Bleeding in vain? How unravelling the mechanisms of dysfunctional oxygen transport in Chronic Mountain Sickness can also deliver better treatments for a neglected disease and wider societal impacts in LMICs with significant highlander populations

Adequate tissue oxygenation is a physiological priority and clinical imperative that necessitates a molecule-to-systems approach to study mechanistically. However, our current understanding cannot explain the paradox why some highlanders develop tissue hypoxia despite a vast increase in the blood’s oxygen-carrying capacity through erythrocytosis, manifesting as chronic mountain sickness (CMS): a debilitating yet neglected disease. We hypothesise a vicious cycle, wherein exposure to a hyper-viscous and chemically-stressed milieu of CMS blood impairs oxygen release from red cells, driving excessive erythropoiesis. We now have the opportunity to interrogate this maladaptive process, down to molecular detail, in humans using innovative techniques by leveraging on a timely need to trial the consequences of phlebotomy, a traditional treatment aimed at resetting the vicious cycle, against a refinement called isovolumic haemodilution. To incentivise public healthcare to provide the best care for CMS patients, we will establish methods to repurpose discarded blood as a product for banking, thereby addressing eminent transfusion shortages in countries with significant highlander populations. Our project, strategically set in the Peruvian Andes, Lima, and Oxford, will address the knowledge-gap in oxygen transport and deliver more personalised treatment guidelines for the global population at risk of CMS and innovative pipelines for increasing blood stocks.