Heparin-induced thrombocytopenia from venous thromboembolism treatment

OBJECTIVES: We aimed to characterize the clinical experiences of patients in whom heparin-induced thrombocytopenia (HIT) complicated heparin therapy for venous thromboembolism (VTE) and who switched to argatroban. DESIGN: A retrospective analysis of previously reported prospective, multicentre, historical-controlled Argatroban-911 and Argatroban-915 studies of argatroban therapy in HIT. SETTING: Inpatient. SUBJECTS: Patients (n = 145) administered heparin for VTE and who developed HIT were identified. INTERVENTIONS: Patients were treated with argatroban 2 mcg kg(-1) min(-1) for up to 14 days, adjusted to maintain activated partial thromboplastin times 1.5 to three times baseline. Patient characteristics, anticoagulation and outcomes were summarized. The primary end-point was a composite of death, amputation, or new thrombosis within 37 days of argatroban initiation. RESULTS: During heparin therapy, platelet counts decreased (mean +/- SD nadir: 78 +/- 67 x 10(9) L(-1)), and 75 (52%) patients developed thrombosis. After heparin was discontinued, patients received argatroban (mean dose 2.1 +/- 1.2 mcg kg(-1) min(-1)) for 6.8 +/- 4.3 days. By day 6 of argatroban therapy, the mean platelet count rose to >150 x 10(9) L(-1). The primary end-point occurred in 41 (28.3%) patients (values of 26-44% are reported for argatroban therapy of HIT from any heparin indication). Seventeen (11.7%) patients, including 12 who had also experienced thrombosis whilst on heparin, developed new thrombosis after argatroban initiation, typically on the day argatroban was discontinued or later (n = 10). Seven (4.8%) patients experienced major bleeding. CONCLUSIONS: For VTE patients with HIT, argatroban provides effective anticoagulation, with outcomes comparable with those reported for other argatroban-treated HIT patients. New thrombosis in this setting occurred most often in patients with existing HIT-associated thrombosis, before HIT recognition or either at/after argatroban discontinuation.     

Heparin-Induced Thrombocytopenia in Patients Administered Heparin Solely for Hemodialysis

Background. Heparin, universally used in patients on dialysis, is the cause for immune-mediated heparin-induced thrombocytopenia (HIT). Methods. From an HIT registry, six patients were identified who received recent heparin solely for dialysis, developed HIT, and were treated with argatroban. Platelets counts, aPTTs, argatroban dosing, and outcomes were assessed. Results. Before HIT was diagnosed, unfractionated heparin was used in doses of 2,000–12,000 units. The mean platelet count fell from 122 ± 62 × 10⁹/L to 35 ± 22 × 10⁹/L, and one patient experienced thrombosis. After HIT was diagnosed, heparin was discontinued, and argatroban therapy (mean dose, 1.7 ± 0.9 μg/kg/min) was administered for 6.5 ± 4.5 days (mean aPTT, 66.1 ± 12.4 s). Patients continued on renal replacement therapy. Platelet counts increased during argatroban therapy. A 37-day composite endpoint of death, amputation, or new thrombosis occurred in four (66.7%) patients: three patients died from causes unrelated to thrombosis, and one patient developed new thrombosis after argatroban was discontinued. One patient experienced a hematocrit drop during treatment without overt bleeding or a need for transfusion. Conclusions. HIT can occur in patients administered heparin solely for hemodialysis. When HIT is suspected, heparin should be discontinued and an alternative anticoagulation initiated. Argatroban, which is not renally cleared, supports continued renal replacement therapy in HIT patients.     

氯吡格雷联合阿加曲班治疗大动脉粥样硬化性脑梗死疗效及安全性的Meta分析

目的 系统评价氯吡格雷与阿加曲班联合治疗大动脉粥样硬化性脑梗死的疗效及安全性。方法 检索中国知网(CNKI)、中文科技期刊数据库(VIP)、万方数据库(Wanfang Data)、生物医学文摘数据库(CBM),以及Pubmed、Cochrane Library、Embase数据库,检索建库至2019年10月31日所有氯吡格雷联合阿加曲班治疗脑梗死患者的文献,对符合纳入和排除标准的随机对照试验(Randomized controlled trial, RCT)进行数据提取和质量评价,应用Review Manager 5.3软件进行Meta分析。结果 共有7篇随机对照试验678例研究对象满足纳入标准。其中氯吡格雷联合阿加曲班组的总有效率高于对照组,合并效应量OR=4.39(P<0.001),联合治疗组能够降低治疗2周后患者的神经功能缺损(NIHSS)评分, 变化均数差MD=-1.97(P<0.001),同时能够明显增加治疗2周后Barthel改变均数差(MD=7.85,P<0.001)。联合治疗组与单用氯吡格雷治疗组相比,出血不良反应并无明显增加(OR=0.72)。结论 氯吡格雷与阿加曲班联合治疗大动脉粥样硬化性脑梗死具有良好的疗效,可提高治疗总有效率,患者短期神经功能缺损及日常生活能力得到显著改善,出血不良反应并无显著增加。     

阿加曲班原料药中催化剂钯残留监测方法建立

目的：建立凝血酶抑制剂阿加曲班原料药中催化剂钯的残留量测定方法。方法采用石墨炉原子吸收分光光度法测定阿加曲班中钯的残留量。试验条件：光源为钯空心阴极灯,波长247.6 nm,狭缝0.5 nm,灯电流10 mA,燃烧器高度2 mm,石墨管以横向加热方式,氩气压力0.4 MPa,进样体积20μL,背景校正D2,石墨炉程序升温。结果钯在0.015－0.2μg·mL-1范围内与吸光度呈良好的线性关系（r=0.9996）;检出限为0.00057μg·mL-1;特征浓度为0.00107μg·mL-1;平均回收率为99.8%;RSD 为4.08%（n=9）。结论该方法经方法学验证可用于阿加曲班原料药中痕量钯含量的测定,可为该原料药质量标准的完善提供参考。     

阿加曲班联合阿司匹林序贯治疗对进展性脑卒中的疗效观察

目的 观察阿加曲班注射液联合阿司匹林肠溶片序贯治疗对进展性脑卒中的疗效。方法 选取2019年1月1日—2021年4月1日重庆市巴南区第二人民医院神经内科收治的91例进展性脑卒中患者为研究对象,进行回顾性研究。根据治疗方法将患者分为对照组（n=54）和观察组（n=37）。两组患者均予以改善循环、稳定斑块等常规治疗;对照组给予阿司匹林肠溶片100 mg/次,1次/d;观察组予以阿加曲班注射液60 mg/次,1次/d,24 h持续静脉泵入,第3～7天改为10 mg/次,2次/d,静脉滴注,7 d后予以阿司匹林肠溶片100 mg/次,1次/d,两组均治疗14 d。观察两组患者的临床疗效,比较两组患者治疗后及出院后3个月美国国立卫生研究院脑卒中（NIHSS）量表评分及改良Rankin量表（mRS）评分,并观察出血、神经功能恶化、过敏等不良事件发生情况。结果 两组治疗14 d后,观察组总有效率为81.08%,显著高于对照组的57.41%（P<0.05）。治疗14 d后,观察组NIHSS评分较对照组显著降低（P<0.05）;出院3个月后观察组NIHSS评分也显著低于对照组（P<0.05）,且mRS评分较对照组显著降低（P<0.05）。观察组和对照组的总药物不良反应发生率分别为8.1%和9.2%,差异无统计学意义（P>0.05）。结论 阿加曲班注射液联合阿司匹林肠溶片序贯治疗能减轻进展性脑卒中患者的神经功能缺损,并能有效改善3个月后的日常独立生活能力,且不增加出血等不良事件的发生率。     

Argatroban for anticoagulation during cardiopulmonary bypass in an infant

Heparin induced thrombocytopenia (HIT) is a rare, but potentially life-threatening complication of heparin therapy. In patients with HIT, alternative means of anticoagulation are necessary. The authors present an infant with HIT who required anticoagulation during cardiopulmonary bypass for tricuspid valve excision in the treatment of bacterial endocarditis. The direct thrombin inhibitor, argatroban, was successfully used. Previous reports regarding the use of argatroban and other nonheparin anticoagulants for anticoagulation are reviewed and suggestions regarding argatroban dosing in infants are presented.     

Argatroban Anticoagulation in Conjunction with Glycoprotein IIb/IIIa Inhibition in Patients Undergoing Percutaneous Coronary Intervention: An Open-Label,Nonrandomized Pilot Study

Background: Argatroban, a direct thrombin inhibitor, blocks clot-bound thrombin more effectively than does heparin. This multicenter, prospective pilot study evaluated the efficacy and safety of argatroban in combination with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention.Methods: Patients (N = 152) received argatroban as a 250- or 300-g/kg bolus, followed by a 15-g/kg/min infusion during percutaneous coronary intervention. An additional 150-g/kg bolus was administered if activated clotting times 5–15 min after initiating argatroban were <275 s. Abciximab (N = 150) or double-bolus eptifibatide (N = 2) was administered simultaneously.Results: Median activated clotting times at the beginning and end of the procedure were approximately 300 s. The primary efficacy endpoint—a composite of death, myocardial infarction, or urgent revascularization at 30 days—occurred in 4 (2.6%) patients (no death, 4 myocardial infarctions, and 2 revascularizations). Two (1.3%) patients had major bleeding by the Thrombolysis in Myocardial Infarction criteria (1 retroperitoneal, 1 groin hematoma).Conclusions: Argatroban in combination with glycoprotein IIb/IIIa inhibition appears to provide adequate anticoagulation and be well tolerated with an acceptable bleeding risk for patients undergoing percutaneous coronary intervention. Additional studies are warranted.     

Heparin and the thrombin inhibitor argatroban enhance fibrinolysis by infused or bolus-injected saruplase (r-scu-PA) in rabbit femoral artery thrombosis

Enhancement by anticoagulation of thrombolysis with infused or bolus-injected saruplase (r-scu-PA) has been studied using heparin and the thrombin inhibitor argatroban. In a rabbit femoral artery thrombosis model infusion of saruplase (3 – 12 mg/kg, 60 min) caused a dose-dependent thrombolysis. Reperfusion rate after infusion of 3 mg/kg saruplase alone was 3/6, reperfusion time 42 ± 3 min and reocclusion rate 2/3; final patency rate at 120 min was 17 %. Combination of 3 mg/kg saruplase with heparin (150 U/kg + 100 U/kg hr i.v.; 5.3-fold PTT-prolongation) resulted in a reperfusion rate of 6/6 after a reperfusion time of 39 ± 7 min; reocclusion rate was 3/6 and final patency rate was 50 %. Argatroban (1 mg/kg + 3 mg/kg.hr i.v.; 2.3-fold PTT prolongation) in combination with saruplase resulted in a reperfusion rate of 6/6 after 26 ± 5 min; no reocclusion occured and final patency rate was 100 % (p < 0.05 vs saruplase alone). Bolus injection of 6 mg/kg saruplase achieved reperfusion in 5/6 arteries after 15 ± 3 min, but reocclusion rate was 4/5; final patency rate was 17 %. Combination of bolus-injected saruplase with heparin resulted in a reperfusion rate of 4/6 after 8 ± 3 min and no reocclusion occured; patency rate was 67 %. With combination of argatroban and bolus-injected saruplase 6/6 arteries were reperfused after 8 ± 3 min; reocclusion was prevented and final patency rate was 100 % (p < 0.05 vs saruplase-bolus alone). Systemic fibrinogenolysis was more pronounced with bolus injection than infusion of saruplase. The results indicate that arterial thrombolysis with saruplase can be enhanced by heparin and the thrombin inhibitor argatroban. The bolus injection of saruplase resulted in persistent reperfusion when simultaneous anticoagulation was performed. Despite less PTT prolongation, enhancement of saruplase-induced thrombolysis was more effective with argatroban than with heparin in rabbit femoral artery thrombosis.     

Frequent off-label use of fondaparinux in patients with suspected acute heparin-induced thrombocytopenia (HIT) – findings from the GerHIT multi-centre registry study

Introduction

In life-threatening immune heparin-induced thrombocytopenia (HIT), treatment with an approved non-heparin anticoagulant is essential. However, off-label use with fondaparinux has been reported in the literature. The study aim was to collect data on “real-life” management of patients with suspected acute HIT regarding diagnostic and therapeutic strategies.

Patients and Methods

In a national multi-centre registry study, patients with a 4 T’s HIT-probability score of ≥ 4 points and treatment with at least one dose of (A)rgatroban, (L)epirudin, (D)anaparoid, or (F)ondaparinux were retrospectively evaluated.

Results

Of 195 patients, the 4 T’s scores were 4/5/6/7/8 points in 46 (23.6%)/50 (25.6%)/74 (38.0%)/13 (6.7%)/7 (3.6%) patients, respectively. During heparin therapy, 47 (24.1%) thromboembolic events, 5 (2.6%) skin lesions, 1 (0.5%) amputation, 24 (12.3%) Hb-relevant bleedings, and 2 (1.0%) fatalities occurred. A functional heparin-induced platelet activation assay was performed in 96.9%, a platelet factor 4/heparin-dependent enzyme immunoassay in 89.2%, a particle gel immunoassay in 12.3%, and a serotonin-release assay in none of the patients. Argatroban was used in 16.4%, lepirudin in 2.1%, danaparoid in 23.6%, fondaparinux in 40.0% of the patients; the sequential therapy strata were: AF (5.6%), DA (5.6%), DF (2.6%), DL (2.1%), ADF (1.5%), and DFL (0.5%).

Conclusions

The current diagnostic laboratory strategy for suspected HIT is mostly (> 96%) based on the recommended 2-step strategy (immunoassay plus functional assay). However, there is a wide fondaparinux off-label use (up to 50.3%) for suspected HIT, even in those patients with a high clinical pretest probability. Efficacy and safety of fondaparinux for HIT-treatment require further evaluation.     

阿加曲班治疗急性缺血性卒中疗效及安全性的系统评价及Meta分析

目的：目前阿加曲班在急性缺血性卒中（acute ischemic stroke,AIS）中的疗效和安全性尚存在争议,临床应用仍存在较大分歧。本文将针对阿加曲班治疗AIS的疗效和安全性展开系统性评价及Meta分析。方法：计算机检索通过PubMed、The Cochrane library、Embase、ClinicalTrials.gov、中国知网（China National Knowledge Infrastructure,CNKI）、中国生物医学文献数据库（China Biology Medicine disc,CBM）、维普网及万方数据知识服务平台收集应用阿加曲班治疗AIS的全部文献,检索的设定时间截至2022年4月。由2名受过培训的研究人员对文献进行筛选、数据提取和偏倚风险评估。采用RevMan 5.4软件对数据进行Meta分析。结果：共有25篇文献纳入本次Meta分析,共包含AIS患者4 696例（其中阿加曲班组2 271例,对照组2 425例）。Meta分析结果显示：阿加曲班能促进AIS患者早期神经功能改善（OR=2.69,95%CI=1.66～4.34,P<0.00...