Detoxifying Haemoglobin

It is difficult to imagine that a molecule as essential to life as haemoglobin (hb) would need a detoxification mechanism. Anyone who has treated a patient with severe intravascular haemolysis knows the havoc cell-free haemoglobin can cause. Haemoglobin is small enough to be filtered by the glomerulus and causes renal failure due to pigment nephropathy. Haemoglobin depletes nitric oxide resulting in vasculopathy. Mechanisms to detoxify cell-free haemoglobin counter the oxidative and pro-inflammatory effects of haemoglobin.

Haemolysis releases cell-free haemoglobin. Haptoglobin (Hp), alpha-2 globulin, secreted by the liver is a haemoglobin scavenger. It rapidly binds cell-free haemoglobin in the plasma protecting the vessels and the kidneys from it’s deleterious effects. When the scavenging capacity of haptoglobin is overwhelmed cell-free haemoglobin appears in the plasma. It converts nitric oxide to biologically inactive nitrate and is itself converted to methemoglobin in the process. Degradation of cell-free haemoglobin results in the formation of heme and free iron which deplete nitric oxide by their oxidizing action. Hemopexin scavenges free heme. Free iron is taken up and transported by transferrin.

The haemoglobin-haptoglobin complex is taken by the CD163 receptor on the reticuloendothelial macrophage and the heme-hemopexin complex is taken up by the CD91 (low density lipoprotein-1, LRP1) receptor. The interactions of haemoglobin-haptoglobin by CD163 and heme-hemopexin by CD91 have an anti-oxidant and anti-inflammatory action by activation of heme oxygenase-1 and IL10. Haptoglobin and hemopexin are acute phase reactants. The body’s capacity the counter the effects of cell-free haemoglobin increases during acute inflammation. The expression of CD163 and CD91 is increased by corticosteroids which are also secreted as a part of response to acute inflammation.

Pigment nephropathy from precipitation of haemoglobin in renal tubules has long been recognized as a serious complication of massive intravascular haemolysis. The vascular effects of cell free-haemoglobin are evident at lesser haemolysis. There is evidence in rodent malaria model that heme, a degradation product of cell-free haemoglobin released during intravascular haemolysis, is involved in the pathogenesis of cerebral and non-cerebral malaria (Proc Natl Acad Sci U S A. 2009 September 15; 106(37): 15837–15842, Nat Med. 2007 Jun;13(6):703-10. Epub 2007 May 13). Heme has been implicated in the pathogenesis of severe sepsis in animal models (Sci Transl Med. 2010 Sep 29;2(51):51ra71). Cell-free haemoglobin has been implicated in the pathogenesis of pulmonary hypertension, leg ulceration, priapism, and cerebrovascular disease related to sickle cell anaemia (Blood Rev. 2007 January; 21(1): 37–47). The list of haemolytic anaemias where cell-free haemoglobin has a pathogenic role is increasing and now includes thalassemia, autoimmune haemolytic anaemia, paroxysmal nocturnal hemoglobinuria, unstable hemoglobinopathy, and hereditary membranopathies. Corticosteroids can increase the clearance of cell-free haemoglobin and its degradation products. They have been shown to benefit patients of sickle cell disease with acute chest syndrome and vaso-occlusive crisis. Thrombotic thrombocytopenic purpura, a disease characterized by intravascular haemolysis, is also treated with corticosteroids in addition to plasmapheresis. Plasmapheresis removes cell-free haemoglobin and corticosteroids enhance its clearance by macrophages.

Too much of a good thing is bad. Haemoglobin is safe when in erythrocytes. Outside erythrocytes it needs detoxification.


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