Necesidades de superación de médicos generales en el manejo de los anticoagulantes orales / Needs to overcome general practitioners in the management of oral anticoagulants

Introducción: el progresivo avance en la edad media de la población ha propiciado un incremento de la prescripción del tratamiento anticoagulante oral en la práctica clínica. Objetivo: caracterizar la preparación sobre el manejo de pacientes con anticoagulantes orales en médicos generales de los policlínicos universitarios "Capitán Roberto Fleites", "Chiqui Gómez-Lubián" y "Santa Clara". Métodos: se realizó un estudio descriptivo transversal en el período enero-diciembre de 2020, en tres policlínicos universitarios del municipio de Santa Clara, Villa Clara, Cuba. Se utilizaron métodos teóricos: análisis-síntesis e inducción-deducción para la fundamentación de la información; empíricos: cuestionario y análisis de documentos; y matemático estadísticos para el procesamientos de los datos. Resultados: el cuestionario permitió valorar los conocimientos sobre el tratamiento con anticoagulantes orales en la categoría Regular en la mayoría de los muestreados; mientras en el análisis del programa se detectaron pocas horas dedicadas al tema investigado y la necesidad sentida de capacitación manifestada por los encuestados. Conclusiones: el diagnóstico realizado confirmó las carencias de los médicos generales en el manejo del paciente en la prescripción del tratamiento con anticoagulantes orales.

Background: the progressive advance in the average age of the population has led to an increase in the prescription of oral anticoagulant treatment in clinical practice. Objective: to characterize the training on the management of patients with oral anticoagulants in general practitioners of the "Capitán Roberto Fleites", "Chiqui Gómez-Lubian" and "Santa Clara" university polyclinics. Methods: a cross-sectional descriptive study was carried out from January to December 2020. Theoretical methods were used: analysis-synthesis and induction-deduction to support the information; Empirical: questionnaire and analysis of documents and statistical mathematics for data processing. Results: the questionnaire allowed to assess knowledge about treatment with oral anticoagulants in the average category in the majority of those sampled; while in the analysis of the program, few hours dedicated to the subject investigated and the felt need for training expressed by the respondents were detected. Conclusions: the diagnosis made confirmed the shortcomings of general practitioners in the management of medicated patients for the prescription of treatment with oral anticoagulants.

Anticoagulantes Orales de Acción Directa y sus Implicancias en la Exodoncia: Una Revisión Sistemática

RESUMEN: El uso de Anticoagulantes Orales de Acción Directa (ACOD) ha aumentado considerablemente en el último tiempo. En procedimientos odontológicos, como la exodoncia, es crucial un manejo óptimo de la hemostasia de pacientes bajo tratamiento con ACOD, para equilibrar el riesgo de hemorragia y tromboembolismo. Aun no existe consenso sobre el protocolo a aplicar en pacientes con ACOD sometidos a exodoncias. El objetivo fue evaluar la necesidad de suspender o continuar el tratamiento con ACOD en pacientes sometidos a exodoncia en relación con la incidencia de episodios hemorrágicos y protocolos utilizados. Se realizó una revisión sistemática en base a los estamentos PRISMA, en las bases de datos Pubmed, Wiley, Scopus. La búsqueda incluyó estudios publicados entre 2010 - 2020 en inglés, realizados en humanos, en pacientes bajo terapia con ACOD sometidos a exodoncia y que evalúan la incidencia de hemorragia en este procedimiento. Se excluyeron estudios que involucran pacientes que reciben otros tratamientos antitrombótico concomitante, o procedimientos distintos a la exodoncia. La calidad de los estudios seleccionados fue evaluada de acuerdo con la clasificación del Centro Oxford de Medicina Basada en la Evidencia. Luego de la búsqueda, en base a criterios de inclusión/exclusión, 34 artículos fueron analizados a texto completo. Trece artículos relevantes fueron seleccionados. Once participaron en la revisión final, contando con ocho estudios de cohorte, dos casos-controles y uno serie de casos. Los estudios evidencian que no es necesario suspender la terapia con ACOD en pacientes sometidos a exodoncia, se sugiere que el momento de baja concentración farmacológica puede ser utilizado a favor del tratante. Sin embargo, existe una gran diversidad de protocolos y medidas aplicadas entre estudios, por lo que es necesario realizar estudios clínicos aleatorizados controlados, para determinar un protocolo estándar en el manejo odontológico de estos pacientes.

ABSTRACT: The use of Direct Acting Oral Anticoagulants (ACOD) has increased considerably in recent times. In dental procedures, such as tooth extraction, optimal management of hemostasis in patients treated with ACOD is crucial to balance the risk of bleeding and thromboembolism. There is still no consensus on the protocol to be applied in patients with ACOD in dental extraction. The aim was to evaluate the need to suspend or continue treatment with ACOD in patients submitted to dental extraction in relation to the incidence of bleeding episodes and the protocols used. A systematic review was carried out based on the PRISMA estates, in the Pubmed, Wiley, Scopus databases. The search included studies published between 2010-2020 in English conducted in humans, in patients under therapy with ACOD submitted to dental extraction and that evaluate the incidence of bleeding in this procedure. Studies involving patients receiving other concomitant antithrombotic treatments or procedures other than dental extraction were excluded. The quality of the selected studies was evaluated according to the Oxford Center for Evidence-based Medicine classification. After the search, based on inclusion/ exclusion criteria, 34 articles were analyzed in full text. 13 relevant articles were selected. 11 participated in the final review, including 8 cohort studies, 2 case-controls and 1 case series. Studies show that it is not necessary to suspend therapy with ACOD in patients who have undergone dental extraction, it is suggested that the moment of low pharmacological concentration can be used in favor of the treatment. However, there is a great diversity of protocols and measures applied between studies, so it is necessary to carry out randomized controlled clinical studies to determine a standard protocol in the dental management of these patients.

Research progress in application of low molecular weight heparin assisted by anti-X activity monitoring in the prevention of thrombosis after traumatic brain injury / 中华创伤杂志

The incidence of venous thromboembolism（VTE）in patients with traumatic brain injury（TBI）, especially in patients with severe TBI, is significantly increased due to disturbance of consciousness and limb movement. In the acute phase of VTE, low molecular weight heparin（LMWH）is the most commonly used safe and effective measure to prevent thrombosis. Due to the changes of injury condition of trauma patients, the deviation of clinicians' understanding of VTE and the medication habits of various medical institutions, there are significant differences in the initial time and dose of LMWH prevention. Insufficient or excessive dose of LMWH will lead to thrombus or bleeding complications. In recent years, administration of LMWH with anti-X activity monitoring has been paid more and more attention in patients with TBI, playing an important role in reducing the incidence of thrombosis. The authors review the research progress in the application of LMWH with anti-X activity monitoring in thrombus prevention in patients with TBI from the aspects of mechanism in LMWH use with anti-X activity monitoring, LWMH medication time window and anti-X activity monitoring, LWMH dose adjustment and anti-X activity monitoring, in order to provide references for clinical treatment.

Effect of Ginkgo biloba extract on anticoagulation of 4 new oral anticoagulants / 中国药科大学学报

@#To explore the effect of Ginkgo biloba extract (GBE) on anticoagulation of 4 new oral anticoagulants (NOACs), dabigatran, apixaban, rivaroxaban and edoxaban in vitro, thrombin time (TT), prothrombin time (PT), activated partial thrombin time (APTT) and the activity of coagulation factor Xa (FXa) of rat plasma were measured at different concentrations of NOACs, GBE or NOACs combined with GBE, respectively. The results showed that TT, PT and APTT were prolonged with the increase of NOACs concentration in the range of 0-500 ng/mL; that except for TT of rivaroxaban, other results showed a good linear correlation with NOACs concentration (r2= 0.78-0.98); and that FXa activity decreased with increased concentration of FXa inhibitors (apixaban, rivaroxaban and edoxaban), with a good linear correlation with concentration of FXa inhibitors in the range of 0-250 ng/mL (r2= 0.85-0.94). GBE had no significant effect on TT, PT and APTT (P>0.05) in the concentration range of 0-500 μg/mL, but FXa activity had a positive linear correlation with GBE concentration (r2= 0.840 4). TT was prolonged with increasing GBE concentration when dabigatran was combined with GBE. When the above FXa inhibitors were combined with GBE, TT shortened and FXa activity increased with rising GBE concentration. There were no significant changes in PT and APTT (P>0.05) when NOACs were combined with GBE. The study results suggest that GBE may synergize with the anticoagulant activity of dabigatran and antagonize the anticoagulant activity of FXa inhibitors, possibly due to its role in increasing FXa activity.

2d And 3d-Qsar Analysis Of Amino (3-((3, 5-Difluoro-4-Methyl-6-Phenoxypyridine-2-Yl) Oxy) Phenyl) Methaniminium Derivatives As Factor Xa Inhibitor

Objective: The main objective of the present study was to evolve a novel pharmacophore of methaniminium derivatives as factor Xa inhibitors by developing best 2D and 3D QSAR models. The models were developed for amino (3-((3, 5-difluoro-4-methyl-6-phenoxypyridine-2-yl) oxy) phenyl) methaniminium derivatives as factor Xa inhibitors. Methods: With the help of Marvin application, 2D structures of thirty compounds of methaniminium derivatives were drawn and consequently converted to 3D structures. 2D QSAR using multiple linear regression (MLR) analysis and PLS regression method was performed with the help of molecular design suite VLife MDS 4.3.3. 3D QSAR analysis was carried out using k-Nearest Neighbour Molecular Field Analysis (k-NN-MFA). Results: The most significant 2D models of methaniminium derivatives calculated squared correlation coefficient value 0.8002 using multiple linear regression (MLR) analysis. Partial Least Square (PLS) regression method was also employed. The results of both the methods were compared. In 2D QSAR model, T_C_O_5, T_2_O_2, s log p, T_2_O_1 and T_2_O_6 descriptors were found significant. The best 3D QSAR model with k-Nearest Neighbour Molecular Field Analysis have predicted q2 value 0.8790, q2_se value 0.0794, pred r2 value 0.9340 and pred_r2 se value 0.0540. The stepwise regression method was employed for anticipating the inhibitory activity of this class of compound. The 3D model demonstrated that hydrophobic, electrostatic and steric descriptors exhibit a crucial role in determining the inhibitory activity of this class of compounds. Conclusion: The developed 2D and 3D QSAR models have shown good r2 and q2 values of 0.8002 and 0.8790 respectively. There is high agreement in inhibitory properties of experimental and predicted values, which suggests that derived QSAR models have good predicting properties. The contour plots of 3D QSAR (k-NN-MFA) method furnish additional information on the relationship between the structure of the compound and their inhibitory activities which can be employed to construct newer potent factor Xa inhibitors.

New progress in laboratory monitoring of the rivaroxaban therapy / 中华检验医学杂志

Rivaroxaban is an oral direct factor FXa inhibitor with predictable pharmacokinetics and no routine monitoring, but the laboratory tests can help to assess the safety and effectiveness of rivaroxaban. The laboratory tests for rivaroxaban include liquid chromatography tandem mass spectrometry (LC-MS / MS), prothrombin time(PT), anti factor Xa activity(anti-Xa), thromboelastography(TEG) and rotational thromboelastography(ROTEM). LC-MS / MS can be used to quantitatively detect the blood concentration of rivaroxaban with good specificity and sensitivity, but the instrument is expensive,technologically complex, and lack standardization, so it belongs to the laboratory developed tests(LDTs).Because of insufficient data of TEG and ROTEM, their clinical performance still needs to be verified. PT can detect "treatment concentration" of rivaroxaban, which can be used as a primary screening method to identify the overdose and the risk of severe bleeding, but the sensitivity of different reagents is different;anti-FXa test can sensitively reflect the change of blood concentration of rivaroxaban, and its clinical efficacy is similar to LC-MS/MS, and therefore it can be used as an effective method to guide doctors to use drugs rationally.

Patent analysis for coagulation factor Xa inhibitors / 中国药科大学学报

@#Anticoagulant drugs are widely used in the prevention and treatment of thromboembolic diseases. In recent years, coagulation factor Xa inhibitors have become a hot spot for the development of new anticoagulant drugs. However, the anticoagulant drugs currently used still have side-effects such as increased bleeding risk. This paper analyzes the patent applications of coagulation factor Xa inhibitors, and summarizes the development route of patent application of Bristol-Myers Squibb Company and Guangdong Dongyang Pharmaceutical Co. , Ltd. as representatives of key enterprises, in order to provide some useful references and recommendations for the development, patent protection countermeasure and intellectual property strategy of coagulation factor Xa for domestic pharmaceutical enterprises.

Real-world Data and Recommended Dosage of Non-vitamin K Oral Anticoagulants for Korean Patients

Regulatory approvals of non-vitamin K antagonist oral anticoagulants (NOACs) have been based on large randomized phase III trials evaluating dabigatran, rivaroxaban, apixaban, or edoxaban relative to warfarin for atrial fibrillation (AF). The results of the trials showed that all NOACs were at least non-inferior to warfarin in the prevention of stroke/thromboembolism and showed lower rates of intracranial bleeding than those associated with warfarin. However, the trials were designed differently, varied in the inclusion/exclusion criteria, and used either one dose or a low/high dose of the NOAC drug. Some of these differences have challenged the ability to directly compare various NOACs, and comparative data on effectiveness and intracranial bleeding are sparse in “real-world” patients. Real-world data complement data from large randomized phase III trials by providing new aspects of the “real-world” absolute risks of ischemic and hemorrhagic stroke associated with NOACs vs. warfarin. Moreover, “real-world” fragile patients might have been included (e.g., patients with increased risk of bleeding, liver disease, and chronic kidney disease), although these patients would be less represented in trials. This paper introduces recently published real-world data of NOACs and further suggests the recommended dosage of NOACs for Korean patients.

Series with complete resolution of left atrial appendage thrombi with apixaban in elderly patients

No abstract available.

New Oral Anticoagulants: General Features and Review of Pivotal Clinical Trials

For the last half century, vitamin K antagonists (VKAs) have been used for treatment and prevention of venous thromboembolism and stroke prevention in patients with atrial fibrillation. However, their fragile pharmacokinetics, need for routine laboratory monitoring and dose adjustments complicated the use of these drugs. Recently, new oral anticoagulants (NOACs) have overcome the limitation of VKA therapy and shows favorable outcomes and better safety, especially for patients with intracranial hemorrhage, both in phase III clinical trials and real-world registry. Currently available NOACs are one thrombin inhibitor, dabigatran, and three Xa inhibitors, rivaroxaban, apixaban, and edoxaban. This review covers the pharmacokinetics, published pivotal clinical trials, and dose adjustments in chronic kidney disease. The reimbursement criteria, discontinuation during elective surgical procedure, issues on reversal agents are also discussed.

Déficit adquirido de factor X en leucemia mielomonocítica crónica: reporte de un caso / Isolated factor X deficiency in chronic myelomonocytic leukemia: Report of one case

Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia.

Correlación de valores de TTPa con anti factor Xa para establecer rango terapéutico en tratamiento anticoagulante con heparina sódica / Correlation between aPTT and antifactor Xa to determine therapeutic ranges for unfractionated heparin

Background: The therapeutic range (TR) of activated partial thromboplastin time (aPTT) for unfractionated heparin (UFH) dosing was established in the 1970 decade. Since then aPTT determination has changed. Current TR may be sub or supra-therapeutic depending on the reagents of the test, and therefore, responsible for complications of therapy. Aim: To establish the TR for UFH dosing in our institution using antifactor Xa analysis as reference standard. Material and Methods: After obtaining an informed consent, 43 blood samples were obtained for aPTT determination and antifactor Xa assay in 23 patients treated with intravenous UFH. Samples were processed at Emergency and Hemostasis Labs. We excluded patients receiving other anticoagulants, with thrombophilia, pregnancy or liver disease. Results: Mean aPTT values in the Hemostasis and Emergency labs ​​were 57.1 ± 18.9 and 56.6 ± 18.3 seconds, respectively (p = 0.77). The squared correlation coefficients between aPTT and antifactor Xa at hemostasis and emergency labs were R2 0.5 and 0.45 respectively, p < 0.001. Using a linear regression analysis, therapeutic aPTT range values ​​in our laboratory were established between 50 and 80 seconds, corresponding to antifactor Xa values of 0.3 to 0.7 IU/mL. Conclusions: According to current recommendations, validation of aPTT determination with reference techniques should be done in every institution.

Analysis of Novel Anticoagulants for Atrial Fibrillation – Pharmacokinetics and Pharmacological Considerations.

Atrial Fibrillation (AF) is the most common arrhythmia. AF is a major risk factor for stoke. Warfarin has been available for more than 60 years and until recently it was the only oral anticoagulant used for the prevention of stroke. Despite the extensive studies and proven efficacy, its utility is limited by multiple factors. Warfarin interacts with a multitude of drugs and foods, has a delayed onset of action, has a narrow therapeutic range, requires routine lab monitoring and exhibits variable responses in patients. The novel agents dabigatran, rivaroxaban and apixaban have the potential to have some of the limitations of warfarin. This article will discuss the pharmacokinetic and pharmacological considerations and different characteristics of the novel anticoagulants when used for the prevention of AF.

Research progress of new oral anticoagulants for prevention of atrial fibrillation thromboembolism / 心血管康复医学杂志

Atrial fibrillation (AF)is a strong risk factor for ischemic cerebral stroke.Some inherent defects of War-farin limit its clinic application,which accelerates research and development of new oral anticoagulants,such as Dabigatran,Apixaban,Rivaroxaban and Edoxaban etc..This article made an overview for these.

Administration of aspirin and rivaroxaban prevents deep vein thrombosis after total knee arthroplasty / 中国组织工程研究

BACKGROUND:To date, rivaroxaban has been a clinical y common anticoagulant in China;however, effective prophylaxis for venous thrombosis is associated with a markedly higher incidence of perioperative hemorrhagic complications. Although it has been reported that aspirin effectively prevents deep vein thrombosis and pulmonary embolism, the use of aspirin as a routine drug for venous thrombosis after total knee arthroplasty is stil controversial. OBJECTIVE:To compare the efficacy and safety of aspirin and rivaroxaban for prevention of deep vein thrombosis after total knee arthroplasty. METHODS:Total y 324 patients with osteoarthritis who underwent primary unilateral total knee arthroplasty were randomly divided into three groups. Twelve hours after the surgery, three groups were given aspirin, rivaroxaban and low-molecular-weight heparin respectively. Al three groups were treated for 14 days, and al of the patients were fol owed for 4 weeks. RESULTS AND CONCLUSION:Compared with the low-molecular-weight heparin group, the incidence of deep vein thrombosis was lower (P0.05). The results confirmed that rivaroxaban has a positive anticoagulation effect but leads to increases in wound complications in patients;there are no differences in efficacy and safety between aspirin and low-molecular-weight heparin, so aspirin as part of a multimodal anticoagulation therapy after total knee arthroplasty has good clinical safety and efficacy.

New oral anticoagulants for preventing ischemic stroke in patients with atrial fibrillation / 国际脑血管病杂志

New oral anticoagulants,including direct thrombin inhibitors and factor Xa inhibitors.They have overcome several shortcomings of warfarin.The efficacy of preventing stroke and systemic embolism is superior to or not inferior to warfarin in patients with non-valvular atrial fibrilhtion,and they can decrease the risk of bleeding (especially intracranial hemorrhage).However,no agent can efficiently reverse its anticoagulant effect now.This article reviews the pharmacological characteristics,clinical efficacy,complications,and its management of the commonly used new oral anticoagulants at present.

Anticoagulant and factor Xa-like activities of Tityus discrepans scorpion venom

Tityus discrepans venom (TdV) produces a variety of haemostatic manifestations including alveoli fbrin deposition and/ or prothrombin and partial thromboplastin time (PT, PTT) alterations in mammals. In vitro studies have demonstrated that TdV contains tissue plasminogen activator-like (t-PA), fbrinolytic and plasmin inhibitory compounds and produces platelets activation through GPVI and a novel Src-dependent signalling pathway. The aim of this study is to describe the initial characterization of procoagulant and anticoagulant components from TdV. This venom was fractionated by exclusion molecular chromatography on a Sephadex G-50 column. The eluted material was collected as fve fractions called S1 to S5. These fractions and the whole venom were used to evaluate factor Xa- and thrombin-like activities, fbrinogen degradation, furthermore thrombin- and factor Xa-inhibitory activities. The results demonstrated that TdV contain components with factor Xa-like activity (procoagulants) as well fbrinogenolytic compounds present in the fraction S1 and components with factor Xa inhibitory activity in the fractions S4 and S5 (anticoagulants).

El veneno de Tityus discrepans (TdV) produce en mamíferos una variedad de manifestaciones hemostáticas tales como depósitos de fbrina en alveolos y/o alteración en los tiempos de protrombina y tromboplastina parcial (PT, PTT). Estudios in vitro han demostrado que el TdV contiene componentes semejantes al activador del plasminógeno tipo tisular (t-PA), fbrino-líticos, compuestos que inhiben la actividad de plasmina y además componentes que promueven la activación de plaquetas a través del receptor GPVI y por una nueva vía de señalización dependiente de las Src kinasas. El objetivo de este estudio es describir la caracterización inicial de componentes procoagulantes y anticoagulantes a partir del TdV. Este veneno fue fraccionado por cromatografía de exclusión molecular sobre una columna Sephadex G-50. El material eluido fue colectado en cinco fracciones denominadas S1 a S5. Estas fracciones y el veneno completo fueron usados para evaluar actividades semejantes a factor Xa y trombina, degradación de fbrinógeno, como también la inhibición de la actividad del factor Xa y de la trombina. Los resultados demostraron que TdV contiene componentes con actividad semejante al factor Xa (procoagulantes) y compuestos fbrinogenolíticos presentes en la fracción S1, además de componentes con actividad inhibitoria del factor Xa presentes en la fracción S4 y S5 (anticoagulantes).

Nuevos anticoagulantes orales en la prevención de fenómenos tromboembólicos en la fibrilación auricular no valvular / New oral anticoagulants in thromboembolism prevention in nonvalvular atrial fibrillation

La fibrilación auricular es la arritmia cardiaca más frecuente en la práctica clínica. El valor de la anticoagulación con antagonistas de la vitamina K -como la warfarina-en la prevención de los fenómenos embólicos está ampliamente demostrada, pero también su difícil manejo por las conocidas interacciones con otros fármacos e incluso los alimentos. En la búsqueda del anticoagulante ideal, en los últimos años han aparecido nuevos agentes antitrombóticos y otros se encuentran en fases avanzadas de investigación. En la presente revisión, se describe los resultados del desarrollo de los nuevos agentes anticoagulantes y sus expectativas, oportunidades y desafíos, que enfrentarán estos nuevos agentes, los inhibidores directos de la trombina y del factor Xa.

Atrial fibrillation is the most frequent cardiac arrhythmia in clinical practice. The value of anticoagulation with vitamin K antagonists like warfarin in the prevention of embolic phenomena is widely demonstrated but managing is difficult because of its known interactions with other drugs and even food. Looking for the ideal anticoagulant in the last years new antithrombotic agents have appeared and others are in advanced phases of investigation. In the current review results of new anticoagulant agents development and expectations, opportunities and challenges are described in regards to direct thrombin and Xa factor inhibitors.

Antifactor Xa Levels in Critically Ill Korean Patients Receiving Enoxaparin for Thromboprophylaxis: A Prospective Observational Study

The aim of this study was to investigate antifactor Xa (aFXa) levels after once daily dose of 40 mg of enoxaparin and to evaluate factors influencing aFXa levels among Korean intensive care unit (ICU) patients. This prospective observational study was conducted between August and December 2011 in medical ICUs at Samsung Medical Center. AFXa levels between 0.1 and 0.3 U/mL were considered to be effective for antithrombotic activity. Fifty-five patients were included. The median aFXa levels were 0.22 (IQR 0.17-0.26) at 4 hr, 0.06 (IQR 0.02-0.1) at 12 hr, and 0 U/mL (IQR 0-0.03) at 24 hr. The numbers of patients showing effective antithrombotic aFXa levels were 48 (87.3%), 18 (32.7%), and 0 (0%) at 4, 12 and 24 hr, respectively. At 12 hr, higher sequential organ failure assessment (SOFA) scores and hyperbilirubinemia were significantly associated with low aFXa levels (OR, 0.58; 95% CI, 0.36-0.93; P = 0.02 and 0.06; 0.003-0.87; 0.04, respectively). Once daily dose of 40 mg of enoxaparin is inadequate for maintaining effective antithrombotic aFXa levels, and the inadequacy is more salient for patients with high SOFA scores and hyperbilirubinemia.