Anemia in the ED Setting: Pearls and Pitfalls

Author: Brandon M. Carius, DSc, MPAS, PA-C (Emergency Medicine PA, US Army) // Reviewed by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Cases:

#1: A 74-year-old male presents with the complaint of lower abdominal pain and dark liquid stools for 2 days.  He states the pain has gotten worse and that his stooling has become increasingly dark and thick, almost looking “tar-like”.  His only medications include a daily aspirin.  His triage vitals include a pulse of 105, blood pressure 100/62, respirations 12, and pulse oximetry of 98% on room air.  As part of the laboratory work-up, the complete blood count (CBC) reports a hemoglobin/hematocrit (H/H) of 8.9/26.2 with a mean corpuscular volume (MCV) of 83.  What are your initial thoughts on management?

#2: A 30-year-old female presents due to heavier-than-normal menstrual bleeding and mild lower abdominal cramping ongoing for 3 days, now additionally having mild lightheadedness when she stands from the sitting position. She uses oral contraceptives daily and denies any chance of being pregnant.  She has been told previously that she has “anemia”.  Her vital signs include a pulse of 80, blood pressure of 110/80, respirations at 14, and pulse oximetry of 99% on room air.  Given her complaints and vaguely described history, you err on the side of caution and order a CBC, which reveals an H/H of 10.8/32.3 and an MCV of 75.  Iron studies reveal a ferritin of 13 ng/mL.  What further management should you consider in this patient?

Background

Anemia encompasses a range of conditions with a decreased number of functioning erythrocytes, more often referred to as red blood cells (RBC) and measured by blood hemoglobin concentration.^1-4 While the World Health Organization broadly defines anemia as a hemoglobin of less than 12 g/dL in adult females and less than 13 g/dL in adult males, this diagnostic cut-off is not consistent throughout the literature and has significant demographic variability.^1,3-10  Diagnostic threshold variation demonstrates the need for anemia to be viewed as part of a broader patient assessment for optimal care.

Studies reveal that anemia affects up to one-third of the world’s population, however these numbers vary due to factors including geography, age, and gender.^1,6-8,11-13 Frequencies of anemia in emergency medicine settings are less well-studied and largely defined only in pediatric (9-14%) and obstetric (14%) populations.^14-16  A higher prevalence of anemia (as high as 47%) is found in geriatric patients, however this is not from emergency medicine literature and likely reflects the influence of chronic comorbidities.^6,11,17

The production signal and driver for RBC development is erythropoietin, stimulated by renal tubular cells based upon perceived oxygenation demands.^1,3,18,19 Born from routine bone marrow differentiation, potential RBCs morph first into a normoblast than to a reticulocyte once the nucleus is expelled during maturation, and ultimately to a RBC when the ribosomal network is lost 3-4 days later.^3,4,20 The average lifespan of healthy RBCs is approximately 120 days, after which normal degradation prompts macrophagic destruction by the liver and spleen.^4,18-21 Around 0.8% of circulating RBCs are cleared daily, resulting in the release of free iron and biliverdin, the latter of which is converted into bilirubin.^3,9,18,19,22 Four hemoglobin chains bind, exchange, and transport oxygen and carbon dioxide in healthy RBCs via an iron-containing heme ring complex.^1,3,4,23 Primary hemoglobin forms include A and A2 while hemoglobin F constitutes less than 2% of circulating hemoglobin in healthy adults, but may be higher in some populations.^1,3,4

Hereditary and environmental factors can affect normal hemoglobin function, impairing RBC oxygen-carrying capacity.  These include methemoglobinemia and hemoglobin S variant, present in sickle cell disease.  Alterations underlying hereditary hemoglobinopathies affect more than oxygen-carrying capacity by changing RBC shape, oxygen affinity, life span, and hemolytic tendency. Additionally, environmental factors may induce hemoglobinopathy in cases of sulfhemoglobinemia, cyanohemoglobinemia, and carbon monoxide toxicity.^1,3,4,20,24  Each hemoglobinopathy compromises tissue oxygenation and triggers compensatory responses.  In addition to increased cardiac output, renal cells detect acute declines in oxygenation and signal vasoconstriction.^4,9  Simultaneously, rightward shifts in the oxyhemoglobin dissociation curve increase oxygen release to improve tissue oxygenation.^9,23 As anemia becomes chronic other adaptations occur, including increased plasma volume to offset lost RBC mass in the intravascular space.^4,9To shore up chronic oxygenation deficits, renally-released erythropoietin surges to boost RBC production.^9,23 Despite these compensatory measures, increased RBC turnover proportionally increase the volume of circulating immature reticulocytes.^4,18,23,25 Literature demonstrates these physiologic adaptations can grossly stabilize patients, concealing some outward signs and symptoms.^1,3,6,23

Background Pearls

• Anemia is common, with some studies finding prevalence in up to one-third of the global population.
• Much literature cites WHO anemia standards of a hemoglobin <12 g/dL in females and <13 g/dL in males, but baselines can vary between demographics.
• Outward signs of anemia on initial evaluation (such as tachycardia and hypoxia) may be tempered by chronic compensatory mechanisms of increased plasma volume and RBC production.

Classification

While there are many types of anemia, emergent evaluation necessitates delineation of acute and chronic causes, while maintaining perspective in the overall clinical picture of stable and unstable presentations for management.^1,3,4,25 The terms ‘acute’ and ‘chronic’ are often not well-defined, but rather described as part of a broader context in patient evaluation for underlying cause.

Acute anemia may be caused by gross or occult hemorrhage, or be less apparent altogether in cases of intravascular hemolysis or chronic anemia exacerbations.  This is most important in the unstable patient.  Every effort should be made to examine suspected hemorrhage, especially areas of trauma, but atraumatic onset of anemia should prompt consideration for gastrointestional and genitourinary bleeding, as well as ruptured aortic aneurysm.^1,4 Other “non-blood loss” causes that can be less apparent upon initial presentation include sickle cell disease with aplastic crisis, disseminated intravascular coagulopathy (DIC), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and malignant hypertension.^1,4,20,21  Lastly, in the setting of triage interventions for unstable vital signs, dilutional anemia should be considered if the patient received crystalloid infusions prior to laboratory evaluation.^4,26

Chronic anemia describes decreased RBC production or increased destruction. In the emergency medicine setting, this may be found incidentally.  Alongside the hemoglobin value itself, efforts should be made to correlate patient history, physical examination, and other laboratory findings to identify an underlying cause.  These chiefly include RBC indices, such as MCV and RBC distribution width (RDW), which can further characterize cellular changes and narrow causes of anemia.^1,3,4,9,20

Classification Pearls

• Anemia can be subclassified between acute and chronic, although stringent time thresholds are not often mentioned. Other classifications include “blood loss” vs. “non-blood loss” anemia and sub-classifications based on RBC indices.

Patient Assessment

Initial assessment in suspected or confirmed anemia begins with hemodynamic stability and addressing or excluding signs of gross hemorrhage.  Unstable patients with or without significant hemorrhage should be stabilized first.^1,3,4,27,28  However, the ability of RBCs to carry four times the oxygen required at rest can preclude hypoxemia and compensatory tachypnea or tachycardia, vital sign stability should not reassure clinicians.^4,23,27 Crystalloid fluids should be avoided for initiation fluid resuscitation, as literature increasingly demonstrates harmful dilution impacts, prompting recent changes to trauma algorithms.^29,30 Considerations for occult or gross hemorrhage should include nasal (epistaxis), pulmonary (hemoptysis), gastrointestinal (hematemesis, hematochezia, melena), and genitourinary (hematuria) sources, while considering others based on demographics, such as ectopic pregnancy in women of childbearing age.^1,4,31 Surgical and medical history may suggest conditions prone to bleeding, including gastrointestinal issues like peptic ulcer disease, Crohn’s disease, and ulcerative colitis.³² Family history of hemoglobinopathies like sickle cell disease or glucose-6-phosphate deficiency (G6PD) can suggest hereditary causes.  Suspicion of G6PD may increase with medication history, as drug-induced oxidative injury by common antibiotics like nitrofurantoin and sulfa-based drugs are the most common cause of hemolytic anemia in G6PD patients.^33,34 However, these and other medications can independently cause drug-induced immune hemolytic anemia, including non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and cephalosporins.^35-37

Patients with acute or chronic anemia patient can present with a wide spectrum of symptoms including shortness of breath, dyspnea, weakness, fatigue, irritability, and headache, though most will not display outward evidence of active bleeding.^1,3,4,9,20 Many of these symptoms may manifest once hemoglobin values drop below 7 g/dL given compensatory mechanisms, although no literature correlates laboratory values with symptoms.^1,3,4,20 Those with chronic anemia may have significantly lower baselines with only mild symptoms given a more gradual rate of decline and adaptation to decreased hemoglobin levels.

Evaluation of the acutely anemic patient may include poor compensation with hemodynamic instability, including hypotension, tachycardia, tachypnea, and even hypoxemia.^4,20,27,28 Additional findings include decreased urine output, increased thirst, and altered mental status.  Vital sign changes are not consistent, and can change significantly based on patient demographics, especially age, as well as possible comorbidities and current medication usage.  While acutely anemic pediatric patients may have delayed compensatory vital signs, elderly patients do not consistently have this response, and the use of blood pressure medications like beta-blockers may prevent tachycardia.^4,6,20  Physical examination findings in anemia can differ based on chronicity and underlying cause.  Outward findings may include pallor, scleral icterus, jaundice, and petechiae.^4,20,21 Abnormal enlargement of the spleen (splenomegaly), liver (hepatomegaly), thyroid (thyromegaly), and lymph (lymphadenopathy) may be present, with or without associated tenderness, suggesting idiopathic hemolysis or malignant processes.^3,4,20 Auscultation may reveal cardiac murmur or crackles in cases of pulmonary hemorrhage.^1,4,20 Additionally, unexplained joint swelling and/or tenderness should be assessed, and rectal examination should search for gross blood or melena to evaluate for gastrointestinal bleeding.^4,20 

Assessment Pearls

• Initial evaluation should focus on patient hemodynamics. When anemia is suspected, crystalloids should be avoided if possible.
• Stable vital signs should not be used to exclude the diagnosis of anemia, given early onset with compensation in acutely anemic patients and long-term adaptation measures in those with chronic anemia.

Laboratory Evaluation

While patient history and physical exam may suggest anemia, diagnosis relies on laboratory testing, chiefly the complete blood count (CBC) and hemoglobin levels.  However, in the setting of hemorrhage, initial testing may not demonstrate anemia, and therefore repeat testing should be performed as indicated with vital sign changes or following resuscitation measures.⁴  Finger prick testing is possible but prone to inaccuracy with decreased capillary flow in cold or shock patients, or simple dilution from interstitial fluid.³⁸ Other CBC indices, such as hematocrit and RBC values, are derived from the hemoglobin concentration.^1,4,39 These can further describe the anemia and help narrow its etiology, primarily through the use of RDW and MCV.  The MCV can help delineate anemia between microcytic, normocytic, and macrocytic classifications, narrowing etiologies.  Overlap can occur between these groups, especially with iron-deficiency anemia (IDA).

Microcytic anemia (MCV < 80, Table 1) is most commonly the result of IDA,  with MCV levels diagnostic when correlated with a low ferritin, generally ranging from 15-40 ng /mL for diagnosis.^3,4,9  However, low ferritin value is not a prerequisite for IDA, and thus IDA should not be dismissed if ferritin levels are normal.⁴   An increased RDW may instead be the initial sign of iron depletion in microcytic anemia even if ferritin levels are unremarkable.^1,3  Transferrin saturation below 20% can also be diagnostic for IDA, even if the ferritin is normal or only slightly low.^2,4,40 Suspicion of IDA should prompt evaluation for causes of occult bleeding, including gastrointestinal.^20,40 An increased reticulocyte count suggests thalassemia, while a low or normal reticulocyte count may indicate IDA, ACD, sideroblastic anemias, or other etiologies.

Causes of normocytic anemia (MCV = 80–100, Table 2) can be further differentiated through the use of reticulocyte counts, RDW, and other testing.  High reticulocyte counts in the setting of normocytic anemia should prompt a Coombs test for further evaluation, as this may indicate acute microcytic hemolytic anemia.²¹ A normocytic anemia with a normal RDW should prompt consideration of renal failure and anemia of chronic disease.⁴  Renal causes should be suspected in those with known chronic kidney disease, especially if the glomerular filtration rate is less than 30.⁴¹ Normocytic anemia may occur due to several emergent causes of hemolysis such as hemolytic uremic syndrome (HUS) or disseminated intravascular coagulation (DIC, table 3), as well as acute hemorrhage without timely commensurate marrow response. A Coombs test will additionally help differentiate between concerns for autoimmune hemolytic anemia (when positive) and possible RBC membrane defects or microangiopathic hemolysis (when negative).^4,21

Macrocytic anemia (MCV > 100, Table 4) may be further classified into megaloblastic and non-megaloblastic anemia due to faulty erythropoiesis.^4,42,43 Megaloblastic describes an enlarged, oval-shaped erythroblast taken from bone marrow samples that demonstrate an immature, “lacy” appearing nucleus.⁴³  Most macrocytic anemias are megaloblastic in nature, and most of these are caused by deficiencies in the vitamin B12 and/or folate.^4,42,43 History concerning dietary intake, especially vegetarian regimens, and chronic alcohol use is needed.^42,44 Pernicious anemia, where a lack of intrinsic factor impairs B12 absorption, is often cited as a possible cause for macrocytic anemia, but is rare.^4,32 While B12 and folate levels can support diagnosis, they may conversely confound investigations given that macrocytic anemia manifests after chronic deficiency, while measured vitamin levels can rebound quickly with acute dietary or supplemental changes.^4,42 Non-megaloblastic anemia is more likely caused by toxins or drugs, most commonly alcohol, and thus further evaluation should include detailed history of use of medications such as hydroxyurea and methotrexate, as well as other toxins.⁴³

Several laboratory tests may directly identify the source of anemia based on RBC morphology.  A peripheral smear may reveal malarial parasites or sickled RBCs amongst other things, however their perceived clinical value has been recently debated.^45-47 Nevertheless, this testing is still recommended to aid evaluation of the undifferentiated anemic patient.^2,45  Reticulocytes are immature RBCs that show a proportional increase generally when hastened RBC production occurs in response to anemia, and elevated values include greater than 1.5% in men and 2.5% in women.^4,48 A reticulocyte index (figure 1) greater than 2 is an appropriate response, while an index less than 2 implies an abnormal bone marrow response.^1,3,4,20,48  Hemolysis may increase bilirubin levels, typically indirect as destroyed RBCs may overwhelm hepatic conjugation.^4,20 The elevation of blood urea nitrogen (BUN) and creatinine can occur, and a ratio of 30:1 suggests the presence of an upper GI bleed.^4,20 Haptoglobin is a liver-produced protein that binds free hemoglobin in the blood.²¹  Decreased levels suggest increased hemolysis.^4,21 A Coombs test evaluates for the presence of erythrocyte antibodies which suggests the presence of autoimmune hemolytic anemia.^4,20,21 A direct globulin test is used for diagnostic purposes, while indirect testing evaluates for free minor antibodies in serum as part of pre-transfusion testing procedures.

Laboratory Evaluation Pearls

• Anemia differential primarily utilizes MCV, however there is some overlap of etiologies between these categories and further laboratory evaluation is generally required.
• While IDA is common, its presence should not be presumed to be isolated, and further evaluation is recommended for causes of occult bleeding.
• Peripheral blood smears can help recognize specific RBC dysmorphia that can identify anemia etiologies.

Management

Initial management centers on active bleeding, patient hemodynamics, and peripheral perfusion.  Clinicians should continuously assess for indications of blood product transfusion.  This is especially critical in populations where initial vital signs may prove falsely reassuring given either proximal onset of hemorrhage or compromised compensatory mechanisms.  This includes pediatric patients, who may not manifest tachycardia or hypotension until late in the course of hemorrhage, as well as populations on heart rate-controlling medications such as beta-blockers.

Clinically stable patients (with vital sign stability, non-ill appearing, and without obvious hemorrhage) found to be anemic on evaluation should be further assessed for etiology with focused history and evaluation, with proper intervention and consultation as warranted by subsequent laboratory findings and suspected etiology.  Some anemic patients who are hemodynamically stabile may not need further emergent evaluation or management.^4,20 All patients found to have anemia should understand the need for follow-up for further evaluation.^4,20

In the incidentally anemic patient, or one who is otherwise stable, outpatient management indicators are not universal, but some suggest this is possible if the patient is otherwise healthy and the hemoglobin is greater than 6 g/dL.^4,49 Patients found to have IDA should be considered for outpatient therapy with oral supplementation, usually through ferrous sulfate 300mg, dosed once daily to be taken with food intake.^40,49,50 The use of vitamin C supplementation may increase absorption of oral iron.^49,50 However, while emergency medicine clinicians can prescribe oral iron upon discharge, follow-up to evaluate for causes of IDA should be stressed to all patients.^1,3,20 Patients with gastrointestinal comorbidities (celiac disease, prior history of gastric bypass) may subsequently have poor absorption of oral supplements, and therefore an intravenous (IV) load of iron can be administered prior to discharge.^4,40,51 IV dosing is also recommended in those who are symptomatic, as well as those who do not respond to PO dosing within several weeks. IV iron is typically administered in the form of single-dose iron sucrose (300mg in 250mL of saline given over 2 hours) or two-dose ferumoxytol (510mg in 17mL with 50mL of saline, given over 1 hour). These initial doses demonstrate hemoglobin level increases of 2-3 g/dL 4 weeks after IV iron loading.⁵² Another option is low molecular weight iron dextran, often given as a 1g initial dose.  Historical literature cautions for anaphylactic reactions with dextran, though these concerns were largely based on experiences with high molecular weight versions, and newer research shows now significant differences in safety compared to other iron formulations.^53,54  Even after initial IV loads however, oral supplementation is still recommended.^4,40

If a patient is unstable due to suspected or confirmed hemorrhage, immediate pressure on exposed sites is warranted, with tourniquet application if on the extremities, as well as the transfusion of whole blood if available. Whole blood is generally type O-negative for women who are of reproductive age (to prevent sensitization and pregnancy complications), and O-positive for all other populations.⁴ Even if emergency release blood products are available, a blood type and crossmatch should be sent immediately to lower risk of transfusion-related reactions with subsequent blood products.⁴  For suspected or visible internal hemorrhage, such as that of the gastrointestinal or pulmonary systems, proper consultation with surgical and/or interventional radiology should be considered for source control.

Consideration for blood products centers on goals of intervention in the anemic patient, largely dependent on underlying etiology and acute concomitant factors.  These primarily include the need for ongoing tissue oxygenation with regards to hemoglobin concentration for oxygen carrying capacity, relative to cardiac output and pulmonary function.  A single unit of packed red blood cells (pRBC) increases hemoglobin by 1 g/dL and hematocrit by 3%.^4,55 Whole blood (WB) contains the equivalent of 2 units of packed red blood cells (pRBCs), with additional platelets and serum coagulation factors.  While these components together can improve anemia as well as coagulopathy in the hemorrhagic and/or acutely ill patient, certain limitations should be recognized, chiefly the mechanism of preservatives that bind with serum calcium to prevent clotting during storage.  Transfused WB therefore lacks calcium needed for the coagulation pathway and cardiac function.⁵⁶ In the bleeding patient, clinicians should consider administration of calcium gluconate with WB to offset this disparity and further correct coagulopathy.⁵⁶ Additionally, tranexamic acid (TXA) can be considered for additional help with clotting.

In those patients without suspected or visualized gross hemorrhage, anemia can be multifaceted, especially in the setting of critical illness, where iron deficiency and decreased erythropoietin production can result, either causing or exacerbating anemia.  Thus, underlying etiologies of infection or other illness should be simultaneously addressed.  Historically universal transfusion thresholds for a hemoglobin of 10 g/dL have shifted in light of growing literature supporting a restrictive strategy for a hemoglobin of 7 or 8 g/dL.^27,28,57 This includes individual and systematic reviews demonstrating no significantly increased risk in mortality or morbidity when employing a restrictive strategy.⁵⁷ A restrictive strategy of 7 g/dL is supported by multiple trials involving acute illnesses like sepsis and gastrointestinal bleeding.^58-61 The American College of Obstetricians and Gynecologists recommends transfusion in pregnant patients with a hemoglobin of 6 g/dL or less regardless of symptoms or other findings.⁶²

Management Pearls

• Outpatient management for anemic patients with stable vital signs centers on iron supplementation with encouraged follow-up. Vitamin C may help with absorption.
• In patients with gastrointestinal comorbidities or who may not tolerate oral iron supplementation can be considered for IV iron ‘loading’ in the emergency department prior to discharge.
• Emergent transfusion with O-negative whole blood should be used for the reproductive age female who is unstable and O-positive for all others
• Previously-universal transfusion thresholds of hemoglobin < 10 g/dL have been superseded by a 7 g/dL cut-off in most situations.

Disposition

Patients with active bleeding, unstable vital signs, or who are otherwise critically ill with anemia should be admitted for further evaluation, stabilization, and consideration of further transfusions.^1,3,4,20 Those who are hemodynamically stable without indications of significant active bleeding may be considered for discharge, given a defined plan for follow-up and strict return precautions.

Case Resolution

#1: You have significant suspicion for a gastrointestinal bleed, possibly secondary to an abdominal aortic aneurysm, which is confirmed by CT imaging.  While the patient is mildly tachycardic, he is not otherwise ill-appearing, and with his initial hemoglobin level of 8.9 g/dL you do not automatically start transfusions with emergency release whole blood. You consult vascular surgery, who takes the patient to the OR.

#2: Given the findings of microcytic anemia with a hemoglobin of 10.8 g/dL and MCV of 75 on your evaluation of a female with a described heavy menstrual cycle and vague history of anemia, you repeat a thorough history to ensure no other gross sources of bleed.  A low ferritin level (13 mg/dL) is further suggestive of IDA with a heavy menstrual cycle in a female of reproductive age.  A negative urine hCG confirms that her presentation is not concerning for ectopic pregnancy.  Given her stable presentation, you recommend oral iron supplementation of ferrous sulfate 300mg three times a day and encourage her to follow-up with her primary care in a few weeks for reevaluation and further management.

DISCLAIMER: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, or the Department of Defense or the U.S. Government.

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