Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, LE3 9QP, UK.
Thromb Haemost. 2013 Jun;109(6):1099-107. doi: 10.1160/TH12-11-0793. Epub 2013 Mar 14.
Previously we demonstrated that heparin administration during carotid endarterectomy (CEA) caused a marked, but transient increase in platelet aggregation to arachidonic acid (AA) and adenosine diphosphate (ADP), despite effective platelet cyclo-oxygenase-1 (COX-1) inhibition with aspirin. Here we investigated the metabolism of AA via platelet 12-lipoxygenase (12-LOX) as a possible mediator of the observed transient aspirin resistance, and compared the effects of unfractionated (UFH) and low-molecular-weight (LMWH) heparin. A total of 43 aspirinated patients undergoing CEA were randomised in the trial to 5,000 IU UFH (n=22) or 2,500 IU LMWH (dalteparin, n=21). Platelet aggregation to AA (4x10⁻³) and ADP (3x10⁻⁶) was determined, and the products of the COX-1 and 12-LOX pathways; thromboxane B₂ (TXB₂) and 12-hydroxyeicosatretraenoic acid (12-HETE) were measured in plasma, and in material released from aggregating platelets.Aggregation to AA increased significantly (10-fold) following heparinisation (p<0.0001), irrespective of heparin type (p=0.33). Significant, but smaller (2-fold) increases in aggregation to ADP were also seen, which were significantly lower in the platelets of patients randomised to LMWH (p<0.0001). Plasma levels of TxB2 did not rise following heparinisation (p=0.93), but 12-HETE increased significantly in the patients' plasma, and released from platelets stimulated in vitro withADP, with both heparin types (p<0.0001). The magnitude of aggregation to ADP correlated with 12-HETE generation (p=0.03). Heparin administration during CEA generates AA that is metabolised to 12-HETE via the 12-LOX pathway, possibly explaining the phenomenon of transient heparin-induced platelet activation. LMWH has less effect on aggregation and 12-HETE generation than UFH when the platelets are stimulated with ADP.
先前我们已经证明，在颈动脉内膜切除术（CEA）期间给予肝素会导致血小板对花生四烯酸（AA）和二磷酸腺苷（ADP）的聚集明显增加，但短暂，尽管阿司匹林有效地抑制了血小板环氧化酶-1（COX-1）。在这里，我们研究了血小板 12-脂氧合酶（12-LOX）代谢 AA 的情况，作为观察到的短暂阿司匹林抵抗的可能介导物，并比较了未分级（UFH）和低分子量（LMWH）肝素的作用。总共随机将 43 名接受 CEA 的患者分为试验组，接受 5000 IU UFH（n=22）或 2500 IU LMWH（达肝素，n=21）。测定 AA（4x10⁻³）和 ADP（3x10⁻⁶）诱导的血小板聚集，并测量 COX-1 和 12-LOX 途径的产物；血栓素 B₂（TXB₂）和 12-羟基二十碳四烯酸（12-HETE）在血浆中和从聚集的血小板中释放的物质中测量。肝素化后 AA 诱导的聚集显着增加（10 倍）（p<0.0001），与肝素类型无关（p=0.33）。ADP 诱导的聚集也显着增加，但较小（2 倍），LMWH 随机分组的患者血小板中明显降低（p<0.0001）。肝素化后血浆 TXB2 水平没有升高（p=0.93），但 12-HETE 在患者血浆中显着增加，并且在两种肝素类型刺激的 ADP 体外刺激的血小板中释放（p<0.0001）。ADP 诱导的聚集程度与 12-HETE 生成相关（p=0.03）。CEA 期间给予肝素会产生 AA，其通过 12-LOX 途径代谢为 12-HETE，这可能解释了短暂肝素诱导的血小板激活现象。当血小板被 ADP 刺激时，LMWH 对聚集和 12-HETE 生成的影响小于 UFH。
