COVID-19 Time of Intubation Mortality Evaluation (C-TIME): A System for Predicting Mortality of Patients with COVID-19 Pneumonia at the Time They Require Mechanical Ventilation.

Background: An accurate system to predict mortality in patients requiring intubation for COVID-19 could help to inform consent, frame family expectations and assist end-of-life decisions. Research objective: To develop and validate a mortality prediction system called C-TIME (COVID-19 Time of Intubation Mortality Evaluation) using variables available before intubation, determine its discriminant accuracy, and compare it to APACHE IVa and SOFA. Methods: A retrospective cohort was set in 18 medical-surgical ICUs, enrolling consecutive adults, positive by SARS-CoV 2 RNA by reverse transcriptase polymerase chain reaction or positive rapid antigen test, and undergoing endotracheal intubation. All were followed until hospital discharge or death. The combined outcome was hospital mortality or terminal extubation with hospice discharge. Twenty-five clinical and laboratory variables available 48 hours prior to intubation were entered into multiple logistic regression (MLR) and the resulting model was used to predict mortality of validation cohort patients. AUROC was calculated for C-TIME, APACHE IVa and SOFA. Results: The median age of the 2,440 study patients was 66 years; 61.6 percent were men, and 50.5 percent were Hispanic, Native American or African American. Age, gender, COPD, minimum mean arterial pressure, Glasgow Coma scale score, and PaO2/FiO2 ratio, maximum creatinine and bilirubin, receiving factor Xa inhibitors, days receiving non-invasive respiratory support and days receiving corticosteroids prior to intubation were significantly associated with the outcome variable. The validation cohort comprised 1,179 patients. C-TIME had the highest AUROC of 0.75 (95%CI 0.72-0.79), vs 0.67 (0.64-0.71) and 0.59 (0.55-0.62) for APACHE and SOFA, respectively (Chi2 P<0.0001). Conclusions: C-TIME is the only mortality prediction score specifically developed and validated for COVID-19 patients who require mechanical ventilation. It has acceptable discriminant accuracy and goodness-of-fit to assist decision-making just prior to intubation. The C-TIME mortality prediction calculator can be freely accessed on-line at https://phoenixmed.arizona.edu/ctime.

Evaluation of Xa inhibitors as potential inhibitors of the SARS-CoV-2 Mpro protease

Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 Mpro. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 Mpro with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 Mpro inhibition is rather negligible.

Comparison of Anti-factor Xa Levels in Female and Male Patients with Obesity After Enoxaparin Application for Thromboprophylaxis

Purpose Venous thromboembolic events (VTEs) are common complications after bariatric surgery, and enoxaparin is commonly used to prevent VTEs. The risk for VTEs is sex-specific. Whether enoxaparin application results in similar anti-factor Xa activities (aFXa) in males and females with obesity remains to be determined. We investigated whether our dosage regimen of enoxaparin resulted in similar serum aFXa levels in female and male patients undergoing bariatric surgery. Materials and Methods We administered enoxaparin twice daily in patients undergoing bariatric surgery. Patients with a body mass index (BMI) > 60 kg/m2 (n = 11) received 60 mg enoxaparin (group 2), and patients with lower BMI (n = 86) received 40 mg per dose (group 1). Peak aFXa levels were measured 3 days after surgery. The primary outcome was the aFXa level. As a secondary outcome, we detected VTEs and major bleeding events and explored the possible influencing factors of aFXa. Results Women had higher aFXa than men, but after matching for anthropometric values, the two groups were similar (females: 0.17 ± 0.08 U/ml; males: 0.18 ± 0.08 U/ml). Linear regression revealed a moderate relationship between weight and aFXa levels. The 3-month follow-up was attended by 94.9%, at which one patient had pulmonary embolism. Conclusion Individual enoxaparin dosage regimens for men and women do not seem to be required. Weight-based dosing regimen seems to be a more reasonable choice. Graphical abstract

Pharmacodynamic profiles of dual-pathway inhibition with or without clopidogrel vs dual antiplatelet therapy in patients with atherosclerotic disease

Aim: Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy. Methods and Results: This investigation was conducted in selected cohorts of patients (n=40) with stable atherosclerotic disease enrolled within a larger prospective PD study who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI) or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays assessing of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF [collagen‐related peptide +adenosine diphosphate (ADP) +tissue factor (TF)], markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and TRAP), thrombin generation and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend towards reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP‐induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase‐1 mediated activity. Conclusions: Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations support that modulating thrombin generation by means of factor Xa inhibition in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of DPI observed in clinical

The Role of Factor Xa-Independent Pathway and Anticoagulant Therapies in Cancer-Related Stroke

Background: The optimal strategy for stroke prevention in cancer patients is unknown. We compared the underlying mechanisms of coagulopathy and the effects of anticoagulants in patients with active cancer and atrial fibrillation (AF). Methods: We retrospectively enrolled 46 consecutive patients with embolic stroke of unknown source and active cancer (cancer stroke). We consecutively screened patients with cancer patients without stroke (n = 29), AF stroke (n = 52), and healthy subjects (n = 28), which served as controls. Patients with cancer stroke were treated with either enoxaparin (a low-molecular-weight heparin) or a factor Xa inhibitor, and those with AF stroke were treated with factor Xa inhibitors. D-dimer, factor Xa, and circulating cell-free DNA (cfDNA), a marker of neutrophil extracellular traposis, were measured at both before and after anticoagulation. Results: In AF stroke, factor Xa activity and cfDNA and D-dimer levels were decreased by treatment with factor Xa inhibitors. In contrast, in cancer stroke, factor Xa activity was decreased, D-dimer levels were unchanged, and cfDNA levels were increased by treatment with factor Xa inhibitors. In cancer stroke patients treated with enoxaparin, D-dimer levels were decreased (p = 0.011) and cfDNA levels were unchanged. Conclusion: The anticoagulation effects of factor Xa inhibitors differed between cancer stroke and AF stroke.

Green by Design: Convergent Synthesis, Computational Analyses, and Activity Evaluation of New FXa Inhibitors Bearing Peptide Triazole Linking Units

Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.

Antithrombin III infusion improves anticoagulation in congenital diaphragmatic hernia patients on extracorporeal membrane oxygenation

Purpose Achieving effective anticoagulation during neonatal extracorporeal membrane oxygenation (ECMO) without increasing the risk of hemorrhage remains challenging. The use of antithrombin III (AT-III) for this purpose has been examined, but studies have been limited to intermittent bolus dosing. We aimed to evaluate the efficacy and safety of an institutionally developed AT-III continuous infusion protocol in neonates receiving ECMO for the treatment of congenital diaphragmatic hernia (CDH). Methods In this single center, retrospective study, all neonates with a CDH who received ECMO support during the study period were included. Data on anticoagulation labs and therapy, life-threatening bleeding, and circuit changes were analyzed. Results Eleven patients were divided into two groups: patients with AT-III continuous infusion ( n = 5) and without ( n = 6). There were no differences in the gestational age ( p = 0.29), sex ( p = 1.00), ECMO duration ( p = 0.59), or initial AT-III levels ( p = 0.76) between groups. Patients in the AT-III infusion group had on average 18.5% higher AT-III levels ( p < 0.0001). Patients receiving continuous AT-III infusions spent a significantly higher percentage of ECMO time within the therapeutic range, measured using anti-Factor Xa levels (64.9±4.2% vs. 29.1±8.57%, p = 0.008), and required fewer changes to the heparin infusion rate (6.48±0.88 vs 2.38±0.36 changes/day changes/day, p = 0.005). Multivariate analysis revealed continuous infusion of AT-III did not increase the rate of intracranial or surgical bleeding ( p = 0.27). Conclusion AT-III as a continuous infusion in CDH neonates on ECMO provides a decreased need to modify heparin infusion and more consistent therapeutic anticoagulation without increasing the risk of life-threatening bleeding.

Antimicrobial Prophylaxis and Anticoagulation Therapy in Pediatric ECMO: A Survey Study

OBJECTIVE The purpose was to characterize antimicrobial and anticoagulation therapies used in health systems with children receiving extracorporeal membrane oxygenation (ECMO). METHODS An anonymous electronic survey assessing health system demographics and antimicrobial and anticoagulation therapies during ECMO was distributed to the American College of Clinical Pharmacy Pediatric Practice and Research Network and the Pediatric Pharmacy Association Critical Care Special Interest Group. The primary objective was to identify the number of respondents using antimicrobial prophylaxis for ECMO cannulation and ECMO runs. Secondary objectives included the first- and second-line anticoagulants and anticoagulation laboratory parameters. Additionally, the antimicrobial regimens and the dosing and administration of antithrombin III (AT III) with systemic anticoagulation were collected. Descriptive statistics were employed. RESULTS The questionnaire was completed by 38 respondents from 33 health systems; respondents practiced in the pediatric ICU (n = 20; 52.6%), cardiovascular ICU (n = 14; 36.8%), and neonatal ICU (n = 4; 10.5%). Twenty-eight (73.6%) respondents use antimicrobial prophylaxis during ECMO cannulation or ECMO runs, with most units using cefazolin monotherapy. Thirty-five (92.1%) respondents use heparin as the first-line anticoagulant and used a variety of laboratory tests including anti-factor Xa, activated clotting time, and activated partial thromboplastin time. The most common second-line anticoagulant was bivalirudin (n = 24; 63.2%). Thirty-six (94.7%) respondents use AT III with heparin, with most patients receiving AT III dosing calculated based on a formula for the desired AT III concentration. CONCLUSIONS The majority of respondents use antimicrobial prophylaxis, but variations in the regimens were noted. Heparin was the most common anticoagulant, but variations in laboratory monitoring and concomitant use of AT III were found.

A Recent Update on Oral Anticoagulants

Atrial Fibrillation is very common among Americana; it is the irregular rhythm of the heart usually present with or without symptoms. It causes the formation of clots, clots go to the brain and cause a stroke. Anticoagulants have been known for a few decades to cause abrupt decrease around 50%) in the rate of stroke and prevent clotting at the required location and can cause bleeding. Anticoagulants aims for the safeguard and therapy of thromboembolism to prevent stroke. Previously used Anticoagulants are Warfarin, low molecular weight heparin and heparin. There were shortcoming of the drugs like parenteral route of administration, requires frequent monitoring due to variability in response, the onset of action is slow and there is bleeding in response to the drugs .In addition to heparin and vitamin k antagonist, anticoagulants that act on enzymatic agility or vigor brought about by of thrombin and factor Xa was exquisitely formulated. Implementation of the foresaid oral Anticoagulants requires knowledge of necessitate the comprehension of discrete indication, contraindications, characteristics. Research and repeated clinical trials have led to acceptance of few newer drugs which are working classically styled but better than Warfarin. In the last few years, Pradaxa (dabigatran), Xarelto (rivaroxaban), and Eliquis (dabigatran) have all been authorised by the FDA (apixaban). All three are ‘blood thinners,’ like warfarin, that lessen the overall risk of stroke associated with atrial fibrillation while also causing bleeding.