Haptoglobin (abbreviated as Hp) is the protein that in humans is encoded by the HP gene.[5][6] In blood plasma, haptoglobin binds to free hemoglobin[7], compared to hemopexin that binds to free heme,[8] released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen).

Available structures
PDBOrtholog search: PDBe RCSB
AliasesHP, BP, HP2ALPHA2, HPA1S, haptoglobin
External IDsOMIM: 140100 MGI: 96211 HomoloGene: 121756 GeneCards: HP
Gene location (Human)
Chr.Chromosome 16 (human)[1]
Band16q22.2Start72,054,505 bp[1]
End72,061,055 bp[1]
RNA expression pattern
More reference expression data









RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 16: 72.05 – 72.06 MbChr 8: 109.58 – 109.58 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse
A model of α,β-hemoglobin/haptoglobin hexamer complex. There are 2 α,β-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.[9] 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.[7] 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.[7]

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.[7]


Haptoglobin is produced mostly by hepatic cells but also by other tissues such as skin, lung and kidney. In addition, the haptoglobin gene is expressed in murine and human adipose tissue.[10]

Haptoglobin had been shown to be expressed in adipose tissue of cattle as well.[11]


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.

In other species

Hp has been found in all mammals studied so far, some birds, e.g., cormorant and ostrich but also, in its simpler form, in bony fish, e.g., zebrafish. Hp is absent in at least some amphibians (Xenopus) and neognathous birds (chicken and goose).

Clinical significance

Mutations in this gene or its regulatory regions cause ahaptoglobinemia or hypohaptoglobinemia. This gene has also been linked to diabetic nephropathy,[12] the incidence of coronary artery disease in type 1 diabetes,[13] Crohn's disease,[14] inflammatory disease behavior, primary sclerosing cholangitis, susceptibility to idiopathic Parkinson's disease,[15] and a reduced incidence of Plasmodium falciparum malaria.[16]

Since the reticuloendothelial system will remove the haptoglobin-hemoglobin complex from the body,[8] haptoglobin levels will be decreased in case of intravascular hemolysis or severe extravascular hemolysis. In the process of binding to free hemoglobin, haptoglobin sequesters the iron within hemoglobin, preventing iron-utilizing bacteria from benefiting from hemolysis. It is theorized that, because of this, haptoglobin has evolved into an acute-phase protein. HP has a protective influence on the hemolytic kidney.[17][18]

Some studies associate certain haptoglobin phenotypes with the risk of developing schizophrenia.[19]

Test protocol

Measuring the level of haptoglobin in a patient's blood is ordered whenever a patient exhibits symptoms of anemia, such as pallor, fatigue, or shortness of breath, along with physical signs of hemolysis, such as jaundice or dark-colored urine. The test is also commonly ordered as a hemolytic anemia battery, which also includes a reticulocyte count and a peripheral blood smear. It can also be ordered along with a direct antiglobulin test when a patient is suspected of having a transfusion reaction or symptoms of autoimmune hemolytic anemia. Also, it may be ordered in conjunction with a bilirubin.


A decrease in haptoglobin can support a diagnosis of hemolytic anemia, especially when correlated with a decreased red blood cell count, hemoglobin, and hematocrit, and also an increased reticulocyte count.

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.[20]

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.

See also


  • This article incorporates text from the United States National Library of Medicine, which is in the public domain.
  1. GRCh38: Ensembl release 89: ENSG00000257017 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000031722 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Dobryszycka W (September 1997). "Biological functions of haptoglobin--new pieces to an old puzzle". European Journal of Clinical Chemistry and Clinical Biochemistry. 35 (9): 647–54. PMID 9352226.
  6. Wassell J (2000). "Haptoglobin: function and polymorphism". Clinical Laboratory. 46 (11–12): 547–52. PMID 11109501.
  7. Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW (28 October 2014). "Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development". Frontiers in Physiology. Frontiers Media SA. 5: 415. doi:10.3389/fphys.2014.00415. PMC 4211382. PMID 25389409.
  8. "Intravascular hemolysis". eClinpath. Retrieved 8 May 2019.
  9. "Entrez Gene: HP".
  10. Trayhurn P, Wood IS (September 2004). "Adipokines: inflammation and the pleiotropic role of white adipose tissue". Br. J. Nutr. 92 (3): 347–55. doi:10.1079/BJN20041213. PMID 15469638.
  11. Saremi B, Al-Dawood A, Winand S, Müller U, Pappritz J, von Soosten D, Rehage J, Dänicke S, Häussler S, Mielenz M, Sauerwein H (May 2012). "Bovine haptoglobin as an adipokine: Serum concentrations and tissue expression in dairy cows receiving a conjugated linoleic acids supplement throughout lactation". Vet Immunol Immunopathol. 146 (3–4): 201–11. doi:10.1016/j.vetimm.2012.03.011. PMID 22498004.
  12. Asleh R, Levy AP (2005). "In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease". Vasc Health Risk Manag. 1 (1): 19–28. doi:10.2147/vhrm. PMC 1993923. PMID 17319095.
  13. Sadrzadeh SM, Bozorgmehr J (June 2004). "Haptoglobin phenotypes in health and disorders". Am. J. Clin. Pathol. 121 Suppl: S97–104. doi:10.1309/8GLX5798Y5XHQ0VW. PMID 15298155.
  14. Papp M, Lakatos PL, Palatka K, Foldi I, Udvardy M, Harsfalvi J, Tornai I, Vitalis Z, Dinya T, Kovacs A, Molnar T, Demeter P, Papp J, Lakatos L, Altorjay I (May 2007). "Haptoglobin polymorphisms are associated with Crohn's disease, disease behavior, and extraintestinal manifestations in Hungarian patients". Dig. Dis. Sci. 52 (5): 1279–84. doi:10.1007/s10620-006-9615-1. PMID 17357835.
  15. Costa-Mallen P, Checkoway H, Zabeti A, Edenfield MJ, Swanson PD, Longstreth WT, Franklin GM, Smith-Weller T, Sadrzadeh SM (March 2008). "The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease". American Journal of Medical Genetics. 147B (2): 216–22. doi:10.1002/ajmg.b.30593. PMID 17918239.
  16. Prentice AM, Ghattas H, Doherty C, Cox SE (December 2007). "Iron metabolism and malaria". Food Nutr Bull. 28 (4 Suppl): S524–39. doi:10.1177/15648265070284S406. PMID 18297891.
  17. Pintera J (1968). "The protective influence of haptoglobin on hemoglobinuric kidney. I. Biochemical and macroscopic observations". Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch. 90 (1): 82–91. PMID 4176393.
  18. Miederer SE, Hotz J (December 1969). "[Pathogenesis of kidney hemolysis]". Bruns Beitr Klin Chir (in German). 217 (7): 661–5. PMID 5404273.
  19. Gene Overview of All Published Schizophrenia-Association Studies for HP Archived 21 February 2009 at the Wayback Machine - SzGene database at Schizophrenia Research Forum.
  20. Temple, Victor. "HEMOLYSIS AND JAUNDICE: An overview" (PDF). Retrieved 9 July 2011.

Further reading

  • Haptoglobins at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Overview of all the structural information available in the PDB for UniProt: P00738 (Haptoglobin) at the PDBe-KB.

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.