When red blood cells break apart, they spill heme, the iron-bearing molecule at the core of haemoglobin. Researchers at Lund University have now shown that free heme binds to and activates factor XII, switching on the kallikrein-kinin system, an inflammatory protein cascade in the blood. The cascade releases bradykinin, which dilates vessels and makes them leaky, allowing fluid to escape into tissue and producing swelling, inflammation and falling blood pressure.
The team, led by Diana Karpman, Professor of Paediatrics at Lund University and senior consultant at Skåne University Hospital, studied haemolytic uraemic syndrome, a serious complication of EHEC infection in children marked by red blood cell destruction and acute kidney injury. Using blood samples from 34 affected children alongside healthy controls and experimental models, they found that activation of the cascade correlated with the degree of red cell fragmentation and with kidney involvement. The work appears in Kidney International.
Because haemolysis also occurs in sickle cell anaemia, malaria, trauma, burns, cardiopulmonary bypass and contact with mechanical heart valves, the mechanism may matter well beyond this single syndrome. Encouragingly, the researchers blocked the pathway in their experimental models using C1-inhibitor, a drug already approved for another indication. They caution that this has not been tested in patients, but it marks out a credible therapeutic route for conditions driven by red blood cell breakdown.