Anemia, Screening

Article Author:
Andrew Freeman

Article Editor:
Donald Morando

Managing Editors:
Frank Smeeks
Scott Dulebohn
Erin Hughes
Pritesh Sheth
Mark Pellegrini
James Hughes
Richard Ciresi
Phillip Hynes

10/27/2018 12:31:22 PM


Anemia is a common sign found in both inpatient and outpatient management. Although it is routinely listed as a "freestanding" diagnosis, it is a sign (like tachycardia or rash) that needs to be worked up and further elucidated. Anemia is a prevalent condition that by some estimates is under-recognized and undertreated. It has both the obvious, primary, direct, negative consequences of diminished tissue oxygenation and a secondary indirect negative consequence of complicating the progression of many coexisting diseases. Despite the gravity of the diagnosis of the sign anemia, there remains clinical discordance in both the formal definition of anemia and in the protocols to screen for it.

Symptoms of anemia include fatigue, weakness, lightheadedness, headache, pallor/jaundice, tachycardia/palpitations, chest pain, dyspnea, and cold distal extremities, and claudication. These symptoms can be quite limiting and are primary negative consequences of anemia. The cause of the anemia modulates the presence and magnitude of these symptoms. The greater the lethal underlying pathology, the more dramatic the symptomatology.

The presence of anemia in conjunction with other pathology adds additional concern. Anemia frequently complicates diabetes, various cancers, chronic kidney disease, cardiovascular disease, hepatitis C, HIV/AIDS, inflammatory bowel disease, rheumatoid arthritis and, despite compensatory polycythemia, chronic obstructive pulmonary disease (COPD).

It is universally agreed that anemia is a decrease in the relative number of circulating erythrocytes (red blood cell mass) with a consequent diminished ability to deliver oxygen to tissues. Opinions diverge on the subject of absolute numbers and concentrations to diagnose individuals of various genders, ethnicities, and ages as being anemic. In addition, opinions differ on who is to be routinely screened for anemia and who is to be tested on a "need to know" basis. Finally, the threshold for treatment and the final targets of treatment are subject to variation according to discipline and medical condition.

The World Health Organization anemia standard of 2010 is a Hb less than 12 g/dl in premenopausal females and 13 g/dl in postmenopausal females and men of all ages. The Journal Blood disagreed citing the paucity of WHO data and methods and set down standards divided by race, gender and decade of life. Their standards concluded that the standard in white men from 20 to 60 years of age was 13.7 g/dl and after 60 declined to 13.2 g/dl and women of all ages were considered anemic at 12.2 g/dl. This noted a significant difference in Hb in black men and women but did not cite standards. At this point, the majority of the literature utilizes the WHO standards for consistency.

There is similar discordance concerning screening for anemia between the US Preventative Services Task Force, and various individual medical academies and, what is done in the day-to-day practice of medicine. For example, the USPTF issued a statement on screening for iron deficiency anemia in asymptomatic children 6 to 24 months of age. The conclusion was that there was insufficient evidence on the benefits and harms of screening for anemia in children of this age. At the same time, the American Academy of Family Practice released their position statement: "Universal screening for anemia should be performed at 12 months of age, with measurement of hemoglobin levels and an assessment of risk factors associated with iron deficiency and iron deficiency anemia."

The issue of screening in pregnant women presented a similar discordance. "The USPTF concludes that the evidence of the effect of routine screening for iron deficiency anemia in asymptomatic pregnant women on maternal health and birth outcomes is insufficient...and the balance of benefits and harms cannot be determined." The American Academy of Family Practice voiced agreement with the USPSTF. The American College of Obstetrics and Gynecology in Practice Bulletin No. 95 issued the position statement, "all pregnant women should be screened for anemia and treated if necessary."

At present, there are no recommendations for routine anemia screening of non-gravid, well adults.

Etiology and Epidemiology

Anemia has multiple etiologies that can be attributed to one of 3 processes:

  1. Decreased production of RBCs: As RBCs have a limited lifespan of 90 to 120 days, hematopoiesis must be an ongoing process to keep pace with this natural attrition. Any process disruptive to hematopoiesis can cause a net loss of RBC mass over time-anemia.
  2. Increased destruction of RBCs: Any process that either destroys RBC's or significantly shortens the lifespan of the cell in such a fashion that hematopoiesis cannot match will cause anemia.
  3. Loss of blood: Any loss of blood, microscopic or macroscopic that exceeds hematopoiesis will result in anemia.

The above processes can be further subdivided into their specific causative etiologies. These include but are not limited to:

  1. Frank loss of blood via trauma, bleeding from an organ or visceral system (otolaryngological [ENT], gastrointestinal [GI], genitourinary  [GU], gynecological [GYN], among others)
  2. Lack of a nutritional substrate for hematopoiesis including iron, vitamin B-12, folate or generalized malnutrition
  3. Chronic disease and/or chronic inflammation. Common culprits include chronic hepatic or renal disease, cancer, chronic infection, and collagen vascular disease.
  4. Genetic illness: Common syndromes include but are not limited to the thalassemia, hemoglobinopathies, and enzyme abnormalities of the glycolytic pathways. Less common genetic syndromes include Fanconi anemia, abetalipoproteinemia, and hereditary xerocytosis.
  5. Infectious etiologies include bacterial, viral and protozoan infections. Of note, malaria is a major global infectious cause of anemia.
  6. Drug and chemical exposures are common etiologies for bone marrow suppression and resultant anemia
  7. Primary or idiosyncratic bone marrow suppression
  8. Autoimmune disease

Epidemiological reporting of anemia is fragmented because of the use of different diagnostic criteria in the United States as opposed to the WHO criteria used for the rest of the world. Also, demographic subsets, genetic subsets and geographic subsets of anemia prevalence exist. There is no single consensus at this time. Best estimates indicate that anemia prevalence is statistically similar in the United States, Canada, and northern Europe. In this manner, 4% of males and 8% of females qualify for the diagnosis of anemia in these territories. There is substantially more limited data for the rest of the world. Estimates from the available data are inexact and but do indicate 2 to 5-times greater anemia prevalence.

Common sub-segments of the population with increased anemia include:

  1. African, Indian and Mediterranean basin: Sickle cell disease
  2. Mediterranean basin: Thalassemia
  3. Endemic malaria/protozoal illness: Anemia of chronic disease
  4. Impoverished areas: Nutritional anemia


Red Blood Cells (RBC)

RBC is released from the bone marrow as a reticulocyte. The reticulocytes are so named as they have a network of rRNA that persists in the cell until it is absorbed and matures into adult RBC. The maturation process takes 24 hours, and for that reason, a relative count of reticulocytes is a gauge of relative bone marrow response to anemia. The RBC contains 2 alpha and 2 beta chains and a single heme moiety that reversibly binds oxygen. The majority of the multiple genetic variants in the configuration of the chains are without clinical consequence. However, sickle cell disease and thalassemia variants of alpha and beta chains are causes of anemia. Genetic variants in the cell membrane, cell metabolism, and cell morphology are additional causes of anemia.

Bone Marrow

The bone marrow requires approximately 21 days transitioning a pluripotent stem cell to a reticulocyte released into circulation. The initial stimulation to produce a reticulocyte is the renal release of erythropoietin, and continued erythropoietin is required for transformation of a pluripotent stem cell into a proerythroblast. This initial stage requires approximately 10 to 15 days. The next step is the addition of iron (to form a heme moiety) to the proerythroblast to complete the transformation to reticulocyte. The step is iron-dependent and requires 3 to 4 days. Significant bone marrow related causes of anemia include:

  • Suppression of the marrow ability to function secondary to absence of substrates (iron, vitamin B12 or folate)
  • Direct suppression of the marrows functions by medications, toxins, infections or radiation exposure
  • Replacement of the bone marrow by neoplasm or fibrosis


The kidneys have a dual role in the pathophysiology of anemia. First off, they are responsible for the production of 90% of the erythropoietin needed to stimulate bone marrow transformation of pluripotent stem cells to proerythroblasts. Any renal dysfunction that interferes with erythropoietin production and release will result in anemia. Second, the hypervolemia associated with acute anemia results in ADH secretion. In response, the kidney will reabsorb water. In direct response to the decreased renal perfusion resulting from acute onset anemia, the kidney will activate the renin-angiotensin system with increased vascular tone and stimulation of aldosterone and resultant increased intravascular volume.

Central Nervous System (CNS)

The medulla, cerebral cortex, and the pituitary gland coordinate the response to sudden acute anemia and resultant volume change via increasing sympathetic tone and secreting ADH.

The Acuity of Onset of the Anemia

Acute onset anemia via blood loss or rapid hemolysis is compensated by the CNS-directed, renal-mediated response to the loss of volume and perfusion. This compensatory mechanism has an upper threshold and is well defined by The American College of Surgeons ATLS protocols for management of volume loss:

  • Class I Hemorrhage involves up to 15% of blood volume and produces no significant change in vital signs and requires no intervention.
  • Class II Hemorrhage involves 15% to 30% of blood volume, typically can produce tachycardia, reduced pulse pressure and peripheral vasoconstriction. Volume repletion with crystalloids is usually the only necessary treatment and blood transfusion is not usually necessary.
  • Class III Hemorrhage involves loss of 30% to 40% of blood volume and results in hypotension, tachycardia, and shock. Crystalloid resuscitation and blood transfusion are necessary for the patient
  • Class IV Hemorrhage involves loss of greater than 40% of blood volume, exceeds the compensatory mechanism thresholds, and is lethal unless rapid, aggressive resuscitation is pursued with blood products, crystalloids, and pressors.

On the other hand, very low hemoglobin’s are tolerated in the setting of chronic slowly progressing anemia wherein the RBC mass is greatly decreased but circulating blood volume is preserved. Management of blood products and anemia specific therapy (RBC substrates erythropoietin) varies on a case and cause basis.

Diagnostic Tests

The array of laboratory testing and imaging in the evaluation of anemia includes:

  1. Complete blood count (CBC): The CBC includes the hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and the mean corpuscular hemoglobin concentration (MCHC). 
  2. Reticulocyte count: An estimation of bone marrow red blood cell output
  3. Iron profile: The iron profile includes a serum iron, ferritin and total iron binding content (TIBC).
  4. Peripheral blood smear: Microscopic evaluation of red blood cell morphology
  5. Serum creatinine: Evaluation of renal function
  6. Thyroid function tests: The profile contains a T4 and a thyroid-stimulating hormone level (TSH)
  7. Liver function tests: The liver function tests contain an LDH, bilirubin, transaminase levels, gamma-glutamyl transferase (GGT) and 5 prime nucleosides
  8. Hemolysis profile: The profile contains haptoglobin, LDH, and indirect bilirubin
  9. Macrocytosis profile: The profile contains vitamin B-12, folate, methylmalonic acid, and homocysteine 
  10. Hemoglobin electrophoresis: Evaluation of the Hemoglobin amino acid chains
  11. Abdominal sonogram: Evaluation of spleen size
  12. Bone marrow analysis: A Hematology consult is required to obtain

Results, Reporting, Critical Findings

Thorough patient history and physical exam are necessary to direct diagnostic testing and subsequent treatment. In the case of obvious cues on history or physical exam, the workup can be streamlined and focused on clear therapeutic choices and timing evident. If the etiology of anemia is not obvious, generalized diagnostic testing is used to focus down on to specific algorithms.

The differential for anemia is broad:

  1. Chronic disease and neoplasia
  2. Nutritional deficiency
  3. Injury
  4. Genetic illness
  5. Infection
  6. Auto-immune
  7. Medication and chemical exposure

The first question to ask is if the patient is actively bleeding and, if so, how much, and how rapid should intervention be. ATLS outlines clear guidelines to treat trauma-related hemorrhage. The most common non-traumatic causes of hemorrhage include GI, GYN, and GU bleeding, and the patient's hemodynamic stability is a primary guide to appropriate intervention. More subtle hemorrhage can be observed with anticoagulation and occult chest, abdominal and pelvic bleeding and hematoma formation. As always, treatment is aimed at restoring blood volume and treating the cause of the bleeding.

Once acute hemorrhage is deemed unlikely, it is important to categorize the anemia by cell size and hemoglobin density and to look at red blood cell morphology on peripheral smear. Anemia falls into the categories of macrocytic, microcytic and normocytic concerning size and hypo or normochromic concerning relative hemoglobin concentration. Characteristic cell dysmorphisms may also be evident on a blood smear. An additional view of red cell dysmorphism can be elicited with Hemoglobin electrophoresis to define the cell structure at the level of the amino acid chains binding the Heme moiety. 

Two additional fundamental questions to answer are:

  1. Is the patient's bone marrow actively producing red blood cells to compensate for his anemia; a reticulocyte count and % of reticulocytes though somewhat non-specific is the best peripheral estimate available.
  2. Is hemolysis present; Elevated LDH, haptoglobin and indirect bilirubin are individually non-specific for hemolysis but as a group can allow inference of hemolysis possible.

With the above pool of data in hand, some algorithms are applied by red blood cell size:

  1. Microcytic anemia is further evaluated and differentiated concerning the iron profile.
  2. Macrocytic anemia is further evaluated and differentiated by B-12, folate, methylmalonic acid and homocysteine levels and possible thyroid disease.
  3. Normocytic anemia can be classified into hemolysis, blood loss and decreased bone marrow red cell production.

Per the AAFP position statement of March 15, 2011, in AFP:

"Transfusion of RBCs should be based on the patient's clinical condition. Indications for RBC transfusion include acute sickle cell crisis, or acute blood loss of greater than 1500 cc or 30% of blood volume. Patients with symptomatic anemia should be transfused if they cannot function without treating the anemia."

The authors go on to site an updated Cochrane review supporting the use of a restrictive transfusion trigger in non-cardiac patients that supports maintaining hemoglobin of at least 7 g/dl. This more restrictive criteria, a significant change from the commonly cited 10mg/dl resulted from statistical analysis demonstrating a 54% relative decrease in the number of units of blood transfused and decreased 30-day mortality rate with the new criteria.

Clinical Significance

In conclusion, anemia is a sign that needs to evaluated for its etiology and must be appreciated for both its primary medical impact on the patient and it's secondary impact on the patient's comorbidities.

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Anemia, Screening - Questions

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Per trauma protocol, transfusion is reserved for which categories of hemorrhage?

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Hemolytic anemia causes anemia by which mechanism(s)?

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Which of the following tests is not part of the assessment of macrocytic anemia?

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An asymptomatic 56-year-old female with a hemoglobin of 7.8 mg/dl and an MCV of 80 fL is found to have the following laboratory values: vitamin B-12 level 488 pg/ml (200 - 600), serum creatinine 2.2 mg/dl (0.6 - 1.0) , iron 18 micrograms/dl (50 - 170), and TIBC 22 micromoles/L (45 - 66). What is the best working diagnosis for this anemia?

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Anemia, Screening - References


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