Incomplete dabigatran reversal with idarucizumab

Context: With increasing use of direct oral anticoagulants (DOACs), urgent reversal of these agents becomes a growing concern. Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with higher affinity than thrombin, rapidly neutralizing its anticoagulant effect without increased risk of thrombosis.

Case details: We describe two cases in which the recommended dose of idarucizumab was unsuccessful in completely reversing the anticoagulant effects of dabigatran. Both of these patients were noted to have supratherapeutic international normalized ratios (INRs) and high dabigatran concentrations. In the first case, an 86-year-old male underwent an emergent procedure and experienced excessive hemorrhaging refractory to blood product repletion, idarucizumab, and factor eight inhibitor bypass activity (FEIBA). In the second case, a 62-year-old female in shock was found to have elevated dabigatran concentrations despite two doses of idarucizumab, continuous renal replacement therapy (CRRT), blood product repletion, and FEIBA. Both patients ultimately expired from their coagulopathies.

Discussion: These cases illustrate the potential for incomplete reversal of dabigatran with the recommended 5?g of idarucizumab and emphasize the importance of early detection of dabigatran toxicity. While direct dabigatran serum concentrations are not readily available, the INR may be a useful surrogate marker for supratherapeutic dabigatran concentrations.     

Comparison of the ecarin chromogenic assay and diluted thrombin time for quantification of dabigatran concentrations

Essentials

• Routine monitoring is unnecessary but measuring dabigatran levels is helpful in certain situations.
• We compared ecarin chromogenic assay (STA‐ECA‐II) and dilute thrombin time (dTT) in patient samples.
• Both tests provided accurate measurements over a wide range of dabigatran concentrations.
• Adoption of STA‐ECA‐II and dTT into routine clinical practice will improve patient care.

     

Idarucizumab for dabigatran overdose

Context: An overdose of oral anticoagulants represents a challenging scenario for emergency physicians. Dabigatran, an oral direct thrombin inhibitor, is increasingly used in place of warfarin. The lack of an antidote is a concern in patients who overdose on dabigatran, even though the drug can be eliminated with hemodialysis. Idarucizumab is an antibody fragment that binds dabigatran with high affinity. It reverses the anticoagulant effect of dabigatran within minutes and is approved for the reversal of dabigatran during emergency situations.

Case details: We describe the use of idarucizumab in the management of a 68-year-old woman who was taking dabigatran 150?mg twice daily and ingested 125 capsules. Despite gastric lavage and administration of activated charcoal within two hours of drug intake, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) remained prolonged. The administration of 5?g of intravenous idarucizumab promptly and completely reversed the anticoagulant activity of dabigatran as assessed by routine and specific coagulation assays (aPTT from to 75 to 26?s, PT from 26 to 11?s and diluted thrombin time from 92 to 27?s). The initially planned emergency hemodialysis was canceled.

Discussion: This case highlights the potential use of idarucizumab for the management of massive dabigatran overdoses.     

Idarucizumab for the treatment of hemorrhage and dabigatran reversal in patients requiring urgent surgery or procedures

Introduction: Idarucizumab is a specific antagonist for dabigatran etexilate (DE). The recent market authorization of idarucizumab in Europe and the USA may reassure prescribers of DE, as it can increase the safety of the emergency management of patients taking this anticoagulant. However, idarucizumab use should be limited to specific indications to avoid unnecessary risks to patients and costs to healthcare systems.

Areas covered: The authors provide an overview of idarucizumab development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial RE-VERSE AD and a review of recent case reports of idarucizumab use in emergency contexts are also discussed.

Expert opinion: Although idarucizumab has shown clear efficacy in reversing dabigatran-induced coagulopathy, its overall effects on patient outcome have not been proven. Information regarding the clinical context in which patients on DE are admitted for emergency treatment, and accurate laboratory tests of dabigatran plasma level during reversal may inform selection and help with the follow-up of patients who may benefit from idarucizumab. Idarucizumab should be integrated into protocol for the emergency management of patients on DE. Furthermore, the benefit of idarucizumab in specific indications such as acute ischemic stroke should be investigated.     

Thromboelastography (TEG®) compared to conventional coagulation tests in surgical patients – a laboratory evaluation

Abstract

Background. Several methods exist for evaluation of hypocoagulation in patients with perioperative bleeding, e.g. thromboelastography (TEG^®) and conventional methods (platelet count, aPTT, INR and fibrinogen). Considering the vast experience of conventional methods it is important to investigate how well the methods correspond. Methods. Sixty surgical patients were included prospectively and blood samples were taken perioperatively. TEG^® and conventional parameters were analyzed simultaneously. An assessment of coagulopathy, based on a synthesis of the conventional methods, was done by two experienced coagulation specialists, blinded from the results of TEG^® and from the results of each other. Hypocoagulation, defined by TEG^® parameters; reaction time (R-time), angle, maximal amplitude (MA) and fibrinolysis, was evaluated according to a commonly used algorithm. Results. To detect a platelet count below 150 × 10⁹ L^?1, the sensitivity of TEG was 17% (95% CI, 7–36%) with angle and 25% (95% CI, 11–45%) with MA. The sensitivity to detect fibrinogen below 2 g/L was 11% (95% CI, 3–29%) with angle and 21% with MA (95% CI, 8–43%). To detect aPTT more than 40 s and INR more than 1.2 with R-time, the sensitivity was 19% (95% CI, 8–37%) and 0% (95% CI, 0–69%) respectively. The agreement of the evaluator's assessments of hypocoagulation was 100%, but the agreement with the overall TEG^® analysis was poor with a sensitivity of 33% and a specificity of 95%. Conclusion. The agreement between conventional laboratory tests and TEG is poor, but it remains uncertain which type of coagulation tests that best reflects the actual bleeding risk.     

妊娠晚期孕妇凝血功能检测与分析

目的探讨妊娠晚期孕妇凝血功能检测的临床意义。方法采用Sysmex-1500型全自动凝血分析仪测定280例妊娠晚期孕妇（观察组）及140例健康育龄妇女（对照组）的凝血酶原时间（PT）、国际化标准比值（INR）、活化部分凝血活酶时间（APTT）、凝血酶时间（TT）、纤维蛋白原（Fbg），并进行分析比较。结果观察组的PT、INR、APTT均较对照组明显缩短，Fbg高于对照组，P〈0．01；而两组TT差异无统计学意义（P〉0．05）。结论妊娠晚期妇女血液处于高凝状态。检测其凝血功能，对预防或早期治疗弥散性血管内凝血（DIC）有一定的帮助。     

Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring

Context: Dabigatran etexilate (dabigatran) is a direct thrombin inhibitor anticoagulant agent. There is limited information about the changes in coagulation profile and outcomes in overdose. A monoclonal antibody has been developed to neutralize the anticoagulant effect of dabigatran. Case reports describe enhanced clearance of dabigatran by haemodialysis as an intervention to prevent haemorrhagic complications – however, the threshold for initiating haemodialysis is not well defined in an asymptomatic patient with normal renal function. Case details: Two patients presented following deliberate dabigatran overdoses. A 55-year-old woman ingested 10?×?150?mg dabigatran. A 21-year-old woman with a history of systemic lupus erythematosus and pulmonary embolus ingested 100?×?110?mg dabigatran. Both were admitted to the intensive care unit and managed expectantly. Serial coagulation tests normalized over 60 h. The half-life of dabigatran was not prolonged following overdose, being calculated between 7 and 11 h in each case. There was positive correlation between international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) with plasma dabigatran levels. Conclusion: There is limited experience with dabigatran overdoses. Normal aPTT, PT and INR assays 12 h following deliberate ingestion indicate that the drug concentration is not high. Individual risk assessment of bleeding risk needs to be formulated for each patient and expectant management is reasonable in the presence of normal renal function and absent risk factors for bleeding.     

Idarucizumab for a traumatic head injury patient taking dabigatran

Background

Dabigatran is one of the four drugs currently used as a direct oral anticoagulant in Japan. Idarucizumab, which specifically targets dabigatran, was recently approved in Japan. We present a case of intracranial hemorrhage in a traumatic brain injury patient taking dabigatran who was treated by administering idarucizumab.

Case presentation

A 72-year-old man was injured in a traffic accident and was transferred to our emergency room. On arrival, his Glasgow Coma Scale score was 14 (eye, 3; verbal, 5; motor, 6), and his other vital signs were stable. Computed tomography (CT) imaging on arrival showed a small intracranial hematoma. A second CT 3 h later revealed expansion of the hematoma. We received information that he was taking dabigatran only after the second CT. Idarucizumab was then promptly administered, and emergency craniotomy for hematoma removal was performed. There was no tendency for bleeding during the operation, and blood transfusion was not required during the perioperative period. Although the patient underwent additional surgery for subdural effusion and hydrocephalus, his postoperative course was uneventful. He was transferred to a rehabilitation hospital on postoperative day 102.

Conclusion

We managed a patient taking dabigatran who suffered traumatic intracranial hemorrhage by administering idarucizumab preoperatively without the need for blood transfusion perioperatively. We suggest that idarucizumab could be a potent therapeutic bridge to definitive surgical management in such patients with traumatic brain injury who are taking dabigatran.

     

达比加群酯在非瓣膜性房颤患者抗凝治疗中的应用效果

目的探讨达比加群酯在非瓣膜性房颤患者抗凝治疗中的应用效果。方法选取2017年5月至2019年6月入我院治疗的120例非瓣膜性房颤患者,采用信封法将其分为对照组和研究组,每组60例。对照组给予华法林治疗,研究组给予达比加群酯治疗。比较两组的凝血指标、肝肾功能指标、出血事件、栓塞事件及不良反应发生情况。结果治疗后,研究组的TT、APTT、PT长于对照组,INR低于对照组(P<0.05)。治疗后,研究组的Cr、BUN、三酰甘油、转氨酶水平均低于对照组(P<0.05)。研究组的出血事件及栓塞事件的总发生率均低于对照组(P<0.05)。研究组的不良反应总发生率低于对照组(P<0.05)。结论达比加群酯治疗非瓣膜性房颤可调节患者凝血指标水平,不会对肝肾功能造成损伤,且不会增加栓塞事件及出血事件的发生率,不良反应少,应用效果理想,可考虑推广。     

Effects of the oral,direct factor Xa inhibitor edoxaban on routine coagulation assays,lupus anticoagulant and anti-Xa assays

Edoxaban is an oral direct factor Xa inhibitor for prophylaxis and treatment of thromboembolic disorders. The effects on common coagulation assays are clinically valuable information and in certain clinical situations a quick assessment of the anticoagulant is wanted. Our aim was to investigate the effect of edoxaban on routine coagulation methods and evaluate anti-Xa assays, commonly used for other direct factor Xa inhibitors, for estimation of the drug concentration. Edoxaban was spiked to plasma samples from healthy subjects in the concentration range 0–742 µg/L and analyzed using different reagents for activated partial thromboplastin time (APTT) and prothrombin time (PT). Assays for antithrombin, activated protein C resistance, lupus anticoagulant (LA) and chromogenic anti-Xa assays were also included. Edoxaban displayed similar effects in vitro to other oral direct Xa inhibitors. The concentration needed to double the coagulation time varied between assays and reagents; 539–758 µg/L for the APTT and between 329 and 2505 µg/L for the PT. Edoxaban gave false high antithrombin activities in assays based on Xa-inhibition. Two integrated assays for LA, both based on activation with dilute Russell’s viper venom, displayed different results. Chromogenic anti-Xa assays displayed linear dose-response curves with edoxaban up to approximately 500 µg/L. In conclusion, therapeutic concentrations of edoxaban variably affect different coagulation assays, and even different reagents within an assay group. In comparison with other oral Xa-inhibitors, the in vitro effects of edoxaban were more similar to rivaroxaban than apixaban. For measurement of edoxaban concentration in plasma, it is possible to use the chromogenic anti-Xa assays.     

恶性血液病菌血症患者凝血功能紊乱及其与感染炎性因子的相关性研究

本研究旨在探讨恶性血液病（急性早幼粒白血病除外）菌血症患者血浆凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）,凝血酶时间（TT）,血浆纤维蛋白原（FIB）、抗凝血酶Ⅲ（ATⅢ）以及D二聚体（D-D）与感染相关炎性指标降钙素原（PCT）、C反应蛋白（CRP）、白介素-6（IL-6）、血清淀粉样蛋白A（SAA）的相关关系及其临床意义.回顾性分析四川大学华西医院2011年3月至2013年4月确诊为恶性血液病伴发热的2062例住院患者,按照严格的纳入排除标准选取326例,根据血培养结果分为非菌血症组（n=176）,非菌血症低蛋白组（n=78）和菌血症组（n=72）,分别记录PT、APTT、FIB、TT、ATⅢ、D-D、Plt、PCT、CRP、IL-6、SAA水平和分析数据.结果表明,菌血症组血浆凝血时间中位PT水平、中位APTT水平、中位D-D水平、中位Plt水平高于非菌血症组,炎性因子中位PCT水平、中位CRP水平、中位IL-6水平、中位SAA水平均高于非菌血症组,差异具有统计学意义（P＜0.05）.菌血症组中位ATⅢ的水平低于非菌血症组,差异具有统计学意义（P＜0.05）.两组间血浆TT、FIB水平差异无统计学意义（P＞0.05）.非菌血症组与非菌血症低蛋白组比较,各项指标差异均无统计学意义（P＞0.05）.相关性分析结果显示,炎性因子PCT水平与APTT、D-二聚体呈正相关,（P＜0.05）,与AT-Ⅲ呈负相关（P＜0.05）.结论：恶性血液病菌血症患者全身炎症反应与凝血反应有密不可分的关系,菌血症组炎症反应水平明显高于非菌血症组,同时伴有凝血功能障碍.     

大黄对脓毒症患者凝血功能的影响

目的:探讨大黄对脓毒症患者凝血功能的影响。方法:将30例无凝血功能障碍的脓毒症患者随机分为两组,对照组15例给予常规综合治疗,治疗组15例加用大黄10 g鼻饲。分别检测两组患者治疗前及治疗后1、3和7 d的凝血酶原时间(PT)、凝血酶时间(TT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FBG)和血小板(PLT)计数。结果:两组治疗后PT、TT、APTT均延长,FBG和PLT下降。治疗组治疗后第7日PT、TT、APTT均显著升高,FBG和PLT均显著降低,与对照组比较差异均有显著性(P均<0.05)。结论:大黄对脓毒症患者的凝血功能有保护作用。     

Idarucizumab for Reversal of Dabigatran-Associated Bleeding: Misnomer or Miracle?

Background

The development of novel oral anticoagulants (NOACs) has revolutionized oral anticoagulation. Rapid incorporation of NOACs into general practice has heightened the demand for directed reversal agents. Idarucizumab is a targeted reversal agent that is approved for the urgent reversal of the anticoagulant effects of dabigatran. While it is a welcome addition to reversal strategies of dabigatran, a number of clinical questions exist regarding its place in therapy.

脓毒症患者凝血功能的改变及其意义

目的研究脓毒症患者凝血功能的变化及其意义。方法按照脓毒症诊断标准,将76例患者分为生存组50例和死亡组26例,一经确诊即抽血检查凝血四项、D-二聚体浓度、血小板及白细胞计数。结果与生存组比较,死亡组的APTT、PT显著延长,D-二聚体浓度、白细胞计数显著增高,纤维蛋白原浓度、血小板计数显著降低（P〈0．05）。结论脓毒症患者存在凝血系统功能紊乱,其中D-二聚体浓度、血小板计数与脓毒症的严重程度有显著相关性,对判断患者的预后及评估病情、严重程度有重要意义。     

妊娠期糖尿病孕妇血栓弹力图和传统凝血功能指标结果比较

目的分析血栓弹力图和传统凝血功能指标在妊娠期糖尿病(GDM)孕妇凝血功能中的评估价值。方法选取该院2017年10月至2018年12月收治的60例GDM孕妇纳入研究组,选取60例健康孕妇纳入对照组。使用全自动血凝仪对所有研究对象的凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)和纤维蛋白原(FIB)指标进行测定,根据PT计算国际标准化比值(INR);使用血栓弹力图仪检测两组R值、K值、α角、MA和CI值。采用全自动血细胞分析仪进行血小板计数(PLT)检测。比较两组传统凝血功能指标和血栓弹力图指标的差异。结果除APTT外,研究组PT、FIB及INR均明显高于对照组,差异有统计学意义(P<0.05)。研究组R值、K值明显高于对照组,α角、MA和CI值明显低于对照组,差异均有统计学意义(P<0.05)。研究组、对照组的PLT、妊娠不良结局发生率比较,差异无统计学意义(P>0.05)。结论使用血栓弹力图对GDM孕妇的凝血功能异常状态进行观察是对传统凝血功能指标的补充,对于预测GDM孕妇是否有存在凝血功能异常,以及是否有血栓形成倾向有重要意义,值得临床推广。     

294例蜂蛰伤患者凝血功能分析

目的探讨蜂蛰伤患者凝血指标的变化。方法选取蜂蛰伤患者294例作为研究对象,根据蛰伤针数分为轻度蜂蛰伤组(A组,1~2针)、中度蜂蛰伤组(B组,3~10针)、重度蜂蛰伤组(C组,11~20针)和极重度蜂蛰伤组(D组,≥21针),同时选取健康人群40例作为健康对照组,观察凝血酶原时间(PT)、国际化比值(INR)、部分凝血活酶时间(APTT)和纤维蛋白原(FIB)等指标的变化。结果重度蜂蛰伤组、极重度蜂蛰伤组在蛰伤后4~9h内APTT、PT较健康对照组明显延长(P0.05),APTT、PT、INR分别与蛰伤针数之间呈明显的剂量-效应正相关(r值分别为0.583、0.340、0.327,P0.01)。结论 APTT与蛰伤针数及就医时间密切相关,可以作为蜂蛰伤治疗过程中的有效监测指标。     

不同血凝分析仪检测结果的一致性研究

目的 探讨不同实验室以及同一实验室的不同血凝分析仪检测结果的一致性.方法 将不同实验室的14台血凝分析仪分为3组,分别为STA系列(A组)、ACL系列(B组)、CA系列(C组),同时检测同一批号不同水平质控品(水平1、2、3)的凝血酶原时间(PT)、国际标准化比值(INR)、活化部分凝血活酶时间(APTT)、纤维蛋白原含量(FIB)及凝血酶时间(TT);并以同一实验室检测原理基本一致的2台血凝分析仪同时检测139份受检血浆的PT、INR、APTT、PT演算法测定FIB(PT-FIB)、Clauss法测定FIB(FIB-C).结果 3组血凝分析仪检测INR水平3的结果分别为5.35±0.20、4.35±1.00、4.46±0.30,差异无统计学意义(P＞0.05);检测TT水平3的结果分别为(17.1±0.3)s、(15.5±1.1)s、(14.8±1.8)s,差异无统计学意义(P＞0.05);其他各检测指标结果间差异有统计学意义(P＜0.05);两两比较的结果表明,B组和C组检测结果的符合率高达66.7%(10/15).同一实验室的ACL Futura和CA 510血凝分析仪检测PT的结果分别为(17.7±6.7)s、(20.1±10.9)s,检测INR的结果分别为1.75±1.07、1.64±0.91,检测PT-FIB的结果分别为(3.51±1.50)g/L、(3.68±1.93)g/L,检测FIB-C的结果分别为(2.61±1.31)g/L、(2.58±1.45)g/L,上述指标间差异均无统计学意义(P＞0.05);而检测APTT的结果分别为(49.9±21.5)s、(39.1±16.7)s,差异具有统计学意义(P＜0.05);同时,二者检测PT、INR、APTT、PT-FIB和FIB-C结果的相关性良好,r值分别为0.984 3、0.988 8,0.987 0,0.975 6,0.994 0;偏倚分析结果显示,2台血凝分析仪检测PT、INR、PT-FIB和FIB-C结果的一致性较好.结论 检测原理基本相同的不同血凝分析仪,其检测结果具有较好的一致性.不同血凝分析仪应通过定期比对和试剂的标准化,以改善和保证其检测结果的一致性.     

Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model

Introduction

New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.

Methods

Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.

Results

Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.

Conclusion

In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.     

凝血常规试验在血凝分析仪上的比对分析

目的评价成都中医药大学附属医院检验科两台血凝分析仪(法国Stago公司Stago CT型和StagoRE型)检测凝血酶原时间(PT)、国际标准化比值(INR)、活化部分凝血活酶时间(APTT)、纤维蛋白原(Fib)的准确性和一致性。方法对两台血凝分析仪用配套校准物进行校准;用配套质控物常规室内质控评价凝血常规的稳定性;使用比对试验评价两台仪器检测凝血常规的准确性和一致性。结果 PT、INR、APTT、Fib 4项试验比对结果的变异百分率(CV)符合卫生部临床检验中心凝血室间质量评价标准。两台血凝分析仪的检测结果有较好的相关性,除Fib相关系数r值为0.959 8,其余检测项目相关系数均大于0.975 0。结论通过不同血凝分析仪检测PT、APTT、Fib的比对试验,有效提高了本科室不同血凝分析仪器间的可比性,有效地保证了检验结果的准确性和精密度,提高了检验的质量。     

凝血功能分析的系统差异性对临床决策的影响探讨

目的通过研究临床标本凝血功能检验的系统差异及其对临床决策的影响程度,探索进行系统数据校正的可能性。方法以STAEvolution、CA7000和ACLAdvance凝血分析系统为研究对象,检测247例临床标本的凝血酶原时间(PT)、国际标准化比值(INR)、活化部分凝血活酶时间(APTT)和纤维蛋白原(FIB),通过完全随机区组方差分析和相关性分析,INR按量值水平分为<2、2～3和>3三组进行多个相关样本非参数检验,判断系统差异对抗凝治疗的影响。结果系统间PT、APTT和FIB的差异有统计学意义(F=32.570,P<0.01;F=134.076,P<0.01;F=99.873,P<0.01),STA-R和CA-7000测量PT(r=0.984,P<0.01)和APTT(r=0.944,P<0.01)相关性良好。使用系统特异的ISI时,INR的系统差异有统计学意义(χ2=7.583,P<0.05)。Clauss法FIB定量与演算法的差异有统计学意义(F=99.873,P<0.01),其中ACLAdvance与STA-R的相关性较好(r=0.909,P<0.01),在低浓度区间最接近。结论尽管系统间相关性良好,其差异仍不便用方程式简单校正,提高对试剂性能与溯源性要求,倡导系统特异性对于保证数据准确性至关重要。