Red Blood Cell Indices: Implications for Practice

Terri A. Cavaliere, MS, RNC, NNP

NAINR. 2004;4(4):231-239.

Ontogeny of RBC production

Embryonic and fetal hematopoiesis occurs in three phases: megaloblastic, hepatic, and myeloid. At each phase of RBC development both the sites of production and the cell composition change.^[4] Erythrocytes, lymphocytes, granulocytes, and megakaryocytes (platelets) all originate from the same common progenitors called pleuripotent stem cells,^[1,4,5] however, only RBC development is presented in this article. Figure 1 illustrates the sites and stages of erythropoiesis in utero.

(Enlarge Image)

Sites and stages of fetal erythropoiesis. Primitive erythropoiesis begins in the yolk sac at 2 to 3 weeks after conception. By the end of the first trimester, the liver has become the main erythroid organ. The liver is the primary source of red blood cells during the second trimester, and the bone marrow is the primary source of red blood cells during the last trimester. From Ohls RK: Developmental erythropoiesis, in Polin RA, Fox WW, Abman SH (eds): Fetal and Neonatal Physiology (ed 3). Philadelphia, PA, Saunders, 2004, p 1398 (Fig 146 1).

Extraembryonic erythropoiesis is detected in the yolk sac at approximately 14 days after conception.^[1,3] RBCs enter the circulation at 3 to 4 weeks when the umbilical and vitelline circulations are joined. The yolk sac is the principle site of RBC production until 6 to 8 weeks' gestation and by 10 to 12 weeks extraembryonic erythropoiesis has virtually ceased.^[3]

Small groups of erythroblasts, hematocytoblasts, are detected in the mesenchyme and endoderm of the yolk sac. These primordial cells give rise to two distinctive types of RBCs: megaloblasts and normoblasts (erythroblasts). Megaloblasts are the most primitive RBCs. They differ morphologically from more definitive erythroblasts produced later in gestation in that they are large (macrocytic), remain nucleated throughout their life span, and have a greater mean cell volume (MCV) (see Table 1 ). As gestation progresses megaloblasts are gradually replaced by normoblastic erythrocytes.^[1–3]

The hepatic phase begins by the 5^th to 6^th gestational week. The exact source of hepatic stem cells continues to be a subject of investigation. Either stem cells from the yolk sac migrate to the liver and other hematopoietic organs or there is independent production of stem cells at these sites during fetal development.^[1,3,4,6]

Normoblasts are the predominant form of circulating RBCs by 10 weeks of gestation. They are smaller than yolk sac cells and they lose their nuclei in the course of maturation.^[1]–^[4]

The production of RBCs in the fetal liver increases until the 2^nd trimester when the rate of synthesis begins to decline as erythropoiesis increases in the bone marrow. RBCs are still produced in the liver for approximately 1 week after birth.^[1,3]

Bone marrow RBCs are first noted at 8 to 9 weeks' gestation and output from this site becomes more significant as gestation progresses. The myeloid period begins at the 4^th to 5^th month and the bone marrow becomes the principle site of erythropoiesis during the 3^rd trimester of gestation.^[1,3]

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Abstract and Introduction
Ontogeny of RBC production
Maturation of RBCs
Erythrocyte Structure and Function
Postnatal Changes
Approach to the Neonate/Young Infant With Anemia
Conclusion

Glossary of Terms ^{[2,8,10,14–17]}
Term	Definition/Description	Clinical Application
Acanthocyte	Erythrocyte identified by numerous spiny cytoplasmic projections; similar to a Burr cell	Acanthocytosis, condition in which the majority of erythrocytes are acanthocytes.
Anemia	Deficiency in the concentration of erythrocytes and/or hemoglobin concentration; further defined as a hematocrit or hemoglobin greater than 2 standard deviations below the mean for age and sex	Can be classified on physiologic (hemolytic, hypoplastic) or morphologic basis (macrocytic, microcytic)
Anisocytosis	Term denoting a condition in which RBCs have variable and abnormal sizes; evaluated on a peripheral smear	May be a normal variation in neonates.
Anisopoikilocytosis	Condition in which RBCs display both sizes and shapes that are variable and abnormal
Basophilic Stippling	Immature RBCs display bluish flecks or punctate granules when exposed to basic stains or dyes	Seen in lead poisoning, thalassemia syndromes, or iron deficiency anemia
Elliptocyte	An oval shaped RBC (ovalocyte)	Elliptocytosis, condition in which 50–90% of RBCs are elliptocytes.
Erythroblast	A immature RBC containing a nucleus	1) May be pathologic (megaloblast) or normal (normoblast). Normally seen in hematopoietic organs. Megaloblast are found in certain types of anemia (pernicious anemia) 2) Erythroblastemia, presence of NRBCs in peripheral circulation 3) Erythroblastosis, presence of considerable numbers of erythroblasts in the blood 4) Erythroblastopenia, deficiency of erythroblasts in bone marrow (Diamond-Blackfan Syndrome)
Erythrocyte	RBC; a nonnucleated biconcave disk approximately 7 µm in diameter, containing hemoglobin. The characteristic shape and flexible lipid membrane facilitate passage through narrow capillaries.
Heinz Bodies	Intracellular inclusions usually attached to RBCs; composed of denatured hemoglobin	Seen in hemoglobinopathies, RBC enzyme deficiencies, or after splenectomy
Hemolysis	Destruction of RBCs with subsequent release of hemoglobin; occurs normally at the end of the life span of RBCs but also occurs under a variety of pathologic conditions	Hemolytic anemia, condition in which there is marked or accelerated destruction of erythrocytes; may be due to infections, inherited RBC disorders, or as a response to drugs or other toxins
Howell-Jolly Bodies	Nuclear remnants seen in RBCs after Wright's staining	Seen in types of anemia, asplenia/hyposplenia, and severe iron deficiency
Hyperchromic	Description of RBCs that contain or appear to contain more hemoglobin than normal	Seen in hyperviscosity
Hypochromic	Description of RBCs containing less than the normal amount of hemoglobin	In hypochromic anemia the percentage of hemoglobin in erythrocytes is less than the normal range; usually seen in chronic anemia
Hypoplastic Anemia	Decreased production of RBCs by the bone marrow	Seen in bone marrow dysfunction (Diamond-Blackfan Syndrome)
Macrocyte	A mature RBC of abnormally large size; usually >9 µm in diameter	Macrocytic anemia, classification of anemia denoting impaired RBC production and large fragile RBCs. Most commonly results from nutritional deficiency (folic acid and vitamin B12)
Megaloblast	Large nucleated immature erythrocyte normally seen in large numbers in the bone marrow but also found in certain types of anemia (See erythrocyte)	Megaloblastic anemia, classification of anemia marked by production and peripheral proliferation of large, immature, dysfunctional RBCs; see in severe pernicious anemia or folic acid deficiency
Mean Corpuscular Hemoglobin (MCH)	Represents an estimate of the amount of hemoglobin in an average RBC; normal adult value is 28–32 pg of hemoglobin per erythrocyte	This parameter is calculated from the ratio between the amount of hemoglobin and the number of RBCs in a specimen
Mean Corpuscular Hemoglobin Concentration (MCHC)	An estimate of the concentration of hemoglobin in grams per 100 ml of packed red blood cells, normal adult value is between 32 and 36%	This parameter is calculated from the ratio of hemoglobin to hematocrit; expressed as a percentage
Mean Corpuscular Volume (MCV)	Estimates the average volume of each RBC, normal adult value is between 82 and 92 fl (µm³)	This parameter is calculated from the ratio of the hematocrit to the total number of RBCs
Microcytic	Describes small size of RBCs	Microcytic anemia, classification of anemia characterized by abnormally small RBCs; usually seen in chronic blood loss or iron deficiency anemia. MCV is low and RDW is increased. Certain genotypes of α-thalassemia present with microcytosis at birth.
Normochromic	Describes RBCs that are normal in color, containing the normal amount ofhemoglobin	Normochromic cells are seen in anemia following acute blood loss
Normocyte	Normal sized, nonnucleated erythrocyte; 7.5 µm in diameter	Normocytic anemia, classification of anemia in which RBCs are normal in size; MCV is within normal range
Poikilocytosis	Variation in the shape of erythrocytes	May be normal in newborn period or seen in anemia due to RBC defects
Polychromasia	Abnormal tendency of an RBC to be dyed by a variety of laboratory stains
Red Blood Cell Indices	Series of relationships characterizing erythrocytes by size and content and concentration of hemoglobin. Useful in establishing the differential diagnosis of anemia, calculated by automated blood profiling machine from RBC count, hematocrit and hemoglobin
Red Cell Distribution Width (RDW)	Expresses differences in erythrocyte size in an individual specimen	Used to detect anisocytosis. Increased in immune hemolytic anemia, SS and SC disease, and hereditary spherocytosis
Reticulocyte	Immature nonnucleated erythrocyte; reticulocyte count reflects erythropoiesis	Elevated count indicates bone marrow production of new RBCs
Spherocyte	Abnormally shaped spherical erythrocyte containing a greater than normal amount of hemoglobin	Presence of large numbers can cause hemolytic anemia. See Figure 3
Target Cell	Abnormal erythrocyte	May be seen in peripheral blood after splenectomy, in anemia and certain hemoglobinopathies. See Figure 3

Mean Red Blood Cell (RBC) Values During Gestation
Age (Wk)	Hemoglobin (g/dL)	Hematocrit (%)	RBCs (10 U/mm³)	Mean Cell Volume (fL)	Mean Corpuscular Hemoglobin (pg)	Mean Corpuscular Hemoglobin Concentration (g/dL)	Nucleated RBCs (% of RBCs)	Recticulocytes (%)	Diameter (U)
12	8.0–10.0	33	1.5	180	60	34	5.5–8.0	40	10.5
16	10.0	35	2	140	45	33	2.0–4.0	10–25	9.5
20	11.0	37	2.5	135	44	33	1.0	10–20	9.0
24	14.0	40	3.5	128	38	31	1.0	5–10	8.8
28	14.5	45	4.0	120	40	31	0.5	5–10	8.7
34	15.0	47	4.4	118	38	32	0.2	3–10	8.3

Modified from Oski FA: Normal blood values in the newborn period. In Oski FA, Naiman JL (eds): Hematologic Problems in the Newborn, 3rd ed. Philadelphia, WB Saunders, 1982, p 4
From: Ohls R. (2001). Anemia in the newborn. Ch 7. In R.A. Polin, M.C. Yoder, & F. Burg (EDS). Workbook in Practical Neonatology, 3^rd Edition, Phila: Saunders. Page 124^[3]

Normal Hematologic Values During the First 2 Weeks of Life in the Term Infant*
Value	Cord Blood	Day 1	Day 3	Day 7	Day 14
Hemoglobin (g/dL)	16.8	18.4	17.8	17	16.8
Hematocrit (%)	53.0	58.0	55.0	54.0	52.0
Red cells (mm³) 10⁶/mm³	5.25	5.8	5.6	5.2	5.1
Mean cell volume (fL)	107	108	99.0	98.0	96.0
Mean corpuscular hemoglobin (pg)	34	35	33	32.5	31.5
Mean corpuscular hemoglobin concentration (g/dL)	31.7	32.5	33	33	33
Reticulocytes (%)	3–7	3–7	1–3	0–1	0–1
Nucleated red blood cells (mm³)	500	200	0–5	0	0290
Platelets (100s/mm³)	290	192	213	248	252

Modified from Oski FA, Naiman JL: Hematologic Problems in the Newborn, 2nd ed. Philadelphia, WB Saunders, 1972, p 12
From: Ohls R. (2001). Anemia in the newborn. Ch 7. In R.A. Polin, M.C. Yoder, & F. Burg (EDS). Workbook in Practical Neonatology, 3^rd Edition, Phila: Saunders. Page 125^[3]
*During the first 2 weeks of life, a venous hemoglobin less than 13 g/dl or a capillary hemoglobin less than 14.5 g/d/l should be regarded as anemia

Postnatal Changes in Hemoglobin and Red Blood Cell (RBC) Indices in Term Infants
RBC Parameters	Age of Infants
	Days			Weeks		Months
	1	3	7	2	4	2	3	4	6
Hemoglobin (g/dL)
X	19.4	18.6	18.7	17.6	13.9	11.2	11.4	12.0	12.1
+/– 2 SD	17.2	16.5	16.5	13.9	10.6	9.3	9.5	10.7	10.4
(N)	(78)	(66)	(78)	(275)	(272)	(271)	(73)	(123)	(114)
Mean cell volume (fL)
X	114	110	108	106	101	95	88	84	77
+/– 2 SD	101–128	104–116	102–114	88–125	90–112	83–107	78–98	74–95	67–87
(N)	(78)	(66)	(78)	(275)	(272)	(271)	(73)	(123)	(114)
Mean corpuscular hemoglobin (pg)
X	36.6	36.7	36.2	33.6	32.5	30.4	30.4	28.1	26.4
(N)	(59)	(47)	(66)	(232)	(240)	(241)	(60)	(123)	(114)
Mean corpuscular hemoglobin concentration (%)
X	33.0	33.1	33.9	31.7	32.1	32.0	34.6	33.3	34.2
(N)	(78)	(66)	(78)	(275)	(271)	(271)	(73)	(123)	(114)

Modified from Guest GM Brown, EW: Erythrocytes and hemoglobin of the blood in infancy and childhood. III Factors in variability, statistical studies. Am J Dis Child 1957;93:486–509' Saarinen, UM, Simes MA: Developmental changes in red blood cell counts and indices of infants after exclusion of iron deficiency by laboratory criteria and continuous iron supplementation. J Pediatr 1978;92:412–416; and Matoth Y, Zaizov R, Varsona I: Postnatal changes in some red cell parameters. Acta Paediatr Scand 1971;60:317–323.
From: Ohls R. (2001). Anemia in the newborn. Ch 7. In R.A. Polin, M.C. Yoder, & F. Burg (EDS). Workbook in Practical Neonatology, 3^rd Edition, Phila: Saunders. Page 126^[3]

Serial Hemoglobin Values in Low-Birth-Weight Infants
Birth Weight (g)	Age (Wk)
Birth Weight (g)	2	4	6	8	10
800–1000	16.0 (14.8–17.2)	10.0 (6.8–13.2)	8.7 (7.0–10.2)	8.0 (7.1–9.8)	8.0 (6.9–10.2)
1001–1200	16.4 (14.1–18.7)	12.8 (7.8–15.3)	10.5 (7.2–12.3)	9.1 (7.8–10.4)	8.5 (7.0–10.0)
1201–1400	16.2 (13.6–18.8)	13.4 (8.8–16.2)	10.9 (8.5–13.3)	9.9 (8.0–11.8)	9.8 (8.4–11.3)
1401–1500	15.6 (13.4–17.8)	11.7 (9.7–13.7)	10.5 (9.1–11.9)	9.8 (8.4–12.0)	9.9 (8.4–11.4)
1501–2000	15.6 (13.5–17.7)	11.0 (9.6–14.0)	9.6 (8.8–11.5)	9.8 (8.4–12.1)	10.0 (8.6–11.8)

Modified from Williams ML, Shott RJ, O'Neal PL, et al: Dietary iron and fat in vitamin E deficiency anemia of infancy. N Engl J Med 1975;292:877.
From: Ohls R. (2001). Anemia in the newborn. Ch 7. In R.A. Polin, M.C. Yoder, & F. Burg (EDS). Workbook in Practical Neonatology, 3^rd Edition, Phila: Saunders. Page 127^[3]

Mean Red Blood Cell (RBC) Values During Gestation
Age (Wk)	Hemoglobin (g/dL)	Hematocrit (%)	RBCs (10 U/mm³)	Mean Cell Volume (fL)	Mean Corpuscular Hemoglobin (pg)	Mean Corpuscular Hemoglobin Concentration (g/dL)	Nucleated RBCs (% of RBCs)	Recticulocytes (%)	Diameter (U)
12	8.0–10.0	33	1.5	180	60	34	5.5–8.0	40	10.5
16	10.0	35	2	140	45	33	2.0–4.0	10–25	9.5
20	11.0	37	2.5	135	44	33	1.0	10–20	9.0
24	14.0	40	3.5	128	38	31	1.0	5–10	8.8
28	14.5	45	4.0	120	40	31	0.5	5–10	8.7
34	15.0	47	4.4	118	38	32	0.2	3–10	8.3

Normal Hematologic Values During the First 2 Weeks of Life in the Term Infant*
Value	Cord Blood	Day 1	Day 3	Day 7	Day 14
Hemoglobin (g/dL)	16.8	18.4	17.8	17	16.8
Hematocrit (%)	53.0	58.0	55.0	54.0	52.0
Red cells (mm³) 10⁶/mm³	5.25	5.8	5.6	5.2	5.1
Mean cell volume (fL)	107	108	99.0	98.0	96.0
Mean corpuscular hemoglobin (pg)	34	35	33	32.5	31.5
Mean corpuscular hemoglobin concentration (g/dL)	31.7	32.5	33	33	33
Reticulocytes (%)	3–7	3–7	1–3	0–1	0–1
Nucleated red blood cells (mm³)	500	200	0–5	0	0290
Platelets (100s/mm³)	290	192	213	248	252

Postnatal Changes in Hemoglobin and Red Blood Cell (RBC) Indices in Term Infants
RBC Parameters	Age of Infants
	Days			Weeks		Months
	1	3	7	2	4	2	3	4	6
Hemoglobin (g/dL)
X	19.4	18.6	18.7	17.6	13.9	11.2	11.4	12.0	12.1
+/– 2 SD	17.2	16.5	16.5	13.9	10.6	9.3	9.5	10.7	10.4
(N)	(78)	(66)	(78)	(275)	(272)	(271)	(73)	(123)	(114)
Mean cell volume (fL)
X	114	110	108	106	101	95	88	84	77
+/– 2 SD	101–128	104–116	102–114	88–125	90–112	83–107	78–98	74–95	67–87
(N)	(78)	(66)	(78)	(275)	(272)	(271)	(73)	(123)	(114)
Mean corpuscular hemoglobin (pg)
X	36.6	36.7	36.2	33.6	32.5	30.4	30.4	28.1	26.4
(N)	(59)	(47)	(66)	(232)	(240)	(241)	(60)	(123)	(114)
Mean corpuscular hemoglobin concentration (%)
X	33.0	33.1	33.9	31.7	32.1	32.0	34.6	33.3	34.2
(N)	(78)	(66)	(78)	(275)	(271)	(271)	(73)	(123)	(114)

Serial Hemoglobin Values in Low-Birth-Weight Infants
Birth Weight (g)	Age (Wk)
Birth Weight (g)	2	4	6	8	10
800–1000	16.0 (14.8–17.2)	10.0 (6.8–13.2)	8.7 (7.0–10.2)	8.0 (7.1–9.8)	8.0 (6.9–10.2)
1001–1200	16.4 (14.1–18.7)	12.8 (7.8–15.3)	10.5 (7.2–12.3)	9.1 (7.8–10.4)	8.5 (7.0–10.0)
1201–1400	16.2 (13.6–18.8)	13.4 (8.8–16.2)	10.9 (8.5–13.3)	9.9 (8.0–11.8)	9.8 (8.4–11.3)
1401–1500	15.6 (13.4–17.8)	11.7 (9.7–13.7)	10.5 (9.1–11.9)	9.8 (8.4–12.0)	9.9 (8.4–11.4)
1501–2000	15.6 (13.5–17.7)	11.0 (9.6–14.0)	9.6 (8.8–11.5)	9.8 (8.4–12.1)	10.0 (8.6–11.8)

RDW in Premature Neonates on Day of Life 1 ^[22]
	23–25 weeks	26–28 weeks	29–31 weeks
RDW (%)	15.9 ± 1.4	16.5 ± 1.9%	16.4 ± 1.5%

Relationship Between RBC Characteristics on Peripheral Blood Smear and Diagnosis of Anemia ^[2,7,13,24]
^{Characteristic}	^{Etiology/Diagnosis}
^Anisocytosis	^{Chronic anemia}
^{Basophilic Stippling}	^{Thalassemias, lead poisoning}
^Elliptocytes	^{Hereditary elliptocytosis, structural RBC membrane defects, thalassemias}
^{Heinz Bodies}	^{Thalassemias, hemoglobinopathies, after splenectomy}
^{Howell-Jolly Bodies}	^{Severe iron deficiency, splenic dysfunction, asplenia, after splenectomy}
^Hypochromic	^{Chronic anemia (maternal fetal transfusion), iron deficiency, thalassemia, lead poisoning}
^Macrocytic	^{Nutritional deficiencies (folic acid, Vit B₁₂, Diamond-Blackfan anemia, Fanconi anemia, reticulocytosis, acquired aplastic anemia, inborn error of metabolism (organic aciduria)}
^Microcytic	^{Chronic infection, iron deficiency, lead poisoning, thalassemia}
^Normochromic	^{Acute hemorrhage (placental abruption)}
^Normocytic	^{With low reticulocyte count—infection (bacterial or viral), chronic disease, hemolytic anemia (immune, non-immune), drugs, hemoglobinopathy, unstable hemoglobin, transient erythroblastopenia of childhood}
	^{With normal or high reticulocyte count—blood loss, sequestration, RBC enzyme defects}
^{Nucleated RBC}	^{Chronic hemorrhage, hemolysis}
^{Poikilocytosis}	^{RBC fragmentation syndrome, intrinsic RBC defects}
^{Polychromasia}	^{Proliferative reaction seen in anemia}
^{Reticulocytosis}	^{Chronic hemorrhage, hemolysis}
^{Sickle Cells}	^{Hgb S disease and other variants}
^{Spherocytosis}	^{G6PD deficiency, immune hemolytic anemia (Rh, ABO), structural RBC membrane defects}
^{Target Cells}	^{Hgb C, Hgb S, or Hgb E diseases; thalassemia, liver disease}

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Red Blood Cell Indices: Implications for Practice

Ontogeny of RBC production

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