Hematology Oncology

Anemia

Bernard J. Silver

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Definition

Generally defined, anemia is present when the hemoglobin concentration is below a normal value based on the reference population. The mean normal value of hemoglobin is dependent on age, gender, race, and altitude. According to WHO criteria, the lower limit of normal in adults is 13 g/dL in men and 12 g/dL in women. The blood hemoglobin concentration is believed to reflect more accurately the total red cell mass or status of the erythron (erythroid precursors of the marrow and circulating mature red cells) compared with the hematocrit. A drop in the hemoglobin level is observed in older men that may be the result of reduced androgen levels. This assumption does not, however, obviate the need for evaluation, especially if the patient is known to have had normal values in the recent past; the detection of a slight decrease in the hemoglobin level is often a signal of underlying disease, such as myelodysplastic syndrome. Other features that should prompt investigation include microcytic or macrocytic indices, elevated reticulocyte count (signifying hemolysis), and leukocyte or platelet abnormalities.

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Prevalence

It's been estimated that 3.4 million Americans have anemia. Approximately 20% to 30% of hospitalized patients have some degree of anemia, with the highest percentage being found in intensive care units. The most common causes of anemia seen in general practice are illustrated in Figure 1.

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Pathophysiology

Anemia can also be defined physiologically by the degree of impairment of tissue oxygenation. Oxygen supply to tissues is controlled by a well-balanced mechanism that depends on the relative rate of oxygen supply and demand. Tissue oxygen delivery is dependent on the hemoglobin concentration, oxygen saturation and oxygen affinity, the degree and rate of change in blood volume, and the capacity for the cardiovascular and pulmonary systems to compensate. These, in turn, determine the clinical manifestations of anemia, on which the decision to transfuse should ultimately be based. Tissue oxygen delivery is also the major controlling factor of erythropoiesis through the synthesis and release of erythropoietin (EPO) by the proximal tubular cells or the peritubular interstitial cells in the kidney. EPO synthesis is governed by the activation of hypoxia inducible factor-1 (HIF-1), which controls the metabolic responses of multiple gene products to hypoxia. HIF-1 binds and activates the hypoxia-responsive transcriptional enhancer in the erythropoietin gene regulatory region that upregulates EPO expression. EPO stimulates erythroid precursor cells (CFU-E [colony-forming units—erythroid]), leading to increased proliferation and shortening of their maturation time. The marrow responds to increased EPO maximally in 4 to 7 days if enough iron is available. Erythropoiesis can be increased by as much as a factor of 8. Typical of an endocrine loop feedback mechanism, there is an inverse relation between the hemoglobin and EPO levels measured in the blood (Fig. 2). Although this relation holds true in simple iron deficiency, it is somewhat distorted in the anemia associated with inflammation or chronic disease, in which there may be a blunted EPO response. This has made prediction of the hemoglobin response to treatment with exogenous EPO unpredictable, except in limited circumstances (see later).

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Signs and symptoms

The clinical manifestations of anemia depend on the individual's ability to compensate for a loss in oxygen-carrying capacity. The more abrupt the onset of the anemia, the more dramatic the presentation. A sudden loss of more one third of a patient's blood volume, for example, usually results in hypotension, respiratory distress, and acute mental status change, even in a young, previously healthy patient. With the more typical chronic development of anemia, the clinical changes are subtler and depend on the patient's age and comorbid conditions. The most familiar of these changes is an increase in cardiac output causing symptoms of palpitations and tachycardia, breathlessness, especially on exertion, and dizziness or lightheadedness. The patient may also complain of noise in the ears. This is not true tinnitus, but rather a roaring sound caused by accelerated blood flow through the ear. Some patients develop a feeling of profound generalized fatigue that can be accompanied by a loss of mental acuity, resulting in reduced ability to perform simple tasks such as reading a newspaper. These chronic symptoms are made worse by underlying coronary artery disease, congestive heart failure, and intrinsic pulmonary or cerebrovascular disease.

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Diagnosis

The evaluation of anemia can be a complex and difficult endeavor that may not yield a definitive diagnosis, even after exhaustive testing, including a bone marrow biopsy. Often, anemia exists in a milieu of chronic organ dysfunction or medical conditions that cloud the diagnosis because of their effect on erythropoiesis or red cell survival. These conditions may also create discrepancies in laboratory results, leading to further obfuscation in the differential diagnosis. Even bone marrow findings can be so subtle as to be nondefinitive, and only after long-term follow-up does the diagnosis become apparent in retrospect.

These difficulties arise in two of the most common types of anemia, iron deficiency anemia and the anemia of chronic disease. This review will emphasize the pathogenesis and diagnosis of these two types of anemias, how they are differentiated from each other, and how erythropoietin is used therapeutically in select patients to avoid or lessen the requirement for transfusion.

Once anemia has been identified, classification of the physiologic mechanism is the most useful first step (Box 1). This kinetic classification is a useful first approach for any type of cytopenia. In this schema, red blood cells are being lost (blood loss), destroyed (hemolysis), or underproduced. The last category is further divided into hypoproliferative and ineffective erythropoiesis. Three patterns of erythropoiesis are identified based on the reticulocyte count, appearance of the bone marrow, and tests for hemolysis, such as the indirect bilirubin assay (Table 1). More than one mechanism can exist, or one category can evolve from another. The last example is best illustrated by iron deficiency anemia, caused first by blood loss and then by underproduction of red cells caused by lack of sufficient iron. Although the mechanism of anemia may be considered in kinetic terms, the mean corpuscular volume (MCV), measured directly by automated cell counters, is used to classify and diagnose the anemia further and guide the rest of the laboratory workup.

Box 1: Kinetic Classification of Anemia
Red blood cell loss (bleeding)
Red blood cell destruction (hemolysis)
Extracorpuscular hemolytic disease
Antibodies
Infection (e.g., malaria)
Splenic sequestration and destruction
Associated diseases (e.g., collagen-vascular, lymphoproliferative, immunodeficiency)
Drugs, chemicals, physical agents
Red cell trauma (e.g., microangiopathic hemolytic anemia)
Intracorpuscular hemolytic disease, hereditary
Disorders of glycolysis
Faulty synthesis or maintenance of reduced glutathione (e.g., glucose-6-phosphate dehydrogenase [G6PD] deficiency)
Hemoglobinopathies
Red cell membrane abnormalities
Erythropoietic porphyria
Intracorpuscular hemolytic disease, acquired
Paroxysmal nocturnal hemoglobinuria
Lead poisoning
Red blood cell underproduction
Nutritional deficiencies-iron, vitamin B12, folic acid, pyridoxine
Bone marrow aplasia or hypoplasia
Pure red cell aplasia
Bone marrow infiltration
Myelodysplasia
Leukemia, lymphoma
Multiple myeloma
Carcinoma
Myelofibrosis
Endocrinopathy (e.g., thyroid, adrenal, pituitary hypofunction)
Chronic renal disease
Chronic inflammatory disease
Cirrhosis

Adapted from Wintrobe MM, Lukens JN, Lee GR: The approach to the patient with anemia. In Lee G, Bithell T, Foerster J et al (eds): Wintrobe's Clinical Hematology, 9th ed. Philadelphia, Lea & Febiger, 1993, pp 715-744.


Table 1: Patterns of Abnormal Erythropoiesis
Disorder Reticulocytes Marrow Erythropoiesis Bilirubin
Hemolytic anemia

(appropriate for Hb)
Erythroid hyperplasia

Hypoproliferative anemia Inappropriately low for Hb Erythroid hypoplasia

Ineffective erythropoiesis Inappropriately low for Hb Erythroid hyperplasia

Hb, hemoglobin.
Adapted from Hillman, RS, Finch, CA (eds): Red Cell Manual, 7th ed. (1996). Philadelphia, FA. Davis, 1996, pp 1-38.

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Types of anemia

Iron Deficiency Anemia

Iron is an essential nutrient found mostly in heme proteins (e.g., hemoglobin, myoglobin), but also in a host of enzymes of intermediary metabolism. About two thirds of the body's iron are incorporated into the hemoglobin of the erythron. The distribution of iron between the erythron, the plasma, and reticuloendothelial storage sites (e.g., hepatocytes, macrophages) is a tightly controlled process; both iron deficiency and iron overload are serious disorders. There has been a rapid increase in our understanding of the regulation of iron distribution. More than 15 newly identified proteins have been described in recent years. These proteins regulate the absorption of iron from the gastrointestinal (GI) tract, transport to the erythron, and storage of iron in reticuloendothelial cells.

Iron deficiency is one of the most common causes of anemia in the United States and worldwide. The three stages of iron deficiency are iron depletion (reduced stores), early iron deficiency anemia (depleted stores, normal MCV, and red cell morphology), and advanced iron deficiency anemia. Bleeding is the most common cause, typically GI bleeding or menstruation, although other causes of blood loss (e.g., pulmonary, urinary, and even factitious) occasionally present themselves (Box 2).1 A rare cause of iron deficiency is paroxysmal nocturnal hemoglobinuria. Although dietary lack of iron alone is rarely a cause of iron deficiency, it does contribute to the loss of iron brought about by otherwise minor bleeding, such as with normal menstruation. Iron malabsorption is rarely the cause of iron deficiency. Malabsorption of iron may result from achlorhydria (e.g., that seen in vitamin B12 deficiency), gastric bypass surgery, and celiac disease. Gastric resection alone would not be expected to cause iron deficiency unless the upper duodenum, the major site of iron absorption, was also removed or bypassed. About 50% of patients who have undergone a subtotal gastric resection will have impaired food iron absorption, but will still absorb exogenous iron. Inflammatory bowel disease involving the upper jejunum and duodenum may also cause malabsorption of iron. It has been estimated that approximately two thirds of patients with iron deficiency anemia have GI lesions that can be detected by endoscopy, and 10% to 15% have a GI malignancy.

Box 2: Causes of Iron Deficiency
Increased Loss
  • Gastrointestinal blood loss: epistaxis, varices, gastritis, ulcer, tumor, Meckel's diverticulum, parasitosis
  • Milk-induced enteropathy of early childhood: vascular malformations, inflammatory bowel disease, diverticulosis
Inadequate Absorption
  • Poor bioavailability
    1. Antacid therapy or high gastric pH
    2. Excess dietary bran, tannin, phytates, or starch
    3. Competition from other metals (e.g., copper, lead)
  • Loss or dysfunction of absorptive enterocytes
    1. Bowel resection
    2. Celiac disease
    3. Inflammatory bowel disease
    4. Intrinsic enterocyte defects
  • Other blood loss
    1. Trauma
    2. Excessive phlebotomy
    3. Large vascular malformations
    4. Chronic infection
  • Pulmonary blood loss
    1. Pulmonary hemosiderosis
    2. Infection
  • Menorrhagia
  • Cancer
  • Genitourinary blood loss
  • Hemorrhoids

Data from Andrews N: Disorders of iron metabolism. N Engl J Med 1999;341:1986-1995.


The clinical manifestations of iron deficiency consist of those related to anemia, but there also appear to be effects on the central nervous system causing neuromuscular abnormalities and cognitive defects, especially in children. Pica occurs in children and adults. Effects on epithelial tissues, such as the nails (koilonychia), oropharyngeal mucosa (glossitis, angular stomatitis, and mucosal webs [Plummer-Vinson syndrome]), are rarely seen today because of earlier diagnosis and treatment.

The pure case of iron deficiency anemia is straightforward to diagnose.2 By the time red cell production is slowed and microcytic anemia occurs, iron stores are depleted, as determined by a low serum ferritin level, the major iron storage protein. The familiar laboratory tests of determination of the serum iron level, total iron-binding capacity (TIBC; transferrin), transferrin saturation, and ferritin level accurately reflect body iron stores, and obviate the need for a bone marrow biopsy in most cases. Although an MCV lower than 80 fL and a serum ferritin lower than 20 ng/mL are traditionally used to diagnose iron deficiency anemia, an MCV of 95 fL or a serum ferritin lower than 45 ng/mL were found to be predictive of iron deficiency secondary to serious GI lesions in one prospective study.

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Summary

Diagnosis of Iron Deficiency

  • Use all four laboratory parameters to make an accurate diagnosis—serum iron level, total iron-binding capacity, percentage transferrin saturation, and serum ferritin level.
  • Bleeding is the most common cause.
  • Search for GI malignancy.
  • Malabsorption is rarely the cause unless there is a specific defect in the duodenum or upper jejunum.
Treatment

After searching for a source of blood loss, iron replacement is begun, starting with ferrous sulfate, 325 mg three times daily, preferably taken 1 hour before meals. Both patient and physician must realize that several months of therapy are needed to replenish body iron stores. Although the most frequent cause of failure of iron therapy is patient noncompliance, it must be recognized that many patients cannot tolerate oral iron. This may be circumvented by switching to other iron salts (e.g., ferrous gluconate, ferrous fumarate) or to an iron-polysaccharide complex (Nu-IronPlus®) that may produce fewer side effects. Patients may tolerate delayed-release products better, but iron absorption could be impaired because of bypass of the major iron absorption sites in the upper jejunum and duodenum. Some patients tolerate oral iron yet do not respond to therapy. This could result from defects in the iron transport abnormalities in the intestinal epithelium as well as from the more common causes of malabsorption. These patients may benefit from parenteral iron replacement, with iron dextran, sodium ferric gluconate (Ferrlecit®), or iron sucrose (Venofer®). Test doses of iron dextran should be given first because anaphylactic reactions could occur.

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Summary

Treatment of Iron Deficiency

  • Use ferrous sulfate for iron replacement; if not well tolerated, try other iron salts (e.g., ferrous gluconate, ferrous fumarate) or polysaccharide iron complex.
  • Proton pump inhibitors can interfere with iron absorption; add vitamin C.
  • IV iron replacement should be done sparingly and only if malabsorption is present.

Chronic Disease Anemia

Chronic disease anemia (CDA), or the anemia of inflammation, is a mild to moderate anemia accompanying infectious, inflammatory, or neoplastic disease that is characterized by abundant reticuloendothelial iron unavailable to bone marrow erythroid precursors.3 Iron-deficient erythropoiesis results from this defect in iron recycling, triggered by cytokines (e.g., tumor necrosis factor α [TNF-α, interleukin-1 or interleukin-6 [IL-1, IL-6]) that lower the serum iron level and affect macrophage iron storage so as to prohibit iron uptake. Hepcidin is a major regulator of iron absorption and iron efflux from macrophages. Studies have indicated that it may play a major role in the pathogenesis of CDA in that hepcidin decreases iron absorption in the small intestine and inhibits iron release from macrophages. It is also inducible by IL-1 and IL-6 and has been found to cause hypoferremia and anemia. Other mechanisms in CDA that limit erythropoiesis include inappropriately low EPO secretion and diminished EPO responsiveness. This same pattern of iron diversion and altered response to EPO can be seen in acutely ill patients in the intensive care unit with multiorgan dysfunction or sepsis. Although typically found in inflammatory conditions or malignancy, CDA is also associated with noninflammatory disorders, such as congestive heart failure, COPD, alcoholic liver disease, and chronic kidney disease. In diabetics, for example, the EPO response to anemia is blunted, even in those patients without renal insufficiency.4 In anemic COPD patients, moderately elevated erythropoietin levels have been described, suggesting relative EPO resistance. Anemia develops 1 to 2 months after the onset of illness, does not progress, and parallels the severity of the underlying condition. Iron therapy is ineffective because of limited iron absorption and trapping of iron in macrophage storage sites.

The diagnosis of CDA can be difficult, especially if it coexists with iron deficiency. Other contributing causes of anemia should be ruled out, including blood loss, malnutrition, folate or vitamin B12 deficiency, and hemolysis. Myelodysplastic syndrome frequently masquerades as CDA until it progresses, and the threshold for performing a bone marrow biopsy should be low, particularly for those in older age groups or in the absence of an obvious chronic disease. Laboratory findings of CDA include a mild to moderate anemia with normocytic or slightly microcytic indices, reduced serum iron and TIBC (transferrin) levels, and increased ferritin level, reflecting the increase in iron stores (Table 2). Although the serum ferritin level is useful when there is no accompanying inflammation, it is influenced by acute phase responses. The soluble transferrin receptor (TFR) is present in human plasma and its concentration is determined by marrow erythroid activity and iron status. Its synthesis is induced by iron deprivation, so in iron-deficient states the level of TFR rises. The TFR concentration is not increased with infection or inflammation, providing a way of differentiating iron deficiency from CDA. Patients who have a combination of iron deficiency and an infectious, inflammatory, or malignant disorder can be more accurately diagnosed by using a combination of the ferritin and TFR concentrations to derive the TFR-ferritin index. This index is the TFR concentration divided by the log of the ferritin concentration (see Table 2).

Table 2: Iron Values in Chronic Disease Versus Iron Deficiency Anemia
Parameter Chronic Disease Anemia Iron Deficiency
Iron level ↓ to N
Transferrin level ↓ to N
Transferrin saturation ↓ to N
Ferritin level N to ↑
TFR level N
TFR/log ferritin Low (<1) High (>4)

TFR, transferrin receptor.

Treatment

Whereas CDA will improve with recovery from the chronic disorder, this is usually not possible, although the anemia will wax and wane with the activity of an associated inflammatory process, and may resolve altogether with successful treatment of an underlying infection. Because the anemia is relatively mild and the time course for its development is prolonged, allowing adequate compensatory mechanisms to come into play, patients are usually asymptomatic from the anemia itself and do not require treatment. Patients with compromised cardiac function and other chronic diseases, however, may have more exaggerated anemia-related symptoms. Transfusions result in immediate correction of anemia, and may be useful in differentiating anemic symptoms from those of the underlying disease process. Chronic blood replacement, however, is not recommended because of the potential complications of iron overload, alloimmunization, delayed and immediate transfusion reactions, and potential viral transmission.

The major objectives for the use of recombinant human erythropoietin (rHuEPO) therapy are to reduce transfusion requirements and to improve quality of life. Initiation of therapy should be based on the same rationale as one would use in deciding whether a transfusion is indicated—that is, whether or not the patient has clinical signs and symptoms of anemia that would be resolved or lessened by an increase in oxygen delivery. The three approved erythropoietic agents approved for use in the United States are epoetin alfa (Epogen, Procrit) and darbopoetin alfa (Aranesp). The latter is a recombinant erythropoietin that has been modified to increase the plasma half-life. It yields an equivalent erythropoietic response but requires less frequent dosing. Guidelines have been developed for the treatment of the anemia of cancer and for anemia of chronic kidney disease (CKD).5,6 Erythropoietin therapy has been successful in patients with other types of chronic disease anemia, especially rheumatoid arthritis, in whom improvements in disease activity as well as anemia have been reported.7

In patients with cancer, CKD, and chronic inflammatory diseases, erythropoietin levels may be inappropriately low for the degree of anemia, suggesting that measuring EPO levels would be useful in predicting responses to therapy. In myelodysplastic syndromes, for example, an EPO level higher than 200 mU/L predicted a lack of response. Those with a level lower than 100 mU/L are said to be most likely to respond. This was substantiated in patients with advanced cancer, but only when an initial response (within 2 weeks) to rHuEPO was also observed. For other malignancies, and in most other chronic diseases, there is insufficient evidence to show that measuring serum EPO levels alone is clinically useful for predicting treatment responses, and current guidelines do not recommend it because it is unlikely to guide clinical decision making.

In the anemia related to cancer chemotherapy, evidence from clinical trials has supported the use of rHuEPO at a dosage of 150 U/kg subcutaneously three times weekly.8 Once-weekly dosing, however, has become common practice, at a starting dosage of 40,000 U/week. If there is no response after 4 weeks, the dose can be titrated upward to 60,000 U/week. Randomized, placebo-controlled studies have demonstrated that rHuEPO therapy improves anemia, reduces transfusion requirements, and improves quality-of-life scores in cancer patients.

In general, erythropoietin therapy is safe and, in many cases, results in the resolution of anemic symptoms, allowing responding patients to avoid the detrimental effects of chronic red cell transfusions. An uncommon complication is the development of neutralizing antierythropoietin antibodies and pure red cell aplasia. Most of these cases have been described in Europe in patients treated with either the Eprex brand of epoetin alfa or, to a lesser extent, epoetin beta (NeoRecormon), agents not in use in the United States. Clinicians should also be aware, however, of recent U.S. Food and Drug Administration (FDA) warnings regarding the increased risk of venous thrombosis, stroke, and myocardial infarction in orthopedic, renal failure, and cancer patients treated with rHuEPO. A possible detrimental effect on survival has been noted in patients with head and neck cancers. Further revisions of guidelines for the use of these agents are likely to be forthcoming. Treating physicians are advised to follow the hemoglobin level closely when starting therapy and adjust the dose of erythropoietin to maintain the lowest level required to avoid transfusion.

Iron requirements are increased during rHuEPO therapy. If there is no increase in the hemoglobin level or a patient stops responding during therapy, iron deficiency should be excluded, because it will limit the erythropoietic response. Recommendations for iron replacement, however, are variable, and there is some debate as to the optimal route, dose, and indication for initiating iron supplements in patients receiving rHuEPO. In end-stage renal disease, oral iron supplements have been largely abandoned and replaced by newer generation IV preparations; these are believed to be superior in achieving more rapid repletion of iron stores in patients known to have increased iron losses and possibly poor iron absorption.9 Rapid responses to rHuEPO and IV iron are observed. However, there are contrasting results among the few published randomized trials. In predialysis patients, for example, a randomized comparison in rHuEPO-treated patients between oral ferrous sulfate and IV iron sucrose showed no differences in hemoglobin response or required rHuEPO doses. Opposite results were seen in chemotherapy-induced anemia. One randomized controlled study has suggested that patients treated with IV iron have a higher hematopoietic response rate to rHuEPO than those given oral iron.10 Iron dextran preparations have a low but significant incidence of serious adverse effects, including anaphylactic reactions. Newer nondextran iron preparations, such as ferric sodium gluconate (Ferrlecit) and iron sucrose (Venofer), are associated with a lower incidence of immediate toxicities. In these and other patient populations, there is concern that IV nontransferrin bound iron may have long-term effects through the production of excess free radicals, exacerbation of atherosclerosis, and risk of infection. The potential for iron toxicity and iron overload with IV iron supplementation, as well as its role in rHuEPO-treated patients, remain to be determined.

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References

  1. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999, 341: 1986-1995.
  2. Ioannou GN, Spector J, Scott K, Rockey DC. Prospective evaluation of a clinical guideline for the diagnosis and management of iron deficiency anemia. Am J Med. 2002, 113: 281-287.
  3. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005, 352: 1011-1023.
  4. Thomas MC, Cooper ME, Tsalamandris C, et al: Anemia with impaired erythropoietin response in diabetic patients. Arch Intern Med. 2005, 165: 466-469.
  5. Rizzo JD, Somerfield MR, Hagerty KL, et al: Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008, 111: 25-41. Prepublished online October 22, 2007; DOI 10.1182/blood-2007-08-109488
  6. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease, 2006. Available at http://www.kidney.org/professionals/kdoqi/guidelines_anemia/index.htm
  7. Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: A systematic review of the literature. Am J Med. 2004, 116: (Suppl 7A): 50S-57S.
  8. Witzig TE, Silberstein PT, Loprinzi CL, et al: Phase III, randomized, double-blind study of epoetin alpha compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol. 2005, 23: 2606-2617.
  9. Stoves J, Inglis H, Newstead CG. A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. Nephrol Dial Transplant. 2001, 16: 967-974.
  10. Auerbach M, Ballard H, Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol. 2004, 22: 1301-1307.

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Suggested Readings

  • Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999, 341: 1986-1995.
  • Auerbach M, Ballard H, Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol. 2004, 22: 1301-1307.
  • Ioannou GN, Spector J, Scott K, et al: Prospective evaluation of a clinical guideline for the diagnosis and management of iron deficiency anemia. Am J Med. 2002, 113: 281-287.
  • National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology, vol 1, 2005. Available at http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf
  • National Kidney Foundation. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. Am J Kidney Dis. 2001, 37: (Suppl 1): S182-S238.
  • Stoves J, Inglis H, Newstead CG. A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. Nephrol Dial Transplant. 2001, 16: 967-974.
  • Thomas MC, Cooper ME, Tsalamandris C, et al: Anemia with impaired erythropoietin response in diabetic patients. Arch Intern Med. 2005, 165: 466-469.
  • Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005, 352: 1011-1023.
  • Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: A systematic review of the literature. Am J Med. 2004, 116: (Suppl 7A): 50S-57S.
  • Witzig TE, Silberstein PT, Loprinzi CL, et al: Phase III, randomized, double-blind study of epoetin alpha compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol. 2005, 23: 2606-2617.