Haptoglobin, hemopexin, and related defense pathways—basic science, clinical perspectives, and drug development

Abstract

Hemolysis, which occurs in many disease states, can trigger a diverse pathophysiologic cascade that is related to the specific biochemical activities of free Hb and its porphyrin component heme. Normal erythropoiesis and concomitant removal of senescent red blood cells (RBC) from the circulation occurs at rates of approximately 2 × 106 RBCs/second. Within this physiologic range of RBC turnover, a small fraction of hemoglobin (Hb) is released into plasma as free extracellular Hb. In humans, there is an efficient multicomponent system of Hb sequestration, oxidative neutralization and clearance. Haptoglobin (Hp) is the primary Hb-binding protein in human plasma, which attenuates the adverse biochemical and physiologic effects of extracellular Hb. The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD163. Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization. When Hb is released from RBCs within the physiologic range of Hp, the potential deleterious effects of Hb are prevented. However, during hyper-hemolytic conditions or with chronic hemolysis, Hp is depleted and Hb readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric Hb. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein able to bind heme with high affinity. Hx sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion. In the present review we discuss the components of physiologic Hb/heme detoxification and their potential therapeutic application in a wide range of hemolytic conditions.

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

“…Data obtained in Hx -/-mice indicate that Hx has a key homeostatic role in preserving ventricular function under steady-state, when the physiological rate of hemolysis is very low and is wellcontrolled by physiologic systems such as Hx or haptoglobin [44]. Although a role for pathologic free iron (non-transferrin bound iron, NTBI) has been suggested in non-transfusion-dependent and transfusion-dependent hemolytic anemias [45,46], our data highlight a novel concept that heart might be susceptible to acute exposure to free heme (non-hemopexin bound heme, NHBH), and that Hx critically maintains cardiomyocyte function by scavenging free heme and avoiding cell heme overload ( Figure 7).…”

Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease

“…[1][2][3] To counteract the potentially detrimental effects of Hb and heme, mammals are equipped with extracellular scavenging systems, namely haptoglobin (Hp) and hemopexin (Hx), that bind Hb and heme, respectively. 4 Hp-Hb and Hx-heme complexes are taken up by receptor-mediated endocytosis into macrophages and hepatocytes, respectively. 1,[5][6][7][8][9] Reticulo-endothelial macrophages located in liver and spleen constitute the major sites for the clearance of aged or damaged RBCs.…”

Intravenous infusion of haptoglobin for the prevention of adverse clinical outcome in Sickle Cell Disease

“…In addition, ACEi do not intercept the proposed cascade and hence its usefulness is limited to nephropathy, whereas Hp has the potential of being useful in other SCD-associated events. The idea that Hp can be of therapeutic value in SCD is not new, however, as previously stated by another author, the selection of the appropriate clinical outcome that can readily demonstrate measurable progress has been a challenge to the drug development process [49]. We have outlined a protocol that has the potential to overcome this roadblock.…”

“…Hp infusions have been approved for therapeutic purposes in Japan since 1985 and have been applied in multiple clinical conditions with mostly positive results barring one undetermined outcome [49,50]. No adverse reactions have been reported.…”