Postoperative Anaemia

Anaemia is common after major surgery and seems easily explained by blood loss during and after surgery. Moreover, therapy is simple: either transfusions with red cells are given or iron tablets are prescribed. Although the clinical use of blood transfusion has opened new perspectives in surgery, transfusions are associated with risks that can cause morbidity and mortality. There are two general types of adverse events related to blood transfusions: transmission of infectious diseases and immunological sequella. Transmission of infection is largely reduced because of modern blood donor testing, and the main concern are viruses like hepatitis C (
These two statements warrant a closer look at the pathophysiological mechanisms underlying postoperative anaemia.



The characteristics of iron metabolism in plain iron deficiency anaemia and phlebotomized healthy individuals are a reduced serum iron and ferritin concentration (the storage protein for iron), reduced transferrin saturation and increased serum transferrin concentration (the transport protein for iron) and increased transferrin receptor concentration <|[3]|>. Transferrin receptors are found in highest concentration on erythroid precursor cells and in the placenta. In iron deficiency, transferrin receptors in plasma are elevated and this reflects the increased density of surface transferrin receptors on iron deprived cells <|[8]|>.



After surgery, a decreased serum iron, serum transferrin and transferrin saturation was found, together with a two-fold increase in serum ferritin concentration, while serum transferrin receptor values remained normal <|[2, 9]|>. These findings regarding iron metabolism are compatibel with the anaemia of chronic disease (ACD).



ACD is the second most common form of chronic anaemia after iron deficiency and particularly the anaemia associated with inflammation. It is seen in patients with chronic infectious or inflammatory disorders and neoplastic diseases but is not due to marrow replacement by tumor, bleeding or haemolysis. ACD is usually a mild to moderate normocytic, normochromic anaemia <|[11, 12]|>. Several mechanisms may or have been suggested to play a role in the pathogenesis of ACD, such as the altered iron metabolism as described above, leading to hypoferraemia in the presence of adequate iron stores, a shortened red cell survival, inhibition of marrow erythropoiesis and inhibition of erythropoietin (EPO) production, the hormone that plays a critical role in regulation of red cell production.



The hypoferraemia, reflected by the low serum iron and transferrin saturation found for two to three weeks after a large surgical procedure, results in a diminished availability of iron in the postoperative period. Iron can only be internalized by (erythroid) cells if bound to transferrin following interaction with the transferrin receptor and is necessary for haemoglobin synthesis. This temporarily inavailability of iron in the postoperative phase contributes to the hampered erythropoiesis in this period and persistence of the anaemia. This is further proofed by the fact that minor surgery (e.g. correction of hallux valgus, removing of exostosis) appeared to induce a state of hypoferraemia in the presence of adequate iron stores and a marked acute phase response, too. Despite the absence of blood loss, a slight although significant decrease in haemoglobin level is found for some weeks after these procedures <|[9]|>.

Given the fact that a functional iron deficiency exists postoperatively, it is noteworthy that oral iron supplementation is often not effective to increase postoperative haemoglobin levels. Iron bound to transferrin ex vivo, and given intravenously is rapidly and almost completely consumed by red cells during the first week after surgery, as shown by ferrokinetic measurements. So, iron hunger exists after surgery. The problem is therefore likely to be an un-increased iron absorption after surgery and impairment of iron release from the mononuclear phagocytic system (MPS), like in ACD <|[11, 12]|>. Following the inflammatory period after surgery, oral iron may be supplementary to the iron released from the MPS. Furthermore, the use of intravenous iron may add to the availability of iron postoperatively. Intravenous iron was more effective in restoring postoperative anaemia in infants and adolescents who underwent spinal surgery, a procedure often associated with massive bleeding. Whether intravenous iron is beneficial in adults after surgical procedures with less blood loss seems still to be determined.



In case the analogy between the postoperative anaemia and ACD is true, one would expect an inflammatory state after surgery and possible involvement of the other pathophysiological mechanisms underlying ACD in the postoperative anaemia.



Indeed, interleukin-6 (Il-6), one of the most important acute phase-mediators, is found in plasma after a variety of surgical procedures, e.g. elective aorta aneurysma repair and other vascular surgery, (laparoscopic) cholecystectomy, inguinal hernia repair, total hip replacement, colorectal surgery and various minor surgical procedures, like repair of varicose veins. Peak values are usually found within 24 hours (range: 4-48 hours) after the incision and the magnitude of the Il-6 response is correlated with the extensiveness of the surgical procedure <|[1]|>. Tumor necrosis factor _ (TNF-_) and interferon _ (IFN-_) were not found after major aortic surgery, while the interleukin-1_ (Il-1_) response to major surgery is early (peak at two hours after surgery), short-lived and small. These pro-inflammatory cytokines are produced by a variety of cell types like activated macrophages/monocytes (TNF-_, Il-1_, Il-6); endothelial cells, fibroblasts and T-/B-cells (Il-6) and T-cells and natural killer cells (IFN-_). C-reactive protein (CRP), one of the major acute phase proteins, also increases after surgical procedures; peak values are found after 2-3 days and are proportional to the extensiveness of the surgery performed.



Inflammatory mediators influence iron metabolism in several ways. The synthesis of ferritin, the storage protein for iron, is enhanced by Il-1_ and Il-6, cytokines both found after a surgical insult <|[13]|>. Il-6 may induce iron uptake in hepatocytes, leading to hypoferraemia. Il-1_ and TNF-_ (the latter is usually not found after surgery) increase iron uptake by macrophages and impair iron release from macrophages. Lactoferrin produced by neutrophils in inflamed areas is suggested to bind iron; its iron affinity is different from transferrin as it is able to bind iron at a much lower pH. However, hypoferraemia is also present during neutropenia, making this mechanism less plausible.



Not only iron (and vitamin B12 and folic acid) is necessary for an appropriate production or red cells but also EPO is required for the stimulation of erythropiesis. EPO is a glycoprotein with a MW of 34 kD and is mainly produced in the peritubular cells of the cortex and outer medulla of the kidney. The liver is the other site of EPO synthesis, contributing 10-15% to the total EPO production, while in fetuses the liver is the most important source of EPO. EPO acts on the two specific erythroid progenitor cells: the burst forming unit erythroid (BFU-E) and the colony forming unit erythroid (CFU-E) which are derived from the pluripotent haematopoietic stem cell. BFU-E, the earliest erythroid progenitor, is dependent on EPO for its proliferation and maturation, as well as on other haematopoietic growth factors like interleukin-3 and granulocyte-monocyte colony stimulating factor. The late progenitor CFU-E depends only on EPO and gives rise to erythroblast colonies in about 7 days. The primary stimulus for EPO production is hypoxia and a reduced red cell mass (by a lowered haemoglobin level and oxygen transport). Normally, an inverse correlation between haemoglobin and EPO concentration exists: if the haemoglobin concentration decreases, EPO levels increase. In ACD, like in patients with rheumatoid arthritis, cancer and AIDS, a blunted EPO response to anaemia is found. Meaning, EPO levels detected are lower than in patients who are equally anaemic without these disorders.



In the postoperative phase, a short period of relative erythropoietin (EPO) deficiency is found up to the fourth day after surgery. Those EPO levels are inadequate to immediately raise erythrocyte production after surgery. This is also reflected by unelevated serum transferrin receptor levels in the postoperative period <|[2, 9]|>. Such a delayed appearance of adequate erythropoietin levels can be attributed to several factors, like the process of EPO production in the kidney itself, and the fact that a limited amount of blood loss (500 ml) is not a trigger powerful enough to stimulate the hypoxia sensor in the kidney to increase EPO production. Furthermore, several inflammatory mediators are found in plasma after surgery, such as Il-6 and Il-1_, and the latter may inhibit EPO production, like in ACD <|[5]|>. With this knowledge, a rationale for therapy with recombinant human erythropoietin (rhuEPO) during the perioperative phase was found, and indeed studies with weekly rhuEPO for three weeks before the surgical procedure or daily rhuEPO from ten days before to four days after surgery show increased perioperative haemoglobin levels and less need for homologous blood transfusions <|[6, 7]|>.

This ACD-like inflammatory anaemia after surgery might be considered a physiological event. High plasma and tissue iron concentrations may be unfavourable, since these can promote bacterial growth. Furthermore, a low haematocrit may be favourable from a rheologic point of view, thus leading to less thrombo-embolic events after the operation.



In conclusion, the postoperative anaemia may be considered an acute variant of the anaemia of chronic disease due to the inflammatory effect of the procedure. This inflammatory effect exerts its influence on erythropoiesis through a disturbance of iron metabolism, inducing functional iron deficiency and through a blunted erythropoietin response and these findings may have implications for its treatment.

Appendix: 

References

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