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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1930-1942
Number of pages13
JournalStroke
Volume54
Issue number7
DOIs
StatePublished - Jul 1 2023

Bibliographical note

Publisher Copyright:
© 2023 American Heart Association, Inc.

Keywords

  • blood
  • haptoglobins
  • hemoglobins
  • subarachnoid hemorrhage
  • therapeutics

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