Anemia affects a third of the global population and accounted for the primary hospital discharge diagnosis in approximately 188,000 emergency department (ED) visits in 2014 as reported by the Centers for Disease Control (CDC). Anemia is an absolute decrease in the number of circulating red blood cells (RBCs). The diagnosis is made when laboratory measurements fall below accepted normal values ( Table 109.1 ).

Anemia is divided into two broad categories: emergent, having immediate life-threatening complications, and typically secondary to acute blood loss; and non-emergent, with less imminent danger to the patient and many times can be further evaluated on an outpatient basis. Factors other than the absolute number of circulating RBCs may place the patient in one category or another (e.g., rate of onset and underlying hemodynamic reserve of the patient). Both groups necessitate a sound diagnostic approach, though emergent anemia may require immediate supportive therapy concomitant with or in advance of the definitive diagnosis. Although patients with non-emergent anemia are usually referred to a specialist, the urgency of consultation depends predominantly on the patient’s hemodynamic tolerance of the anemia.

Understanding anemia starts with the structure and function of the RBC. RBCs are primarily composed of hemoglobin, which has a quaternary structure containing 4 heme polypeptide subunits bound to an iron molecule that is contained in the center of a porphyrin ring. The major function of the RBC is oxygen transport from the lung to the tissue, and carbon dioxide transport in the reverse direction. Oxygen transport is influenced by the amount of hemoglobin and its oxygen affinity, as well as blood flow. An alteration in any of these major components usually results in compensatory changes in the other two. For example, a decrease in hemoglobin is compensated for by both inotropic and chronotropic cardiac changes that result in increased blood flow and decreased hemoglobin affinity at the tissue level, thereby allowing more oxygen release. Due to disease severity or underlying pathologic conditions, these compensatory responses may fail, resulting in tissue hypoxia and cell death.

Anemia stimulates the compensatory mechanism of erythropoiesis controlled by the hormone erythropoietin, which is a glycoprotein produced in the kidney (90%) and liver (10%). It regulates the production of RBCs by controlling differentiation of committed erythroid stem cells and is stimulated by tissue hypoxia or products of RBC destruction during hemolysis. Elevated in many types of anemia, erythropoietin enhances the growth and differentiation of erythroid progenitors.

Bone marrow contains pluripotent stem cells that can differentiate into erythroid, myeloid, megakaryocytic, or lymphoid progenitors. When the late normoblast extrudes its nucleus, it still contains a ribosomal network, which identifies the reticulocyte. The reticulocyte retains its ribosomal network for approximately 4 days, 3 days of which are spent in bone marrow and 1 day in the peripheral circulation. The RBC matures as the reticulocyte loses its ribosomal network and becomes an erythrocyte which circulates for 110 to 120 days in the peripheral circulation. Erythrocytes are anucleate, flexible, biconcave discs. The erythrocyte is scavenged and removed by macrophages that detect senescent signals. Under steady-state conditions, RBC mass remains constant as an equal number of reticulocytes replace the destroyed, senescent erythrocytes.

The most common cause of emergent anemia is acute blood loss. Common sites of blood loss in the trauma patient include pleural, peritoneal, pelvic, long bone (e.g., thigh), and retroperitoneal spaces. In non-traumatic circumstances, especially in patients receiving anticoagulants, the gastrointestinal tract, retroperitoneal space, uterus, or adnexa need to be considered. Certain hemolytic conditions, such as disseminated intravascular coagulopathy (DIC), can also cause rapid intravascular destruction of RBCs leading to emergent anemia ( Box 109.1 ).

Non-emergent anemias can be subdivided into microcytic, normocytic, and macrocytic based on the mean corpuscular volume (MCV), which measures size and volume of the RBC. Microcytic anemias are caused by low iron production, gene mutations, toxins (e.g., lead poisoning), or defective heme synthesis. Normocytic anemias can be caused by primary or secondary bone marrow failure and can be further subdivided into hemolytic and non-hemolytic. Anemia of chronic disease is the most common non-hemolytic anemia, caused by an inflammatory response to underlying disease states. Hemolytic anemias are either intrinsic or extrinsic in nature. Intrinsic hemolytic anemias are typically caused by underlying genetic mutations or enzyme deficiencies (e.g., sickle cell disease) that lead to abnormal RBC production. Extrinsic hemolytic anemias result from defects outside of the RBC (e.g., DIC). Macrocytic anemias are caused primarily by nutritional deficiencies such as folate or vitamin B ₁₂ , as well as various disease states (e.g., alcoholism) that retard the maturation of the RBC.

In a patient suspected of acute blood loss, the following initial laboratory tests may be helpful, depending on clinical circumstances:

• •

  Complete blood count and peripheral smear

• •

  Blood sample for type and crossmatch

• •

  Prothrombin time and international normalized ratio

• •

  Partial thromboplastin time

• •

  Serum electrolyte levels

• •

  Glucose level (particularly if the patient has altered consciousness)

• •

  Creatinine level

• •

  Urinalysis for free hemoglobin

Obtaining a hemoglobin and hematocrit in the emergency department (ED) is useful for determining a baseline even though it may not be reflective of the true degree of blood loss for many hours. Depending on severity, a blood sample should be sent for type and crossmatch.

The initial laboratory evaluation for a patient with non-emergent anemia also includes a complete blood count with leukocyte differential, reticulocyte count, peripheral smear ( Fig. 109.2 ), as well as RBC indices, including MCV, mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). RBC indices are useful in classifying anemias caused by a production deficit ( Table 109.2 ). MCV is a measure of RBC size and volume; decreases or increases reflect microcytosis and macrocytosis, respectively. MCH incorporates both RBC size and hemoglobin concentration. It is influenced by both and is rarely helpful in the ED setting. The MCHC index is a measure of the concentration of hemoglobin. Low values represent hypochromia, whereas high values are noted in patients with decreased cell membrane relative to cell volume, such as in the case of spherocytosis. An additional index is the RBC distribution width (RDW), a measure of RBC homogenicity. RDW is automatically calculated as the standard deviation of MCV divided by MCV multiplied by 100. A normal RDW is 13.5 ± 1.5%. The RDW is elevated in anemias caused by nutritional deficiencies; however, it is not specific for any abnormality.

Normal Smear.

From Hoffbrand AV, Pettite JE. Color Atlas of Clinical Hematology. 3rd ed. London: Mosby; 2000:22.

Measurements of coagulation status, serum electrolytes, glucose, blood urea nitrogen, and creatinine are useful in the diagnosis of underlying disease processes that may relate to the patient’s anemia. When the cause of anemia is unknown and the patient requires transfusion, consider ordering folate, vitamin B ₁₂ , iron, total iron-binding capacity (TIBC), reticulocytes, and direct antiglobulin (Coombs test) pretreatment. Post-transfusion, these levels will be unreliable and could mask an underlying diagnosis.

Stabilization of emergent anemia commonly runs in parallel with assessment. If the signs and symptoms suggest potential life-threatening conditions, multiple large bore intravenous lines are placed in preparation for resuscitation and transfusion.

Iron deficiency is a frequent cause of chronic anemia seen in the ED. It is the most common cause of anemia globally. It is defined by microcytic, hypochromic RBC. Iron deficiency can either be absolute or functional. Absolute iron deficiency reflects low or exhausted total body iron stores, while functional iron deficiency is caused by inadequate iron supply to the bone marrow. Iron is a critical component needed for effective erythropoiesis, and also essential for mitochondrial function, DNA synthesis, and cellular enzymatic reactions. Dietary iron is absorbed in the duodenum, thus nutritional deficiency or malabsorption syndromes can be a cause of iron deficiency anemia. Occult blood loss should always be excluded in the setting of iron deficiency anemia. This is common in older patients, especially with gastrointestinal blood loss, as well as in menstruating women. Changes in RBC size, number, and hemoglobin content occur only after bone marrow and cytochrome iron stores are depleted; therefore, a patient may have early symptoms of iron deficiency (e.g., fatigue) without anemia. These non-hematologic symptoms are the result of impaired muscle-tissue oxidative capacity and decreased activity of iron-containing enzymes in the setting of iron deficiency.

Most anemias secondary to iron deficiency are non-emergent in nature. The symptoms related to anemia are secondary to the body’s ability to adapt to the low hemoglobin levels over time, and the eventual inability of the tissues to receive adequate oxygen for metabolic demands.

The diagnosis is made by laboratory evaluation of the fasting level of serum iron, serum ferritin, and TIBC. The laboratory interpretation and pitfalls are outlined in Table 109.3 . A concentrated search for occult blood loss remains an important component of the evaluation.

Therapy consists of oral iron replacement. A cost-effective form is ferrous sulfate. The dosage is 325 mg PO for adults (65 mg of elemental iron) three times daily, or 2 mg/kg/day of elemental iron orally for children. This medication is generally well tolerated, although it may cause nausea, vomiting, or constipation. Ascorbic acid can improve the bioavailability of iron and is recommended in conjunction with iron replacement, although it can increase the frequency of side effects. Patients should be warned that iron frequently leads to black stools, and that bleeding from the digestive tract can also be manifested as black stool. In patients with poor oral tolerance or absorption, parenteral iron therapy may be necessary. Parenteral iron replenishes iron stores more effectively than oral replacement in CKD, inflammatory bowel disease, and in the post-partum period. ^,

The patient may experience a sense of improvement in as few as 24 hours after initiating replacement therapy. Reticulocytosis appears during a 3- to 4-day period in children, but may take more than 1 week in adults, with complete repletion of iron stores in approximately 3 to 6 months. The hemoglobin concentration rises on a similar schedule. Failures of iron replacement therapy can occur due to a variety of causes, including patient noncompliance with iron supplementation, insufficient replacement, incorrect diagnosis, or presence of an additional process complicating the iron deficiency, such as anemia of chronic disease.

The hemoglobin molecule is present as two-paired globin chains. Each type of hemoglobin is made up of different globins. Normal adult hemoglobin (HbA) is made up of two alpha chains and two beta chains (α ₂ β ₂ ). HbA ₂ is a variant of hemoglobin A that contains two alpha and two delta chains (α ₂ δ ₂ ). Fetal hemoglobin (HbF) contains two alpha and two gamma chains (α ₂ γ ₂ ). A separate autosomal gene controls each globin chain.

Thalassemia is a genetic autosomal recessive disorder reflected by the decreased synthesis of and abnormal structure of globin chains. Deletions in these globin genes result in an absence or decreased function of the messenger RNA that codes for particular globins. The various globins (α, β, δ, and γ) may be affected by a number of genetic combinations. Decreased globin production in thalassemia precipitates the formation of reactive oxygen species leading to apoptosis of erythroblasts, decreased hemoglobin synthesis, and ineffective erythropoiesis, leading to hemolytic anemia. Beta thalassemia is associated with reduced or absent beta-globin synthesis and an excess of alpha-globins, leading to the formation of alpha-globin tetramers. Alpha thalassemia results in an excess of β-globins and the formation of β-globin tetramers termed hemoglobin H. The abnormal formation of hemoglobin at various concentrations results in complications, including red cell membrane breakage and hemolysis. A common method of classification is by phenotype. Beta thalassemias are broken down into silent (carrier), minor, intermedia, and major variants. Alpha thalassemias include silent (carrier), alpha thalassemia trait, HbH, and Hb Barts. This historical classification method is now being replaced by a simpler system: transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT), with patients often shifting clinically between the two categories depending on their transfusion needs. NTDT includes thalassemia minor, mild HbE, HbH disease, and alpha-thalassemia trait. Despite its name, NTDT treatments can range from no transfusion requirement to intermittent transfusions required. Transfusion is also offered to some NTDT patients to prevent or manage disease complications. TDT includes thalassemia major, severe HbE/Beta-thalassemia, and Hb Barts hydrops. Hb Barts is almost always fatal at birth. TDT, as reflected in its name, typically requires regular, lifelong transfusions for survival, usually starting before the age of 2 years.

Thalassemia is a microcytic, hypochromic anemia. Hypochromia, target cells, and basophilic stippling are noted on the peripheral smear. The MCV is commonly lower than seen with iron deficiency, and serum iron levels are typically normal. The diagnosis is made with hemoglobin electrophoresis and genetic testing. Screening for carriers is performed by measurement of RBC indices and estimation of the HbA ₂ concentration. Prenatal diagnosis can be made by analysis of fetal blood or by fetal DNA obtained by chorionic villus sampling.

Usually, no treatment is necessary for silent carriers, beta thalassemia minor, and alpha thalassemia trait. Therapy for the remaining types of thalassemia consists of blood transfusions, where the goals of transfusion therapy include correction of anemia, suppression of ineffective erythropoiesis, and inhibition of increased gastrointestinal iron absorption. TDT requires transfusions every 2 to 5 weeks to maintain a pre-transfusion hemoglobin between 9 and 10.5g/dL. Transfusion is usually started when patients are young to ensure normal growth and physical activity capacity. Recurrent transfusion does increase risk of blood-borne infection, alloimmunization, and iron overload, the latter of which may lead to multi-organ dysfunction and is a common cause of death. Guidelines for transfusion are not well established in patients with NTDT, but transfusion should be considered during times of significant stress such as pregnancy, surgery, or infection, or when hemoglobin levels are low. More frequent transfusion may be used in children with NTDT if they develop signs of growth failure or reduced exercise tolerance.

Transfusion therapy improves long-term survival in patients with TDT when combined with iron chelation therapy. Iron chelation therapy can also reduce systemic and hepatic iron burden in NTDT, but it is not effective in all patients. Deferoxamine can be administered parenterally or subcutaneously. It was the first commercially available chelator. Its demanding treatment regimen, however, often leads to poor adherence. Dosages are weight based, with treatments required for 8 to 12 hours, 5 to 7 nights per week. Two oral chelators are available, deferiprone and deferasirox. Deferiprone is administered two or three times daily, and deferasirox is a once-daily medication. ^,

Hydroxyurea, a cytotoxic anti-metabolite that induces fetal hemoglobin, is also used in some cases of NTDT. Hydroxyurea is hypothesized to improve chronic anemia and reduce the need for transfusion by reducing alpha and beta chain imbalance through the production of fetal hemoglobin. It is well tolerated by patients and has no major long-term adverse effects. Commonly reported side effects included mild transaminitis, nausea or vomiting, and transient bone marrow suppression. It is associated with a decrease in the need for recurrent transfusions. In patients with mild NTDT, it can raise baseline Hb by at least 1 g/dL and in some patients with severe NTDT (>3 transfusions per year) it can lead to a complete cessation of transfusion requirement.

Splenectomy is considered in some patients and can improve hemoglobin concentration, decreasing the need for recurrent transfusions. Hematopoietic stem cell transplantation (HSCT) is another therapy in use and is potentially curative in patients with TDT with disease-free survival rates greater than 80% at 2 years. It is, however, only appropriate for a subset of patients due to age restrictions and the need for sibling donor compatibility. HSCT carries with it a 5% to 10% risk of mortality, as well as potential permanent fertility impairment.

Gene therapy and gene editing are becoming more promising as possible future treatment modalities for thalassemia; data from clinical trials is in progress.

Sideroblastic anemia involves a defect in porphyrin synthesis and can be congenital, idiopathic, or acquired. The resultant impaired hemoglobin production causes excess iron to be deposited in the mitochondria of the RBC precursor as well as increased serum iron, ferritin, and transferrin saturation levels. The defective heme synthesis results in ineffective erythropoiesis, mild to moderate anemia, and a dimorphic peripheral smear with hypochromic microcytes along with normal and macrocytic cells, as well as characteristic ringed sideroblasts. A ringed sideroblast is an erythroid precursor with a minimum of five siderotic granules covering the nucleus after Prussian blue staining.

Congenital sideroblastic anemia is a relatively rare disease resulting from iron metabolism related gene mutations. The most common congenital cause is X-linked sideroblastic anemia (XLSA) which occurs secondary to missense substitutions in 5′-Aminolevulinste Synthase 2 (ALAS2) genes. Idiopathic sideroblastic anemia is a common type of refractory anemia in elderly patients. Pallor and splenomegaly may be noted, and iron staining of the peripheral smear may demonstrate iron-containing inclusion bodies in RBCs. Idiopathic sideroblastic anemia is considered a pre-leukemic state, with acute myelogenous leukemia developing in approximately 5% of patients.

Acquired causes of sideroblastic anemia include drugs, alcoholism, copper deficiency, lead poisoning, zinc toxicity, myelodysplastic syndrome, or myeloproliferative disorders. Chloramphenicol, isoniazid, linezolid, and penicillamine are known causes of drug-induced sideroblastic anemia. Lead poisoning, one reversible cause of sideroblastic anemia, may be suggested by basophilic stippling on the peripheral smear and the presence of metaphyseal lead lines on imaging. Elevated blood lead levels are diagnostic. Alcohol abuse may also result in disordered heme synthesis, which can be corrected by alcohol cessation or by parenteral pyridoxal phosphate (active form of vitamin B6) in cases of continued abuse. Oral pyridoxine (vitamin B6) may be ineffective because of impaired conversion to the active form in alcoholic patients.

Management varies based on underlying cause. Most congenital or acquired sideroblastic anemia is treated with pyridoxine (vitamin B ₆ ) and responds to treatment with 100 mg PO three times a day. Although a trial of treatment with pyridoxine is advised, most patients remain anemic and will require transfusion. If long-term transfusion therapy is necessary, iron overload will need to be managed and usually responds well to chelation therapy. Stem cell transplantation can be curative in some patients with congenital or myelodysplastic sideroblastic anemias. ^,

Symptoms are usually those related to the underlying disease and not from the anemia itself.

Anemia of chronic disease is common and typically normochromic, normocytic, though can be microcytic. It is characterized by low serum iron levels, low TIBC, and normal or elevated ferritin levels. Bone marrow is typically normal, but staining reveals an abnormality in the mobilization of iron from reticuloendothelial cells. This anemia can be differentiated from iron deficiency by TIBC, ferritin, bone marrow examination, and non-responsiveness to a trial of iron therapy. A complete search for occult blood loss is prudent during evaluation. It should be recognized that true iron deficiency may also be superimposed on anemia of chronic disease.

Acute or emergent therapy is not usually required, as the hemoglobin and hematocrit is typically modest. Treatment should be directed at the underlying cause.

Macrocytic anemia is the hematologic manifestation of a total-body alteration in DNA synthesis caused primarily by vitamin B ₁₂ or folic acid deficiency, which appears clinically in tissues with rapid cell turnover, including hematopoietic cells or those of mucosal surfaces, particularly in the gastrointestinal tract. This deficiency is characterized by ineffective erythropoiesis and pancytopenia. Vitamin B ₁₂ and folate deficiencies have different developmental histories, but the clinical result is similar. Differentiation of folate and vitamin B ₁₂ deficiencies usually depends on laboratory measurements.

Macrocytic anemias can be divided into megaloblastic and nonmegaloblastic categories. Megaloblastic macrocytic anemia is the most common cause of macrocytic anemia and pancytopenia. Table 109.4 lists a number of the problems associated with megaloblastic anemia and their underlying pathologic states. Nonmegaloblastic macrocytic anemia is caused by disease states such as alcoholism, liver dysfunction, hypothyroidism, myelodysplastic syndromes, and certain drugs (e.g., hydroxyurea, methotrexate, zidovudine, valproic acid). Like other causes of anemia, easy fatigability is the most common symptom reported in patients with macrocytic anemia. Additional symptoms include anorexia, dyspnea on exertion, palpitations, oral ulcers, or weight loss. A unique feature of vitamin B ₁₂ deficiency is its neurologic involvement. Patients may have paresthesias of their hands or feet, decreased proprioception, or decreased vibratory sense; weakness and spasticity of the lower extremities with altered reflexes; and variable mental changes, such as depression, paranoid ideation, irritability, or forgetfulness. The neurologic manifestations of folic acid deficiency overlap with those of vitamin B ₁₂ deficiency, but the neuropsychiatric manifestations (e.g., depression and forgetfulness) predominate in folic acid deficiency. A devastating consequence of vitamin B ₁₂ deficiency is the development of subacute combined degeneration of the spinal cord resulting from loss of myelin in the dorsal and lateral columns. The syndrome has a gradual and uniform onset of progressive weakness, spastic paresis, ataxia, and loss of proprioception. Vitamin B ₁₂ deficiency can also cause elevated homocysteine levels which can lead to thrombosis. ^,

TABLE 109.4

Clinicopathologic Correlation of Manifestations of Megaloblastic Anemia

Clinical Features	Pathologic Condition
Lemon yellow skin	Combination of pallor with low-grade icterus from ineffective erythropoiesis
Petechiae, mucosal bleeding	Thrombocytopenia
Infection	Leukopenia
Fatigue, dyspnea, orthostasis	Anemia
Sore mouth or tongue	Megaloblastosis of mucosal surfaces
Diarrhea and weight loss	Malabsorption from mucosal surface change
Paresthesias and ataxia	Related to myelin abnormality in vitamin B 12 deficiency only

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