A model of ?,?-hemoglobin/haptoglobin hexamer complex. There are 2 ?,?-hemoglobin dimers depicted: one space filling model (yellow/orange), and one ribbon model (purple/blue). Each is bound by a haptoglobin molecule (both haptoglobin molecules are shown in pink, with one as a space filling model and one as a ribbon model).
In clinical settings, the haptoglobin assay is used to screen for and monitor intravascular hemolytic anemia. In intravascular hemolysis, free hemoglobin will be released into circulation and hence haptoglobin will bind the hemoglobin. This causes a decline in haptoglobin levels.
This gene encodes a preproprotein that is processed to yield both alpha and beta chains, which subsequently combines as a tetramer to produce haptoglobin. Haptoglobin functions to bind free plasma hemoglobin, which allows degradative enzymes to gain access to the hemoglobin while at the same time preventing loss of iron through the kidneys and protecting the kidneys from damage by hemoglobin. For this reason, it is often referred to as the suicide protein.
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.
Differentiation with hemopexin
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.
Haptoglobin had been shown to be expressed in adipose tissue of cattle as well.
Haptoglobin, in its simplest form, consists of two alpha and two beta chains, connected by disulfide bridges. The chains originate from a common precursor protein, which is proteolytically cleaved during protein synthesis.
Hp exists in two allelic forms in the human population, so-called Hp1 and Hp2, the latter one having arisen due to the partial duplication of Hp1 gene. Three genotypes of Hp, therefore, are found in humans: Hp1-1, Hp2-1, and Hp2-2. Hp of different genotypes have been shown to bind hemoglobin with different affinities, with Hp2-2 being the weakest binder.
If the reticulocyte count is increased, but the haptoglobin level is normal, this may indicate that cellular destruction is occurring in the spleen and liver, which may indicate a drug-induced hemolysis, or a red cell dysplasia. The spleen and liver recognize an error in the red cells (either drug coating the red cell membrane or a dysfunctional red cell membrane), and destroy the cell. This type of destruction does not release hemoglobin into the peripheral blood, so the haptoglobin cannot bind to it. Thus, the haptoglobin will stay normal if the hemolysis is not severe. In severe extra-vascular hemolysis, haptoglobin levels can also be low, when large amount of hemoglobin in the reticuloendothelial system leads to transfer of free hemoglobin into plasma.
If there are symptoms of anemia but both the reticulocyte count and the haptoglobin level are normal, the anemia is most likely not due to hemolysis, but instead some other error in cellular production, such as aplastic anemia
Haptoglobin levels that are decreased but do not accompany signs of anemia may indicate liver damage, as the liver is not producing enough haptoglobin to begin with.
As haptoglobin is indeed an acute-phase protein, any inflammatory process (infection, extreme stress, burns, major crush injury, allergy, etc.) may increase the levels of plasma haptoglobin.
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