204 Emergency Management of Red Blood Cell Disorders

• Anemia is the absolute reduction in the amount of oxygen-carrying pigment hemoglobin (Hgb) that represents a relative decrease in the capacity of blood to carry oxygen to the tissues.

• Anemia is not a diagnosis. It is an indication of an underlying disease, disorder, or deficiency.

• Transfusion of red blood cells provides immediate correction of low Hgb levels helpful in the context of either severe anemia (in which the Hgb is <8.0 g/dL) or life-threatening anemia (in which the Hgb is <6.5 g/dL).

• Most cases of anemia (chronic) do not require acute interventions and drug therapy in the emergency department (ED). Patients can be referred for follow-up to their primary care physician or gastroenterologist.

• The cardinal features of acute chest syndrome are fever, pleuritic chest pain, referred abdominal pain, cough, lung infiltrates, and hypoxia.

• Pneumococcal sepsis is a leading cause of death among infants with sickle cell anemia because a damaged spleen cannot clear pneumococci from the blood.

• Transfusions are not needed for the usual anemia or episodes of pain associated with sickle cell disease.

• Splenic sequestration is life-threatening and requires intensive care admission with transfusion and possible splenectomy.

• ED-based pain management protocols have been shown to decrease ED visits and hospitalizations and to increase use of primary care clinics by patients with sickle cell disease.

• Patients with severe pain should be given an opiate parenterally at frequent, fixed intervals until the pain has diminished, at which time the dose of the opiate can be tapered and then stopped, and oral analgesic therapy can be instituted.

• For polycythemia vera, phlebotomy is the only therapy indicated for isolated erythrocytosis when its mechanism cannot be established.

Perspective

The red blood cell (RBC) disorders include a distinct group of disease entities that are diverse in presentation yet similar in their emergency diagnosis and management. These disorders include anemia (acute, chronic), sickle cell anemia, and polycythemia vera (PV). Patients with both malignant and nonmalignant hematologic disease may present with dramatic and often life-threatening complications. Emergency management of these disorders requires a thorough understanding of the underlying pathologic processes, as well as a concise and systematic approach to diagnosis, stabilization, and treatment.

Anemia

Anemia is more common than is generally realized. The World Health Organization defines anemia as a condition characterized by hemoglobin (Hgb) levels lower than 13 g/dL in men or lower than 12 g/dL in women.¹ Data from the National Center for Health Statistics that likely underestimate the frequency of anemia indicated that approximately 3.4 million U.S residents have anemia, and that the groups with the highest prevalence are women, African Americans,² older persons, and those with the lowest incomes. Using laboratory data from the general U.S. population, the second National Health and Nutrition Survey reported anemia to be the most prevalent in infants, teenage girls, young women, and older men.³ In another survey, the prevalence of anemia declined significantly among U.S women and children from 1988 to 2002, but the cause of this decline was unknown.⁴ In persons 65 years and older, anemia was present in 11.0% of men and 10.2% of women, and the prevalence rose to more than 20% in people 85 years and older. One third of the cases of anemia were the result of nutritional deficiencies, and one third of cases were secondary to chronic illness, including but not limited to chronic renal disease.

Pathophysiology

Anemia is classified into three broad categories: (1) disorders of decreased RBC production, (2) disorders of increased RBC destruction, and (3) disorders resulting from RBC loss. Disorders in each of these categories may manifest differently and ultimately have their own management approaches (Table 204.1).

Table 204.1 Classification of Anemia

CATEGORY	CLASSIFICATION	DISEASE PROCESS
Decreased RBC production (hypoproliferative)	Microcytic	Iron deficiency Thalassemia Sideroblastic Chronic disease (neoplasm, infection, diabetes, uremia, thyroid disease, cirrhosis)

	Normocytic	Primary bone marrow problem (aplastic, myeloid metaplasia, myelofibrosis, myelophthisic anemia, Diamond-Blackfan anemia)
		Secondary bone marrow problem (uremia, liver disease, endocrinopathy, chronic inflammation)
	Macrocytic	Folic acid deficiency
		Liver disease
		Vitamin B₁₂ deficiency
		Scurvy
		Hypothyroidism
		Chemotherapy, immunosuppressive therapy
Increased RBC destruction (hemolytic)	Intrinsic	Membrane disorder (spherocytosis, sickle cell, stem cell disorder, elliptocytosis, spur cell)
	Extrinsic	Hemoglobin disorder (thalassemia, autoimmune, hemoglobinopathies)
		Infections (hepatitis and cytomegalovirus, Epstein-Barr virus, typhoid fever, Escherichia coli)
		Medications (penicillin, antimalarials, sulfa drugs, or acetaminophen)
		Leukemia or lymphoma
		Autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, Wiskott-Aldrich syndrome, ulcerative colitis)
		Enzyme defect (G6PD)
RBC loss (hemorrhagic)	Acute or chronic	Gastrointestinal tract
		Traumatic
		Intraperitoneal
		Extraperitoneal
		Gynecologic
		Urinary
		Pelvic
		Drug related
		Epistaxis, hemoptysis

G6PD, Glucose-6-phosphate dehydrogenase; RBC, red blood cell.

RBCs, or erythrocytes, contain fluid Hgb encased in a lipid membrane and are the predominant cellular component of blood. RBCs make up 45% of the blood volume and are responsible for carrying oxygen from the lungs to the peripheral tissues. A 70-kg person has approximately 30 trillion RBCs, resulting in approximately 300 million RBCs in each drop of blood. The normal RBC is composed of three types of Hgb: Hgb A (97%), Hgb F (1%) or fetal Hgb, and Hgb A₂ (2%).⁵ Hgb A is composed of two β-globin chains and two α-globin chains bonded to four iron-containing heme groups. Hgb production requires iron, the synthesis of the protoporphyrin ring, and the production of the globin chains. Reductions in any of these processes result in anemia.

RBC precursors develop in bone marrow at rates usually determined by the body’s demand for sufficient circulating Hgb to oxygenate tissues adequately. Once produced, the mature RBC remains in circulation for approximately 120 days before it is engulfed and destroyed. Given the life span, chronic anemias that are caused by RBC underproduction generally develop and progress slowly over weeks to months. In contrast, acute anemias that are caused by bleeding or hemolysis generally occur rapidly over days to weeks. The tempo of anemia development depends on the pace of bleeding or hemolysis in relation to RBC production. The aggressiveness of intervention and management depends on the acuteness of onset and the severity of the clinical presentation.

Presenting Signs and Symptoms

Because anemia either can be a primary disorder or can occur secondary to other systemic processes, a careful history and physical examination provide valuable insight into the potential cause. All patients require a focused yet thorough history. For critically ill and noncommunicative patients, the history should be obtained from caretakers, paramedics, or primary care physicians.

The extent of the symptoms, whether mild or life-threatening, depends on several contributing factors. If anemia develops acutely, compensatory adjustments may not have enough time to take hold, and consequently, the patient may have more pronounced symptoms than if the anemia developed over weeks to months. Furthermore, underlying chronic comorbidities such as myocardial ischemia and transient cerebral ischemia may be unmasked in the presence of anemia.

Acute Anemia

Patients with anemia resulting from acute bleeding present with hypovolemia. The combined effects of hypovolemia and anemia may cause tissue hypoxia or anoxia through diminished cardiac output, resulting in decreased oxygen-carrying capacity (anemic hypoxia). When the Hgb concentration falls to less than 7.5 g/dL as a result of losses ranging from 5% to 15% in blood volume, the resting cardiac output rises significantly, with an increase in both heart rate and stroke volume. These patients are symptomatic at rest and may be aware of this hyperdynamic state; they often complain of palpitations, lightheadedness, dizziness, or a pounding pulse. Larger losses cause progressive increases in heart rate, decreases in arterial blood pressure, and evidence of organ hypoperfusion. Hypovolemic shock is seen when vital organ systems such as the kidneys, the central nervous system, and the heart are affected. In the emergency department (ED), a source of blood loss may be readily apparent on evaluation (e.g., trauma with hemorrhage from the extremities, gastrointestinal bleeding, menstrual blood loss); however, this may not be the case in, for example, aortic dissection or retroperitoneal hemorrhage.

Mild to moderate hypovolemia may be tolerated in the young patient. In older patients, however, these responses are modified by the rapidity of blood loss and by characteristics such as comorbid illnesses, preexisting volume status, Hgb values, and the use of medications that have cardiac or peripheral vascular effects (e.g., beta-blockers, antihypertensive agents). Therefore, the emergency physician (EP) should elicit a thorough and focused history, including medications, while assessing the airway, stabilizing breathing, and initiating resuscitation as needed.

Chronic Anemia

Because anemia can be a primary disorder or can occur secondary to hypoproliferation or chronic blood loss, a careful history and physical examination provide valuable insight into the potential cause. Individuals with mild anemia are often asymptomatic and are able to sustain a relatively normal level of function at Hgb levels that are significantly lower than normal. Other patients may present with myriad nonspecific symptoms (Box 204.1). Because fatigue is nonspecific, determining the concomitant presence of a systemic inflammatory disorder, infection, or malignant disease may be critical in determining the underlying causes of anemia.

Box 204.1 Chronic Anemia

Dizziness (vertigo, especially postural)

Past medical history is quite informative. For instance, a history of diabetes mellitus is associated with significantly impaired renal production of erythropoietin.⁶ Certain medications are associated with bone marrow depression. Therefore, all pharmacologic agents, both prescribed drugs and over-the-counter agents, including alternative medications, should be reviewed. Occupational history is relevant, as in the case of welders, who may have been exposed to lead or other agents potentially toxic to the bone marrow. Social history is important because a history of intravenous drug use may suggest the possibility of human immunodeficiency virus infection, which can be associated with anemia.⁷ Dietary history is relevant. For example, the finding of pica in adults (most commonly from the ingestion of nonfood items) is well known to be associated with iron deficiency anemia. A family history of anemia is important; for example, adults with congenital hereditary spherocytosis often develop symptoms later in life.

Physical findings in either acute or chronic anemia are myriad and often nonspecific, and they may relate to the underlying disease process and the duration (Table 204.2). Pathognomonic findings are not the norm. Furthermore, patients with chronic anemia usually do not have the typical physical findings associated with acute anemia.

Table 204.2 Physical Findings in Anemia

ORGAN	FINDING
Skin	Pallor Usefulness limited by color of skin, Hgb concentration, and fluctuation of blood flow to skin Palmar crease color a better indicator, if as pale as surrounding skin, Hgb usually <7 g/dL
Hematologic	Purpura, petechiae, and jaundice
Cardiovascular	Tachycardia Wide pulse pressure Orthostatic hypotension Hyperdynamic precordium Systolic eject murmur over pulmonic area
Respiratory	Tachypnea Rales
Gastrointestinal	Hepatomegaly and/or splenomegaly Ascites Masses Positive result on Hemoccult test
Ophthalmologic	Pale conjunctiva Scleral icterus Retinal hemorrhages
Neurologic	Peripheral neuritis or neuropathy Mental status changes

Hgb, Hemoglobin.

Differential Diagnosis and Diagnostic Testing

The differential diagnosis of anemia is myriad, as documented in Table 204.3. Once anemia is suspected, the initial diagnosis involves the complete blood count (CBC). The variables to focus on when examining the CBC are hematocrit (as a general indicator of anemia or polycythemia), mean corpuscular volume ([MCV] a key parameter for the classification of anemias), RBC distribution width (a relatively useful parameter in the differential diagnosis of anemia), RBC count (an increased RBC count associated with anemia is characteristic in the thalassemia trait), platelet count (to detect either thrombocytopenia or thrombocytosis), and white blood cell (WBC) count with differential (usually gives important clues to the diagnosis of acute leukemia and chronic lymphoid or myeloid disorders, as well as clues to the presence of leukopenia and neutropenia).⁸

Table 204.3 Differential Diagnosis of Anemia

CATEGORY	DIFFERENTIAL DIAGNOSIS	CBC CLUES
Microcytic	Iron deficiency anemia	Elevated RDW Thrombocytosis
	Thalassemia	Normal or elevated RBC count Normal or elevated RDW
	Anemia of chronic disease	Normal RDW
Normocytic	Hemolysis	Normal or elevated RDW Thrombocytosis
	Bleeding	Unchanged
	Nutritional anemia	Elevated RDW
	Anemia of chronic disease	Normal RDW
	Primary bone marrow disease	Elevated RDW Leukocytosis Thrombocytosis Monocytosis
Macrocytic	Alcohol use, liver disease	Normal RDW Thrombocytopenia
	Drug induced	Elevated RDW
	Bone marrow disorder	Elevated RDW
	Hypothyroidism	Normal RDW
	Hemolysis	Normal or elevated RDW
	Nutritional	Elevated RDW

CBC, Complete blood cell count; RBC, red blood cell; RDW, red blood cell distribution width.

The first step in approaching anemia is to classify the process as microcytic (MCV < 80 fL), normocytic (MCV, 80 to 100 fL), or macrocytic (MCV > 100 fL). Clues to the diagnostic possibilities for the three major classes are listed in Table 204.3.

Along with anemia, another characteristic laboratory feature of hemolysis is reticulocytosis, the normal response of the bone marrow to the peripheral loss of RBCs. Patients with aplastic anemia or some other insult to the bone marrow from drugs or toxins have a reduced reticulocyte count. Some patients require special correction of their reticulocyte count (see the “Facts and Formulas” box).

Facts and Formulas

Corrected reticulocyte count (%) = Observed count × Measured count (%) / 45%

Finch reticulation production index = Corrected reticulocyte count (%) / Expected maturation time (days)

• Patients with hemolytic anemias may require a Finch reticulocyte count, which corrects for the anemia and the expected maturation time.

• For example, a 2-day life span (versus a 1-day life span, typically) is used for immature reticulocytes. The Finch count is the measured reticulocyte count, multiplied by the measured hematocrit level, divided by 45, and then divided by 2.

• Patients with sickle cell disease may use a simple corrected reticulocyte count.

• This is the measured reticulocyte count, multiplied by the measured hematocrit level, divided by 45.

• Normal reticulocyte counts are 0.5% to 1%.

Finch CA, Marshall PN, Brecher G, et al. Method for reticulocyte counting. NCCLS proposed standard H16-P. Villanova, Penn: National Committee for Clinical Laboratory Standards; 1985.

Blood type and cross should be sent to the blood bank so that type-specific or type-matched and crossmatched blood can be readied. Other tests to obtain are unconjugated bilirubin and lactate dehydrogenase. These values are increased when RBCs are destroyed. In patients with severe intravascular hemolysis, the binding capacity of haptoglobin is exceeded rapidly, and free Hgb is filtered by the glomeruli, thus leading to decreased haptoglobin and increased hemoglobinuria or urobilinogen levels.

Imaging studies are disease specific and depend on the patient’s symptoms. Chest radiographs are indicated in all patients with significant anemia. Cardiomyopathy may be present in patients with chronic anemia. An electrocardiogram is required for older patients, those with chest pain, patients with profound anemia, or those who have an underlying disease or increased risk factors for cardiac ischemia.

Patients with blood loss may benefit from an ultrasound examination, which is a quick, noninvasive, and relatively simple bedside test useful for diagnosing intraperitoneal bleeding. The focused abdominal sonography for trauma (FAST) examination detects blood in the hepatorenal fossa, paracolic gutters, splenorenal area, and pelvis. Ultrasound is also useful for detecting pregnancy-related bleeding, especially that emanating from a ruptured ectopic pregnancy. Stable patients with intraabdominal blood loss benefit from computed tomography (CT) scanning. CT scanning has sensitivities similar to those of ultrasound, yet it identifies causes, including retroperitoneal, pelvic, and subcapsular sites, more clearly.

A nasogastric tube may be indicated in the acute setting to diagnose and manage an ongoing upper gastrointestinal hemorrhage. Bile must be aspirated to rule out bleeding proximal to the ligament of Treitz. Once upper gastrointestinal bleeding is established, esophagogastroduodenoscopy is the study of choice for determining the source of bleeding and for treatment. Emergency esophagogastroduodenoscopy can be performed in the ED, and its use is indicated in the hemodynamically unstable patient. Consultation with a gastroenterologist is required. Sigmoidoscopy or colonoscopy may be useful in diagnosing and treating lower gastrointestinal bleeding, but it is rarely helpful in the acute setting.