Hemolytic anemia is characterized by a shortened survival of red blood cells (RBCs). A large number of diseases are characterized and/or accompanied by hemolysis, including sickle cell disease, autoimmune hemolytic anemia and hemolytic transfusion reactions, paroxysmal nocturnal hemoglobinuria, malaria or microangiopathic hemolytic anemia (e.g. thrombotic thrombocytopenic purpura (TTP), sepsis). Regardless the cause, intravascular destruction results in the release of the intracellular contents of RBCs characterized by clinical symptoms, such as fever, hypotension, disseminated intravascular coagulation (DIC) and organ dysfunction (e.g renal failure). Recent insights show that the destruction of RBC in the circulation culminates in the release of highly effective pro-inflammatory mediators, including hemoglobin, heme and iron. Heme itself is highly cytotoxic by interfering with cellular membranes. The pro-inflammatory effects of these mediators released during hemolysis significantly contribute to morbidity and mortality of hemolytic diseases. Plasma proteins are crucially involved to prevent the deleterious effects of free iron and heme, respectively. Haptoglobin, an Alpha-2-glycoprotein can bind free hemoglobin with a high affinity forming a stable complex, which is efficiently removed via CD163 on macrophages in the liver. Hemopexin (Hpx), a plasma protein with an extremely high binding affinity to heme, forms complexes with heme which are subsequently removed from the circulation via CD91 expressed on macrophages. Although being positive acute phase proteins, both, haptoglobin and Hpx are rapidly consumed due to complex formation with their targets. As a result free hemoglobin and heme can exert their detrimental effects. Therapeutic administration of haptoglobin and Hpx in these clinical situations could potentially limit the detrimental effects of free hemoglobin and heme. The aim of this project is to produce functional Hpx and haptoglobin from plasma and from waste fractions (fraction IV) from Cohn fractionation. Cellular in-vitro tests will be set up in order to test the efficacy of purified Hpx and haptoglobin to neutralize the toxic effects of hemoglobin, heme and iron. The purified functional proteins Hpx and haptoglobin can be used in the future as therapeutic protein in animal models and patients suffering from hemolytic anemia. Unit: The group of Dr. Sacha Zeerleder, which makes part of the department of Immunopathology, is dedicated to study the pathogenesis of inflammation induced by damage-associated molecular pattern (DAMPs), eg. cell-free DNA, histones or heme. The main interest focuses on the specific effects of the various DAMPs in the pathogenesis of inflammation, on the mechanism and regulation of DAMP release and how the detrimental effects of circulating DAMPs can be neutralized efficiently in order to develop therapeutics to improve morbidity and mortality of inflammatory disease. 

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