【原】新型P2Y12抑制剂Cangrelor在心脏手术中预防肝素诱导血小板凝聚的潜力和局限性：体外研究

罂粟花anesthGH 2021-07-21

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新型P2Y₁₂抑制剂Cangrelor在心脏手术中预防肝素诱导血小板凝聚的潜力和局限性：体外研究

翻译：任文鑫编辑：冯玉蓉审校：曹莹

背景：肝素诱导的血小板减少症(HIT)会使心脏手术患者面临致命并发症的高风险。如果存在抗PF4/肝素抗体(抗PF4/Hep Ab)，有两种方案可防止搭桥术中的血小板聚集：第一，使用替代抗凝剂，第二，肝素和抗聚集剂联合使用。新型P2Y₁₂抑制剂——Cangrelor，可能是后一种方案中一个有价值的候选药物，一些研究者已经报告了它的成功应用。本项体外研究评价了Cangrelor在抗PF4/Hep抗体存在情况下抑制肝素诱发的血小板聚集的能力。

方法：将30例功能性抗PF4/Hep 抗体阳性患者的血小板缺乏性血浆(PPP)与5例健康献血者血小板富集性血浆(PRP)混合。

在血浆中加入0.5 IU·mL⁻¹肝素（HIT）后，使用光透射聚集法测量血小板聚集，并与添加生理盐水的样品（对照组）、加入Cangrelor 500 ng·mL⁻¹和肝素0.5 IU·mL⁻¹（处理组）的样品进行比较。组间比较采用Friedman检验和事后Dunn-Bonferroni检验。

结果：肝素0.5 IU·mL⁻¹触发了44种PPP-PRP混合物中的22种发生聚集，中位数聚集率为86%（四分位间距[IQR]，69-91）。这22个阳性样本各自对照试验的中位数聚集率为22%（IQR，16-30）（P<0.001）。Cangrelor处理的样本的中位数聚集率为29%（IQR，19–54），显著低于HIT样本（P<0.001）。Cangrelor抑制肝素诱导的血小板聚集的中位数为91%（IQR，52-100）。在22个阳性样本中有10例（45%）样本，Cangrelor抑制肝素诱发的血小板聚集＞95%。在22个阳性样本中有5个(22%)样本，Cangrelor抑制肝素诱发的血小板聚集<50%；有3例样本(14%)，Cangrelor抑制肝素诱发的血小板聚集<10%。

结论：本项体外研究发现，在抗PF4/Hep抗体存在的情况下，Cangrelor并非肝素诱发血小板聚集的可靠抑制剂。我们的结论是，Cangrelor不应作为标准抗血小板聚集药用于心脏病患者，其手术期间受HIT影响。除非Cangrelor对特定患者的疗效已在术前血小板聚集试验中得到确认，否则应选择其他方案。

文献来源：Emmanuelle Scala, MD,Christiane Gerschheimer,Francisco J. Gomez,Lorenzo Alberio, MD,and Carlo Marcucci, MD.Potential and Limitations of the New P2Y12 Inhibitor, Cangrelor, in Preventing Heparin-Induced Platelet Aggregation During Cardiac Surgery: An In Vitro Study.[J]Anesth Analg 2020;131:622–30.

Potential and Limitations of the New P2Y12 Inhibitor, Cangrelor, in Preventing Heparin-Induced Platelet Aggregation During Cardiac Surgery: An In Vitro Study

Abstract

BACKGROUND: Heparin-induced thrombocytopenia (HIT) can put cardiac surgery patients at a high risk of lethal complications. If anti-PF4/heparin antibodies (anti-PF4/Hep Abs) are present, 2 strategies exist to prevent intraoperative aggregation during bypass surgery: first, using an alternative anticoagulant, and second, using heparin combined with an antiaggregant. The new P2Y12 inhibitor, cangrelor, could be an attractive candidate for the latter strategy; several authors have reported its successful use. The present in vitro study evaluated cangrelor’s ability to inhibit heparin-induced platelet aggregation in the presence of anti-PF4/Hep Abs.

METHODS: Platelet-poor plasma (PPP) from 30 patients with functional anti-PF4/Hep Abs was mixed with platelet-rich plasma (PRP) from 5 healthy donors.

Light transmission aggregometry was used to measure platelet aggregation after adding 0.5 IU·mL−1 of heparin (HIT) to the plasma, and this was compared with samples spiked with normal saline (control) and samples spiked with cangrelor 500 ng·mL−1 and heparin 0.5 IU·mL−1(treatment). Friedman test with post hoc Dunn-Bonferroni test was used for between-group comparisons.

RESULTS: Heparin 0.5 IU·mL−1 triggered aggregation in 22 of 44 PPP–PRP mixtures, with a median aggregation of 86% (interquartile range [IQR], 69–91). The median aggregation of these 22 positive samples’ respective control tests was 22% (IQR, 16–30) (P < .001). Median aggregation in the cangrelor-treated samples was 29% (IQR, 19–54) and significantly lower than the HIT samples (P < .001). Cangrelor inhibited heparin-induced aggregation by a median of 91% (IQR, 52–100). Cangrelor only reduced heparin-induced aggregation by >95% in 10 of the 22 positive samples (45%). Cangrelor inhibited heparin induced aggregation by <50% in 5 of the 22 positive samples (22%) and by <10% in 3 samples (14%).

CONCLUSIONS: This in vitro study found that cangrelor was an unreliable inhibitor of heparin-induced aggregation in the presence of anti-PF4/Hep Abs. We conclude that cangrelor should not be used as a standard antiaggregant for cardiac patients affected by HIT during surgery. Unless cangrelor’s efficacy in a particular patient has been confirmed in a presurgery aggregation test, other strategies should be chosen.