge in STEMI patients undergoing PCI. Common indicators of thrombotic risk were not associated with FXIa levels or their variability. These findings aim to stimulate further research into anticoagulant therapies tailored to the patient's coagulative state and disease.

Direct factor Xa inhibitors versus low molecular weight heparins or vitamin K antagonists for prevention of venous thromboembolism in elective primary hip or knee replacement or hip fracture repair.

Direct factor Xa inhibitors versus low molecular weight heparins or vitamin K antagonists for prevention of venous thromboembolism in elective primary hip or knee replacement or hip fracture repair.

The effect of coagulation traits on the risk of retinal vein occlusion: a mendelian randomization study

Retinal vein occlusion (RVO) is the leading cause of vision loss due to an obstruction in the retinal venous system. While RVO is often linked to thrombotic tendencies and coagulation abnormalities, the exact role of coagulation traits in its development is not fully understood. This study aims to investigate the potential causal relationship between coagulation traits and the risk of RVO by analyzing publicly available genome-wide association study (GWAS) summary statistics. A two-sample Mendelian randomization (MR) analysis framework was employed to investigate the causal relationship between coagulation traits and the risk of RVO. Stringent quality control measures were applied to select appropriate instrumental variables strongly linked to exposure, such as coagulation factor III (FIII), coagulation factor V (FV), coagulation factor VIII (FVIII), coagulation factor XI (FXI), coagulation factor VII (FVII) and coagulation factor X (FX), as well as plasmin, platelet count, platelet crit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW). The study utilized the FinnGen project RVO GWAS summary statistics cohort, consisting of 372 RVO cases and 182,573 controls. The analysis focused on 11 coagulation traits. The research suggests that genetically predicted plasma levels of FIII, FVII, MPV, and PCT may be potentially causative for reducing the risk of RVO, and that levels of FVIII may be potentially causative for increasing the risk of RVO. Our MR analysis, utilizing GWAS data from a comprehensive population-based study, revealed a causal association between plasma levels of FIII, FVII, FVIII, MPV, and PCT with the risk of RVO.

Andexanet alfa in patients with factor Xa inhibitor associated intracranial hemorrhage: the prospective observational multicenter ASTRO-DE study.

Hematoma expansion after intracranial hemorrhage (ICH) in anticoagulated patients signifi-cantly influences clinical outcomes and mortality, emphasizing the need for effective reversal agents. Andexanet alfa is a specific reversal agent for factor Xa associated major bleeding. The ASTRO-DE study collected real-world evidence on the effect of andexanet alfa on mitigat-ing hematoma expansion and altering prognosis in rivaroxaban- or apixaban-treated patients with ICH. ASTRO-DE was a prospective non-interventional cohort study conducted at 25 certified stroke centers in Germany. The primary outcome was the hematoma volume change and the propor-tion of patients with hematoma growth ≤33% within 12-72 h or until first control imaging. Sec-ondary endpoints included in-hospital thromboembolic events and mortality up to 90 days. A total of 137 patients (47.4% male, mean age 80.0 years) with ICH (92.6% spontaneous, 87.4% intracerebral), mean NIHSS on admission of 11.2 points, and mean initial hematoma volume of 26.5 mL (median: 14.1 mL) were analyzed. Ninety patients (65.7%) suffered ICH while treated with apixaban and 47 (34.3%) with rivaroxaban. The median time between symptom onset and application of andexanet alfa was 3.3 h, door-to-needle time was 1.3 h. The mean change in hematoma volume until the first control imaging, conducted after a median of 15.6 h, was 2.3 mL (95% CI: 0.4 to 4.2), while the change within 12-72 h was 1.8 mL (95% CI: 0.4 to 3.2). Hema-toma growth ≤33% was achieved in 90.3% of the 93 evaluable patients based on first control imaging and in 90.5% of the 63 evaluable patients, considering only imaging performed within the 12-72 h window. During hospitalization, death occurred in 30/137 patients (21.9%) and 17 thromboembolic events in 11/137 (8.0%) patients. The 90-day-mortality was 47/128 (36.7%). ASTRO-DE is the first prospective observational study systematically collecting standardized clinical routine data with andexanet alfa treatment. The study demonstrated favorable hemo-stasis and minimal mean hematoma volume growth in patients with ICH associated with apixa-ban or rivaroxaban treatment.

Emulation of ARISTOTLE and ROCKET AF trials in real-world atrial fibrillation patients results in similar efficacy and safety as original landmark trials: insights from the GARFIELD-AF registry

AimsThis study aimed to determine the robustness, reproducibility and representativeness of the landmark Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (AF) (ARISTOTLE) and Rivaroxaban Once...

Adverse Events of Factor Xa Inhibitors in Pediatric Patients: A Meta-analysis and Pharmacovigilance Study.

This study aimed to provide a comprehensive review of adverse events (AEs) associated with factor Xa (FXa) inhibitors in pediatric patients. We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and the European Union Clinical Trials Register for English-language records from the establishment of the database up to October 17, 2023. Both randomized controlled trials and single-arm trials were included. AEs were analyzed using a Bayesian hierarchical model. For the pharmacovigilance study, data from the US Food and Drug Administration Adverse Event Reporting System from January 1, 2007, to December 31, 2023, were obtained. The proportional imbalance method and the Medicines and Healthcare products Regulatory Agency method were used to detect AE signals. Further characterization of patients presenting with AEs was performed. Of 451 records identified, 12 eligible studies were included. A total of 50.6% (95% Bayesian credible interval [CrI] 33.1-67.2, τ = 0.796) of patients experienced at least one AE, and 9.9% (95% CrI 3.9-19.5, τ = 0.552) developed at least one serious AE. Major and clinically relevant non-major bleeding occurred in 2.4% (95% CrI 0.8-4.8, τ = 1.61) of patients. The most common bleeding AEs were epistaxis (8.4% [95% CrI 3.9-14.9, τ = 1.96]), subcutaneous hematoma (6.4% [95% CrI 0.5-26.2, τ = 0.54]), and wound hemorrhage (3.7% [95% CrI 0.4-13.3, τ = 0.55]). Non-hemorrhagic AEs were pyrexia (9.2% [95% CrI 4.6-15.3, τ = 1.18]), vomiting (7.8% [95% CrI 4.0-12.3, τ = 0.08]), and abdominal pain (7.4% [95% CrI 1.5-19.4, τ = 0.84]). A total of 39 AE signals were detected in the pharmacovigilance study. The top three highest overall relative odds ratio (ROR) for AEs were observed for haemorrhoidal hemorrhage at 1211.82 (95% CI, 312.69-4696.29), thrombophlebitis at 134.64 (95% CI, 42.18-429.81), and deep vein thrombosis at 68.3 (95% CI, 42.53-109.68). Patients experiencing bleeding AEs had received a mean dosage of rivaroxaban 0.16 mg/kg and apixaban 0.08 mg/kg. Systematically quantified AEs of FXa inhibitors in clinical trials and real-world studies provide an important guide for clinicians. The use of FXa inhibitors in pediatric patients is associated with an acceptable rate of AEs. The most common bleeding AE was epistaxis. Pediatric patients treated with FXa inhibitors were more prone to hemorrhoidal hemorrhage. A safe approach may involve prior use of other anticoagulants followed by careful administration of FXa inhibitors, with a dosing regimen tailored to age and weight. Close monitoring is recommended for peri-procedural anticoagulation and vomiting.

Binding-Site Directed Selection and Large-Scale Click-Synthesis of a Coagulation Factor XIa-Inhibiting Circular DNA Aptamer.

Factor XIa (FXIa) is a plasma protease thatplays a crucial role in the intrinsic pathway of blood coagulation, making it a promising target for antithrombotic therapy.Circular DNA aptamers, with their dramatically enhanced biological and structural stability, hold great potential as new-generation DNA-based anticoagulants. However, the functional selection and large-scale synthesis of them remains a substantial challenge. Here, we explored a selection strategy to enrich circular DNA aptamers that can target the catalytic domain of FXIa and inhibit its function. An asymmetrical dumbbell structured DNA library featuring a hairpin-like primer-binding site was utilized for selection. This approach has resulted in the identification of a circular DNA aptamer, named FICAPT1, which exhibits high binding affinity (Kd= 20 nM), notable stability (half-life of 16 hoursin human plasma) and outstanding anticoagulationactivity (significantly prolonged aPTT), showing great promise as a novel anticoagulant. The hairpin-like constant region further served as a scaffold for the large-scale click-synthesis (~ 2 mg/mL) of the refined circular aptamer. The approach presented in this study enables the efficient generation of functional circular DNA aptamers and their synthesis at a satisfactory scale, making it adaptable for the production of various circular aptamers for therapeutic applications.

A RETROSPECTIVE INVESTIGATION OF BLOOD COAGULATIVE PARAMETERS PT, KPTT, PROTEIN C, AND ANTITHROMBON III IN 95 PATIENTS WITH LIVER DISEASE

Background: The liver is a crucial synthesis of blood coagulation factors and anticoagulative serine proteases such as protein C(PC) and antithrombin III (ATIII), which exerts a key role in the regulation of hemostatic balance. Activated protein C(APC) and protein S complex inactivate the activated factor Va and VIIIa, thus limiting Xa and thrombin formation. The excess protein S can drive cancer cellular proliferation and cell survival through oncogenic receptor Axl. In presence of heparin binding, antithrombin III (ATIII) and thrombin form an inactive complex in a 1:1 molar ratio. ATIII also inactivate factor IXa, Xa, XIa and XIIa at slow rate. In the setting of liver diseases, this reduced dysregulation can be attributed to decreased synthesis by the liver and increased consumption of coagulative factors and protein C and ATIII. Methods: In current study, using routine detection for the blood coagulative parameters in 75 patients with liver diseases. Results: The results showed that there exist one or three coagulative parameters PT, KPTT, and TT abnormal longer. Moreover, the abnormal intensity of coagulative parameters was associated to the severity of liver diseases. In our detection of 20 liver cirrhosis, the results showed significantly decreased plasma protein C antigen (PC:Ag 0.5501 vs 1.0578 µ/ml) and antithrombin III level (ATIII: Ag 21.8 vs 39.8 mg/dl, ATIII:C 40.25 vs 105.04%), respectively. Conclusions: The measurement of multidispillary analyses of coagulative and anticoagulative system protein C and ATIII level are helpful to monitoring the liver diseases and might play a predictable marker. Peer Review History: Received 13 September 2024; Reviewed 20 November; Accepted 26 December; Available online 15 January 2025 Academic Editor: Dr. Marwa A. A. Fayed, University of Sadat City, Egypt, maafayed@gmail.com Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.0/10

Real-world clinical practice of current periprocedural anticoagulation management in catheter ablation of atrial fibrillation: Data from a large prospective ablation registry.

The guidelines recommend anticoagulation management with uninterrupted warfarin or direct thrombin inhibitors (DTIs) during the atrial fibrillation (AF) ablation periprocedural period. To clarify the Japanese real-world latest periprocedural anticoagulation management during AF ablation. This multicenter observational study included 6232 consecutive AF patients (68.7 ± 10.9 years, 4346 men) who underwent periprocedural anticoagulation therapy using direct oral anticoagulants (DOACs) between January 2022 and August 2023. The mean CHADS2 and CHA2DS2VASc scores were 1.2 ± 1.1 and 2.3 ± 1.5. Bleeding and thromboembolic events occurred in 79 (1.3%) and eight (0.12%) patients. During the periprocedural period, factor Xa inhibitors (FXaIs) were used in 3063 patients (rivaroxaban in 624, apixaban in 1093, and edoxaban in 1345) and DTIs in 3170 including 2583 in whom DTIs were switched from FXaIs. Both the bleeding (0.85% vs. 1.69%, p = .003) and thromboembolic event rates (0.03% vs. 0.23%, p = .036) were significantly lower in the DTI- than FXaI-group. A multivariate analysis showed periprocedural FXaI use was significantly associated with both bleeding events (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.20-3.08, p = .006) and cardiac tamponade (OR = 2.74, 95% CI = 1.27-5.9, p = .01). The interval between the last DOAC administration and the procedure was significantly shorter in the DTI- than FXaI-group (4.2 ± 4.9 vs. 19.3 ± 10.7 h, p < .01). In the FXaI-group, the bleeding rate tended to be lower in the minimally interrupted (n = 2105) than uninterrupted group (n = 821) (1.47% vs. 2.56%, p = .06). Two patients in the uninterrupted FXaI-group required surgical management for cardiac tamponade. Our multicenter real-world data demonstrated that anticoagulation with DTIs was a reasonable periprocedural anticoagulation regimen to reduce periprocedural complications.

Epistaxis Versus Nonepistaxis Bleeding in Anticoagulated Patients With Atrial Fibrillation: Results From the ENGAGE AF-TIMI 48 Trial.

Epistaxis is common with antithrombotic therapy and is often troublesome to patients, yet its frequency, severity, and outcomes are poorly characterized. Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) randomized 21 105 patients with atrial fibrillation and CHADS2 risk score ≥2 to higher-dose edoxaban regimen (60 mg daily, dose-reduced to 30 mg), lower-dose edoxaban regimen (30 mg, dose reduced to 15 mg, daily), or warfarin. Bleeds were adjudicated using International Society on Thrombosis and Haemostasis criteria. Patients with intracranial hemorrhage during follow-up were excluded; those with >1 bleeding event were categorized according to their most severe event. The safety cohort with interval censoring during drug interruption was analyzed. Proportions were compared using Pearson's chi-square test and treatment arms were compared using a Cox proportional hazards model. Among 5247 patients with a bleeding event, 1008 (19.2%) had epistaxis and 4239 (80.8%) had nonepistaxis bleeding. Epistaxis events were less severe than nonepistaxis bleeds (International Society on Thrombosis and Haemostasis major: 3.2% versus 20.7%; clinically relevant nonmajor: 64.7% versus 60.1%; minor: 32.1% versus 19.2%; P<0.001). Permanent drug discontinuation was similar following epistaxis versus nonepistaxis bleeding in patients with major (59.4% versus 53.6%; P=0.52) or clinically relevant nonmajor (32.5% versus 33.3%; P=0.70) bleeding but was significantly higher in patients with minor epistaxis versus other minor bleeds (33.3% versus 23.9%; P=0.001). Compared with warfarin, higher-dose edoxaban regimen had similar risk of epistaxis (hazard ratio [HR], 1.09 [95% CI, 0.95-1.26]), whereas lower-dose edoxaban regimen conferred reduced risk (HR, 0.73 [95% CI, 0.62-0.86]). Epistaxis was frequent, and despite being overall less severe than nonepistaxis bleeding, was associated with similar rates of anticoagulant discontinuation. Compared with warfarin, lower-dose edoxaban regimen reduced the risk of epistaxis by 27% whereas higher-dose edoxaban regimen had no effect. URL: https://clinicaltrials.gov; Unique Identifier: NCT00781391.

Thromboelastography may assess the effect of anticoagulation reversal in intracranial hemorrhage.

Intracranial hemorrhage (ICH) is a complication of oral anticoagulation and is associated with significant morbidity and mortality. Clinical need exists for biomarkers to measure anticoagulation in patients with factor Xa inhibitor-associated ICH to assess the hemostatic effect of reversal agents. This study explored the utility of thromboelastography (TEG) to assess anticoagulation in emergency department (ED) patients who received activated prothrombin complex concentrate (aPCC) reversal for factor Xa-inhibitor-associated ICH. This was a prospective, single-center, cohort study in a convenient sample of adult patients presenting to the ED with acute factor Xa-associated ICH. Exclusion criteria included pregnancy, incarceration, polytrauma, hepatic failure, or other known coagulopathic conditions. TEG samples were collected prior to anticoagulation reversal, as well as at 30-minutes, 12-hours, and 24-hours post-reversal. Only patients who received aPCC reversal were included in the final analysis. Pre-reversal TEG was collected on 10 participants prior to aPCC administration. A significant decrease in TEG R-time was observed at 30 minutes post-aPCC reversal (Beta = -0.91, p = 0.035). R-time increased at 12- and 24-hours post-aPCC reversal to baseline levels. Significant changes were not observed in K-time, clot strength, maximum amplitude, or coagulation index. TEG R-time decreases acutely after anticoagulation reversal with aPCC and rebounds at 12- and 24-hours post-reversal. TEG R-time may serve as a potential sensitive biomarker of the residual anticoagulation activity of factor Xa inhibitors in patients with ICH that undergo anticoagulation reversal with aPCCs.

Improvement in XIa Selectivity of Snake Venom Peptide Analogue BF9-N17K Using P2' Amino Acid Replacements.

Coagulation factor XIa is a new serine-protease family drug target for next-generation anticoagulants. With the snake venom Kunitz-type peptide BF9 as the scaffold, we obtained a highly active XIa inhibitor BF9-N17K in our previous work, but it also inhibited the hemostatic target plasmin. Here, in order to enhance the selectivity of BF9-N17K toward XIa, four mutants, BF9-N17K-L19A, BF9-N17K-L19S, BF9-N17K-L19D, and BF9-N17K-L19K, were further designed using the P2' amino acid classification scanning strategy. The anticoagulation assay showed that the four P2' single-point mutants still had apparent inhibitory anticoagulation activity that selectively inhibited the human intrinsic coagulation pathway and had no influence on the extrinsic coagulation pathway or common coagulation pathway, which indicated that the single-point mutants had minimal effects on the anticoagulation activity of BF9-N17K. Interestingly, the enzyme inhibitor assay experiments showed that the XIa and plasmin inhibitory activities were significantly changed by the P2' amino acid replacements. The XIa inhibitory activity of BF9-N17K-L19D was apparently enhanced, with an IC50 of 19.28 ± 2.53 nM, and its plasmin inhibitory was significantly weakened, with an IC50 of 459.33 ± 337.40 nM. BF9-N17K-L19K was the opposite to BF9-N17K-L19D, which had enhanced plasmin inhibitory activity and reduced XIa inhibitory activity. For BF9-N17K-L19A and BF9-N17K-L19S, no apparent changes were found in the serine protease inhibitory activity, and they had similar XIa and plasmin inhibitory activities to the template peptide BF9-N17K. These results suggested that the characteristics of the charge of the P2' site might be associated with the drug selectivity between the anticoagulant target XIa and hemostatic target plasmin. In addition, according to the molecular diversity and sequence conservation, a common motif GR/PCR/KA/SXIP-XYGGC is proposed in the XIa-inhibitory Kunitz-type peptides, which might provide a new clue for further peptide engineering. In conclusion, through P2' amino acid classification scanning with the snake venom Kunitz-type peptide scaffold, a new potent and selective XIa inhibitor, BF9-N17K-L19D, was discovered, which provides a new XIa-targeting lead drug template for the treatment of thrombotic-related diseases.