Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation
Authors: Galea Ian , Bandyopadhyay Soham , Bulters Diederik , Humar Rok , Hugelshofer Michael , Schaer Dominik J. , Abdulazim Amr , Alalade Andrew F. , Alexander Sheila A. , Amaro Sergi , Amin-Hanjani Sepideh , Andersen Christopher R. , Anderson Craig , Anstey Matthew H. , Balla József , Bankole Nourou Dine Adeniran , Bellapart Judith , Bhagat Hemant , Blackburn Spiros L. , Brechmann Markus , Buehler ; Paul W. , Burkhardt Jan-Karl , Chen Yujie , Cohen Jeremy , Cooper P. David , Coulthard Liam G. , Cuadrado-Godia Elisa , Dalton Joan , Delaney Anthony , Doré Sylvain , Downer Jonathan , Dye Justin , Fernandez-Perez Isabel , Flower Oliver , Fülesdi Béla , Gaastra Ben , Gaberel Thomas , Galea James , Gankpe Gbetoho Fortuné , Garland Patrick , Gentinetta Thomas , Gram Magnus , Graversen Jonas Heilskov , Grover Patrick J. , Guisado-Alonso Daniel , Hasan David , Helmy Adel , Höhne Julius , Charlotte Hostettler Isabel , Hrishi Ajay Prasad , Iihara Koji , Irwin David C. , Jangra Kiran , Jiménez-O’Shanahan Aruma , Keep Richard F. , Koch Matthew , Korja Miikka , Kumar Munish , Llull Laura , Loan James JM , Lopez-Gonzalez Miguel Ángel , Loch Macdonald R. , Mahajan Shalvi , Martí-Fàbregas Joan , Medina-Suárez Jose , Moestrup Soren , More John , Morgan Eghosa , Muthuchellappan Radhakrishnan , Nyquist Paul , Sosa Pérez Coralia , Pillai Promod , Plesnila Nikolaus , Javier Provencio Jose , Raith Eamon , Ramos-Pachón Anna , Raymond Scott B. , Regli Luca , Ruigrok Ynte Marije , Saharan Poonam , Samaniego Edgar A. , Schubert Gerrit Alexander , Seppelt Ian , Sriganesh Kamath , Suarez Jose I. , Taylor Jonathon , Terpolilli Nicole A. , Testai Fernando D. , Tolosano Emanuela , Toma Ahmed K. , On Tsang Anderson Chun , Udy Andrew A. , Vallelian Florence , Vargas-Caballero Mariana , Vercellotti Gregory M , Vergouwen Mervyn D.I. , Waak Michaela , Warming Hannah , Whitfield Peter C. , Kwok-chu Wong George , Wright Jason , Zuercher Adrian W. 
Published: May 2023

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.