Direct thrombin inhibitors

This review deals with a newly-developed category of antithrombotic drugs – the direct thrombin inhibitors. These agents interact with thrombin and block its catalytic activity on fibrinogen, platelets and other substrates. Heparin and its derivatives (low molecular weight heparins and the active pentasaccharide) inhibit thrombin and/or other coagulation serine proteases indirectly via antithrombin, and the warfarin-type drugs interfere with the synthesis of the precursors of the coagulation serine proteases. The direct thrombin inhibitors approved for clinical use at present (lepirudin, desirudin, bivalirudin, argatroban) and another in the advanced clinical testing stage (melagatran/ximelagatran), are the subject of this review. The chemical structure; kinetics of thrombin inhibition; pharmacokinetics and clinical use of each of these is discussed.     

阿加曲班治疗下肢深静脉血栓及其并发症肺栓塞的临床疗效观察

目的 比较阿加曲班和普通肝素治疗下肢深静脉血栓及其并发症肺栓塞的临床疗效和不良反应。方法 将200例下肢深静脉血栓形成患者随机分成治疗组（100例）和对照组（100例）,对照组患者入院后绝对卧床休息,患肢制动、抬高,忌按压、热敷;使用肝素钠抗凝,肝素钠注射液2 mL＋生理盐水10 mL,用微量泵以2 mL/h持续静脉泵入,治疗7 d后停用普通肝素,改为口服华法令治疗;使用注射用纤溶酶溶栓;合并肺栓塞者给予3 L/min吸氧及前列地尔扩张支气管。治疗组患者给予阿加曲班注射液抗凝,开始2 d,60 mg/d,持续静脉泵入;后5 d,20 mg/d,3 h内泵入,2 次/d。治疗7 d后改为口服华法令,其他治疗方案同对照组患者。治疗时间为2周,比较两组患者治疗前后症状和体征的变化,并在治疗过程中监测凝血酶原时间、活化部分凝血活酶时间及血小板。结果 治疗2周后,两组患者患肢疼痛、肿胀,肺栓塞患者咳嗽、咯血、呼吸困难等症状均有好转,治疗组患者症状改善更明显,且患肢周径较治疗前明显减小（P＜0.05）,治疗组和对照组总有效率分别为98%、90%,两组比较差异有统计学意义（P＜0.05）。治疗组无血小板减少症（HIT）发生,对照组发生1例;对照组与治疗组相比,PT及APTT波动较大,差异有统计学意义（P＜0.05）。结论 阿加曲班治疗下肢深静脉血栓及其并发的肺栓塞与常规普通肝素治疗相比临床疗效及安全性均有提高,值得临床推广。     

阿加曲班治疗轻型急性缺血性脑卒中的疗效及安全性

目的 观察阿加曲班在治疗轻型缺血性脑卒中的疗效和安全性。方法 回顾性选择2022年1月—2022年12月于南方医科大学附属何贤纪念医院神经内科因急性缺血性脑卒中住院的分类为轻型卒中［美国国立卫生研究院卒中量表（NIHSS）小于9分］患者61例为研究对象,根据治疗期间有无规范使用阿加曲班药物治疗分为试验组和对照组,对照组按照常规急性缺血性脑卒中诊疗方案治疗,即在时间窗内对于符合静脉溶栓和机械取栓的患者进行急性期治疗,在非时间窗内就诊的患者进行抗血小板、改善循环、监控血压、血糖等支持治疗;试验组在常规治疗基础上给予阿加曲班注射液治疗,即发病48 h内的患者在入院后24 h内以5 mL·h^-1持续静脉泵入,随后以每天20 mg,分2次以0.9%氯化钠注射液250 mL稀释后静脉滴注,疗程7 d。分别记录患者出院时NIHSS评分及入院与出院NIHSS评分差值,同时记录入院和出院时的改良Rankin（mRS）评分,所有患者均进行系统性检查并进行TOAST分型。记录住院期间的血小板减少、便血或颅内出血等不良事件发生情况。结果 试验组患者住院期间NIHSS评分较对照组改善明显（P<0.05）;但出院时mRS评分良好率（mRS评分为0～2分患者占比）两组比较差异不明显（P>0.05）;两组患者均无不良事件发生。结论 阿加曲班可以改善轻型缺血性卒中患者的临床症状并安全性较高。     

阿加曲班治疗急性缺血性脑卒中的有效性及安全性

 目的 评价国产阿加曲班注射液治疗急性脑梗死的有效性及安全性。方法 将106例急性缺血性脑卒中患者随机分为治疗组和对照组, 每组各53例, 对照组用常规治疗方法 (右旋糖酐-40、尼莫地平、胞磷胆碱钠、阿司匹林等), 治疗组在常规治疗的基础上加用阿加曲班, 用药7 d, 总观察时间为14 d。依据NIHSS评分进行临床疗效评价, 检测肝功能(ALT)、凝血功能(PT、aPTT)、血小板计数(PLT)的变化评价其安全性。结果 治疗组第7天(9.28±3.25)和第14天 (7.61±2.44)NIHSS评分均显著降低, 与治疗前(14.22±4.27)比较, 差异有统计学意义(P<0.05);与对照组第7天(11.86±3.58)、第14天(9.40±3.45)相比, 差异有统计学意义(P<0.05)。两组治疗后ALT、PT、aPTT和PLT与治疗前比较, 差异无统计学意义。结论 阿加曲班治疗急性缺血性脑卒中临床效果确切, 无明显出血倾向及不良反应, 值得推广。
     

Treatment of heparin-induced thrombocytopenia in cardiovascular patients

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated syndrome associated with heparin exposure, a falling platelet count and a high risk of thrombosis. Cardiovascular patients are at increased risk of HIT due to wide use of heparin in this population. Should HIT be suspected, heparin must be avoided in most situations, and anticoagulation with an alternative anticoagulant should be instituted. Preferred agents include the direct thrombin inhibitors argatroban and lepirudin, whilst bivalirudin or desirudin (other direct thrombin inhibitors) can be used in some situations. The indirect thrombin inhibitors, danaparoid and fondaparinux, can also be considered at times. These agents and their use in cardiac patients, including patients with acute coronary syndrome, percutaneous coronary interventions, acute ST elevation myocardial infarction or cardiac surgery, will be reviewed.     

阿加曲班治疗脑梗死的研究进展

传统抗凝剂由于安全性等原因,在脑梗死的治疗中受到较多限制。阿加曲班作为新型抗凝剂的典型代表之一,具有单靶点、半衰期短、量效稳定等特点,从而全面提高了临床抗凝的安全性。阿加曲班在脑梗死治疗方面积累了大量的研究和证据,但尚缺乏系统的梳理。按照TOAST分型、OCSP分型以及不同的治疗时机,对阿加曲班治疗脑梗死的研究进行分类介绍,以期为脑梗死的抗凝治疗和阿加曲班的临床应用提供更多依据和建议。     

Argatroban during percutaneous transluminal coronary angioplasty: Results of a dose-verification study

Background. Thrombin is a key enzyme in thrombogenesis. In animals, specific antithrombotic therapy at the time of coronary angioplasty reduced the incidence of subacute occlusion and inhibited the restenosis response. Argatroban is a highly selective synthetic thrombin antagonist that binds in a competitive manner. This is a report of a dose-verification study, assessing the safety and feasibility of intravenous Argatroban administration in patients undergoing percutaneous transluminal coronary angioplasty. Methods. Before angioplasty an intravenous bolus of 30 g/kg argatroban was administered, followed by a continuous infusion of 3.5 g/kg/min for 72 hours. Bolus injection was repeated, and the infusion rate was increased in order to achieve an activated coagulation time (ACT) of over 300 seconds. Following interim analysis, the bolus and initial infusion rate for the subsequent treatment groups was determined. Study endpoints were the occurrence of adverse events, coagulation tests, and qualitative angiogram reading. Patients were monitored by continuous 12-lead electrocardiographic recording over 24 hours, and underwent control angiography 18–24 hours following angioplasty. Results. Four treatment groups, comprised of 2, 8, 9, and 11 patients, respectively, were studied. The first two patients were excluded from analysis, since the initial dose was ineffective to attain an ACT-authorizing coronary angioplasty. The group with the highest dosage received a 250 g/kg intravenous bolus of argatroban, followed by a 4 hour infusion of 15 g/kg/min. At 4 hours the infusion rate was lowered to 3.8 g/kg/min and was continued for 68 hours without adjustment for catheter removal. The adverse event profile included myocardial infarction, aortocoronary bypass graft, bailout procedures, and repeat coronary angioplasty. Thrombin-time (TT), activated partial thromboplastin time (APTT), and prothrombin time (PT) were significantly related to argatroban plasma concentration, as demonstrated by regression analyses (R-square 0.64, 0.71, and 0.84, respectively). Prothrombin fragments 1 and 2 and thrombin-antithrombin III complex did not fit into a mathematical model, but showed slightly increased levels after reduction or cessation of the infusion rate. Conclusions. This dose-verification study, including 30 patients at four dose levels, indicated that argatroban infusion in coronary angioplasty patients can be administered safely, and results in an adequate and predictable level of anticoagulation.     

阿加曲班对下肢动脉硬化闭塞合并血栓形成老年患者的疗效及对凝血功能的影响

目的 探讨阿加曲班对下肢动脉硬化闭塞合并急性血栓形成的老年患者的治疗效果以及治疗过程中对凝血功能的影响。方法 回顾性选取2018年5月—2021年10月民航总医院收治的下肢动脉硬化闭塞合并急性血栓形成的年龄≥65岁的老年患者67例,随机分为对照组（n＝33）和试验组（n＝34）,对照组采用那屈肝素钙注射液（每次4 100 U,每12小时给药1次）抗凝,试验组采用阿加曲班注射液（20 mg加入到160 mL 0.9%氯化钠注射液中,泵速20 mL·h⁻¹,每天2次,2次之间间隔2 h）抗凝,两组患者均连续治疗7 d。比较两组患者治疗效果、凝血功能指标变化及治疗过程中并发症及不良反应发生的情况。结果 治疗后,对照组总有效率为78.79%;试验组总有效率为82.35%,两组总有效率比较,差异无统计学意义（P＞0.05）。与治疗前相比,治疗后两组患者D-二聚体、纤维蛋白原（FBG）、血小板计数（PLT）水平均显著降低（P＜0.05）,活化部分凝血活酶时间（APTT）、凝血酶原时间（PT）明显延长（P＜0.05）,血浆黏度及红细胞比积均显著降低（P＜0.05）;治疗第3天试验组D-二聚体水平显著低于对照组（P＜0.05）;治疗后试验组FBG、血浆黏度、红细胞比积水平降低程度,APTT、PT延长程度与对照组比较差异无统计学意义（P＞0.05）。试验组不良反应发生率显著低于对照组（P＜0.05）。结论 阿加曲班治疗下肢动脉硬化闭塞合并急性血栓形成的老年患者临床疗效显著,对患者D-二聚体、FBG、APTT、PT指标改善有积极作用,并可调节血液流变学状态,安全性高。     

Management of heparin-induced thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) is a rare but severe prothrombotic adverse effect of heparin treatment. The underlying cause is the formation of highly immunogenic complexes between negatively charged heparin and positively charged platelet factor 4 (PF4). Resulting antibodies against these PF4/heparin complexes can activate platelets via the platelet FcγIIa receptor, leading to thrombin generation and thus to the paradox of a prothrombotic state despite thrombocytopenia and application of heparin. Prompt diagnosis of HIT is important in order to change treatment to prevent severe thromboembolic complications. However, this is often difficult as thrombocytopenia is frequent in hospitalized patients and the commercially available laboratory tests for HIT antibodies have a high negative predictive value but only a poor positive predictive value. This leads to overdiagnosis and overtreatment of HIT, which also bear the risk for adverse outcomes.

Areas covered: This review aims at resuming recent data on HIT, thereby focusing on the role of new anticoagulants and providing a framework for diagnosis and treatment. Furthermore, it provides some insights into the pathogenesis of this peculiar adverse drug reaction and ventures a guess at its future relevance in clinical practice.

Expert opinion: New drugs which are strongly negatively charged should be assessed for their capacity to form complexes with PF4. If they do so, they bear the risk of inducing a HIT-like immune response. The immunology of HIT is still largely unresolved. Understanding HIT might provide insights into other immune and autoimmune response mechanisms.