The function of RBCs is to carry oxygen to the tissues at pressures sufficient to permit its rapid diffusion. This is accomplished through the following mechanisms: a carrier molecule, hemoglobin (Hgb); a vehicle (RBC) capable of bringing the intact Hgb to the cellular level; and a metabolism geared to protect both the RBC and the Hgb from damage. Interference with synthesis or release of Hgb, production or survival of RBCs, or metabolism causes disease.
Hgb is a complex molecule, formed of four heme units attached to four globins (two α and two β globins). Iron is added in the last step by the ferrochelatase enzyme. Interference with the normal production of heme or globin leads to anemia. Causes include copper or iron deficiency and lead poisoning. Hemoglobinopathies such as thalassemias and sickle cell anemia, important genetic diseases of people, have not been seen in other animals. In these diseases, the production of globins (α or β or both) does not balance heme production, and the Hgb is not functional. The only known hemoglobinopathy of animals is porphyria. Although described in several species, it is most important as a cause of photosensitivity in cattle (see also Photosensitization).
Red cell mass, and thus oxygen-carrying capacity, remains constant over time in healthy animals. Mature RBCs have a finite life span; their production and destruction must be carefully balanced, or disease ensues.
Erythropoiesis is regulated by erythropoietin, which increases in the presence of hypoxia and regulates RBC production. In most species, the kidney is both the sensor organ and the major site of erythropoietin production, so chronic renal failure is associated with anemia. Erythropoietin acts on the marrow in concert with other humoral mediators to increase the number of stem cells entering RBC production, to shorten maturation time and to cause early release of reticulocytes. Other factors that affect erythropoiesis are the supply of nutrients (eg, iron, folate, or vitamin B12) and cell-cell interactions between erythroid precursors, lymphoid cells, and other components of the hematopoietic microenvironment. Factors that may suppress erythropoiesis include chronic debilitating diseases and endocrine disorders (such as hypothyroidism or hyperestrogenism).
Two mechanisms exist for removal of senescent RBCs; both conserve the principal constituents of the cell for reuse. Removal of aged RBCs normally occurs by phagocytosis by the fixed macrophages of the spleen. As the RBC ages it may change antigenically, acquiring senescent antigens and losing its flexibility due to impaired ATP production. Both of these changes increase the risk that the cell will become trapped in the spleen and removed by macrophages. After phagocytosis and subsequent disruption of the cell membrane, Hgb is converted to heme and globin. Iron is released from the heme moiety and either stored in the macrophage as ferritin or hemosiderin or released into the circulation for transport back to the marrow. The remaining heme is converted to bilirubin, which is released by the macrophages into the systemic circulation, where it complexes with albumin for transport to the hepatocytes; there, it is conjugated and excreted into the bile. In extravascular hemolytic anemias, RBCs have a shortened life span, and the same mechanisms occur at an increased rate.
Approximately 1% of normal aging RBCs are hemolyzed in the circulation, and free Hgb is released. This is quickly converted to Hgb dimers that bind to haptoglobin and are transported to the liver, where they are metabolized in the same manner as products from RBCs removed by phagocytosis. In intravascular hemolytic anemia, more RBCs are destroyed in the circulation (hemoglobinemia) than can be bound to haptoglobin. The excess Hgb and, therefore, iron are excreted in the urine (hemoglobinuria).
The principal metabolic pathway of RBC is glycolysis, and the main energy source in most species is glucose. Glucose enters the RBC by an insulin-independent mechanism, and most is metabolized to produce ATP and reduced nicotinamide adenine dinucleotide (NADH). The energy of ATP is used to maintain RBC membrane pumps so as to preserve shape and flexibility. The reducing potential of the NADH is utilized via the methemoglobin reductase pathway to maintain the iron in Hgb in its reduced form (Fe2+).
The glucose not used in glycolysis is metabolized via a second pathway, the hexose monophosphate (HMP) shunt. No energy is produced via the HMP shunt; its principal effect is to maintain reducing potential in the form of reduced nicotinamide adenine dinucleotide phosphate (NADPH). In conjunction with the glutathione reductase/peroxidase system, NADPH maintains the sulfhydryl groups of globin in their reduced state.
Some disorders are the direct result of abnormal RBC metabolism and interference with glycolysis. Inherited deficiency of pyruvate kinase, a key glycolytic enzyme, causes ATP deficiency, which leads to reduced RBC life span and hemolytic anemia. Excessive oxidant stress may overload the protective HMP shunt or methemoglobin reductase pathways, causing Heinz body hemolysis or methemoglobin formation, respectively. Hemolytic anemia caused by a drug, such as acetaminophen in cats, is an example of this mechanism. (See also Anemia.)
A decreased RBC mass (anemia) may be caused by blood loss, hemolysis, or decreased production. In acute blood loss anemia, RBCs are lost, but mortality is usually related to loss of circulating volume rather than to loss of RBC. Iron is the limiting factor in chronic blood loss. Hemolysis may be caused by toxins, infectious agents, congenital abnormalities, or antibodies directed against RBC membrane antigens. Decreased RBC production may result from primary marrow diseases (eg, aplastic anemia, hematopoietic malignancy, or myelofibrosis) or from other causes such as renal failure, drugs, toxins, or antibodies directed against RBC precursors. Malignancy of RBCs or their precursors may be acute (eg, erythroleukemia) or chronic (eg, polycythemia vera). Animals with erythroleukemia are anemic despite having a marrow filled with rubriblasts, whereas those with polycythemia vera have erythrocytosis.
Also see pet health information regarding red blood cells.