P1490: role of hemolysis and its effects on iron distribution and immune cell polarization linked to organ injury

Topic: 29. Iron metabolism, deficiency and overload Background: Acute or chronic hemolysis occurs in wide-spread pathological conditions, of which cardiopulmonary bypass (CPB) is possibly the most extreme. However, the impact of exposure to hemoglobin (Hb) degradation products, such as heme or non-transferrin bound iron (NTBI) on immune cells and diverse organ functions is poorly understood. Addressing this question is a challenge due to complex interactions between immune cells, erythrocytes, and patient specific risk factors. Increased levels of lysed red blood cells (RBCs) together with an exhaust of endogenous scavengers such haptoglobin (Hp) and hemopexin (Hpx) is associated with a variety of serious clinical events and increased mortality. Aims: The overall aim of this project is to understand the fate of excess heme and NTBI released in conditions of acute hemolysis as observed during CBP. We want to understand how heme and NTBI are detoxified, how this affects immune cell functions (e.g., macrophages) and whether iron accumulation affects not only tissues with known functions for iron recycling but also contributes to pathologies associated with hemolysis in CBP. Methods: We performed a clinical prospective observational study to analyze changes in iron parameters due to cardiopulmonary bypass-associated hemolysis in patients undergoing open-heart aortic valve replacement. Blood was taken before the procedure (T1), directly after the intervention (T2) and on the 3rd postoperative day (POD, T3). Results: Patients whose blood was processed through the heart lung machine developed massive hemolysis, that only normalized by the 3rd POD. Consistently, Hp, a marker of hemolysis after surgery was depleted at T2 and normalized on the 3rd POD. In line, we observed a reduced hematocrit, erythrocyte count, and Hb after surgery at T2, despite the fact that ~50% of patients received allogeneic blood transfusions to compensate for anemia. In addition, patients had significantly increased systemic iron levels at T2 directly after the intervention. On the 3rd POD, free iron was cleared from the circulation and serum ferritin slightly increased. Serum Tf is reduced after the intervention at T2, and a significant increase of the transferrin saturation after the surgery was observed that normalized until the 3rd POD. In addition, patients showed an increase of inflammatory markers exemplified by elevated levels of C-reactive protein and increased numbers of leukocytes. Importantly, CPB patients exhibit exaggerated systemic inflammation and iron-deficiency at the 3rd POD. Furthermore, decreased Tf levels will result in a decreased capacity to handle the excess iron that is released following hemolysis and transfusion. Summary/Conclusion: Acute or chronic hemolysis occurs in wide-spread pathological conditions, including sepsis, pregnancy complications (preeclampsia), genetic disease (e.g., hemoglobinopathies), blood transfusions or due to the application of medical devices, such as hemodialysis or CPB. However, the impact of exposure to hemoglobin degradation products, such as heme or NTBI on immune cells and diverse organ function is poorly understood. Addressing this question is a challenge due to complex interactions between immune cells, erythrocytes, and patient specific risk factors. Future perspectives may include the application of iron scavengers during CPB to prevent heme-induced proinflammatory phenotypic switching of macrophages and to reduce the amount of redox-active serum iron that will induce cellular stress and organ damage. Keywords: Iron