Anemia

Anemia is a common presentation in all medical practice settings. Symptoms are related to poor oxygen-carrying capacity. Anemia is defined as reduced red-cell mass quantitated by hemoglobin (Hb) and hematocrit (Hct) levels and red blood cell (RBC) count. The differential diagnosis of the etiology and type of anemia is broad. The following factors must be considered when determining the severity and type of anemia:

Chronicity is based on the clinical manifestations of the anemia (tachycardia, hypotension, dyspnea, fatigue, decreased level of consciousness, angina) and whether the patient is experiencing active blood loss and in need of acute repletion.
Reticulocyte count (See a reticulocyte index calculator)
- A high reticulocyte index indicates either blood loss or destruction of RBCs (see hemolytic anemia below) with marrow that is able to respond.
- A low reticulocyte index is more common and requires evaluation of mean corpuscular volume (average volume of red cells).
Mean corpuscular volume (MCV)
Macrocytic anemia (MCV >100 femtoliters [fL]) can be either megaloblastic or nonmegaloblastic:
- Megaloblastic anemia results from impaired DNA synthesis during RBC production due to vitamin B₁₂ deficiency, effects of certain drugs (e.g., zidovudine, methotrexate, hydroxyurea), and rarely from folate deficiency or inherited disorders.
- Nonmegaloblastic anemia causes include alcohol use disorder, liver disease, hypothyroidism, and bone-marrow disorders (including myelodysplasia).
Normocytic anemia (MCV ≥80 fL and ≤100 fL) can occur with increased reticulocytes due to blood loss or hemolysis. Low reticulocytes suggest anemia of chronic disease, iron deficiency combined with a macrocytic disorder, or a bone-marrow disorder (infiltration, red-cell aplasia, aplastic anemia). Early iron-deficiency anemia can be normocytic but is more likely to be microcytic as the severity worsens.
Microcytic anemia (MCV <80 fL) is most often caused by iron deficiency or thalassemia. These two etiologies can be differentiated by the red-cell distribution width (RDW), which is a measure of anisocytosis. RDW is elevated in iron deficiency and is usually normal in thalassemia. Other causes of microcytic anemia to consider include chronic disease, lead poisoning, and sideroblastic anemia.

See an algorithm depicting the basic evaluation for anemia.

Aplastic Anemia

Aplastic anemia is a form of hypoproliferative anemia often caused by autoimmune destruction of red-cell lineage cells with hypoplastic marrow. The cause of the damage can be acquired or inherited (see table below). Patients with aplastic anemia are at risk of developing acute myeloid leukemia (AML).

[Image] — **Diverse Pathophysiological Features That Lead to a Common Pathologic Process in Bone-Marrow Failure**

A comprehensive review of aplastic anemia can be found here.

Hemolytic Anemia

Hemolytic anemia results from shortened survival of RBCs due to premature destruction. Causes are usually classified as acquired or hereditary.

Evaluation of hemolytic anemia requires careful review of the patient’s history, physical examination, and the following key laboratory tests:

complete blood count (CBC)
red-cell indices
peripheral-blood smear
reticulocyte count (percent and absolute)
liver function tests (including direct and indirect bilirubin)
lactate dehydrogenase (LDH) and haptoglobin
direct antiglobulin (Coombs) test (DAT)

Clinically significant acute hemolysis is essentially ruled out if the patient’s laboratory results do not show an appreciable elevation in the indirect bilirubin, aspartate transaminase (AST), and LDH level. Haptoglobin is a very sensitive marker for intravascular hemolysis, but even a miniscule amount of hemolysis usually depletes haptoglobin. Therefore, the degree of hemolysis cannot be determined from a low haptoglobin level alone.

If intravascular hemolysis is suspected, consider measuring free plasma/urinary hemoglobin or urinary hemosiderin as part of the workup.

Treatment of hemolytic anemias depends on severity and etiology and is often aimed at treating the underlying condition.

Research

Landmark clinical trials and other important studies

Research

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia

de Latour RP et al. N Engl J Med 2022.

In this phase 1-2 study, the addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects.

Folate Deficiency in an Urban Safety Net Population

Hildebrand et al. Am J Med 2021.

In contrast with a previous study that reported low utility and poor cost-effectiveness associated with folate testing, the results of this study in a safety net hospital in Boston indicated that serum folate testing detected higher rates of folate deficiency, a lower charge per deficient test, and was more likely to impact management.

Effects of Interleukin-1β Inhibition on Incident Anemia: Exploratory Analyses from a Randomized Trial

Vallurupalli M et al. Ann Intern Med 2020.

In the randomized double-blind Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), treatment with canakinumab (monoclonal antibody targeting IL-1β) was associated with a decreased incidence of anemia and increased hemoglobin levels as compared with placebo. Canakinumab was also associated with increased rates of infection and mild cases of thrombocytopenia and neutropenia.

Read the NEJM Journal Watch Summary

Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis

Chen N et al. N Engl J Med 2019.

In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy.

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

Townsley DM. N Engl J Med 2017.

The addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort.

Read the NEJM Journal Watch Summary

Lower Versus Higher Hemoglobin Threshold for Transfusion in Septic Shock

Holst LB et al. N Engl J Med 2014.

The Transfusion Requirements in Septic Shock (TRISS) trial showed that in patients with septic shock, 90-day mortality and rates of ischemic events were similar among those assigned to blood transfusion at a higher or lower hemoglobin threshold.

Read the NEJM Journal Watch Summary

Utility, Charge, and Cost of Inpatient and Emergency Department Serum Folate Testing

Theisen-Toupal J et al. J Hosp Med 2013.

In this retrospective analysis, routine folate testing in inpatients and emergency department patients in a Boston hospital had low utility and poor cost-effectiveness.

A Phase III Randomized Trial Comparing Glucocorticoid Monotherapy Versus Glucocorticoid and Rituximab in Patients with Autoimmune Haemolytic Anaemia

Birgens H et al. Br J Haematol 2013.

This RCT demonstrated that rituximab plus prednisolone improved response rate and relapse-free survival, compared to prednisolone alone, in patients with warm autoimmune hemolytic anemia.