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The REG2 Anticoagulation System consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen. Its effect on thrombin generation is unknown. A prospectively designed thrombin generation study was conducted within the phase 1 ascending dose study of REG2 to assess the effect of REG2 on thrombin generation kinetics. A total of 32 healthy volunteers were recruited into four cohorts of ascending dose pegnivacogin for the phase 1 study. In this pre-specified substudy, blood samples were drawn in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. Thrombin generation was initiated with tissue factor and thrombin generation kinetics were measured using the Calibrated Automated Thrombogram (CAT). REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose and concentration-dependent response to pegnivacogin [time to peak thrombin generation (PTm), endogenous thrombin potential, peak thrombin generation, and velocity index (VIx)]. Reversal of the effect of pegnivacogin with anivamersen demonstrated restoration of thrombin generation without rebound effect. This first-in-human study of the effect of the REG2 Anticoagulation System on thrombin generation demonstrates concentration-dependent suppression of thrombin generation that is reversible without rebound effect, as measured by the CAT assay.

Most fibrinogen replacement strategies focus on quantitative deficiencies. A thrombin time (TT) mixing study helped to assess qualitative defects caused by dysfibrinogens. Plasma samples were collected from non-anticoagulated subjects (n=6) meeting laboratory criteria for suspected dysfibrinogenaemia (TT > 22 s; fibrinogen activity <180) and from a control group. TT mixing studies were performed on subject plasma with increasing volumes of pooled normal plasma at 1:2, 1:4 and 1:5 dilutions. No subjects with dysfibrinogenaemia demonstrated a complete TT correction at 1:2, but 50% corrected at 1:4 and 100% at 1:5 dilution. Based on these data, a correction factor (CF), defined as the reciprocal dilution yielding complete correction, was incorporated into our clinical practice formula for fibrinogen dosing in patients with dysfibrinogenaemias. Our study incorporates TT mixing studies for assessment of dysfibrinogens. The addition of a mix-derived CF to classical formulae may better approximate dosing in patients with dysfibrinogenaemia.

Our objective was to evaluate the efficacy and safety of natural hirudin and low molecular weight heparin (LMWH) in the prevention of perioperative deep venous thrombosis (DVT) in elderly patients with intertrochanteric fracture. From June 2014 to June 2017, 96 patients with intertrochanteric fractures were treated with proximal femoral nail antirotation (PFNA) were randomly divided into two groups. For DVT prevention, 45 patients were treated with oral natural hirudin and subcutaneous LMWH-calcium (test group) and 51 patients were treated with subcutaneous LMWH-calcium (control group). The mean intraoperative bleeding, wound drainage and incisional hematoma were higher in the test group, with no significant differences between the groups. There were significant differences in distal intramuscular venous thrombosis ( P  = 0.043). Both activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT) lengthened in both groups postoperatively, and there was a significant difference between the two groups two weeks postoperatively. D-dimer were significantly different and platelet count (PLT) did not differ between groups two weeks postoperatively. In elderly patients with unilateral intertrochanteric fracture after PFNA on anticoagulant therapy, the combination of natural hirudin and LMWH was more effective than that of LMWH-calcium alone, with no significant difference with regard to safety.

Idarucizumab was 100% effective in reversing the anticoagulant effect of dabigatran among 300 patients with uncontrolled bleeding (median time to bleeding cessation, 2.5 hours) and among 200 patients who required an urgent procedure (median time to procedure initiation, 1.6 hours).

We evaluated the correlation between thrombin generation (TG) parameters with bleeding symptoms and disease severity in patients with hemophilia. In this cross-sectional study, 59 patients with hemophilia without inhibitors and regardless of their severity were randomly selected from southern Iran and TG assays were conducted. Bleeding score (BS) was calculated by performing a clinical evaluation using Tosetto questionnaire. Only lag time showed a statistically significant correlation with BS (rs = .316, P = .016). All TG parameters except peak showed association with disease severity (P < .05). Endogenous thrombin potential showed a significant correlation with factor activity level (rs = .459, P < .001). Both lag time and start tail showed significant negative correlations with factor activity level (rs = −0.488, P < .001 and rs = − .289, P < .026, respectively). Although most of the TG parameters evaluated were not significantly correlated with the BS of patients with hemophilia, the majority of TG parameters were significantly associated with factor activity level and disease severity.

Background Current use of prescribed or over the counter non-steroidal anti-inflammatory drugs (NSAIDs) for pain and osteoarthritis (OA) have untoward gastrointestinal and cardiovascular related side effects, as a result the need for a safe and effective alternative has become unequivocally crucial. Method A randomized, double blind, placebo and active controlled pilot study of a novel dual pathway, COX1/2 and LOX, inhibitor anti-inflammatory agent of botanical origin, UP446 was conducted. Sixty subjects (age 40-75) with symptomatic OA of the hip or knee were assigned to 4 treatment groups (n = 15); Group A0 (Placebo, CMC capsule), Group A1 (UP446 250 mg/day), Group A2 (UP446 500 mg/day) and Group A3 (Celecoxib, 200 mg/day). MOS-SF-36 and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) data were collected at baseline and after 30, 60 and 90 days of treatment as a measure of efficacy. Erythrocyte sedimentation rate, C-reactive protein, plasma thrombin time (PTT), fructosamine, Hematology, clinical chemistry and fecal occult blood were monitored for safety. Results Statistically significant decrease in WOMAC pain score were observed for Group A1 at day 90, Group A2 at 30 and 90 days and Group A3 at 60 and 90 days. Statistically significant decrease in WOMAC stiffness score were observed for Group A1 and Group A2 at 30, 60 and 90 days; but not for Group A0 and Group A3. The mean change in WOMAC functional impairment scores were statistically significant for Group A1 and Group A2 respectively at 30 days (p = 0.006 and p = 0.006), at 60 days (p = 0.016 and p = 0.002) and at 90 days (p = 0.018 and p = 0.002), these changes were not significant for Group A0 and Group A3. Based on MOS -SF-36 questionnaires, statistically significant improvements in physical function, endurance and mental health scores were observed for all active treatment groups compared to placebo. No significant changes suggestive of toxicity in routine hematologies, serum chemistries, liver enzymes or PTT were noted in any of the treatment groups. Conclusion Based on current findings UP446 is safe and efficacious alternative to established anti-inflammatory medications for alleviating OA symptoms as measured by the WOMAC Index.

Abstract Objectives Activated partial thromboplastin time (aPTT) is the primary test used to monitor intravenous (IV) direct thrombin inhibitors (DTIs) but has many limitations. The plasma diluted thrombin time (dTT) has shown better correlation with DTI levels than aPTT. This study compared dose-response curves for dTT and aPTT in pediatric patients receiving argatroban and bivalirudin. Methods A retrospective review of pediatric patients treated with argatroban (n = 45) or bivalirudin (n = 14) monitored with dTT and aPTT. Results The dTT assay was calibrated to report DTI concentrations in µg/mL for argatroban and bivalirudin with good analytic sensitivity and specificity. The dTT was fivefold more likely to show a stable dose-response slope than the aPTT (P < .0002; odds ratio, 4.9). For patients in whom both dTT and aPTT showed a significant correlation between dose and assay results, dTT had a higher average correlation factor compared with aPTT (P = .007). Argatroban dose-response slopes showed more inter- and intrapatient variation than bivalirudin (dose-response slope coefficient of variation, 132% vs 52%). Conclusions The dTT assay was more likely to show a stable dose response and have a stronger correlation with DTI dose than aPTT. Argatroban shows more variation in dose response than bivalirudin.

Objective. To investigate the value of coagulation indicators D-dimer (DD), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (Fg) in predicting the severity and prognosis of COVID-19. Methods. A total of 115 patients with confirmed COVID-19, who were admitted to Tianyou Hospital of Wuhan University of Science and Technology between January 18, 2020, and March 5, 2020, were included. The dynamic changes of DD, PT, APTT, and Fg were tested, and the correlation with CT imaging, clinical classifications, and prognosis was studied. Results. Coagulation disorder occurred at the early stage of COVID-19 infection, with 50 (43.5%) patients having DD increased and 74 (64.3%) patients having Fg increased. The levels of DD and Fg were correlated with clinical classification. Among 23 patients who deceased, 18 had DD increased at the first lab test, 22 had DD increased at the second and third lab tests, and 18 had prolonged PT at the third test. The results from ROC analyses for mortality risk showed that the AUCs of DD were 0.742, 0.818, and 0.851 in three times of test, respectively; PT was 0.643, 0.824, and 0.937. In addition, with the progression of the disease, the change of CT imaging was closely related to the increase of the DD value (P<0.01). Conclusions. Coagulation dysfunction is more likely to occur in severe and critically ill patients. DD and PT could be used as the significant indicators in predicting the mortality of COVID-19.

Dabigatran acylglucuronide, an active metabolite of dabigatran, exhibits higher plasma concentrations and distinct anticoagulant effects compared to dabigatran, suggesting that it may play a more significant role in overall anticoagulant activity than previously assumed. Idarucizumab, a monoclonal antibody fragment, binds to both free and thrombin-bound dabigatran, neutralizing its anticoagulant effects. However, its efficacy in reversing anticoagulation induced by dabigatran acylglucuronide remains unclear. This study aimed to evaluate whether idarucizumab differentially reverses the anticoagulant effects of dabigatran and dabigatran acylglucuronide. In vitro experiments were conducted using blood from healthy, drug-free donors. Plasma samples were spiked with either dabigatran or dabigatran acylglucuronide, followed by idarucizumab. Standard coagulation assays, including prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), as well as thrombin generation assays (TGA), were performed. At a concentration of 1 µM, idarucizumab demonstrated significantly greater reversal of dabigatran acylglucuronide-induced anticoagulation than that of dabigatran in PT, aPTT, and TT assays. Consistently, TGA showed stronger neutralization of dabigatran acylglucuronide, with IC 50 values for C max , endogenous thrombin potential, and lag time at least 2.0-fold higher than those of dabigatran. These findings indicate that idarucizumab exerts a more potent reversal effect on dabigatran acylglucuronide compared to dabigatran.

Myo -inositol plays a key role in the vasculature and may be beneficial for preventing harmful environmental effects. In this study aortic rings were isolated from middle-aged (12-month-old) male Wistar rats and preincubated with myo -inositol (0.01–100 mg/L) for 2 h. A stable thromboxane A 2 analog was added (0.1 nM, 2 h) to analyze vascular dysfunction. The concentration of myo -inositol in the organ baths was determined via gas chromatography. In another experiment, human blood plasma was subjected to pro-oxidant - hydrogen peroxide administration, and myo -inositol was added to analyze lipid and protein oxidation processes. The thromboplastin time, prothrombin time, and thrombin time were also studied. Myo -inositol administration protected thiol groups against oxidative stress, meanwhile decreased vascular contraction and potentiated vasodilation (concentrations 1–100 mg/L, but not ≤ 0.1 mg/L), and changed the level of 8-isoprostane (concentrations: 0.1–100 mg/L, but not 0.01 mg/L) in plasma treated with H 2 O 2 /Fe 2+ . A dose above 100 mg/L additionally protected lipids (measured as thiobarbituric acid reactive substances) and increased thrombin time. Moreover, significant differences in vascular relaxation were observed between the studied myo -inositol concentrations (1 vs. 10 vs. 100 mg/L), which was not detected under the 0.1 mg/L. The concentration of myo -inositol in the organ baths determined via gas chromatography revealed that this nutraceutical agent was not used by the aortic rings during the incubation period in physiological processes. A protective effect of myo -inositol against prooxidant damage to human plasma and rat thoracic arteries has been demonstrated.