Basics of Blood Management - part 2 docx

Anemia Therapy I: Erythropoiesis-Stimulating Proteins 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 setting Roundtable of Experts in Surgery Blood Management Semin Hematol, 1996 33(2, Suppl 2): p 78–80 Chun, T.Y., S Martin, and H Lepor Preoperative recombinant human erythropoietin injection versus preoperative autologous blood donation in patients undergoing radical retropubic prostatectomy Urology, 1997 50(5): p 727–732 Mak, R.H Effect of recombinant human erythropoietin on insulin, amino acid, and lipid metabolism in uremia J Pediatr, 1996 129(1): p 97–104 Fagher, B., H Thysell, and M Monti Effect of erythropoietin on muscle metabolic rate, as measured by direct microcalorimetry, and ATP in hemodialysis patients Nephron, 1994 67(2): p 167–171 Lewis, L.D Preclinical and clinical studies: a preview of potential future applications of erythropoietic agents Semin Hematol, 2004 41(4, Suppl 7): p 17–25 Erbayraktar, S., et al Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo Proc Natl Acad Sci U S A, 2003 100(11): p 6741–6746 Ehrenreich, H., et al Erythropoietin therapy for acute stroke is both safe and beneficial Mol Med, 2002 8(8): p 495– 505 Calvillo, L., et al Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling Proc Natl Acad Sci U S A, 2003 100(8): p 4802–4806 Baker, J.E Erythropoietin mimics ischemic preconditioning Vascul Pharmacol, 2005 42(5–6): p 233–241 Semba, R.D and S.E Juul Erythropoietin in human milk: physiology and role in infant health J Hum Lact, 2002 18(3): p 252–261 Tarng, D.C and T.P Huang A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload Nephrol Dial Transplant, 1998 13(11): p 2867–2872 Danielson, B R-HuEPO hyporesponsiveness—who and why? Nephrol Dial Transplant, 1995 10(Suppl 2): p 69–73 Horl, W.H Is there a role for adjuvant therapy in patients being treated with epoetin? Nephrol Dial Transplant, 1999 14(Suppl 2): p 50–60 Kuhn, K., et al Analysis of initial resistance of erythropoiesis to treatment with recombinant human erythropoietin Results of a multicenter trial in patients with end-stage renal disease Contrib Nephrol, 1988 66: p 94–103 Bommer, J Saving erythropoietin by administering l-carnitine? Nephrol Dial Transplant, 1999 14(12): p 2819– 2821 Wolchok, J.D., et al Prophylactic recombinant epoetin alfa markedly reduces the need for blood transfusion in patients with metastatic melanoma treated with biochemotherapy Cytokines Cell Mol Ther, 1999 5(4): p 205–206 Colomina, M.J., et al Preoperative erythropoietin in spine surgery Eur Spine J, 2004 13(Suppl 1): p S40–S49 33 44 Christodoulakis, M and D.D Tsiftsis Preoperative epoetin alfa in colorectal surgery: a randomized, controlled study Ann Surg Oncol, 2005 12(9): p 718–725 45 Weber, E.W., et al Effects of epoetin alfa on blood transfusions and postoperative recovery in orthopaedic surgery: the European Epoetin Alfa Surgery Trial (EEST) Eur J Anaesthesiol, 2005 22(4): p 249–257 46 Breymann, C., R Zimmermann, R Huch, and A Huch Erythropoietin zur Behandlung der postpartalen Ană mie In a Hă matologie, Mă nchen Sympomed, 1993 2: p 4955 a u 47 Kumar, P., S Shankaran, and R.G Krishnan Recombinant human erythropoietin therapy for treatment of anemia of prematurity in very low birth weight infants: a randomized, double-blind, placebo-controlled trial J Perinatol, 1998 18(3): p 173–177 48 Ohls, R.K Erythropoietin to prevent and treat the anemia of prematurity Curr Opin Pediatr, 1999 11(2): p 108–114 49 Goodnough, L.T and R.E Marcus The erythropoietic response to erythropoietin in patients with rheumatoid arthritis J Lab Clin Med, 1997 130(4): p 381–386 50 Wilson, A., et al Prevalence and outcomes of anemia in rheumatoid arthritis: a systematic review of the literature Am J Med, 2004 116(Suppl 7A): p 50S–57S 51 Fischl, M., et al Recombinant human erythropoietin for patients with AIDS treated with zidovudine N Engl J Med, 1990 322(21): p 1488–1493 52 Stasi, R., et al Management of cancer-related anemia with erythropoietic agents: doubts, certainties, and concerns Oncologist, 2005 10(7): p 539–554 53 Jilani, S.M and J.A Glaspy Impact of epoetin alfa in chemotherapy-associated anemia Semin Oncol, 1998 25(5): p 571–576 54 Laupacis, A and D Fergusson Erythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials The International Study of Peri-operative Transfusion (ISPOT) Investigators Transfus Med, 1998 8(4): p 309–317 55 Cazzola, M., F Mercuriali, and C Brugnara Use of recombinant human erythropoietin outside the setting of uremia Blood, 1997 89(12): p 4248–4267 56 Seidenfeld, J., et al Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials J Natl Cancer Inst, 2001 93(16): p 1204–1214 57 Svensson, E.C., et al Long-term erythropoietin expression in rodents and non-human primates following intramuscular injection of a replication-defective adenoviral vector Hum Gene Ther, 1997 8(15): p 1797–1806 58 Rinsch, C., et al A gene therapy approach to regulated delivery of erythropoietin as a function of oxygen tension Hum Gene Ther, 1997 8(16): p 1881–1889 59 Glaspy, J Phase III clinical trials with darbepoetin: implications for clinicians Best Pract Res Clin Haematol, 2005 18(3): p 407–416 34 Chapter 60 Macdougall, I.C Novel erythropoiesis stimulating protein Semin Nephrol, 2000 20(4): p 375–381 61 Brunkhorst, R., et al Darbepoetin alfa effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoietin in dialysis patients Nephrol Dial Transplant, 2004 19(5): p 1224–1230 62 Schwartzberg, L.S., et al A randomized comparison of every2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer Oncologist, 2004 9(6): p 696–707 63 Cvetkovic, R.S and K.L Goa Darbepoetin alfa: in patients with chemotherapy-related anaemia Drugs, 2003 63(11): p 1067–1074; discussion 1075–1077 64 Teruel, J.L., et al Androgen versus erythropoietin for the treatment of anemia in hemodialyzed patients: a prospective study J Am Soc Nephrol, 1996 7(1): p 140–144 65 Gascon, A., et al Nandrolone decanoate is a good alternative for the treatment of anemia in elderly male patients on hemodialysis Geriatr Nephrol Urol, 1999 9(2): p 67–72 66 Teruel, J.L., et al Androgen therapy for anaemia of chronic renal failure Indications in the erythropoietin era Scand J Urol Nephrol, 1996 30(5): p 403–408 67 Teruel, J.L., et al Evolution of serum erythropoietin after androgen administration to hemodialysis patients: a prospective study Nephron, 1995 70(3): p 282–286 68 Cervantes, F., et al Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients Br J Haematol, 2005 129(6): p 771–775 69 Cervantes, F., et al Danazol treatment of idiopathic myelofibrosis with severe anemia Haematologica, 2000 85(6): p 595–599 70 Harrington, W.J., Sr., et al Danazol for paroxysmal nocturnal hemoglobinuria Am J Hematol, 1997 54(2): p 149–154 71 Hardman, J Goodman and Gilman’s The Pharmacological Basis of Therapeutics McGraw-Hill, New York, 1995 p 1441ff 72 Woody, M.A., et al Prolactin exerts hematopoietic growthpromoting effects in vivo and partially counteracts myelosuppression by azidothymidine Exp Hematol, 1999 27(5): p 811–816 73 Jepson J.H and E.E McGarry Effect of the anabolic protein hormone prolactin on human erythropoiesis J Clin Pharmacol, 1974(May–June): p 296–300 74 Akiyama, M., et al Successful treatment of DiamondBlackfan anemia with metoclopramide Am J Hematol, 2005 78(4): p 295–298 75 Abkowitz, J.L., et al Response of Diamond-Blackfan anemia to metoclopramide: evidence for a role for prolactin in erythropoiesis Blood, 2002 100(8): p 2687–2691 76 Koenig, H.M., et al Use of recombinant human erythropoietin in a Jehovah’s Witness J Clin Anesth, 1993 5(3): p 244– 247 Anemia therapy II (hematinics) Erythropoiesis depends on three prerequisites to function properly: a site for erythropoiesis, that is, the bone marrow; a regulatory system, that is, cytokines acting as erythropoietins; and raw materials for erythropoiesis, among them hematinics This second chapter on anemia therapy will introduce the latter, their role in erythropoiesis, and their therapeutic value Objectives of this chapter Review the physiological basis for the use of hematinics Relate the indications for the therapeutic use of hematinics Define the role of hematinics in blood management Definitions Hematinics: Hematinics are vitamins and minerals essential for normal erythropoiesis Among them are iron, copper, cobalt, and vitamins A, B6 , B12 , C, E, folic acid, riboflavin, and nicotinic acid Iron: Iron is a trace element that is vital for oxidative processes in the human body Its ability to switch easily from the ferrous form to the ferric state makes it an important player in oxygen binding and release Physiology of erythropoiesis and hemoglobin synthesis Hematinics are the fuel for erythropoiesis When treating a patient with anemia, it is necessary to administer hematinics in order to support the patient’s own erythropoiesis in restoring a normal red blood cell mass A review of erythropoiesis and hemoglobin synthesis will provide the necessary background information to prescribe hematinics effectively Erythropoiesis starts with the division and differentiation of stem cells in the bone marrow In the course of erythropoiesis, DNA needs to be synthesized, new nuclei need to be formed, and cells need to divide For all these processes, hematinics are needed Folates and vitamin B12 are important cofactors in the synthesis of the DNA They are necessary for purine and pyrimidine synthesis Folates provide the methyl groups for thymidylate, a precursor of DNA synthesis Erythropoiesis continues while the newly made red cell precursors synthesize hemoglobin This synthesis consists of two distinct, yet interwoven processes: the synthesis of heme and the synthesis of globins The heme synthesis, a ring-like porphyrin with a central iron atom, starts with the production of ␦-aminolevulinic acid (ALA) in the mitochondria (Table 4.1) ALA then travels to the cytoplasm There, coproporphyrinogen III is synthesized out of several ALA molecules The latter molecule travels back to the mitochondria where it reacts with protoporphyrin IX With the help of the enzyme ferrochelatase, iron is introduced into the ring structure and the resulting molecule is heme Parallel to the synthesis of heme, the synthesis of globin chains takes place Physiologically, it matches the needs of erythropoiesis After the globins are synthesized, the pathway of globin synthesis and heme synthesis comes together This final pathway, the assembly of the hemoglobin molecule, occurs in the cytoplasm of the red cell precursor In the process of folding the primary amino acid sequence, each globin molecule binds a heme molecule After this process, dimers of an alpha-chain and a non-alpha-chain form Later, the dimers are assembled into the functional hemoglobin molecule During life, the human body synthesizes different kinds of hemoglobins The differences between those hemoglobins are the result of the type of globin chains produced (Table 4.2) Apart from a short period in embryogenesis, healthy humans always have hemoglobins that consist of two alpha-chains and two non-alpha-chains During fetal life and 7–8 months thereafter, considerable 35 36 Chapter Table 4.1 Hemoglobin synthesis Step Enzyme Place Cofactor Succinyl CoA + glycine forms ALA ALA synthase, pyridoxal phosphatase Mitochondria Pyridoxal phosphate 2× ALA form porphobilinogen 4× porphobilinogen form uroporphyrinogen III ALA dehydratase Two-step process: hydroxymethylbilane synthase (= porphobilinogen deaminase), uroporphyrinogen III cosynthase Uroporphyrinogen decarboxylase, converting four acetates to methyl residues Two-step process: coproporphyrinogen III oxidase for decarboxylation of propionate to vinyl residues, protoporphyrin oxidase for oxidation of the methylene bridges between pyrrole groups Ferrochelatase Cytoplasm Cytoplasm Uroporphyrinogen converted to coproporphyrinogen III Coproporphyrinogen III converted to protoporphyrin IX Insertion of iron in protoporphyrin IX Cytoplasm Mitochondria Mitochondria ALA, ␦-aminolevulinic acid; CoA, coenzyme A amounts of hemoglobin F are present After this period, hemoglobin A is the major hemoglobin present, with trace amounts (less than 3%) of hemoglobin A2 Alphachains are encoded for on chromosome 16, whereas the non-alpha-chains are encoded for on chromosome 11 A set sequence of non-alpha-globins is found on chromosome 11, beginning from the to the end of the DNA molecule in the sequence epsilon, gamma, delta, and beta The genes are activated in this sequence during human development Based on the molecular pattern given by the genes that encode the globins, RNA and globin chains are synthesized Table 4.2 Human hemoglobin types Type of hemoglobin Globin chains Embryonic hemoglobins Gower1: zeta × plus epsilon × Gower2: alpha × plus epsilon × Portland: zeta × plus gamma × HgbF: alpha × plus gamma × HgbA: alpha × plus beta × HgbA2: alpha × plus delta × Fetal hemoglobin Adult hemoglobin Hgb, hemoglobin Iron therapy in blood management Physiology of iron Iron plays a key role in the production and function of hemoglobin It is able to accept and donate electrons, thereby easily converting from the ferrous (Fe2+ ) to the ferric form (Fe3+ ) and vice versa This property makes iron a valuable commodity for oxygen-binding molecules On the other hand, iron molecules may be detrimental Too much iron stored in the body likely inhibits erythropoiesis Besides, iron can also damage tissues by promoting the formation of free radicals If the storage capacity of ferritin is superseded (in conditions when body iron stores are in excess of 5–10 times normal), iron remains free in the body and may cause organ damage The same happens if iron is rapidly released from macrophages Another interesting feature of iron is that its metabolism is tightly interwoven with immune functions Since iron promotes the growth of bacteria and possibly of cancer, iron metabolism is modified when patients have infections or cancer In these conditions, the body employs several mechanisms to reduce the availability of iron The body iron stores of normal humans contain about 35–45 mg/kg body weight of iron in the adult male and Anemia Therapy II (Hematinics) somewhat less in the adult female More than two-third of this iron is found in the red cell lining Most of the remaining iron is stored in the liver and the reticuloendothelial macrophages Storage occurs as iron bound to ferritin, and mobilization of iron from ferritin occurs by a reducing process using riboflavin-dependent enzymes The turnover of iron mainly takes place within the body Old red cells are taken up by macrophages that process the iron contained in them and load it to transferrin for reuse By this recycling process, more than 90% of the iron needed for erythropoiesis is gained Only a small amount of new iron (1–2 mg) enters the body each day There are no mechanisms to actively excrete iron The loss of iron takes place by shedding endothelial cells containing iron and by blood loss Since the maintenance of adequate iron stores is of vital importance, many mechanisms help in the regulation of iron uptake and recycling Dietary iron is taken up by enterocytes in the duodenum These enterocytes are programmed, during their development, to “know” the iron requirements of the body The low gastric pH in conjunction with a brush border enzyme called ferrireductase helps the iron to be converted from its ferrous form (Fe2+ ) to ferric iron (Fe3+ ) The divalent metal transporter (DMT1) is located close to the ferrireductase in the membrane of the enterocytes This transports iron through the apical membrane of the enterocyte after it was reduced by the ferrireductase The absorption of iron in the gut is regulated by several mechanisms After a diet rich in iron, enterocytes stop taking up iron for a few hours (“mucosal block”), probably believing that there is sufficient iron in the body (although this may not be the case) Iron deficiency can cause a two- to threefold increase in iron uptake by the enterocytes Furthermore, erythropoietic activity is able to increase iron absorption, a process that is independent of the iron stores in the body Acute hypoxia is also able to stimulate iron absorption [1] The absorbed iron is either stored in the enterocyte, bound to ferritin (up to about 4500 iron atoms per ferritin molecule), or it is transported through the basolateral membrane into the plasma The transporter in the basolateral membrane is known to need hephaestin (which is similar to the copper-transporter ceruloplasmin) to carry the iron into the plasma After being transported into plasma, iron is converted back to the Fe3+ form Probably, hephaestin aids in this conversion [2] Transferrin in the plasma accepts a maximum of two incoming Fe3+ ions Iron-loaded transferrin attaches to transferrin receptors on the cell surface of various cells, among them red 37 cell precursors The receptors are located near clarithrincoated pits The clarithrin-coated pits hold the transferrin receptor and the transferrin–iron complex together In addition, a DMT1, which is close to the membrane that contains the clarithrin-coated pit, is incorporated As a result, the pits are ingested by the cell by endocytosis and form endosomes A proton pump in the membrane of the endosomes lowers the pH in the endosome This leads to changes in the protein structure of the transferrin and triggers the release of free iron into the endosome The DMT1 pumps the free iron out of the endosome and the endosome membrane fuses with the cell membrane again to release the transferrin receptor and the unloaded transferrin for further use In erythroid cells, the free iron in the cytoplasm is absorbed by mitochondria This process is facilitated by a copper-dependent cytochrome oxidase The iron in the mitochondria is used to transform protoporphyrin into heme In nonerythroid cells, iron is stored as ferritin and hemosiderin [1] An interesting mechanism for the regulation of iron metabolism was recently found This suggests that the liver is not only a storage place of iron but also acts as the command center While searching for antimicrobial principles in body fluids, Park and his colleagues [2] found a new peptide in the urine that had antimicrobial properties The same peptide was found in plasma Due to the peptide’s synthesis in the liver (hep-) and its antimicrobial properties (-cidin), the peptide was called hepcidin Hepcidin is a small, hair-needle-shaped molecule with 20–25 amino acids (hepcidin-20, −22, −25) and four disulfide bonds that link the two arms of the hair-needle to form a ladderlike molecule From the early experiments with hepcidin, it was concluded that hepcidin is the long-looked-for regulator of iron metabolism It seems to regulate the transmembrane iron transport Hepcidin binds to its receptor ferroportin Ferroportin is a channel through which iron is transported When hepcidin binds to ferroportin, ferroportin is degraded and iron is locked inside the cell [3] By this mechanism, hepcidin locks iron in cells and blocks the availability of iron in the blood Conversely, when hepcidin levels are reduced, more iron is available A closer look at hepcidin revealed its unique properties in the regulation of iron metabolism In the initial studies about hepcidin in the urine, one urine donor developed an infection and hepcidin levels in the urine increased by about 100 times This finding led to more research, the results of which are summarized in Table 4.3 [4, 5] 38 Chapter Table 4.3 Regulation of hepcidin Hepcidin decreases Hepcidin increases – in anemia and hypoxia – by non-transferrin-bound iron (as in thalassemias, some hemolytic anemias, hereditary hemochromatosis, hypo-/a-transferrinemia) – in inflammation – in iron ingestion and parenteral iron application – after transfusion A lack of hepcidin causes r iron accumulation r hyperabsorption of iron r increased release of storage iron r release of iron from macrophages with resulting decrease of iron in the spleen Superfluous hepcidin causes r decreased iron stores r microcytic hypochromic anemia r reduced iron uptake in the small intestine r inhibition of release of iron from macrophages r inhibition of iron transport through the placenta to the fetus It is evident from Table 4.3 that anemia causes a decrease in hepcidin, making iron available for erythropoiesis In contrast, inflammation and infection increase hepcidin levels and reduce the availability of iron This may act as a protection when bacteria or tumor tissue is present since the growth of both of these relies on iron However, under such circumstances, increased hepcidin may also induce anemia due to iron deficiency Overproduction of hepcidin during inflammation may be responsible for anemia during inflammation [6] The concept of hepcidin as a key regulator of iron metabolism offers potential for diagnostic and therapeutic use Patients with hemochromatosis, who are deficient in hepcidin, could be treated with hepcidin or similar peptides, once they become available In chronic anemia due to inflammation, detection of hepcidin provides a new diagnostic tool in the differential diagnosis of anemia Therapeutic use of iron Iron deficiency anemia is the most common form of treatable anemia Absolute iron deficiency develops if the iron intake is inadequate or if blood loss causes loss of iron Iron uptake is impaired if the amount of iron in food is insufficient, if the pH of the gastric fluids is too high (antacids), and if there are other divalent metals that compete with the iron on the DMT1 protein After bowel resection, the surface area available for iron absorption is reduced, also limiting the iron uptake This can also occur in bowel inflammation and in other diseases causing malabsorption Iron loss is increased in all forms of blood loss, such as gastrointestinal hemorrhage, parasitosis, menorrhagia, pulmonary siderosis, trauma, phlebotomy, etc Relative or functional iron deficiency develops as a result of inflammation and malignancy The term “functional iron deficiency” refers to patients with iron needs despite sufficient or even supranormal iron levels in the body stores Iron is stored in the macrophages, but it is not recycled The stored iron is trapped and cannot be mobilized easily for erythropoiesis Anemia develops despite these normal or supranormal iron stores Iron therapy may also be warranted under such circumstances This may be true for patients with anemia due to infection or chronic inflammation being treated with recombinant human erythropoietin (rHuEPO) Iron therapy is indicated in states of absolute or functional iron deficiency If patients are eligible for oral iron therapy, this is the treatment of choice There are many oral iron preparations available Ferrous salts (ferrous sulfate, gluconate, fumarate) are equally tolerable Controlled release of iron causes less nausea and epigastric pains than conventional ferrous sulfate Most cases of absolute iron deficiency can be managed by oral iron administration Iron absorption is best when the medication is taken between meals Occasional abdominal upset, after taking the iron, can be reduced if iron is taken with meals For iron stores to be replenished, the treatment with iron supplements must be continued over several months Several additional factors increase or interfere with the iron absorption from the intestine Ascorbic acid (vitamin C) prevents the formation of less-soluble ferric iron and increases iron uptake Meat, fish, poultry, and alcohol enhance iron uptake as well, while phytates (inositol phosphates, soy), calcium (in calcium salts, milk, cheese), polyphenols (tea, coffee, red wine (with tannin)), and eggs inhibit iron absorption [7] Unlike patients with light to moderate iron deficiency anemia, some groups of patients not respond to nor tolerate oral iron medication Others need a rapid replenishment of their iron reserves For some patients, oral iron may be contraindicated when it adds to the damage already caused by chronic inflammatory bowel diseases In these cases, parenteral iron therapy is warranted The classical intravenous iron preparation is iron dextran It is generally well tolerated However, some concerns arose to its use Side effects of iron dextrane include flushing, dizziness, backache, anxiety, hypotension, and occasionally respiratory failure and even cardiac arrest Such symptoms Anemia Therapy II (Hematinics) remind us of anaphylactic reactions Anaphylaxis is probably due to the dextrane in the product Also a specific effect of free iron contributes to the symptoms Since dextrane is partially responsible for the adverse effects of iron dextrane, it was proposed that iron preparations free of dextrane might be safer Other iron preparations are now available to avoid the use of dextrane Sodium ferric gluconate, a high-molecular-weight complex, contains iron hydroxide, as iron dextrane does However, it is stabilized in sucrose and gluconate and not in dextrane Another iron preparation, iron sucrose (iron saccharate), is also available The dextrane-free products cause similar side effects, such as nausea and vomiting, malaise, heat, back and epigastric pain, and hypotension In contrast to iron dextrane, the reactions are short-lived and lighter It is recommended that, due to their safety, the dextrane-free products should be favored when they are available [8] Even patients who had allergic reactions to iron dextrane can safely be managed with other products When intravenous iron therapy is warranted, the amount of iron to be given can be infused in a single dose or in divided doses It is recommended that iron be diluted in normal saline (not in dextrose, since administration hurts more) The amount of iron can be calculated using the following equations: Dose in mg Fe = 0.0442 × (13.5 − hemoglobin current) × lean body weight × 50 + (0.26 × lean body weight) × 50 Or Dose in mg Fe = (3.4 × hemoglobin deficit × body weight in kg × blood volume in mL/kg body weight)/100 A male has a blood volume of 66 mL/kg and a female about 60 mL/kg In addition to the amount of iron calculated by this formula, an additional 1000 mg should be given to fill iron stores For example, a 70-kg female has a hemoglobin level of g/dL and is scheduled for parenteral iron therapy How much iron does she need? If we consider a hemoglobin level of 14 g/dL to be normal for this woman, she has a deficit of g/dL Therefore, calculate: (3.4 × g/dL × 70 kg × 60 mL/kg = 856,800)/100 = 856.8 mg Meaning the woman has an iron deficit of about 857 mg In addition, a further 1000 mg should be given to replenish the stores 39 Practice tip A simpler way to estimate the iron needs of an adult is to multiply the hemoglobin deficit by 200 mg Additional 500 mg should be given to replenish iron stores The above-mentioned patient would receive approximately 1700 mg of iron (6 × 200 + 500) using this calculation method There are different iron products available for parenteral use Table 4.4 gives vital information [9] for their practical use Markers of iron deficiency It is usually simple to recognize and diagnose iron deficiency anemia Microcytic anemia and hypochromic anemia together with low body iron (as measured by transferrin saturation, serum iron, and ferritin) are the classical findings However, there is an increasing number of patients whose iron needs are not easily monitored by the classical iron markers Among them are patients with the so-called functional iron deficiency Since iron status and immunity are closely related, most biochemical markers of the iron status are affected by inflammation and/or infection Table 4.5 describes commonly used and newer markers of the iron reserves [10–13] Most hospitals not offer all methods to monitor iron status mentioned in Table 4.5 Nevertheless, a reliable differential diagnosis (Table 4.6) is possible using commonly available tests For instance, in addition to the red cell count and the red cell indices (MCV, MCHC), the three following parameters should be sufficient for an exact diagnosis of iron deficiency: r Ferritin concentration: If it is below 12–15 mcg/L, there is a sure indication for iron therapy If ferritin is above 800–1000 mcg/L, there seems to be too much iron stored in the body and iron therapy needs to be adapted r Transferrin saturation: It indicates the amount of iron in circulation If it is below 20%, there seems to be an iron deficit and if it is below 15%, this is a certain indication for iron therapy If it is above 50%, enough iron should be available r Percentage of hypochromic red cells: The percentage of hypochromic red cells indicates if red cell synthesis is iron deficient If the value is above 2.5%, then it 40 Chapter Table 4.4 Commonly used parenteral iron formulas Iron preparation Iron dextrane Iron sucrose Iron gluconate Allergic reactions Anaphylactoid reactions, e.g., due to free iron Availability of iron Stability Recommended dose given in one session (during at least which time) Relatively common Rare Rare Rare Takes 4–7 days until iron available Very stable Do not exceed 20 mg/kg body weight (4–6 h); it has been reported that up to 3–4 g have been given over several hours Yes, 10 mg, (no guarantee that patient will not react allergically) There are different types of iron dextrane with slightly different properties Immediately Stable 500 mg, not exceed mg/kg body weight (3.5 h) ? Occasionally (iron complex instable) Immediately Instable 250 mg safely possible Test dose required Remarks Contains preservatives that may be dangerous for newborns Other available parenteral iron preparations include iron polymaltose (= iron dextrin), chondroitin sulfate iron colloid, iron saccharate, and iron sorbitol is abnormal Values above 10% indicate absolute iron deficiency Copper therapy in blood management Copper deficiency can cause anemia In early experiments in anemia therapy of animals on iron feed, it was shown that iron-deficient anemic animals did not improve if copper was lacking in their feed Adding copper to their feed cured the anemia [14] This was an interesting result, because hemoglobin does not contain copper It was found out later that a lack of copper influences hematopoiesis by interfering with iron metabolism due to impaired iron absorption, iron transfer from the reticuloendothelial cells to the plasma, and inadequate ceruloplasmin activity mobilizing iron from the reticuloendothelial system to the plasma Additionally, copper is a component of cytochrome-c oxidase, an enzyme that is required for iron uptake by mitochondria to form heme Defective mitochondrial iron uptake, due to copper deficiency, may lead to iron accumulation within the cytoplasm, forming sideroblasts Copper deficiency may also shorten red cell survival [15] The average daily Western diet contains 0.6–1.6 mg of copper Meats, nuts, and shellfish are the richest sources of dietary copper Because of the ubiquitous distribution of copper and the low daily requirement, acquired copper deficiency is rare However, it has been reported in premature and severely malnourished infants, in patients with malabsorption, in parenteral nutrition without copper supplementation, and with ingestion of massive quantities of zinc or ascorbic acid Copper and zinc are absorbed primarily in the proximal small intestine Zinc interferes directly with intestinal copper absorption When copper deficiency anemia is present, the patient presents with macrocytic or microcytic anemia, occasionally accompanied by neutropenia or thrombocytopenia [16–19] Erythroblasts in the bone marrow are vacuolized The serum copper level is lower than the normal serum copper level of 70–155 μg/dL The ceruloplasmin level may also be lower than normal Treatment of copper deficiency is administered by copper sulfate solution (80 mg/(kg day)) per os or by intravenous bolus injection of copper chlorite [20] Vitamin therapy in blood management Vitamins play an important role in blood management They not only influence hematopoiesis, but also have an impact on other aspects of blood management such as Anemia Therapy II (Hematinics) 41 Table 4.5 Available essays for the monitoring of iron therapy Essay Reference values Description Use and limitations Bone marrow aspirate Normal: stainable iron present “Gold standard”; if stainable iron is missing, iron deficiency is present Too invasive for routine use in the diagnosis of iron deficiency Iron bound to transferrin Diurnal variations (higher concentrations late in the day); diet-dependent; infection and inflammation lower serum iron Increased by oral contraceptives; decreased in infection or inflammation High in iron deficiency anemia, late pregnancy, polycythemia vera; low in cirrhosis, sickle cell anemia, hypoproteinemia, hemolytic, and pernicious anemia Oral contraceptives cause inappropriately low TS Acute-phase protein; increased in infection/ inflammation, hyperthyroidism, liver disease, malignancy, alcohol use, oral contraceptives; does not reflect iron stores in anemia of chronic disease Classic biochemical markers Serum iron 50–170 μg/dL or female: 10–26 μmol/L; male: 14–28 μmol/L (μmol/L × 5.58 = μg/dL) Transferrin 2.0–4.0 g/L in adults; higher in children Total iron-binding capacity (TIBC) Normal: 240–450 μg/dL Transferrin saturation (TS) Ferritin (F) 20–50% Newer biochemical markers Serum transferrin receptor (sTfR) R/F-ratio