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