Kneer Katharina, Adeyemi Adedolapo Kamaldeen, Sartor-Pfeiffer Jennifer, Wilke Vera, Blum Corinna, Ziemann Ulf, Poli Sven, Mengel Annerose, Feil Katharina
Centre for Neurovascular Diseases Tübingen (ZNET), Tübingen, Germany.
Department of Neurology and Epileptology, Eberhard Karl University of Tübingen, Tübingen, Germany.
Ther Adv Neurol Disord. 2023 Jan 24;16:17562864221149249. doi: 10.1177/17562864221149249. eCollection 2023.
Intravenous thrombolysis (IVT) is standard of care for disabling acute ischemic stroke (AIS) within a time window of ⩽ 4.5 h. Some AIS patients cannot be treated with IVT due to limiting contraindications, including heparin usage in an anticoagulating dose within the past 24 h or an elevated activated prothrombin time (aPTT) > 15 s. Protamine is a potent antidote to unfractionated heparin.
The objective of this study was to investigate the safety and efficacy of IVT in AIS patients after antagonization of unfractionated heparin with protamine.
Patients from our stroke center (between January 2015 and September 2021) treated with IVT after heparin antagonization with protamine were analyzed. National Institutes of Health Stroke Scale (NIHSS) was used for stroke severity and modified Rankin Scale (mRS) for outcome assessment. Substantial neurological improvement was defined as the difference between admission and discharge NIHSS of ⩾8 or discharge NIHSS of ⩽1. Good outcome at follow-up after 3 months was defined as mRS 0-2. Safety data were obtained for mortality, symptomatic intracerebral hemorrhage (sICH), and for adverse events due to protamine. Second, a systematic review was performed searching PubMed and Scopus for studies and case reviews presenting AIS patients treated with IVT after heparin antagonization with protamine. The search was limited from January 1, 2011 to September 29, 2021. Furthermore, we conducted a propensity score matching comparing protamine-treated patients to a control IVT group without protamine (ratio 2:1, match tolerance 0.2).
A total of 16 patients, 5 treated in our hospital and 11 from literature, [65.2 ± 13.1 years, 37.5% female, median premorbid mRS (pmRS) 1 (IQR 1, 4)] treated with IVT after heparin antagonization using protamine were included and compared to 31 IVT patients [76.2 ± 10.9 years, 45% female, median pmRS 1 (IQR 0, 2)]. Substantial neurological improvement was evident in 68.8% of protamine-treated patients 38.7% of control patients ( = 0.028). Good clinical outcome at follow-up was observed in 56.3% 58.1% of patients ( = 0.576). No adverse events due to protamine were reported, one patient suffered sICH after secondary endovascular thrombectomy of large vessel occlusion. Mortality was 6.3% 22.6% ( = 0.236).
IVT after heparin antagonization with protamine seems to be safe and, prospectively, may extend the number of AIS patients who can benefit from reperfusion treatment using IVT. Further prospective registry trials would be helpful to further investigate the clinical applicability of heparin antagonization.
静脉溶栓（IVT）是治疗发病时间≤4.5小时的致残性急性缺血性卒中（AIS）的标准治疗方法。由于存在限制使用的禁忌证，一些AIS患者无法接受IVT治疗，这些禁忌证包括在过去24小时内使用过抗凝剂量的肝素或活化凝血酶原时间（aPTT）升高>15秒。鱼精蛋白是普通肝素的有效解毒剂。
本研究的目的是探讨用鱼精蛋白拮抗普通肝素后对AIS患者进行IVT治疗的安全性和有效性。
对我们卒中中心（2015年1月至2021年9月）在用鱼精蛋白拮抗肝素后接受IVT治疗的患者进行分析。采用美国国立卫生研究院卒中量表（NIHSS）评估卒中严重程度，采用改良Rankin量表（mRS）评估预后。显著神经功能改善定义为入院时与出院时NIHSS差值≥8或出院时NIHSS≤1。3个月随访时良好预后定义为mRS 0 - 2。获取死亡率、症状性脑出血（sICH）以及鱼精蛋白所致不良事件的安全性数据。其次，进行系统评价，在PubMed和Scopus上检索关于用鱼精蛋白拮抗肝素后接受IVT治疗的AIS患者的研究和病例报告。检索时间限制为2011年1月1日至2021年9月29日。此外，我们进行了倾向评分匹配，将接受鱼精蛋白治疗的患者与未使用鱼精蛋白的对照IVT组进行比较（比例2:1，匹配容差0.2）。
共纳入16例在用鱼精蛋白拮抗肝素后接受IVT治疗的患者，其中5例在我院治疗，11例来自文献报道，[年龄65.2±13.1岁，女性占37.5%，病前mRS中位数（pmRS）为1（四分位间距1, 4）]，并与31例IVT患者[年龄76.2±10.9岁，女性占45%，pmRS中位数为1（四分位间距0, 2）]进行比较。68.8%接受鱼精蛋白治疗的患者有显著神经功能改善，而对照患者为38.7%（P = 0.028）。随访时56.3%的患者有良好临床结局，对照患者为58.1%（P = 0.576）。未报告鱼精蛋白所致不良事件，1例患者在大血管闭塞的二期血管内血栓切除术后发生sICH。死亡率分别为6.3%和22.6%（P = 0.236）。
用鱼精蛋白拮抗肝素后进行IVT似乎是安全的，并且前瞻性地可能会增加能够从IVT再灌注治疗中获益的AIS患者数量。进一步的前瞻性注册试验将有助于进一步研究肝素拮抗的临床适用性。
