Anemia and Polycythemia

Background and Importance

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.

Anatomy, Physiology, and Pathophysiology

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.

Diagnostic Testing

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.

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.

Management

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.

Foundations

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.

Clinical Features

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.

Diagnostic Testing

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.

Management

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.

Foundations

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.

Pathophysiology

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.