达比加群酯与低分子肝素预防髋关节置换术后下肢深静脉血栓的作用比较

目的 比较达比加群酯与低分子肝素预防髋关节置换术后并发下肢深静脉血栓（DVT）的疗效与安全性的差异。方法 选择2014年1月至2015年10月在宣城中心医院住院的单髋或双髋关节置换术患者73例，随机分为基础治疗组（对照组）24例，达比加群酯组（DE组）25例，低分子肝素组（LMWH组）24例。置换后行双下肢彩色多普勒检查评估DVT形成情况，并观察比较各组患者治疗前后血小板计数，凝血酶元时间（PT）变化情况及安全性。结果 DE组和LMWH预防DVT效果优于对照组（P<0.05），而DE组和LMWH组患者在预防DVT发生上差异无统计学意义（P>0.05）。DE组和LMWH组在治疗期间均无严重出血。结论 达比加群酯与低分子肝素均具有较好的预防髋关节置换后DVT的发生，达比加群酯疗效及安全性与低分子肝素作用相当。     

达比加群对凝血酶诱导的人气道平滑肌细胞收缩和增殖的影响

目的 探讨这比加群对凝血酶诱导的人气道平滑肌(HASM)细胞收缩和增殖的影响.方法 将原代培养的HASM细胞用于实验.用免疫荧光的方法观察细胞收缩的形态学变化;用Western blot法分析α-actin蛋白相对表达量;用cck8法检测平滑肌细胞增殖能力.结果 达比加群能显著抑制凝血酶诱导的HASM细胞骨架重组和收缩蛋白α-actin的表达(P＜0.05).对血管紧张素Ⅱ(AngⅡ)、转化生长因子-β1、血小板源性生长因子、乙酰甲胆碱、凝血酶的促增殖能力进行比较,凝血酶显著强于AngⅡ,仅次于10％胎牛血清(P＜0.05).达比加群呈浓度依赖性和时间依赖性地抑制了凝血酶诱导的HASM细胞增殖(P＜0.05).结论 达比加群能够显著抑制凝血酶诱导的HASM细胞收缩和增殖.     

Factor Eight Inhibitor Bypassing Agent (FEIBA) for Reversal of Target-Specific Oral Anticoagulants in Life-Threatening Intracranial Bleeding

Introduction

As increasing number of patients present to emergency departments with life threatening hemorrhages, particularly intracranial hemorrhage on anticoagulation physicians must be cognizant of the limitations of the available reversal options. Based upon the available literature, our institution formulated a reversal algorithm for patients with life-threatening bleeding on factor Xa inhibitors by administering factor eight inhibitor bypassing agent (FEIBA) 20 units/kg.

Dabigatran abrogates brain endothelial cell permeability in response to thrombin

Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.     

The fibrinogen prothrombin time‐derived method is not useful in patients anticoagulated with low molecular weight heparins or rivaroxaban

Essentials

• Fibrinogen prothrombin time‐derived (FIBPT‐d) behavior in anticoagulated patients is under studied.
• FIBPT‐d method overestimates fibrinogen in rivaroxaban and low molecular weight heparin samples.
• Unfractionated heparin and dabigatran samples showed similar bias to the control group.
• Rabbit brain and human recombinant thromboplastin behavior was different in rivaroxaban samples.

Summary

Background

The fibrinogen prothrombin time‐derived (FIBPT‐d) method with photo‐optical coagulometers is easy and economical. However, there are few reports on the behavior of this test on samples from patients anticoagulated with direct oral anticoagulants or low molecular weight heparin (LMWH).

Objective

To compare fibrinogen results obtained with the Clauss (FIB C) method and the FIBPT‐d method with two thromboplastins in anticoagulated patients.

Population

The study population comprised 295 consecutive anticoagulated patients: 99 treated with vitamin K antagonists (VKAs), 49 treated with unfractionated heparin (UFH), 47 treated with LMWH, 50 treated with rivaroxaban, 50 treated with dabigatran, and 100 normal controls (NCs).

Methods

Dabigatran samples were analyzed by the use of FIB C with HemosIL Fibrinogen C or 100 NHI thrombin units mL^?1 reagents; rabbit brain and human recombinant thromboplastins with HemosIL PTFibrinogen HS plus (HS) and Recombiplastin 2G (RP) were used for FIBPT‐d method. Heparin and rivaroxaban levels were assessed with HemosIL Liq antiXa with specific calibrators; dabigatran levels were determined with the HemosIL Direct Thrombin Inhibitor Assay. All assays were performed on the ACL TOP platform in two laboratories. Percentage biases for the FIBPT‐d method versus the FIB C method were calculated by the use of Bland–Altman plots.

Results

Positive biases of the FIBPT‐d method versus the FIB C method with both thromboplastins were seen in NC samples (13.7% and 18.9% for HS and RP, respectively), but biases with HS in rivaroxaban and VKA patient samples were higher than that in NC samples, at 31.9% and 34.0%, respectively. LMWH patient samples showed higher bias than NC samples: 26.5% and 29.3.0% with HS and RP, respectively. UFH and dabigatran patient samples showed similar bias as NC samples.

Conclusion

The FIBPT‐d method should not be used in anticoagulated patients, because the FIBPT‐d mathematical algorithm has been validated only in normal subjects, so overestimation could occur in these patients.

     

达比加群与华法林治疗急性心肌梗死合并左心室血栓形成的临床疗效

目的对比达比加群、华法林在急性心肌梗死合并左心室血栓(LVT)中的临床疗效。方法收集2015年9月—2020年3月辽宁省人民医院住院且诊断为急性心肌梗死合并左心室血栓的116例患者为研究对象,随机分为华法林组和达比加群组,观察各组患者卒中发生率、出血事件发生率、治疗前和治疗后3个月凝血功能指标、治疗前和治疗后1个月及3个月肝功能指标,并比较两组患者血栓消失时间、治疗期间新发血栓栓塞事件以及出血事件。结果治疗期间,达比加群组较华法林组总栓塞事件发生率较少(3.4%比24.1%,P=0.002),其中脑栓塞(1.7%比15.5%,P=0.016)差异具有统计学意义(P0.05);两组患者凝血酶原时间(PT)、凝血酶时间(TT)、纤维蛋白原(FIB)比较差异无统计学意义(P0.05),达比加群组活化部分凝血活酶时间(APTT)高于华法林组,两组间比较差异有显著性(P0.05);两组患者治疗后1个月及3个月肝功能指标比较差异无统计学意义(P0.05);与华法林组比较,达比加群组血栓消失时间更短[(47.00±5.30)天比(69.10±7.90)天,P0.01],两组左心室血栓消失率相比,达比加群组明显多于华法林组(77.6%比39.7%,P=0.032);出血事件发生率达比加群组显著低于华法林组(3.4%比17.2%,P0.05)。结论对急性心肌梗死合并左心室血栓的患者,达比加群治疗较华法林更为安全有效。     

达比加群酯降解杂质的合成

目的 为了更好的控制甲磺酸达比加群酯的质量,合成达比加群酯的5个降解杂质。方法 以N-[2-[[(4-氰基苯基)氨基]甲基]-1甲基-1H-5-苯并咪唑]羰基]-N-2-吡啶基-β-氨基丙酸乙酯为原料,经过成脒反应、酰胺反应、水解反应制备了杂质A~E。结果 所得产物经¹H-NMR,LC-MS和¹³C-NMR初步确证了结构,收率≥65%。结论 该合成路线反应条件温和,产品纯度高。