Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

Therapeutic effects and molecular mechanisms of natural products in thrombosis.

Thrombotic disorders, such as myocardial infarction and stroke, are the leading cause of death in the global population and have become a health problem worldwide. Drug therapy is one of the main antithrombotic strategies, but antithrombotic drugs are not completely safe, especially the risk of bleeding at therapeutic doses. Recently, natural products have received widespread interest due to their significant efficacy and high safety, and an increasing number of studies have demonstrated their antithrombotic activity. In this review, articles from databases, such as Web of Science, PubMed, and China National Knowledge Infrastructure, were filtered and the relevant information was extracted according to predefined criteria. As a result, more than 100 natural products with significant antithrombotic activity were identified, including flavonoids, phenylpropanoids, quinones, terpenoids, steroids, and alkaloids. These compounds exert antithrombotic effects by inhibiting platelet activation, suppressing the coagulation cascade, and promoting fibrinolysis. In addition, several natural products also inhibit thrombosis by regulating miRNA expression, anti-inflammatory, and other pathways. This review systematically summarizes the natural products with antithrombotic activity, including their therapeutic effects, mechanisms, and clinical applications, aiming to provide a reference for the development of new antithrombotic drugs.

A Chromosome-Level Genome Assembly of the Non-Hematophagous Leech Whitmania pigra (Whitman 1884): Identification and Expression Analysis of Antithrombotic Genes.

Despite being a non-hematophagous leech, Whitmania pigra is widely used in traditional Chinese medicine for the treatment of antithrombotic diseases. In this study, we provide a high quality genome of W. pigra and based on which, we performed a systematic identification of the potential antithrombotic genes and their corresponding proteins. We identified twenty antithrombotic gene families including thirteen coagulation inhibitors, three platelet aggregation inhibitors, three fibrinolysis enhancers, and one tissue penetration enhancer. Unexpectedly, a total of 79 antithrombotic genes were identified, more than a typical blood-feeding Hirudinaria manillensis, which had only 72 antithrombotic genes. In addition, combining with the RNA-seq data of W. pigra and H. manillensis, we calculated the expression levels of antithrombotic genes of the two species. Five and four gene families had significantly higher and lower expression levels in W. pigra than in H. manillensis, respectively. These results showed that the number and expression level of antithrombotic genes of a non-hematophagous leech are not always less than those of a hematophagous leech. Our study provides the most comprehensive collection of antithrombotic biomacromolecules from a non-hematophagous leech to date and will significantly enhance the investigation and utilization of leech derivatives in thrombosis therapy research and pharmaceutical applications.

Hypolipidemic and Antithrombotic Effect of 6'-O-Caffeoylarbutin from Vaccinium dunalianum Based on Zebrafish Model, Network Pharmacology, and Molecular Docking.

Vaccinium dunalianum leaf buds make one of the most commonly used herbal teas of the Yi people in China, which is used to treat articular rheumatism, relax tendons, and stimulates blood circulation in the body. In addition, 6'-O-caffeoylarbutin (CA) is a standardized extract of V. dunalianum, which has been found in dried leaf buds, reaching levels of up to 31.76%. Because of the uncommon phenomenon, it is suggested that CA may have a potential therapeutic role in hyperlipidemia and thrombosis. This study was designed to study the efficacy of CA on treating hyperlipidemia and thrombosis and the possible mechanisms behind these effects. Hyperlipidemia and thrombosis zebrafish models were treated with CA to observe variations of the integrated optical density within the vessels and the intensity of erythrocyte staining within the hearts. The possible mechanisms were explored using network pharmacology and molecular docking. The results demonstrate that CA exhibits an excellent hypolipidemic effect on zebrafish at concentrations ranging from 3.0 to 30.0 µg/mL and shows thrombosis inhibitory activity in zebrafish at a concentration of 30.0 µg/mL, with an inhibition rate of 44%. Moreover, network pharmacological research shows that MMP9, RELA, MMP2, PRKCA, HSP90AA1, and APP are major targets of CA for therapy of hyperlipidemia and thrombosis, and may relate to pathways in cancer, chemical carcinogenesis-receptor activation, estrogen signaling pathway, and the AGE-RAGE signaling pathway in diabetic complications.

Effects of grafting on chemical constituents, toxicological properties, antithrombotic activity, and myocardial infarction protection of styrax secreted from the trunk of Liquidambar orientalis Mill.

Styrax, the balsam refined from the trunk of Liquidambar orientalis Mill. has a variety of applications in the perfumery and medical industry, especially for use in traditional Chinese medicine. However, the resources of styrax are in shortage due to being endangered of this plant. Grafting can improve the adaptability of plants to unfavorable environmental conditions. We tried to graft the L. orientalis Mill. on L. formosana Hance which was widely distributed in Jiangsu and Zhejiang provinces of China in an attempt to obtain styrax from grafted L. orientalis Mill. (grafted styrax, SG). Whether SG can become an alternative application of commercially available styrax (SC) need be further investigated. The components of SG were analyzed by GC-MS, and the results showed that the chromatograms of SG, SC, and styrax standard (SS) were consistent. The ration of 12 major chemical components based peak area in SG, SC, and SS were 93.95%, 94.24%, and 95.86% respectively. The assessment of toxicity, antithrombotic activity, and myocardial infarction protection of SG and SC was evaluated by using the zebrafish model, the results showed that SG and SC have the similar toxicological properties as evidenced by acute toxicity test, developmental toxicity and teratogenicity, and long-term toxicity test. Both SG and SC significantly decreased the thrombosis and increased blood flow velocity of zebrafish induced by adrenaline hydrochloride, inhibited myocardial apoptosis, myocardial infarction and myocardial inflammation in zebrafish induced by isoproterenol hydrochloride. Moreover, SG had an obvious improvement effect on cardiac output, while SC has no effect. Collectively, SG is similar to SC in chemical composition, toxicological properties, antithrombotic activity, and myocardial infarction protection effects, and may be used as a substitute for styrax to reduce the collection for wild L. orientalis Mill. and increase the available styrax resources.

Omega-3 Fatty Acids and Markers of Thrombosis in Patients with Atrial Fibrillation.

Omega-3 fatty acids (n-3 FAs) are associated with a lower risk of ischemic stroke in patients with atrial fibrillation (AF). Antithrombotic mechanisms may in part explain this observation. Therefore, we examined the association of n-3 FAs with D-dimer and beta-thromboglobulin (BTG), markers for activated coagulation and platelets, respectively. The n-3 FAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were determined via gas chromatography in the whole blood of 2373 patients with AF from the Swiss Atrial Fibrillation cohort study (ClinicalTrials.gov Identifier: NCT02105844). In a cross-sectional analysis, we examined the association of total n-3 FAs (EPA + DHA + DPA + ALA) and the association of individual fatty acids with D-dimer in patients with detectable D-dimer values (n = 1096) as well as with BTG (n = 2371) using multiple linear regression models adjusted for confounders. Median D-dimer and BTG levels were 0.340 ug/mL and 448 ng/mL, respectively. Higher total n-3 FAs correlated with lower D-dimer levels (coefficient 0.94, 95% confidence interval (Cl) 0.90-0.98, p = 0.004) and lower BTG levels (coefficient 0.97, Cl 0.95-0.99, p = 0.003). Likewise, the individual n-3 FAs EPA, DHA, DPA and ALA showed an inverse association with D-dimer. Higher levels of DHA, DPA and ALA correlated with lower BTG levels, whereas EPA showed a positive association with BTG. In patients with AF, higher levels of n-3 FAs were associated with lower levels of D-dimer and BTG, markers for activated coagulation and platelets, respectively. These findings suggest that n-3 FAs may exert antithrombotic properties in patients with AF.

Bioassay-guided identification of antithrombotic compounds from Cnidoscolus aconitifolius (Mill.) I. M. Jhonst.: molecular docking, bioavailability, and toxicity prediction.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Conventional antithrombotic therapy has reported hemorrhagic accidents. Ethnobotanical and scientific reports point to Cnidoscolus aconitifolius as an antithrombotic adjuvant. Previously, C. aconitifolius leaves ethanolic extract displayed antiplatelet, anticoagulant, and fibrinolytic activities. This work aimed to identify compounds from C. aconitifolius with in vitro antithrombotic activity through a bioassay-guided study. Antiplatelet, anticoagulant, and fibrinolytic tests guided the fractionation. Ethanolic extract was subjected to a liquid-liquid partitioning, followed by vacuum liquid, and size exclusion chromatography to obtain the bioactive JP10B fraction. The compounds were identified through UHPLC-QTOF-MS, and their molecular docking, bioavailability, and toxicological parameters were determined computationally. Kaempferol-3-O-glucorhamnoside and 15(S)-HPETE were identified; both showed affinity for antithrombotic targets, low absorption, and safety for human consumption. Further in vitro and in vivo evaluations will better understand their antithrombotic mechanism. This bioassay-guided fractionation demonstrated that C. aconitifolius ethanolic extract has antithrombotic compounds.Communicated by Ramaswamy H. Sarma.

Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

Alleviation of endothelial dysfunction of Pheretima guillemi (Michaelsen)-derived protein DPf3 in ponatinib-induced thrombotic zebrafish and mechanisms explored through ox-LDL-induced HUVECs and TMT-based proteomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Thrombus generation is one of the leading causes of death in human, and vascular endothelial dysfunction is a major contributor to thrombosis. Pheretima guillemi (Michaelsen), a traditional medicinal animal known as "Dilong", has been utilized to cure thrombotic disorders for many years. DPf3, a group of functional proteins extracted from P. guillemi, has been characterized and identified to possess antithrombotic bioactivity via in vitro and ex vivo experiments. AIM OF THE STUDY: This study is aimed to investigate the vascular-protection activity and related mechanism of antithrombotic protein DPf3 purified from Pheretima guillelmi systematically. MATERIALS AND METHODS: The antithrombotic activity and vascular endothelium protection effect of DPf3 was explored in vivo using ponatinib-induced vascular endothelial injury zebrafish thrombus model. Then, (hi) ox-LDL-induced HUVECs was applied to investigate the protection mechanism of DPf3 against the injury of vascular endothelium. In addition, TMT-based proteomics analysis was used to study the biomarkers, biological processes and signal pathways involved in the antithrombotic and vascular protective effects of DPf3 holistically. RESULTS: DPf3 exerted robust in vivo antithrombosis and vascular endothelial protection ability. DPf3 was identified to prevent HUVECs from damage by reducing ROS production, and to reduce monocyte adhesion by decreasing the protein content of adhesion factor VCAM 1. DPf3 was also observed to weaken the migration ability of injured cells and inhibit abnormal angiogenesis. The mechanism of DPf3's antithrombotic and vascular protective activity was mainly related to the regulation of lipid metabolism, energy metabolism, complement and coagulation system, ECM receptor interaction, MAPK signal pathway, etc. CONCLUSIONS: This study demonstrates that DPf3 has strong antithrombotic and endothelial protective effects. The endothelial protective ability and related mechanisms of DPf3 provide a scientific reference for the traditional use of earthworms in the treatment of thrombosis.

Dual antithrombotic therapy dose-dependently alters hemostatic plug structure and function.

BACKGROUND: Antithrombotic medications carry an inherent risk of bleeding, which may be exacerbated when anticoagulant and antiplatelet therapeutics are combined. Prior studies have shown different effects of antiplatelet vs anticoagulant drugs on the structure and function of hemostatic plugs in vivo. OBJECTIVES: We examined whether dual antithrombotic treatment consisting of combined antiplatelet and anticoagulant therapeutics alters hemostatic plug structure and function differently from treatment with either therapeutic alone. METHODS: Mice were treated with the P2Y12 antagonist clopidogrel and the factor Xa inhibitor rivaroxaban across a range of doses, either alone or in combination. The hemostatic response was assessed using a mouse jugular vein puncture injury model. Platelet accumulation and fibrin deposition were evaluated using quantitative multiphoton fluorescence microscopy, and bleeding times were recorded. RESULTS: Mice treated with clopidogrel alone exhibited a decrease in platelet accumulation at the site of injury, with prolonged bleeding times only at the highest doses of clopidogrel used. Mice treated with rivaroxaban alone instead showed a reduction in fibrin deposition with no impact on bleeding. Mice treated with both clopidogrel and rivaroxaban exhibited platelet and fibrin accumulation that was similar to that with either drug given alone; however, dual antithrombotic therapy resulted in impaired hemostasis at doses that had no impact on bleeding when given in isolation. CONCLUSION: Combined administration of antiplatelet and anticoagulant therapeutics exacerbates bleeding as compared to that with either drug alone, potentially via combined loss of both adenosine 5'-diphosphate- and thrombin-mediated platelet activation. These findings enhance our understanding of the bleeding risk associated with dual antithrombotic therapy.

Antarctic Krill Oil from Euphausia superba Ameliorates Carrageenan-Induced Thrombosis in a Mouse Model.

FJH-KO obtained from Antarctic krill, especially Euphausia superba, has been reported to contain high amounts of omega-3 polyunsaturated fatty acids (n-3 PUFA) and to exhibit anticancer and anti-inflammatory properties. However, its antithrombotic effects have not yet been reported. This study aimed to investigate the antithrombotic effects of FJH-KO in carrageenan-induced thrombosis mouse models and human endothelial cells. Thrombosis was induced by carrageenan injection, whereas the mice received FJH-KO pretreatment. FJH-KO attenuated carrageenan-induced thrombus formation in mouse tissue vessels and prolonged tail bleeding. The inhibitory effect of FJH-KO was associated with decreased plasma levels of thromboxane B2, P-selectin, endothelin-1, ß-thromboglobulin, platelet factor 4, serotonin, TNF-α, IL-1ß, and IL-6. Meanwhile, FJH-KO induced plasma levels of prostacyclin I2 and plasminogen. In vitro, FJH-KO decreased the adhesion of THP-1 monocytes to human endothelial cells stimulated by TNF-α via eNOS activation and NO production. Furthermore, FJH-KO inhibited the expression of TNF-α-induced adhesion molecules such as ICAM-1 and VCAM-1 by suppressing the NF-κB signaling pathway. Taken together, our study demonstrates that FJH-KO protects against carrageenan-induced thrombosis by regulating endothelial cell activation and has potential as an antithrombotic agent.

Biomimetic platelet-camouflaged drug-loaded polypyrrole for the precise targeted antithrombotic therapy.

Lower extremity deep venous thrombosis (LEDVT) affects patient's quality of life for a long time, and even causes pulmonary embolism, which threatens human health. Current anticoagulant drugs in clinical treatment are hampered by the risk of bleeding due to poor targeting and low drug penetration. Here, we used platelet (PLT)-like biological targeting to enhance the delivery and accumulation of nanomedicines in thrombus and reduce the risk of bleeding. Meanwhile, the parallel strategy of "thrombus thermal ablation and anticoagulation" was applied to increase the permeability of drugs in thrombus and achieve the optimal antithrombotic effect. Polypyrrole (PPy) and rivaroxban (Riv, an anticoagulant drug) were co-assembled into platelet membrane-coated nanoparticles (NPs), PLT-PPy/Riv NPs, which actively targeted the thrombotic lesion at multiple targets in the platelet membrane and were thermally and drug-specific thrombolysed by 808 nm laser irradiation. The combination therapy resulted in up to 90% thrombolysis in a femoral vein thrombosis model compared to single phototherapy or drug therapy. The results showed that the nanoformulation provided a new direction for remote precise and controlled sustained thrombolysis, which was in line with the trend of nanomedicine towards clinical translation.

Comparative Study of Cytotoxicity and Antioxidant, Anti-Aging and Antibacterial Properties of Unfermented and Fermented Extract of Cornus mas L.

Due to the high demand for products that can help treat various skin conditions, the interest in plant extracts, which are a valuable source of phytochemicals, is constantly growing. In this work, the properties of extracts and ferments from Cornus mas L. and their potential use in cosmetic products were compared. For this purpose, their composition, antioxidant properties and cytotoxicity against skin cells, keratinocytes and fibroblasts were assessed in vitro. In addition, the ability to inhibit the activity of collagenase and elastase was compared, which enabled the assessment of their potential to inhibit skin aging. Microbiological analyses carried out on different bacterial strains were made in order to compare their antibacterial properties. The conducted analyses showed that both dogwood extract and ferment have antioxidant and anti-aging properties. In addition, they can have a positive effect on the viability of keratinocytes and fibroblasts and inhibit the proliferation of various pathogenic bacteria, which indicates their great potential as ingredients in skin care preparations. The stronger activity of the ferment compared to the extract indicates the legitimacy of carrying out the fermentation process of plant raw materials using kombucha in order to obtain valuable products for the cosmetics industry.

Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Correlation Study of Chronic Renal Insufficiency and Long-Term Prognosis of Patients with Acute Ischemic Cerebral Apoplexy After Intravenous rt-PA Thrombolysis.

Objective: To investigate the correlation between chronic renal insufficiency and the long-term prognosis of patients with acute ischemic cerebral apoplexy after intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis. Methods: 290 patients (194 males and 96 females) with acute cerebral infarction who received intravenous rt-PA thrombolysis were admitted to Ningbo Medical Center Lihuili Hospital from May 2018 to December 2020. Their clinical baseline data were recorded. According to the estimated glomerular filtration rate (eGFR) level, patients were divided into the control group (252 cases) and the chronic kidney disease (CKD) group (38 cases). The prognosis of patients was evaluated by a modified Rankin Scale (mRS) 90 days after cerebral apoplexy by telephone interview or outpatient following-up (mRS ≤ 2 reflected good prognosis, mRS >2 reflected unfavorable prognosis). Multivariate logistic regression was used to analyze the prognosis risk relationship of acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis with CKD. Results: Acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis with CKD were older ((79.08 ± 8.96) years vs (65.84 ± 13.31) years, P = .00052, 95% CI = 0.00031-0.00072) than who without CKD, and were more likely to be suffering from hypertension (94.7% (36/38) and 66.3% (167/252), P = .00023, 95% CI = 0.00011-0.00033), atrial fibrillation (50.0% (19/38) and 26.6% (67/252), P = .007, 95% CI = 0.001-0.009), high Uric acidemia (68.4% (26/38) and 17.9% (45/252), P = .00044, 95% CI = 0.00027-0.00061), hyperhomocysteinemia (47.4% (18/38) and 13.1% (33/252), P = .00032, 95% CI=0.00022-0.00053), history of malignant tumor (13.2% (5/38) and 4.4% (11/252), P = .044, 95% CI = 0.0023-0.0053), cardiogenic embolism (Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of cerebral infarction) (47.4% (18/38) and 29.0% (73/252), P = .038, 95% CI = 0.029-0.055). The mortality rate of the CKD group was higher than the control group (13.2% (5/38) and 4.0% (10/252), P = .033, 95% CI = 0.021-0.053), and the good prognosis rate in the CKD group was significantly lower than in the control group (42.1% (16/38) and 73.8% (186/252), P = .00032, 95% CI = 0.00012-0.00043). Multivariate logistic regression analysis showed that CKD was an independent risk factor for acute ischemic cerebral apoplexy patients undergoing intravenous rt-PA thrombolysis (OR = 4.606, 95%CI 1.176~18.041, P = .028, 95% CI = 0.022-0.043). Conclusion: CKD is an independent risk factor for acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis.

Comparison of bleeding and ischemic events with apixaban vs. rivaroxaban in triple antithrombotic therapy regimens.

OBJECTIVE: To compare the risk of readmissions for major bleeding within one year between apixaban and rivaroxaban as a component of triple antithrombotic therapy. METHODS: This study was a multicenter, retrospective cohort study conducted at two academic medical centers in the Western New York and New York City region between July 1, 2011 and September 25, 2019. Adult patients were included if they were diagnosed with atrial fibrillation or venous thromboembolism and discharged on new triple antithrombotic therapy. The primary outcome compared the rates of 1-year readmission for major bleeding between apixaban and rivaroxaban groups. Secondary outcomes included rate of ischemic outcomes. Time to event analysis was determined with a Kaplan-Meier plot and Cox proportional hazard ratios (HR). RESULTS: A total of 378 patients were included in the study, 212 in the apixaban group and 166 in the rivaroxaban group. Within 1 year, readmission for major bleeding events occurred in six (2.8%) patients in the apixaban group and four (2.4%) patients in the rivaroxaban group ( P  = 1.000). After adjustment, the major bleeding event rate was not statistically significantly different between apixaban and rivaroxaban [adjusted hazard ratio (aHR) 0.68, 95% confidence interval (CI) 0.12-3.77; P  = 0.6624]. Higher albumin levels were identified to be protective against major bleeding related readmission events (aHR 0.18, 95% CI 0.05-0.63; P  = 0.0072). The ischemic outcome occurred in seven (3.3%) patients in the apixaban group and three (1.8%) in the rivaroxaban group ( P  = 0.7368). CONCLUSION: Use of apixaban or rivaroxaban in a triple antithrombotic regimen was not associated with bleeding or ischemic outcomes.

Secondary right atrial thrombosis in three dogs: Antithrombotics therapy and echocardiographic follow-up.

Three dogs were diagnosed with right atrial thrombosis, thought to be secondary to systemic diseases. Specifically, two cases had hyperadrenocorticism and one case was diagnosed with pancreatitis with acute renal injury. In all cases, the thrombi were found within the right atrium, necessitating a differentiation from cardiac neoplasia. In all three cases, the structures assumed to be thrombi had irregular margins with interspersed hypoechoic regions, which were later confirmed as thrombi based on the responsiveness to therapy. All three cases were prescribed with the combination of clopidogrel and rivaroxaban.The thrombi gradually disappeared after initiation of the combination therapy. Complete resolution of right atrial thrombosis was noted in each dog treated with clopidogrel and rivaroxaban. This combination therapy appears to be safe and well tolerated. Diligent observation of the echocardiographic findings and clinical course allows the diagnosis of thrombosis.

Antimicrobial, antioxidant, anticancer, and antithrombotic, competency of saponins from the root of Decalepis hamiltonii.

The goal of this study was to extract saponins from the tuberous root of Decalepis hamiltonii and assess their potential clinical applications, which included antioxidant, antibacterial, antithrombotic, and anticancer properties. Surprisingly, the results of this study revealed that the extracted saponins have excellent antioxidant activities, as demonstrated by 2,2-diphenylpicrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), Hydrogen peroxide (H2O2), and Nitric oxide (NO) scavenging assays. Nonetheless, at a concentration of 100 g/mL, crude saponin had excellent antibacterial activity, particularly against gramme positive bacteria (Staphylococcus aureus, Bacillus subtilis, Staphylococcus epidermidis, and Micrococcus luteus), followed by gramme negative bacteria (Escherichia coli, Salmonella typhi, Proteus mirabilis, and Klebsiella pneumonia). Despite this, the crude saponin had no effect on Aspergillus niger and Candida albicans. The crude saponin also possesses outstanding in vitro antithrombotic activity on blood clot. Interestingly, the crude saponins have an outstanding anticancer activity of 89.26%, with an IC50 value of 58.41 µg/mL. Overall, the findings conclude that crude saponin derived from D. hamiltonii tuberous root could be used in pharmaceutical formulations.

Ex Vivo Antiplatelet and Thrombolytic Activity of Bioactive Fractions from the New-Fangled Stem Buds of Ficus religiosa L. with Simultaneous GC-MS Examination.

Different parts of Ficus religiosa are the common components of various traditional formulations for the treatment of several blood disorders. The new-fangled stem buds' powder was extracted with 80% ethanol and successively fractionated by chloroform and methanol. Chloroform and methanol fractions of Ficus religiosa (CFFR and MFFR) were tested for antiplatelet, antithrombotic, thrombolytic, and antioxidant activity in ex vivo mode. The MFFR was particularly investigated for GC-MS and toxicity. The antiplatelet activity of the CFFR, MFFR, and standard drug aspirin at 50 µg/mL was 54.32%, 86.61%, and 87.57%, and a significant delay in clot formation was noted. CFFR at different concentrations did not show a significant effect on the delay of clot formation, antiplatelet, and free radical scavenging activity. The most possible marker compounds for antiplatelet and antioxidant activity identified by GC-MS in the MFFR are salicylate derivatives aromatic compounds such as benzeneacetaldehyde (7), phenylmalonic acid (13), and Salicylic acid (14), as well as Benzamides derivatives such as carbobenzyloxy-dl-norvaline (17), 3-acetoxy-2(1H)-pyridone (16), and 3-benzylhexahydropyrrolo [1,2-a] pyrazine-1,4-dione (35). A toxicity study of MFFR did not show any physical indications of toxicity and mortality up to 1500 mg/kg body weight and nontoxic up to 1000 mg/kg, which is promising for the treatment of atherothrombotic diseases.

Honokiol inhibits epithelial-mesenchymal transition and hepatic fibrosis via activation of Ecadherin/GSK3ß/JNK and inhibition of AKT/ERK/p38/ß-catenin/TMPRSS4 signaling axis.

Though Honokiol was known to have anti-inflammatory, antioxidant, anticancer, antithrombotic, anti-viral, metabolic, antithrombotic, and neurotrophic activities, the underlying mechanisms of Honokiol on epithelial-mesenchymal transition (EMT) mediated liver fibrosis still remain elusive so far. Anti-EMT and antifibrotic effects of Honokiol were explored in murine AML-12 hepatocyte cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, wound healing assay, Western blotting and also in CCl4-induced liver injury mouse model by immunohistochemistry. Honokiol significantly suppressed transforming growth factor ß1 (TGF-ß1)-induced EMT and migration of AML-12 cells along with decreased EMT phenotypes such as loss of cell adhesion and formation of fibroblast like mesenchymal cells in TGF-ß1-treated AML-12 cells. Consistently, Honokiol suppressed the expression of Snail and transmembrane protease serine 4 (TMPRSS4), but not p-Smad3, and activated E-cadherin in TGF-ß1-treated AML-12 cells. Additionally, Honokiol reduced the expression of ß-catenin, p-AKT, p-ERK, p-p38 and increased phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) and JNK in TGF-ß1-treated AML-12 cells via TGF-ß1/nonSmad pathway. Conversely, GSK3ß inhibitor SB216763 reversed the ability of Honokiol to reduce Snail, ß-catenin and migration and activate E-cadherin in TGF-ß1-treated AML-12 cells. Also, Honokiol suppressed hepatic steatosis and necrosis by reducing the expression of TGF-ß1 and α-SMA in liver tissues of CCl4 treated mice. These findings provide scientific evidence that Honokiol suppresses EMT and hepatic fibrosis via activation of E-cadherin/GSK3ß/JNK and inhibition of AKT/ERK/p38/ß-catenin/TMPRSS4 signaling axis.