Intravenous thrombolysis in acute ischemic stroke after antagonization of unfractionated heparin with protamine: case series and systematic review of literature

Abstract

Background and aims: 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. Objectives: The objective of this study was to investigate the safety and efficacy of IVT in AIS patients after antagonization of unfractionated heparin with protamine. Methods: 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). Results: 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 versus 38.7% of control patients ( p = 0.028). Good clinical outcome at follow-up was observed in 56.3% versus 58.1% of patients ( p = 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% versus 22.6% ( p = 0.236). Conclusion: 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.

Case report: Tenecteplase for acute ischemic stroke after heparin reversal

“…. neutralization, however, suggests that re-checking an activated PTT prior to administering thrombolytics may not be required, especially given the time sensitivity for thrombolysis in AIS (Kneer et al, 2023). In a case series and literature review encompassing 11 patients who received alteplase after heparin reversal with protamine sulfate, two patients had small petechial hemorrhagic infarctions, but no symptomatic intracranial hemorrhages occurred (Ranasinghe et al, 2019).…”

Hemiplegia in acute ischemic stroke: A comprehensive review of case studies and the role of intravenous thrombolysis and mechanical thrombectomy

“…Several reviews have been conducted recently in the field of stroke management, 43 focusing on topics such as early recognition, 44 , 45 , 46 , 47 , 48 novel therapeutics, 49 , 50 , 51 comparison of thrombolytic agents, 52 combination of MT with IVT, 53 and safety and efficacy of IVT after antagonization of unfractionated heparin with protamine, 54 among others. This review critically assesses IVT versus MT within a 4.5‐h window, considering pretreatment and posttreatment NIHSS scales—an aspect overlooked in current literature.…”

Extracellular vesicle encapsulated Homer1a as novel nanotherapeutics against intracerebral hemorrhage in a mouse model

“…As we know, intracerebral hemorrhage (ICH) refers to the hemorrhage caused by the rupture of blood vessels in the brain parenchyma due to hypertension or trauma et al, accounting for 20–30% of the total stroke, [ 1 ] and the mortality rate in the acute phase is 30–40% [ 2 , 3 ]. ICH causes inflammation in the brain and accelerates brain edema, resulting in neuronal damage, and lead to elevated disability and mortality of patients [ 4 ].…”