Efficacy and safety of salvianolate and enoxaparin in the prevention of perioperative deep venous thrombosis in gastrointestinal surgery.

OBJECTIVE: In this study, the efficacy and safety of salvianolate were compared with enoxaparin in the prevention of perioperative deep vein thrombosis in gastrointestinal surgery. METHODS: From October 2017 to September 2019, 563 patients who underwent gastrointestinal surgery were collected. Based on the inclusion and exclusion criteria, 119 patients were divided into two groups: enoxaparin group (n = 65) and salvianolate group (n = 54). Comparisons were made regarding the outcomes: prothrombin time (PT), prothrombin activity (PTA), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), D-dimer level (D-D), platelet count (PLT), hematokrit (HCT), and incidence of deep vein thrombosis (DVT). RESULTS: The main outcomes showed no significance between enoxaparin group and salvianolate group (p > .05). The incidence of DVT in salvianolate group was 1.85%, significantly lower than that in enoxaparin group (12.3%) (p < .05). No serious adverse reactions occurred in the two groups during treatment. CONCLUSION: Compared with enoxaparin, salvianolate has an advantage in the prevention of perioperative thrombosis in gastrointestinal surgery with a lower incidence of DVT.

Evaluation of Activated Carbon Treatment on Overcoming the Interference of Rivaroxaban on the Detection of Functional Lupus Anticoagulant.

OBJECTIVE: The aim of this study was to review the role of activated carbon (AC) in eliminating the interference of rivaroxaban in the detection of lupus anticoagulants (LAs). METHODS: Normal pooled plasma was obtained as group N1, group N2 took 1 mL plasma from N1 and added AC, group N3 was prepared by mixing normal plasma with rivaroxaban, and group N3 was treated with AC according to our procedure, as group N4. Plasma from 22 patients was collected before and 6-12 h after rivaroxaban therapy, described as group P1 and group P2, respectively, and 1 mL plasma was taken from group P2 and treated with AC, as group P3. Anti-Xa and diluted Russell's viper venom time (dRVVT)/silica clotting time (SCT) index in each group were measured and compared. RESULTS: Rivaroxaban concentrations and anti-Xa had high intercorrelations in group N3, and the levels of anti-Xa and dRVVT/SCT index had high intercorrelations. After treatment with AC, influence of rivaroxaban was removed, with LA and coagulation factor assays not influenced. Rivaroxaban administration could affect LA assay results in patients, with all LA results increased. After treatment with AC, results of anti-Xa and LA tests recovered to the level before rivaroxaban therapy. CONCLUSIONS: We proposed a reference procedure for the LA detection of patients using rivaroxaban by AC, and activated carbon was proven to be a simple product to eliminate the interference of rivaroxaban.

Evaluation of Hepatoprotective effects of different doses of Lyophilized Beetroot powder in albino rabbits.

Beta vulgaris L. is a vegetable most commonly consumed in salads and has been shown to possess multiple benefits. This research was carried out to observe the effects of Beta vulgaris powder at different doses orally in albino rabbits on liver biochemical parameters and coagulation. The study was carried out on albino rabbits which were divided into three groups designated as Group I (administered distilled water) Group II and III (administered beetroot powder at 500mg/kg and 1000mg/kg dose respectively) orally for 2 month duration. The sample was withdrawn at day 0, 30th and 60th day through cardiac puncture. The results showed that both doses of Beta vulgaris were considered safe for use as all the liver parameters were significantly decreased compared to control. Among both doses 500mg/kg dose was considered safer as it reduced the parameters significantly compared to 1000mg/kg dose. Blood coagulation factors at both the doses showed significant increase which was in reference range. Beta vulgaris is a highly beneficial dietary product with ample amount of flavonoids and anti-oxidant agents which might help in improving the liver function and also play a role in coagulation by increasing both fibrinogen levels and prothrombin time.

Effect of urban air pollution on CRP and coagulation: a study on inpatients with acute exacerbation of chronic obstructive pulmonary disease.

PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an important event in the course of chronic obstructive pulmonary disease that negatively affects patients' quality of life and leads to higher socioeconomic costs. While previous studies have demonstrated a significant association between urban air pollution and hospitalization for AECOPD, there is a lack of research on the impact of particulate matter (PM) on inflammation and coagulation in AECOPD inpatients. Therefore, this study investigated the association of changes in coagulation function and C-reactive protein (CRP) with PM levels in the days preceding hospitalization. PATIENTS AND METHODS: We reviewed the medical records of AECOPD patients admitted to Putuo Hospital, Shanghai University of Traditional Chinese Medicine, between March 2017 and September 2019. We analyzed the association of coagulation function and CRP level in AECOPD patients with PM levels in the days before hospitalization. Multivariate unconditional logistic regression analyses were used to evaluate the adjusted odds ratio (OR) and 95% confidence interval (CI) for the association of CRP data with hospitalization day. Kruskal-Wallis tests were used to evaluate mean aerodynamic diameter of ≥ 2.5 µm (PM2.5) exposure on the day before hospitalization; we assessed its association with changes in prothrombin time (PT) in AECOPD inpatients with different Global Initiative for Chronic Obstructive Lung Disease (GOLD) classes. RESULTS: The peripheral blood PT of AECOPD patients with PM2.5 ≥ 25 mg/L on the day before hospitalization were lower than those of patients with PM2.5 < 25 mg/L (t = 2.052, p = 0.041). Patients with severe GOLD class exposed to greater than 25 mg/L of PM2.5on the day before hospitalization showed significant differences in PT (F = 9.683, p = 0.008). Peripheral blood CRP levels of AECOPD patients exposed to PM2.5 ≥ 25 mg/L and PM10 ≥ 50 mg/L on the day before hospitalization were higher than those of patients exposed to PM2.5 < 25 mg/L and PM10 < 50 mg/L (t = 2.008, p = 0.046; t = 2.637, p = 0.009). Exposure to < 25 mg/L of PM2.5 on the day before hospitalization was significantly associated with CRP levels (adjusted OR 1.91; 95% CI 1.101, 3.315; p = 0.024). CONCLUSION: Exposure of patients with AECOPD to high PM levels on the day before hospitalization was associated with an increased CRP level and shortened PT. Moreover, PM2.5 had a greater effect on CRP level and PT than mean aerodynamic diameter of ≥ 10 µm (PM10). AECOPD patients with severe GOLD class were more sensitive to PM2.5-induced shortening of PT than those with other GOLD classes.

In vitro anticoagulant activity of selected medicinal plants: potential interactions with warfarin and development of new anticoagulants.

OBJECTIVES: Warfarin is the most widely used anticoagulant in the world, but it has several limitations including its narrow therapeutic range, need for dose adjustment and high potential for interactions. The simultaneous use of other drugs or even medicinal plants and certain foods could interfere with its therapeutic activity. In this context, this study aims to investigate the in vitro anticoagulant potential and phytochemical constitution of 17 plants selected from a previous clinical cross-sectional study (2014), that investigated the habits of plant utilization among patients taking warfarin. METHODS: Ethanol extracts and essential oils were evaluated, in vitro, as to their effect in the prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. Four species that presented aPTT >50 s were selected for phytochemical evaluation. RESULTS: Thirteen of the 17 plants selected demonstrated a significant anticoagulant effect in at least one of the evaluated parameters. Citrus sinensis (PT=14.75 and aPTT=53.15), Mentha crispa (aPTT=51.25), Mikania laevigata (PT=14.90 and aPTT=52.10), and Nasturtium officinale (aPTT=50.55) showed greater anticoagulant potential compared to normal plasma pool (PT=12.25 and aPTT=37.73). Chemical profiles of these four species were obtained, and certain compounds were identified: rosmarinic acid from M. crispa and isoorientin from N. officinale. CONCLUSIONS: Thus, the results of this study could be a useful indicator for clinical practice towards the possibility of interaction between these plants and anticoagulants, although further clinical research is needed taking into consideration the limitations of in vitro studies. These findings also suggest that further research into the action of these plants could be of real clinical value in identifying potential alternative anticoagulant therapies.

Vitamin K2 (Menaquinone-7) supplementation does not affect vitamin K-dependent coagulation factors activity in healthy individuals.

BACKGROUND: Vitamin K has long been regarded as a procoagulant drug by physicians, and concerns have been raised with regard to its effects on hemostasis. Although many studies have shown that vitamin K supplementation is safe for thrombotic events, the effect of vitamin K supplementation on the activities of vitamin K dependent procoagulation factors in healthy individuals is not available. OBJECTIVES: This study aimed to investigate whether vitamin K2 supplementation at recommended doses affects the activity of vitamin K dependent procoagulation factors in healthy individuals without any anticoagulation treatment. DESIGN: Forty healthy volunteers between 25 and 40 years of age were recruited. Menaquinone-7 (MK-7) was administrated at 90 µg for 30 days. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and blood coagulation factors II, VII, IX, and X activities and Protein induced by vitamin K absence or antagonist-II (PIVKA-II) were measured on days 0 and 30 after MK-7 administration. RESULTS: PT, APTT, and TT showed no significant differences on day 30 when compared with baseline. The activities of coagulation factors II, VII, IX, and X on day 30 showed no significant differences with those at baseline. PIVKA-II levels were unchanged after 30 days of MK-7 supplementation. CONCLUSIONS: MK-7 supplementation at recommended dosage does not affect vitamin K-dependent coagulation factors' coagulation activity, and does not enhance the carboxylation of prothrombin in healthy individuals. This indicated that MK-7 administration does not alter hemostatic balance in healthy populations without anticoagulation treatment.

The safety and effectiveness of salvianolate in preventing perioperative venous thromboembolism in China: A PRISMA-compliant meta-analysis based on RCTs.

BACKGROUND: Salvianolate, a common drug for stabilizing heart disease and Angina Pectoris, is considered to be off-label for preventing venous thromboembolism (VTE) or anticoagulation at present. However, many clinical studies have showed that salvianolate can effectively inhibit the deep-vein thrombosis (DVT) incidence, and prevent VTE of perioperative patients in the real world in China. OBJECTIVE: This analysis aimed to evaluate the effectiveness and safety of salvianolate in preventing VTE in perioperative patients. METHODS: Databases of PubMed, Cochrane Library, Embase, CNKI, Wanfang and VIP were searched until July 2019. Literature retrieval, data extraction and quality assessment were independently completed by two researchers and checked with each other. Review Manager 5.2 software was applied for meta-analysis. RESULTS: A total of 429 studies were retrieved, including 11 randomized controlled trials (RCTs) with a total of 1149 subjects. Compared with low molecular weight heparin (LMWH) group alone, salvianolate combined LMWH group had lower DVT incidence in preventing perioperative thrombosis (2.75% and 14.23%, OR: 0.21, 95% CI:[0.08,0.53]; P = .0009). The incidence of adverse reactions of experimental group was similar to that of control group (1.79% and 2.31%, OR: 0.65, 95% CI:[0.18,2.35]. P = .51). Compared with the control group, D-dimer level (D-D), platelet count (PLT), fibrinogen (FIB), whole blood high shear viscosity (WBHSV), and whole blood low shear viscosity (WBLSV) were all significantly decreased (P < .01), and prothrombin time (PT) was significantly increased (P < .05). CONCLUSION: Salvianolate combined LMWH has better effectiveness and the same safety in preventing venous thromboembolism in perioperative patients. However, due to the small number of included literatures, large sample studies are still needed to further verify this conclusion.

Coagulopathy and Venous Thromboembolic Events Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Coagulopathy after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is recognized but few details have been studied. OBJECTIVES: The aim of this study was to investigate changes in coagulation biomarkers and their predictive ability for venous thromboembolism (VTE). METHODS: Patients undergoing CRS and HIPEC at Uppsala University Hospital, Sweden, from 2004 to 2014 were included in a prospective study of coagulation biomarkers. Prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), fibrinogen, antithrombin, D-dimer, and platelets were sampled on postoperative days 1, 2, 5, and 10. Logistic regression analysis was used to evaluate predictive capacity for coagulation-related complications. RESULTS: Overall, 380 patients were included (214 females, mean age 56 years); 38 patients had a history of thromboembolism and 57 were active smokers. Mean perioperative blood loss was 1228 mL and 231 (61%) received perioperative blood transfusions. PT-INR and APTT were elevated directly after surgery but returned to normal levels on postoperative day 5. Conversely, fibrinogen, platelet count, D-dimer, and antithrombin increased by postoperative day 5 and continued to increase up to day 10. There were 23 radiologically verified cases of VTE within 6 months. The multivariate analysis identified a completeness of cytoreduction score of 2-3 (p = 0.047) and day 2 D-dimer (p = 0.0082) as independent risk factors for postoperative VTE. CONCLUSION: Significant postoperative changes in coagulation biomarkers occur with dynamic changes over 10 days postoperatively. The incidence of symptomatic VTE was low. Residual tumor at completion of surgery and elevated D-dimer on day 2 were independent risk factors for postoperative VTE.

Newly Invented Micellized Vitamin K2 Recovered Prolonged Prothrombin Time under Obstructive Jaundice in Rats with Bile Duct Ligation.

In cholestatic liver diseases, coagulopathy is induced by malabsorption of vitamin K. Supplementation of vitamin K has previously been shown to prevent coagulopathy. In this study, we tested the efficacy of a newly invented micellized vitamin K2 (m-vitK2) in treating coagulopathy, using a rat bile duct ligation (BDL) model. Experiment 1: m-vitK2 (0.3 mg/kg) or m-vitK2 (0.3 mg/kg) mixed with taurocholic acid (TA) (10 mg/body) was orally administrated every day for 7 d from the fourth day after BDL (n=6 for each). Experiment 2: To evaluate absorption, m-vitK2 (0.3 mg/kg) with or without TA (10 mg/body) was orally administered on the fourth day after BDL and compared with the untreated control BDL (n=2 for each). These data were compared with sham-operated (n=6) and untreated control BDL rats (n=6). The m-vitK2 recovered prothrombin time (PT) in Experiment 1 (control 42.7±5.7 s vs. m-vitK2 24.0±9.3 s, p<0.05). Experiment 2 demonstrated that the mixture of m-vitK2 and TA enhanced absorption compared to m-vitK2 alone. Moreover, in Experiment 1, m-vitK2 mixed with TA completely recovered PT (control 42.7±5.7 s vs. m-vitK2+TA 14.9±1.2 s, p<0.01). Micelle sizes decreased with the m-vitK2 and TA treatment (m-vitK2 86.3±5.6 nm vs. m-vitK2+TA 71.9±4.7 nm, p<0.05). Orally administered, newly invented m-vitK2 recovered coagulopathy even under obstructive jaundice. TA decreased the mean micelle size and improved m-vitK2 absorption.

Polyphenolics from Gymnocarpos decandrus Forssk roots and their biological activities.

Phytochemical investigation of Gymnocarpos decandrus roots lead to the isolation, characterization and evaluation of four compounds: the bis-coumarin daphnoretin, two biflavonoids: wikstrol A and wikstol B in addition to ß-sitosterol glucoside. Their structures were established via spectroscopic data. The crude root extract showed a significant antimicrobial activity against Bacillus subtilis. In addition, Coagulation activity of the same extract and daphnoretin were investigated via measuring their effect on prothrombin time (PT) and activated partial thromboplastin time (aPTT) assay in citrated plasma collected from healthy regular blood donors and they were found to prolong the PT and aPTT assays (p < 0.05). The three polyphenolics were described for the first time from the Caryophllaceae family. Furthermore, this is the first phytochemical and biological study to be carried on G. decandrus roots.

Death in Children After Atractylis gummifera L. Poisoning in Morocco-Report of Three Cases and Review of Literature.

BACKGROUND: Atractylis gummifera L. is a poisonous thistle plant that grows in the Mediterranean regions especially in northern Africa like Morocco and southern Europe. It has been used frequently to treat some diseases in traditional medicine, and its ingestion is a common cause of fatal poisoning. Here, we report 3 death cases in children after accidental ingestion of the Atractylis gummifer L. CASES REPORTS: We report 3 cases of death in children after accidental ingestion of the poisonous plant Atractylis gummifer L. The poisoned children were admitted to hospital in deteriorated general state with clinical symptoms, such as nausea, vomiting, epigastric, and abdominal pain, diarrhea, followed by coma. However, they died a few hours later. The postmortem investigations were performed, and the diagnosis of Atractylis gummifer L. poisoning was confirmed by toxicological examination (chromatography), the latter showed the presence of atractyloside (potassium atractylate), a toxic compound of the plant Atractylis gummifera L.Atractylis gummifer L. poisoning was discussed with review through the literature. CONCLUSIONS: Through the presented cases, we show that Atractylis gummifera L. poisoning remains a health problem that involves children in Morocco, where the plant grows spontaneously. Thus, teaching children to recognize dangerous plants will be helpful to prevent accidental ingestion.

[Effects of Xiangdan Injection on pharmacokinetics and pharmacodynamics of warfarin in rats in vivo].

This study is to explore the effect of Xiangdan Injection on anticoagulation of warfarin in rats. Rats were randomly divided into different groups and then administered, subsequently the blood samples were collected at a set series of time points to measure PT(prothrombin time) and APTT(activated partial thromboplastin time) values, and INR(international normalized ratio) value was calculated. The plasma concentrations of warfarin enantiomers were determined by UPLC-MS/MS technology, and pharmacokinetic parameters were calculated by DAS 2.0 software. Statistical analysis was performed to compare differences between the groups. Single-dose study of warfarin showed that Xiangdan Injection alone had no effects on PT, APTT and INR, but when co-administrated with warfarin, PT and INR values were increased(P<0.01), while APTT was unaffected; after co-administration of the two drugs, C_(max), AUC_(0-t), and AUC_(0-∞) of S-warfarin increased(P<0.01), and t_(1/2) prolonged(P<0.01), while the pharmacokinetic parameters of R-warfarin were not changed significantly. Steady-state study of warfarin showed that after co-administration of the two drugs, the PT and INR values increased(P<0.05), and the plasma concentration of S-warfarin increased(P<0.01), while the plasma concentration of R-warfarin was not changed significantly. The results suggest that Xiangdan Injection itself has no effect on coagulation index, but can enhance the anticoagulant effect of warfarin by slowing metabolism of S-warfarin.

Different Coagulation Indicators in Predicting Clinical Outcomes for Patients With Direct Oral Anticoagulants: A Systematic Review and Meta-analysis.

PURPOSE: There are many anticoagulant test indexes available for direct oral anticoagulants (DOACs), but how to select the appropriate index and the index cutoff values are still controversial. This is the first study, to our knowledge, to assess the association of different coagulation indicators with clinical outcomes among DOACs using a meta-analysis of observational studies. METHODS: A medical literature search was conducted using PubMed, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Library from inception to February 2020. Studies that reported relationships between coagulation indexes and clinical outcomes or the diagnostic value of coagulation assays were included in the analysis. FINDINGS: A total of 17 articles (7 meta-analyses and 10 systematic reviews) from 8904 citations were included in the analysis. In the analysis of bleeding events with coagulation indexes for DOACs, for peak prothrombin time level (cutoff value of 19-25 s), the pooled results found a sensitivity of 0.61 (95% CI, 0.44-0.75) and a specificity of 0.71 (95% CI, 0.49-0.86). For rivaroxaban, the trough anti-factor Xa concentration (AXA-C) (cutoff value of 400-500 ng/mL) had a sensitivity of 0.53 (95% CI, 0.16-0.87) and a specificity of 0.87 (95% CI, 0.71-0.94), with a diagnostic odds ratio of 7 (95% CI, 2-32). For apixaban, trough AXA-C had a sensitivity of 0.85 (95% CI, 0.60-0.96) and a specificity of 0.83 (95% CI, 0.52-0.95). The AUC of the AXA-C peak was higher than that of the trough AXA-C for apixaban, with a higher sensitivity and specificity. Compared with trough concentration of anti-factor IIa for dabigatran, the peak concentration had a higher specificity (98%) at the cutoff value of 484 ng/mL. In the analysis of thromboembolic events with coagulation indexes for DOACs, peak and trough prothrombin time values were not typically correlated with subsequent symptomatic venous thromboembolism, without a sensitivity or specificity higher than 90%. Trough AXA-C had a sensitivity of 100% and but a low specificity (<50%) for rivaroxaban-apixaban. Trough AXA-C had a sensitivity of 100% and a specificity of 32% with a cutoff value of 108 ng/mL for dabigatran. IMPLICATION: Peak prothrombin time (19-25 s) and AXA-C had a better predictive value on bleeding outcomes for rivaroxaban and apixaban, whereas peak concentration of anti-factor IIa activity can be an indicator for dabigatran. Coagulation indexes might not be a good indicator of thromboembolic events of DOACs. Because the limited studies focused on association of coagulation indicators and clinical outcomes, more studies are needed to verify this in the future.

Functional lupus anticoagulant testing in a large retrospective cohort of thrombosis patients with direct oral anticoagulants.

Functional tests for lupus anticoagulants (LA) as part of a thrombophilia workup are commonly performed in patients under anticoagulant therapy that may interfere with assay results. There is no consensus on how these tests should be assessed in patients on direct oral anticoagulants (DOACs). In this retrospective cohort study, we analysed data from patients with a history of thrombosis in whom dilute Russell viper venom time (dRVVT), LA-sensitive aPTT, and solid phase assays for antiphospholipid antibodies (aPL) were performed (n = 3,147, thereof 588 on rivaroxaban, 144 on apixaban, 1,179 on other anticoagulant drugs). The dRVVT ratio was correlated with rivaroxaban (r = 0.30, P < 10-4) but not with apixaban plasma levels. The LA-sensitive aPTT/aPTT ratio showed no correlation with DOAC levels. Correspondingly, the rate of patients with abnormal dRVVT test was significantly higher (P < 10-4) under rivaroxaban (88%) than in thrombosis patients without anticoagulant medication (6%), independent from their aPL plasma levels. No isolated positive results of functional LA testing in patients on anticoagulants could be confirmed in repeated testing after discontinuation of the medication (n = 40). These data indicate that rivaroxaban should be discontinued before functional LA testing is performed. However, viable interpretation of these tests appears to be less affected in patients on apixaban.

Emicizumab Improves Ex Vivo Clotting Function in Patients with Mild/Moderate Hemophilia A.

BACKGROUND: Emicizumab prophylaxis is a promising treatment that reduces bleeding events in severely affected patients with hemophilia A (PwHA). It is anticipated that emicizumab could be similarly effective in mild/moderate PwHA (PwMHA) although this effect has not been investigated. AIM: We evaluated ex vivo coagulant effects of emicizumabin PwMHA. METHODS: Clot waveform analysis (CWA) triggered by prothrombin time/activated partial prothrombin time-mixed reagents was utilized to examine coagulant effects of emicizumabin factor (F)VIII-deficient plasma mixed with recombinant (r)FVIIIand in native plasmas from 16 PwMHA. The CWA parameter, adjusted-|min1| (Ad|min1|), was used. Increases in Ad|min1| (ΔAd|min1|) mediated by emicizumab were calculated from the slopes of regression lines in the presence of rFVIII. RESULTS: Ad|min1| in FVIII-deficient plasma with various concentrations of rFVIII negatively correlated with ΔAd|min1|by adding emicizumab, and these data were defined as standard reference values. Ad|min1| (4.57 ± 0.50) in 16 PwMHA increased to 5.05 ± 0.54 and 5.37 ± 0.60 by adding emicizumab at 50 and 100 µg/mL, respectively, but remained lower than the normal range (7.22 ± 0.21). ΔAd|min1| levels were 1.5 to 2-fold higher in five cases and 0.4 to 0.6-fold lower in four cases, compared with reference values determined by rFVIII. In some cases, genetic analyses suggested that specific point mutations could have contributed to these findings. Further studies using rFVIII mutants indicated, however, that the differences in ΔAd|min1| were not related to individual FVIII gene defects. CONCLUSION: Emicizumab enhances coagulation potential in PwMHA. Assessment of ex vivo coagulant activity of emicizumab could be helpful for predicting coagulant potentials prior to treatment in these patients.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism.

Anticoagulant plasma concentrations and patient characteristics might affect the benefit-risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN-DVT and EINSTEIN-PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure-response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure-efficacy relationships were shallow. Exposure-safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit-risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

The Antithrombotic Effects of Low Molecular Weight Fragment from Enzymatically Modified of Laminaria Japonica Polysaccharide.

BACKGROUND Laminaria japonica polysaccharide (LJP), a fucose enriched sulfated polysaccharide has been demonstrated to have excellent anticoagulant and antithrombotic activities. However, the antithrombotic effect of low molecular weight polysaccharide from enzymatically modified of LJP (LMWEP) remains unknown. MATERIAL AND METHODS LMWEP was prepared by fucoidanase enzymatic hydrolysis, and the antithrombotic and anticoagulant activities, and the underlying mechanism were investigated thoroughly. Rats were randomly divided into 6 groups (8 rats in each group): the blank control group, the blank control group treated with LMWEP (20 mg/kg), the model group, the model group treated with heparin (2 mg/kg), the model group treated with LJP (20 mg/kg), and the model group treated with LMWEP (20 mg/kg). After 7 days of intravenous administration, blood was collected for biochemical parameters examinations. RESULTS LMWEP increased the activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), 6-keto prostaglandin F1alpha (6-Keto-PGF1alpha), and endothelial nitric oxide synthase (eNOS). In addition, LMWEP decreased fibrinogen (FIB), endothelin-1 (ET-1), thromboxane B2 (TXB2), erythrocyte sedimentation rate (ESR), and hematocrit (HCT). CONCLUSIONS LMWEP, an enzymatically modified fragment with a molecular weight of 25.8 kDa, is a potential antithrombotic candidate for treatment of thrombosis related diseases.

Assessment of a rapid diagnostic test to exclude bacteraemia and effect on clinical decision-making for antimicrobial therapy.

Unnecessary antimicrobial treatment promotes the emergence of resistance. Early confirmation that a blood culture is negative could shorten antibiotic courses. The Cognitor Minus test, performed on blood culture samples after 12 hours incubation has a negative predictive value (NPV) of 99.5%. The aim of this study was to determine if earlier confirmation of negative blood culture result would shorten antibiotic treatment. Paired blood cultures were taken in the Critical Care Unit at a teaching hospital. The Cognitor Minus test was performed on one set >12 hours incubation but results kept blind. Clinicians were asked after 24 and 48 hours whether a result excluding bacteraemia or fungaemia would affect decisions to continue or stop antimicrobial treatment. Over 6 months, 125 patients were enrolled. The median time from start of incubation to Cognitor Minus test was 27.1 hours. When compared to 5 day blood culture results from both the control and test samples, Cognitor Minus gave NPVs of 99% and 100% respectively. Test results would have reduced antibiotic treatment in 14% (17/119) of patients at 24 and 48 hours (24% at either time) compared with routine blood culture. The availability of rapid tests to exclude bacteraemia may be of benefit in antimicrobial stewardship.

Alternative processing technology for the preparation of carbonized Zingiberis Rhizoma by stir-frying with sand.

Context: Carbonized ginger, a type of charry herb, has been used as a hemostatic medicine since ancient times. However, there are some serious problems such as inhomogeneous heating and emitting smoke during processing with traditional stir-frying method.Objective: To investigate the feasibility to obtain carbonized ginger by stir-frying with sand instead of stir-frying method.Materials and methods: Dried-ginger (100 g) was processed by stir-frying for 30 min at 270 ± 10 °C, or by stir-frying with sand (1:10, w/w) for 8 min at 240 ± 5 °C. The HPLC fingerprint was established for two samples. The adsorption capacity and major components including tannins, gingerols, shogaols and gingerone were quantitated by UV and HPLC, respectively. The hemostatic effect by prothrombin time (PT) and activated partial thromboplastin time (APTT) was evaluated in vitro.Results: The similarity of the two samples for HPLC fingerprints was >0.93. The sand-fried samples showed significantly higher adsorption capacity compared with the stir-fried samples (4.915 vs. 4.593 mg/g; p < 0.05) and higher contents of major components (4.698 vs. 3.930 mg/g, 1.352 vs. 1.144 mg/g, 2.419 vs. 2.095 mg/g, 0.666 vs. 0.568 mg/g and 1.083 vs. 0.911 mg/g for tannins, gingerone, 6-shogaol, 8-shogaol and 10-shogaol, respectively; p < 0.05); while no significant differences were seen for 6-gingerol, 8-gingerol and 10-gingerol (p > 0.05). The PT and APTT values were similar between the stir-fried and sand-fried test groups and significantly lower compared to controls (p < 0.05).Conclusions: The carbonizing process by stir-frying with sand is superior to the stir-frying method for carbonized ginger.