HEMATOLOGY

Benie T. Constantino, I(ASCP)SH; MLT,ART(CSMLS)

Bessie Cogionis, MLT(CSMLS)

Nucleated RBCs—Significance
in the Peripheral Blood Film

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Nucleated RBCs, (NRBCs) are in the peripheral ABSTRACT Nucleated RBCs (NRBCs) are immature
blood of normal infants up to the fifth day of life.1 RBCs not normally seen in the peripheral blood beyond the
At birth, 3 to 10 NRBCs per 100 WBCs are present neonatal period. Their appearance in peripheral blood of
(Fig 1).1,2 Premature birth3 and fetal hypoxia can
children and adults signifies bone marrow damage or stress
cause this number to increase.4 Beyond the neona-
tal period, the presence of NRBCs in the periph- and potentially serious underlying disease. The presence of
eral blood is usually associated with malignant numerous NRBCs increases the WBC count in automated
neoplasms, bone marrow diseases, and other seri- hematology analyzers. Most analyzers generate suspect flags
ous disorders.1,5,6 to help identify abnormal cells, and the samples involved
The bone marrow has a special architecture should be reviewed manually. Unfortunately, analyzers may
whose disruption leads to predictable changes. Nor-
not detect low levels of NRBCs. We recommend correcting
mal mature bone marrow cells are deformable, so
they can squeeze through small “portholes” in the the WBC count with even 1 NRBC/100 WBCs and reporting
endothelium to enter the peripheral circulation.7 “occasional NRBC seen.” This alerts clinicians of the
Normoblasts and immature granulocytes, however, significance of unexplained normoblastemia.

Scientific Communications
are less deformable and rarely enter the circulation
(Fig 2). Their presence in the peripheral blood Hyposplenism and Asplenia From the Laboratory
means that the bone marrow barrier has been dis- Hyposplenism reflects the developmental immatu- and Diagnostic
rupted or that extramedullary hematopoiesis has rity of the reticuloendothelial system and is the Services, Centre for
Addiction and
been activated. reported cause of physiologic normoblastemia of Mental Health (Mr
This article discusses the conditions associated neonates.5,15 Because normoblasts that escape Constantino), and
with NRBCs in peripheral blood and explains why from the marrow are normally cleared by the Core Laboratory,
it is important to report their presence. spleen, their presence in the peripheral blood sug- Pediatric Laboratory
gests a hyposplenic state.10 In patients with myelo- Medicine, The
Hospital for Sick
Mechanisms Associated With proliferative disorders, cellular overload may Children (Ms

4
Normoblastemia incapacitate splenic function.3 The same phenom- Cogionis), Toronto,

Section
The mechanisms associated with normoblastemia enon develops in patients with sickle cell disease in Ontario.
are not completely understood but may be classi- which abnormal RBCs glut the splenic machinery. Reprint requests to
fied as shown in the Table.8-19 Although it is use- Moreover, marrow stress and release of too many Mr Constantino,
ful to try to attribute the condition to a single normoblasts can overwhelm the ability of a normal Laboratory and
Diagnostic Services,
process, it is important to understand that multi- spleen to clear them from circulation. This occurs
Centre for Addiction
ple interrelated mechanisms are often involved. with hypoxia, hemolytic anemia, anemia under and Mental Health,
treatment, megaloblastic anemia, ineffective ery- 1001 Queen St West,
thropoiesis, collagen vascular diseases, malignant Toronto, Ontario,
neoplasms, and chemotherapy treatment.5,10 Canada M6G 1H4.

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 hypoxia,20 the main stimulus for RBC production.
When hypoxia occurs, the kidneys produce ery-
thropoietin which, when increased markedly,
results in intense marrow erythropoietic activity.
Whether marrow erythropoiesis is effective or
ineffective depends on the underlying cause of the
anemia. With effective erythropoiesis, the resulting
accelerated compensatory activity produces
prominent reticulocytosis, polychromasia, imma-

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ture granulocytes (at times), and occasional
NRBCs in the peripheral blood. Which and how
many of these cells or conditions are present
depends on the severity of the anemia and marrow
response. If the marrow response is exaggerated,
Fig 1. Wright-stained peripheral blood smear from a normal newborn showing NRBCs are plentiful with many “stress” reticulo-
polychromasia, a nucleated RBC, and a neutrophil. Cells are crowded together
cytes, causing pseudomacrocytosis. When erythro-
due to the high RBC count (3 1,000). From Maedel L, Sommer S. Blood Cell
Morphology: Morphologic Changes in Erythrocytes, 4. Chicago, IL: ASCP Press; poiesis is ineffective, NRBCs may be prematurely
1993: Fig 4-31. released into the peripheral blood without reticu-
locytosis. Dysplastic RBC changes may occur, as
shown by the appearance of macro-ovalocytes and
teardrop cells in the peripheral blood.

Hypoxia
Any condition that reduces the quantity of oxygen
transported to the tissues causes an increase in the
rate of RBC production. Although normoblastemia
occurs in response to hypoxia in both anemia and
cardiopulmonary disorders, the cause of hypoxia
differs in these conditions. In anemia, hypoxia
results when the reduced hemoglobin concentra-
tion causes a corresponding decline in the oxygen-
carrying capacity of the blood. Cardiopulmonary
hypoxia, however, may involve several mecha-
nisms, including failure of the blood to absorb
oxygen from the lungs, inadequate ventilation of
alveoli, or right-to-left intrapulmonary shunting
Fig 2. Wright-stained The most useful and sensitive indicator of of the blood. Impaired cardiovascular circulation
bone marrow smear
splenic function, however, is the presence of How- leading to an inadequate supply of oxygenated
showing stages of
erythroid maturation: ell-Jolly bodies (RBC inclusions) in the peripheral blood to the tissues may also cause hypoxia.21,22
basophilic blood film (Fig 3).10-11 The presence of nor- Because some patients with cardiopulmonary dis-
normoblast, moblasts, although useful, may be nonspecific. orders have pulmonary emboli or coronary
polychromatophilic Acanthocytes, target cells, stippled cells, and frag- thrombosis complications, the presence of nor-
normoblast,
ments are also nonspecific findings.10 moblasts in these disorders may indicate unfavor-
orthochomic
normoblast. An able prognosis.23,24
eosinophil is also Anemia and Compensatory Erythropoiesis The hemoglobin concentration also differs in
shown (3 1,000). In all types of severe anemia—hemolytic, nutri- these hypoxic situations. In cardiopulmonary
From Maedel L, tional, or anemia of blood loss—normoblastemia hypoxia, the hemoglobin level is either high or
Sommer S. Blood
is caused by hypoxic erythropoietin-induced com- within the reference interval, whereas in anemic
Cell Morphology:
Normal Cells of the pensatory erythropoiesis.11 The reduced oxygen-
Bone Marrow, 2. carrying capacity of anemic blood causes tissue
Chicago, IL: ASCP
Press; 1993: Fig 2-05.

224 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 4 APRIL 2000

Mechanisms and Conditions Associated With Normoblastemia8-19
Hyposplenism, asplenia Sickle cell anemia8
Newborn (physiologic)1,6
Splenectomy3,9
Essential thrombocytosis10
Hemolytic anemia10
Malaria10
Anemia, compensatory erythropoiesis Severe anemia (any cause)11
Hemolytic anemia8
Iron deficiency anemia8

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Megaloblastic anemia8
Hemorrhage5,12
Anemia under treatment8
Microangiopathic hemolytic anemia8
Thalassemia major8
Hypoxia Severe pulmonary disease5,13
Congestive cardiac failure5,13
Cyanotic heart disease5,13
Marrow replacement, invasion Preleukemia13
Leukemia8,13
Lymphoma13
Neuroblastoma13
Myelodysplasia8
Myelofibrosis8,13
Plasma cell myeloma8
Myeloproliferative disorder8,13
Gaucher and other storage disease14

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Granuloma (ie, tuberculosis)13
Collagen vascular disease5,13
Fungal infection14
Histiocytosis14
Tumor cell presence8,13
Sarcoidosis14
Osteopetrosis13
Extramedullary hematopoiesis Myelophthisis13,15
Osteopetrosis13

4
Myeloid metaplasia13
Myelofibrosis8 Section

Chronic hemolytic anemia15

Polycythemia vera13
Leukemia15
Other Uremia16
Sepsis17
Liver disease18
Diabetic ketoacidosis18
Inflammatory bowel disease18
Renal transplant18
Thermal injury19
Chemotherapy5

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 demand. In cases of transient increases in oxygen
demand (a hypoxic stimulus), normoblastemia, if
present, disappears with relief of the hypoxia.24
Accordingly, a hypoxic stimulus should be sus-
pected whenever normoblastemia is accompanied
by a normal to high hemoglobin level and mild to
moderate polychromasia.

Bone Marrow Replacement and Invasion

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Marrow replacement can occur in association
with a primary hematologic disease such as
leukemia, myeloma, or lymphoma. It can also be
the result of secondary insult by invading tumor
cells, the presence of sarcoidosis, or infectious
Fig 3. Wright-stained peripheral blood smear showing basophilic stippling, agents such as mycobacteria and fungi. Both pri-
Howell-Jolly bodies, and a nucleated RBC (3 1,000). From Maedel L, Sommer S.
mary and secondary reactions can produce mar-
Blood Cell Morphology: Morphologic Changes in Erythrocytes, 4. Chicago, IL:
ASCP Press; 1993: Fig 4-81. row fibrosis (myelofibrosis), which changes the
normal marrow microarchitecture. This disrup-
tion may break down the marrow-blood barrier,
causing untimely and disorderly release of NRBCs
and progenitor cells into the circulation (Fig
4).14,25 Similarly, extensive marrow infiltration
and replacement may cause mechanical “crowding
out” of normal hematopoietic cells, leading to
their escape into the peripheral blood and lodg-
ment in other organs such as the spleen, liver, and
lymph nodes. This process may contribute to
extramedullary hematopoiesis.
The initial peripheral blood picture may present
unexplained normoblastemia, mild macrocytosis,
giant platelets, myelocytes, thrombocytopenia,
and, possibly, leukopenia with or without teardrop
cells or blast cells.

Extramedullary Hematopoiesis
Recognized clinically as splenomegaly or
Fig 4. Wright-stained peripheral blood smear from a patient with myelofibrosis
hepatomegaly, extramedullary hematopoiesis
showing many teardrop RBCs and a myelocyte (3 1,000). From Maedel L,
Sommer S. Blood Cell Morphology: Chronic Hematopoietic Malignancies, 6. appears to be caused by anemia, marrow replace-
Chicago, IL: ASCP Press; 1993: Fig 6-18. ment associated with acute leukemia, or other
nonhematopoietic infiltrative processes (myeloph-
thisis).15 Presumably, hematopoietic stem cells are
hypoxia, it is much lower.21,24 The rate of RBC displaced from the marrow into the spleen or liver
production, however, is not controlled by hemo- where they proliferate to cause hepatomegaly and
globin concentration; it appears to vary with the splenomegaly. Splenomegaly also occurs when the
ability of the cells to transport oxygen to the tissues marrow has been dispossessed by fibrosis. Because
in response to a demand. Thus, if the oxygen sup- the spleen does not retain immature cells as effi-
ply is less than the tissues demand, more RBCs are ciently as normal marrow, it may release NRBCs,
produced, which, in turn, results in a higher hemo-
globin level until the supply of oxygen meets the

226 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 4 APRIL 2000

immature granulocytes, megathrombocytes, and tortuous circulation through deformed marrow
occasional blast cells into the peripheral blood, sinuses and diseased splenic cords.26 The presence
resulting in leukoerythroblastosis or the coexis- of teardrop cells in the peripheral blood is thus
tence of myeloid precursors and NRBCs in the significant and should alert morphologists to
peripheral blood.17 Teardrop cells may be present. search for occasional NRBCs, megathrombocytes,
A leukoerythroblastic reaction may also be seen stippled cells, immature granulocytes, or blast cells
without marrow infiltration in normal newborns that would constitute conclusive evidence of
as well as in patients with thalassemia major with myeloid metaplasia or leukoerythroblastosis.26
severe hemolytic crisis, hemorrhage, postsplenec-

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tomy, septicemia,26 and therapy with granulocyte Other Mechanisms
colony-stimulating factor (G-CSF).27,28 Why normoblastemia occurs with these disorders
In addition, when bone marrow reserve is remains enigmatic. Although the marrow-blood
unable to meet the demand for accelerated erythro- barrier appears to break down, the cause of the
poiesis (as in chronic hemolytic anemia or long- breakdown is unknown.13 Most of the disorders
standing anemia), blood cells may form in tissues involve complex conditions that cause systemic
other than the bone marrow.15 This extramedullary diseases and influence bone marrow response.17
hematopoiesis represents a reversion of the These diseases include uremia, sepsis, liver disease,
involved tissues to their fetal blood-forming func- and thermal injury.18,19
tion, although this compensatory activity may also
occur in myelophthisic anemia with fibrosis. Thus, Role of the Laboratory
differentiating between chronic hemolytic anemia Laboratory professionals play an important role in
and myelophthisic anemia with fibrosis is difficult detecting NRBCs when they review CBC and
without the patient’s clinical history. WBC differential results obtained by automated
Leukoerythroblastosis is evident in peripheral hematology analyzers. Most analyzers generate
blood films, and teardrop cells may or may not be suspect flags, (eg, WBC*R, NRBC, Review Slide,
present. Teardrop cells are not usually seen in Blasts) to help identify abnormal WBCs, and sam-
leukoerythroblastic reactions associated with ples with flags should be microscopically exam-
hemorrhage, infection, or G-CSF therapy. They ined. Although most instruments have >80%

Scientific Communications
can be found in severe iron deficiency anemia,29 specificity for NRBC flags, they cannot consis-
thalassemia, megaloblastic anemia, hemolytic ane- tently detect <5% NRBCs.31,32 The number of
mia, leukemia, myelofibrosis, and drug-induced NRBCs in a 100- or 200-WBC differential count is
Heinz body formation.26 Teardrop cells may reported as the number of NRBCs per 100 WBCs.
reflect dyspoiesis and thus are not specific for a In addition, the corrected WBC count is reported.
single condition. Although the exact mechanism It is also good practice to manually scan all blood
of teardrop cell formation is unclear, the forma- films of new patients (without a diagnosis) for
tion of these cells from inclusion-containing RBCs abnormalities that may not have been flagged.
is well documented. As cells with large rigid inclu-
sions try to pass through the small splenic sinus To Correct or Not To

4
openings, parts with large inclusions get pinched, Correct the WBC Count
Section
causing the cells to stretch with irreversible loss of Recognizing NRBCs is important not only
their shape. The result is teardrop cells.30 More- because their presence affects the WBC count, but
over, teardrop cell formation represents the cells’ also because only a few NRBCs can have ominous
implications in some patients. We therefore rec-
ommend that WBC counts with even 1
NRBC/100 WBCs be corrected and reported. This

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 alerts clinicians of the significance of unexplained more cells per specimen are characterized, and
normoblastemia. The correction can be made the new data might show that “rare” NRBCs
with a simple formula: occur more frequently than previously thought
and that the significance of this should be revis-
Corrected WBC count, 3 109/L = WBC ited. Moreover, except for grossly abnormal
count, 3 109/L 4 (1 + [NRBC/100 WBCs]) results, manual correction of WBC counts may
become unnecessary.
For example, if the WBC count is 6.0 3 109/L The classification of mechanisms associated
and the NRBC count is 50/100 WBCs, the with normoblastemia (see Table), although useful,

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corrected WBC count is oversimplified because it emphasizes only the
= 6.0 3 109/L 4 (1 + [50/100]) predominant cause of the disorders listed. In
= 6.0 3 109/L 4 (1 + 0.5) many conditions, more than one mechanism is
= 4.0 3 109/L operative. The best example is severe hemolytic
anemia of the newborn (erythroblastosis fetalis)
Computerized laboratory systems do these cal- in which the severe stress of anemia and hypoxia
culations automatically. Recent advances in hema- on marrow erythropoiesis is the primary cause of
tology analyzers and their widespread use will normoblastemia. The combination of marrow
alleviate manually correcting WBC counts.33,34 stress with the immaturity (hyposplenism) of the
As the example shows, a sample with an reticuloendothelial system and the availability of
NRBC count of 50/100 WBC and a WBC count extramedullary hematopoiesis probably accounts
of 6.0 3 109/L yields a corrected WBC count of for the extreme normoblastemia or leukoerythrob-
4.0 3 109/L—a difference that may be statisti- lastosis. Similarities to this are evident in leukemia,
cally but not clinically significant. Therefore, set- myelophthisic anemia, or myelofibrosis; although
ting a threshold of more than 4 or 5 NRBCs/100 the primary cause of normoblastemia in these con-
WBCs before correcting the WBC count does ditions is the crowding out of hematopoietic cells
not make clinical sense. In addition, many or the disruption of marrow architecture, concur-
authors26,35-37 advocate different correction for- rent anemia, hyposplenism, or extramedullary
mulae and cutoff values. We recommend cor- hematopoiesis may also contribute to nor-
recting the WBC count with even 1 NRBC/100 moblastemia. Furthermore, in cardiopulmonary
WBCs and reporting “occasional NRBC seen” disorders, normoblastemia is more pronounced
with <1 NRBC/100 WBCs. when anemia is also present. Therefore, it should
be easier to differentiate one disorder (mecha-
Comments nism) from the other by considering the total
Although the appearance of NRBCs in blood does clinical picture.
not in itself provide a diagnosis of disease, it may Although studies show that even 1 NRBC in
give invaluable clues to the presence of a serious the peripheral blood of adults may indicate a seri-
condition. Homeostatically, NRBCs in blood rep- ous disease,5,38 clinicians and laboratory profes-
resent a compensatory response to an excessive sionals do not agree on its clinical significance,
demand on the blood-forming organs (marrow especially when unsupported by other data. The
stress) such as in severe anemia or hypoxia. Clini- differing views are probably due more to percep-
cally, NRBCs may represent marrow fibrosis, mar- tion than reality. In primary health care units,
row replacement by leukemic cells or metastatic normoblastemia is rare and may signify a patho-
tumor cells, or extramedullary hematopoiesis. logic condition. In contrast, normoblastemia is a
Their presence indicates the extent to which bone common finding in an acute care hospital. As a
marrow reacts to stress and disease. result, NRBCs may be perceived as ordinary cells
A recent technological breakthrough enables of questionable clinical significance; in these
new hematology analyzers to identify NRBCs cases, the importance of normoblastemia is rela-
separately from WBCs.33,34 With this technology, tive and depends on the type of hospital and
patient population.

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 We believe that unexplained normoblastemia is 18. Weick JK, Hagedorn AB, Linman JW. Leukoerythroblas-
tosis: diagnostic and prognostic significance. Mayo Clin Proc.
important because it offers invaluable insight into 1974;49:110–113.
disease processes or progressions that occur in 19. Andes WB. Normoblastemia after thermal injury. Am J
conditions such as metastatic carcinoma, bone Surg.1976;131:725-726.
20. Porth CM, ed. Pathophysiology Concepts of Altered Health
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1967;67:1190-1194.
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lead to more timely medical intervention, thus cells in congestive heart failure. Circulation. 1959;20:367-370.
increasing the chance of a positive outcome.l 25. Wang JC, Cheung CP, Ahmed F, et al. Circulating granu-
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