Department of Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Hampshire, United Kingdom (I.G., S.B., D.B.).
Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (I.G., S.B., D.B.).
Stroke. 2023 Jul;54(7):1930-1942. doi: 10.1161/STROKEAHA.123.040205. Epub 2023 May 26.
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.
颅内 haptoglobin 补充作为一种治疗方法的开发:综述目前的知识和进展,基于德尔菲法达成关于细胞外血红蛋白的病理生理作用的全球共识,并确定临床转化血红蛋白清除治疗的研究重点。蛛网膜下腔出血后,红细胞溶解会在脑脊液中产生游离血红蛋白,这是继发性脑损伤和长期临床预后的重要决定因素。触珠蛋白是人体抵抗游离血红蛋白的第一道防线,通过不可逆地结合血红蛋白,防止血红蛋白向脑实质和脑动脉中对一氧化氮敏感的功能隔室转移。在小鼠和绵羊模型中,脑室内给予触珠蛋白可逆转血红蛋白引起的人类蛛网膜下腔出血的临床、组织学和生化特征。这种策略的临床转化带来了独特的挑战,由新的作用模式和预期的鞘内药物给药需求所带来的挑战,需要利益相关者的早期投入。来自五大洲的 72 名执业临床医生和 28 名科学专家参与了这项德尔菲研究。炎症、微血管痉挛、初始颅内压升高和一氧化氮信号转导中断被认为是决定结局的最重要的病理生理途径。细胞外血红蛋白被认为主要在与铁毒性、氧化应激、一氧化氮和炎症相关的途径中发挥重要作用。尽管有用,但共识认为进一步的临床前工作不是当务之急,大多数人认为该领域已经准备好进行早期临床试验。最高的研究重点是确认触珠蛋白预期的安全性、个体化与标准剂量、治疗时机、药代动力学、药效学和结果测量选择。这些结果突出表明,需要对颅内 haptoglobin 进行颅内 haptoglobin 治疗蛛网膜下腔出血的早期临床试验,并且在临床转化的早期阶段,来自全球临床学科的早期投入具有重要价值。
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