治疗浓度的普通肝素对血小板的激活作用以及与低分子量肝素和直接凝血酶抑制剂的比较。

Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor.

作者信息

Xiao Z, Théroux P

机构信息

Department of Medicine, Montreal Heart Institute and University of Montreal, Quebec, Canada.

出版信息

Circulation. 1998 Jan 27;97(3):251-6. doi: 10.1161/01.cir.97.3.251.

DOI:10.1161/01.cir.97.3.251

PMID:9462526

Abstract

BACKGROUND

The growing use of heparin in acute thrombotic disorders, coupled with the availability of many new antithrombotic agents, emphasizes the need for adequate characterization of the platelet effects of the various anticoagulants. Controversial platelet effects have been reported with heparin (eg, enhanced platelet activation in vitro with high doses and no such effect in vivo at therapeutic doses). This study examined platelet receptor activation and platelet aggregation at therapeutic concentrations of unfractionated heparin (UFH), of enoxaparin, a low-molecular-weight heparin, and of argatroban, a direct thrombin inhibitor.

METHODS AND RESULTS

Platelet P-selectin (CD62) and activated GP IIb/IIIa (PAC-1) expression on platelet membrane was quantified in whole blood as well as platelet aggregation in platelet-rich plasma in 43 patients with unstable angina before and during treatment with UFH or enoxaparin. Studies were also carried out in blood of seven normal volunteers after addition ex vivo of UFH (0.25 U/mL), enoxaparin (0.25 U/mL), argatroban (1 ng/mL), and normal saline. UFH in patients with unstable angina increased the percentage of circulating platelets positive to PAC-1 from 2.7+/-1.7% to 4.4+/-3.4% (P<.05) and to CD62 from 1.6+/-0.9% to 2.7+/-1.5% (P<.01). Platelets were also hyperresponsive to stimulation with ADP and with the thrombin-receptor agonist peptide. Aggregation to ADP increased from 6.8+/-4.6% to 11.2+/-7.0% and to TRAP from 5.2+/-3.5% to 11.1+/-6.0% (P<.001). The addition of UFH to blood of normal volunteers resulted also in activation of GP IIb/IIIa receptors, expression of P-selectin, and enhanced platelet aggregation. Enoxaparin had only minor effects on platelet activation in vivo and ex vivo, and argatroban, evaluated ex vivo, had no detectable effects.

CONCLUSIONS

Therapeutic concentrations of UFH are associated with platelet activation.

摘要

背景

肝素在急性血栓性疾病中的使用日益增加，再加上许多新型抗血栓药物的出现，凸显了充分了解各种抗凝剂对血小板作用的必要性。关于肝素对血小板的作用存在争议（例如，高剂量肝素在体外可增强血小板活化，而治疗剂量在体内无此作用）。本研究检测了普通肝素（UFH）、低分子肝素依诺肝素和直接凝血酶抑制剂阿加曲班在治疗浓度下对血小板受体活化及血小板聚集的影响。

方法与结果

对43例不稳定型心绞痛患者在接受UFH或依诺肝素治疗前及治疗期间，检测全血中血小板P-选择素（CD62）和活化的糖蛋白IIb/IIIa（PAC-1）在血小板膜上的表达，以及富血小板血浆中的血小板聚集情况。还对7名正常志愿者的血液进行了体外实验，分别加入UFH（0.25 U/mL）、依诺肝素（0.25 U/mL）、阿加曲班（1 ng/mL）和生理盐水。不稳定型心绞痛患者使用UFH后，PAC-1阳性循环血小板百分比从2.7±1.7%增至4.4±3.4%（P<0.05），CD62阳性血小板百分比从1.6±0.9%增至2.7±1.5%（P<0.01）。血小板对ADP和凝血酶受体激动肽的刺激也反应过度。对ADP的聚集率从6.8±4.6%增至11.2±7.0%，对凝血酶受体激活肽（TRAP）的聚集率从5.2±3.5%增至11.1±6.0%（P<0.001）。向正常志愿者血液中加入UFH也导致糖蛋白IIb/IIIa受体活化、P-选择素表达及血小板聚集增强。依诺肝素在体内和体外对血小板活化仅有轻微影响，体外评估的阿加曲班无明显作用。