60Coγ射线分次照射对犬血浆和红细胞膜8-表氧-PGF2α含量的影响

目的 观察犬放射损伤时血浆与红细胞膜８－表氧－前列腺素Ｆ２α（８－表氧－ＰＧＦ２α）含量的改变，并与丙二醛（ＭＤＡ）比较，探讨测定８－表氧－ＰＧＦ２α对了解脂质过氧化反应的价值以及ＳＯＤ对其的影响，方法 用＾６０Ｃｏγ射线照射１８只成年杂种犬，实验分低剂量ＳＯＤ组，高剂量ＳＯＤ组及对照组，每组６只，吸收剂量率为０．６Ｇｙ／ｄ，共５天，计３．０Ｇｙ，测定照射前，照射过程中及照射后血浆与红细胞膜８－表     

Genetic variation in the first-pass metabolism of ethinylestradiol,sex hormone binding globulin levels and venous thrombosis risk

BackgroundUse of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels.MethodsPremenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study.ResultsTwo copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; OR_MEGA: 2.61) as well as SHBG levels (mean difference 27.6 nmol/L, 95%CI: − 61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis.ConclusionGenetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users.     

Von Willebrand factor – two sides and the edge of a coin

Summary. Von Willebrand factor (VWF) has multiple functions in coagulation. It is a clotting protein and its deficiency causes a primary haemostatic bleeding disorder. Excess VWF, particularly high molecular weight multimers can cause thrombosis. There is also a debatable function of protecting factor VIII (FVIII) in circulation with the prevention of development of FVIII inhibitors. This commentary addresses these functions.     

Standardization of thromboelastography: a report from the TEG‐ROTEM working group

Summary. Laboratory evaluation of bleeding disorders has been performed with the standard clotting assays such as the PT and PTT for several decades. Our improved understanding of the process of blood coagulation has now revealed the important role played by the cellular elements such as platelets, monocytes and red blood cells. The need for a test that can assess clotting in a more ‘global’ manner, beyond the initiation of clot formation, has led to greater interest in assays such as thrombin generation and thromboelastography. Even though there are several publications using thromboelastography it remains a research tool as the methodology is not standardized. In an attempt to show reproducibility and consistency using thromboelastography, a group of investigators from different countries joined hands to form the TEG‐ROTEM Working Group. Two studies were performed using PRP and FVIII deficient plasma and an intrinsic pathway activator. This article summarizes the results of the first international effort at standardization of thromboelastography. Both of the instruments using this technology (TEG^® and ROTEM^®) were used. Nine laboratories from countries around the globe participated in this effort. The results showed a significant inter‐laboratory variance with CV’s greater than 10%. Although these results were not satisfactory, this has been the first effort to standardize this methodology and significant work remains to be done to improve reliability and reproducibility. These studies were performed on PRP and the results may be more reliable when preformed on whole blood samples. We believe that it is important to continue this work so that we may investigate the usefulness and potential applications of thromboelastography in the evaluation of bleeding and thrombosis.     

Management of Hemostatic Disorders in Patients With Advanced Liver Disease Admitted to an Intensive Care Unit

Patients with liver diseases frequently acquire complex changes in their hemostatic system. Traditionally, bleeding complications in patients with liver disease were ascribed to these hemostatic changes, and liver diseases were considered as an acquired bleeding disorder. Nowadays, it is increasingly acknowledged that patients with liver diseases are in “hemostatic rebalance” due to a commensurate decline in pro- and anticoagulant drivers. Indeed, both thrombosis and bleeding may complicate liver disease. Such complications may be particularly worrisome in critically ill patients with liver disease. This review will outline knowns and unknowns in prediction, prevention, and treatment of bleeding and thrombosis in patients with liver disease admitted to an intensive care unit.     

Exploratory evaluation of pharmacodynamics,pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study

Background

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.

Methods

This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5–18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5–2 years, 2–6 years, 6–12 years and 12–18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.

Results

Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.

Conclusions

Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.

Trial registration

ClinicalTrials.gov number, NCT01145859.