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2
Reference Ranges and

Normal Values
Imelda Bates
CHAPTER OUTLINE
Reference ranges, 8 Leucocyte count, 15
Statistical procedures, 9 Platelet count, 16
Confidence limits, 9 Other blood constituents, 16
Normal reference values, 10 Effects of smoking on haematological normal
Physiological variations in the blood count, 13 reference values, 16
Red cell components, 13
A number of factors affect haematological values in appar- a databank of reference values that takes account of the
ently healthy individuals. As described in Chapter 1, these variables mentioned earlier and the test method, so that an
include the technique and timing of blood collection, the individual’s result can be expressed and interpreted relative
transport and storage of specimens, the posture of the sub- to a comparable apparently normal population, insofar as
ject when the sample is taken, the prior physical activity normal can be defined.
and the degree of ambulation (e.g. whether the subject is New haematological parameters such as the number
confined to bed or not). Variation in the analytical methods of immature cells or the number of red cell fragments
used may also affect the measurements. These can all be are often initially developed for research purposes but
standardised. can be used for clinical decision making once internal
More problematic are the inherent variables as a result quality control and external quality assessment processes
of gender, age, occupation, body build, genetic background are in place.3
and adaptation to diet and to environment (especially alti-
tude). These factors must be recognised when establishing
physiologically normal values. It is also difficult to be cer-
REFERENCE RANGES
tain that the ‘normal’ subjects used for constructing normal A reference range for a specified population can be es-
ranges are completely healthy and do not have nutritional tablished from measurements on a relatively small num-
deficiencies, mild chronic infections, parasitic infestations ber of subjects (discussed later) if they are assumed to be
or the effects of smoking. representative of the population as a whole.2 The condi-
Haematological values for the normal and abnormal will tions for obtaining samples from the individuals and the
overlap and a value within the recognised normal range may analytical procedures must be standardised, whereas data
be definitely pathological in a particular subject. For these should be analysed separately for different variables relat-
reasons the concept of ‘normal values’ and ‘normal ranges’ ing to individuals – recumbent or ambulant, smokers or
has been replaced by reference values and the reference range, nonsmokers and so on. One approach is that specimens
which is defined by reference limits and obtained from meas- are collected at about the same time of day, preferably in
urements on the reference population for a particular test. the morning before breakfast; the last meal should have
Unless a reference range is derived in this manner, the term been eaten no later than 9 p.m. on the previous evening,
should not be used. The reference range is also termed the and at that time alcohol should have been restricted to
reference interval.1,2 Ideally, each laboratory should establish one bottle of beer or an equivalent amount of another
8
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2 Reference Ranges and Normal Values 9
alcoholic drink.4 An alternative approach is that, unless normal population. Limits representing the 95% reference
a test is usually done on a fasting patient, specimens are range are calculated from the arithmetic mean ±2SD (or
collected throughout the day on subjects who are not more accurately ±1.96SD).
fasting or resting, as this will produce a reference range When there is a log normal (skewed) distribution of
that is more relevant to results from patients. It is some- measurements, the range to −2SD may even extend to
times appropriate that the reference population is defined zero (Fig. 2-2, A). To avoid this anomaly, the data should
as having normal results for specific laboratory tests. For be plotted on semilogarithmic graph paper to obtain a
example, if determining a reference range for blood count normal distribution histogram (Fig. 2-2, B). To calculate
components it may be necessary, in some populations, the mean and SD the data should be converted to their
to exclude iron deficiency, β thalassaemia heterozygosity logarithms. The log–mean value is obtained by adding the
and, when relevant, α thalassaemia. logs of all the measurements and dividing by the number
of observations. The log SD is calculated by the formula
STATISTICAL PROCEDURES on page 566 and the results are then converted to their
antilogs to express the data in the arithmetic scale. This
In biological measurements, it is usually assumed that the process is now generally carried out using an appropriate
data will fit a specified type of pattern, either symmet- statistical computer program.
ric (Gaussian) or asymmetric with a skewed distribution When it is not possible to make an assumption about
(non-Gaussian). With a Gaussian distribution, the arith- the type of distribution, a nonparametric procedure may
metic mean (x) can be obtained by dividing the sum of all be used instead to obtain the median and SD. To obtain
measurements by the number of observations. The mode is an approximation of the SD, the range that comprises the
the value that occurs most frequently and the median (m) middle 50% spread (i.e. between 25 and 75% of results) is
is the point at which there are an equal number of obser- read and divided by 1.35. This represents 1SD.
vations above and below it. In a true Gaussian distribution
they should all be the same. The standard deviation (SD)
can be calculated as described on page 565.
Confidence limits
If the data fit a Gaussian distribution, when plotted as In any of the methods of analysis, a reasonably reliable
a frequency histogram the pattern shown in Figure 2-1 is estimate can be obtained with 40 values, although a larger
obtained. Taking the mode and the calculated SD as ref- number (≥120) is preferable (Fig. 2-3).5 When a large set
erence points, a Gaussian curve is superimposed on the of reference values is unattainable and precise estimation
histogram. From this curve, practical reference limits can is impossible, a smaller number of values may still serve as
be determined even if the original histogram included a useful clinical guide. Confidence limits define the relia-
outlying results from some subjects not belonging to the bility (e.g. 95% or 99%) of the established reference values
Number of subjects
FIGURE 2-1 Example of establishing a reference range. Histogram of data of Hb measurements in a population, with Gaussian curve su-
perimposed. The ordinate shows the number that occurred at each reference point. The mean was 140 g/l; the reference ranges at 1SD, 2SD
and 3SD are indicated.
10 Practical Haematology
FIGURE 2-2 Example of conversion to a log normal distribution. Data of serum cobalamin (vitamin B12) measurements in a population. (A)
Arithmetic scale: mean 340 pg/ml; 2SD range calculated as 10–665. (B) Geometric scale: mean 308 pg/ml; 2SD range calculated as 120–780.
Number of Hb measurements from a group
of normal women
FIGURE 2-3 Effect of sample size on reference values. A smoothed distribution graph was obtained for Hb measurements from a group
of normal women; the ordinate shows the frequency distribution. The 95% reference range is defined by the lower and higher reference
limits, which are 115 and 165 g/l, respectively. The confidence levels for these values are shown for three sample sizes of 20, 40 and 165,
respectively.
when assessing the significance of a test result, especially methods are used. The reference interval, which comprises
when it is on the borderline between normal and abnor- a range of ±2SD from the mean, indicates the lim-
mal. Calculation of confidence limits is described on page its that should cover 95% of normal subjects; 99% of
566. Another important measurement is the coefficient of normal subjects will be included in a range of ±3SD.
variation (CV) of the test because a wide CV is likely to Age and gender differences have been taken into ac-
influence its clinical utility (see p. 566). count for some values. Even so, the wide ranges that
are shown for some tests reflect the influence of various
NORMAL REFERENCE VALUES factors, as described below. Narrower ranges would be
expected under standardised conditions. Because mod-
The data given in Tables 2-1, 2-2 and 2-3 provide general ern analysers provide a high level of technical precision,
guidance to normal reference values that are applicable to even small differences in successive measurements may
most healthy adults and children in high-income coun- be significant. It is thus important to establish and un-
tries. However, slightly different ranges may be found derstand the limits of physiological variation for various
in individual laboratories where different analysers and tests. The blood count data and other test results can
TA B LE 2 - 1
HAEMATOLOGICAL VALUES FOR NORMAL ADULTS (PREDOMINANTLY FROM EUROPE AND

NORTH AMERICA) EXPRESSED AS A MEAN ± 2SD OR AS A 95% RANGE
Red blood cell count Heparin cofactor II 0.55–1.45 u/ml
Men 5.0 ± 0.5 × 1012/l concentration‡
Women 4.3 ± 0.5 × 1012/l Median red cell fragility (MCF)
Haemoglobin concentration* (g/l NaCl)
Men 150 ± 20 g/l Fresh blood 4.0–4.45 g/l NaCl
Women 135 ± 15 g/l After 24 h at 37 °C 4.65–5.9 g/l NaCl
Packed cell volume (PCV) or Cold agglutinin titre (4 °C) <64
haematocrit (Hct) Blood volume (normalised to
Men 0.45 ± 0.05 l/l ‘ideal weight’)
Women 0.41 ± 0.05 l/l Red cell volume
Mean cell volume (MCV) Men 30 ± 5 ml/kg
Men and women 92 ± 9 fl Women 25 ± 5 ml/kg
Mean cell haemoglobin (MCH) Plasma volume 45 ± 5 ml/kg
Men and women 29.5 ± 2.5 pg Total blood volume 70 ± 10 ml/kg
Mean cell haemoglobin Red cell lifespan 120 ± 30 days
concentration (MCHC) Serum iron
Men and women 330 ± 15 g/l Men and women 10–30 μmol/l
Red cell distribution width (0.6–1.7 mg/l)
(RDW) Total iron-binding capacity 47–70 μmol/l
As coefficient of variation (CV) 12.8% ± 1.2% (2.5–4.0 mg/l)
Red cell diameter (mean Transferrin saturation 16–50%
values) Serum ferritin concentration
Dry films 6.7–7.7 μm Men 15–300 μg/l (median
Red cell density 1092–1100 g/l 100 μg/l)
Reticulocyte count 50–100 × 109/l Women 15–200 μg/l (median
(0.5–2.5%) 40 μg/l)
White blood cell count 4.0–10.0 × 109/l Serum vitamin B12 180–640 ng/l
Differential white cell count concentration
Neutrophils 2.0–7.0 × 109/l (40–80%) Serum folate concentration 3–20 μg/l (6.8–45 nmol/l)
Lymphocytes 1.0–3.0 × 109/l (20–40%) Red cell folate concentration 160–640 μg/l
Monocytes 0.2–1.0 × 109/l (2–10%) (0.36–1.45 μmol/l)
Eosinophils 0.02–0.5 × 109/l (1–6%) Plasma haemoglobin 10–40 mg/l
Basophils 0.02–0.1 × 109/l (<1–2%) concentration
Lymphocyte subsets Serum haptoglobin
(approximations from ranges concentration
in published data) Radial immunodiffusion 0.8–2.7 g/l
CD3 0.6–2.5 × 109/l (60–85%) Haemoglobin binding capacity 0.3–2.0 g/l
CD4 0.4–1.5 × 109/l (30–50%) Haemoglobin A2 2.2–3.5%
CD8 0.2–1.1 × 109/l (10–35%) Haemoglobin F <1.0%
CD4/CD8 ratio 0.7–3.5 Methaemoglobin <2.0%
Platelet count 280 ± 130 × 109/l Erythrocyte sedimentation rate
Bleeding time† (mm in 1 h at 20 ± 3 °C)
Ivy method 2–7 min Men
Template method 2.5–9.5 min 17–50 years ≤10
Thrombin time 15–19 s 51–60 years ≤12
Plasma fibrinogen 1.8–3.6 g/l 61–70 years ≤14
concentration >70 years ≤30
Plasminogen concentration‡ 0.75–1.60 u/ml Women
Antithrombin concentration‡ 0.75–1.25 u/ml 17–50 years ≤12
Protein C concentration‡ 51–60 years ≤19
Functional 0.70–1.40 u/ml 61–70 years ≤20
Antigen 0.61–1.32 u/ml >70 years ≤35
Protein S concentration‡ Plasma viscosity
Total antigen 0.78–1.37 u/ml 25 °C 1.50–1.72 mPa/s
Free antigen 0.68–1.52 u/ml 37 °C 1.16–1.33 mPa/s
Premenopausal women§ 0.55–1.55 u/ml
Functional 0.60–1.35 u/ml
Premenopausal women 0.55–1.35 u/ml
*Haemoglobin concentration may sometimes be reported as g/dl.
†
Bleeding time is no longer recommended for routine assessment of haemostasis but may be useful in suspected collagen disorders.
‡
These ranges are for general guidance only because each laboratory should establish its own normal range.
§
From Dykes AC, Walker ID, McMahon AD et al. Protein S antigen levels in 3788 healthy volunteers. Br J Haematol 2001;113:636–641.
TABL E 2 - 2
12
HAEMATOLOGICAL VALUES FOR NORMAL INFANTS (AMALGAMATION OF DATA DERIVED FROM VARIOUS SOURCES;
EXPRESSED AS MEAN ± 2SD OR 95% RANGE)*
Birth Day 3 Day 7 Day 14 1 Month 2 Months 3–6 Months
Red blood cell count 6.0 ± 1.0 5.3 ± 1.3 5.1 ± 1.2 4.9 ± 1.3 4.2 ± 1.2 3.7 ± 0.6 4.7 ± 0.6
(RBC) (×1012/l)
Haemoglobin 180 ± 40 180 ± 30 175 ± 40 165 ± 40 140 ± 25 112 ± 18 126 ± 15
concentration (g/l)
Haematocrit (Hct) 0.60 ± 0.15 0.56 ± 0.11 0.54 ± 0.12 0.51 ± 0.2 0.43 ± 0.10 0.35 ± 0.07 0.35 ± 0.05
Practical Haematology
(l/l)
Mean cell volume 110 ± 10 105 ± 13 107 ± 19 105 ± 19 104 ± 12 95 ± 8 76 ± 8
(MCV) (fl)
Mean cell 34 ± 3 34 ± 3 34 ± 3 34 ± 3 33 ± 3 30 ± 3 27 ± 3
haemoglobin
(MCH) (pg)
Mean cell 330 ± 30 330 ± 40 330 ± 50 330 ± 50 330 ± 40 320 ± 35 330 ± 30
haemoglobin
concentration
(MCHC) (g/l)
Reticulocyte count 120–400 50–350 50–100 50–100 20–60 30–50 40–100
(×109/l)
White blood cell 18 ± 8 15 ± 8 14 ± 8 14 ± 8 12 ± 7 10 ± 5 12 ± 6
count (WBC)
(×109/l)
Neutrophils (×109/l) 4–14 3–5 3–6 3–7 3–9 1–5 1–6
Lymphocytes 3–8 2–8 3–9 3–9 3–16 4–10 4–12
(×109/l)
Monocytes (×109/l) 0.5–2.0 0.5–1.0 0.1–1.7 0.1–1.7 0.3–1.0 0.4–1.2 0.2–1.2
Eosinophils (×109/l) 0.1–1.0 0.1–2.0 0.1–0.8 0.1–0.9 0.2–1.0 0.1–1.0 0.1–1.0
Lymphocyte subsets
(×109/l)†
CD3 3.1–5.6 2.4–6.5 2.0–5.3
CD4 2.2–4.3 1.4–5.6 1.5–3.2
CD8 0.9–1.8 0.7–2.5 0.5–1.6
CD4/CD8 ratio 1.1–4.5 1.1–4.4 1.1–4.2
Platelets (×109/l) 100–450 210–500 160–500 170–500 200–500 210–650 200–550
*There have been some reports of WBC and platelet counts being lower in venous blood than in capillary blood samples.
†
Approximations because wide variations have been reported in different studies.
TA B LE 2 - 3
HAEMATOLOGICAL VALUES FOR NORMAL CHILDREN (AMALGAMATION OF DATA DERIVED FROM
VARIOUS SOURCES; EXPRESSED AS MEAN ± 2SD OR 95% RANGE)
1 Year 2–6 Years 6–12 Years
Red cell count (×10 /l)
12
4.5 ± 0.6 4.6 ± 0.6 4.6 ± 0.6
Haemoglobin concentration (g/l) 126 ± 15 125 ± 15 135 ± 20
Haematocrit (Hct) or packed cell volume (PCV) (l/l) 0.34 ± 0.04 0.37 ± 0.03 0.40 ± 0.05
Mean cell volume (MCV) (fl) 78 ± 6 81 ± 6 86 ± 9
Mean cell haemoglobin (MCH) (pg) 27 ± 2 27 ± 3 29 ± 4
Mean cell haemoglobin concentration (MCHC) (g/l) 340 ± 20 340 ± 30 340 ± 30
Reticulocyte count (×109/l) 30–100 30–100 30–100
White cell count (×109/l) 11 ± 5 10 ± 5 9±4
Neutrophils (×109/l) 1–7 1.5–8 2–8
Lymphocytes (×109/l) 3.5–11 6–9 1–5
Monocytes (×109/l) 0.2–1.0 0.2–1.0 0.2–1.0
Eosinophils (×109/l) 0.1–1.0 0.1–1.0 0.1–1.0
Lymphocyte subsets (×109/l)*
CD3 1.5–5.4 1.6–4.2 0.9–2.5
CD4 1.0–3.6 0.9–2.9 0.5–1.5
CD8 0.6–2.2 0.6–2.0 0.4–1.2
CD4/CD8 ratio 1.0–3.0 0.9–2.7 1.0–3.0
Platelets (×109/l) 200–550 200–490 170–450
*Approximations because wide variations have been reported in different studies.
then provide sensitive indications of minor abnormali- difficult to assess. At birth the Hb is higher than at any
ties that may be important in clinical interpretation and period subsequently (Table 2-2). The RBC is high im-
health screening. mediately after birth,8 and values for Hb above 200 g/l,
It should be noted that in Table 2-1 the differential RBC higher than 6.0 × 1012/l and a haematocrit (Hct) over
white cell count is shown as percentages and in absolute 0.65 are encountered frequently when cord clamping is
numbers. Automated analysers provide absolute counts delayed and blood from the placenta and umbilical artery
for each type of leucocyte and, because proportional (per- re-enters the infant’s circulation. There are rapid fluctua-
centage) counting is less likely to indicate correctly their tions in the blood count of newborn babies, infants and
absolute increase or decrease, the International Council for older children. Reference ranges for preterm infants vary
Standardisation in Haematology has recommended that with gestational age. For example, in preterm infants in
the differential leucocyte count should always be given as the United States between 22 and 41 weeks’ gestation,
the absolute number of each cell type per unit volume of the packed cell volume increases from 0.40 to 0.52 l/l, the
blood.6 The neutrophil:lymphocyte ratio obtained from Hb from 140 to 170 g/l and the platelet count from 200
a differential leucocyte count should be regarded only as to 250 × 109/l, whereas the mean cell volume (MCV) and
an approximation. There are variations in the ability of mean cell haemoglobin (MCH) gradually decrease from
different automated blood cell analysers to characterise, 121 to 105 fl and from 40.5 to 35.5 pg, respectively.9
quantify and flag different types of cells. Most analysers After the immediate postnatal period, the Hb falls
show good correlation for neutrophils and eosinophils but fairly steeply to a minimum by about the second month
counts and flags for basophils, blasts and immature granu- (Fig. 2-4). The RBC and Hct also fall, although less steeply,
locytes may not be reliable enough for clinical use.7 and the cells may become microcytic with the develop-
ment of iron deficiency. The changes in the MCH, mean
PHYSIOLOGICAL VARIATIONS IN cell haemoglobin concentration (MCHC) and MCV from
THE BLOOD COUNT the neonate through infancy to early childhood are shown
in Tables 2-2 and 2-3.
Red cell components The Hb and RBC increase gradually through childhood
to reach almost adult levels by puberty. The lower normal
Age and gender limits for Hb (i.e. 2SD below the mean) are usually taken
There is considerable variation in the red blood cell count as 130 g/l for men and 120 g/l for women. The levels in
(RBC) and Hb at different periods of life and there are also women tend to be significantly lower than those in men10
transient fluctuations, the significance of which is often partly due to a hormonal influence on haemopoiesis, and
FIGURE 2-4 Changes in Hb values in the first 2 years after birth. The horizontal lines show the means and the perpendicular lines the
2SD ranges.
possibly subclinical iron deficiency in women. The extent TAB LE 2 -4

to which menstrual blood loss is a significant factor is not
clear because a loss of up to 100 ml of blood with each pe- HAEMOGLOBIN CONCENTRATION VALUES
riod may lead to iron depletion without causing anaemia. IN PREGNANCY
There may also be ethnic differences in Hb (e.g. the Hb is
First trimester 124–135 g/l
5–10 g/l lower in black Americans than in socially com-
Second trimester 110–117 g/l
parable white counterparts). In older adults the threshold Third trimester 106–109 g/l*
Hb level at which mortality increases is lower.11 Mean values postpartum
Day 2 104 g/l
Pregnancy Week 1 107 g/l
In normal pregnancy, there is an increase in erythropoietic Week 3 116 g/l
activity and a simultaneous increase in plasma volume oc- Month 2 119 g/l
curs, which overall results in a progressive decrease in Hb,
*Higher values (120 g/l or higher) may be found when supplementary
Hct and RBC (Table 2-4). There is a slight increase in MCV iron is being given.
during the second trimester. Serum ferritin decreases in
early pregnancy and usually remains low throughout
pregnancy, even when supplementary iron is given.12 The Moderate or severe anaemia should never be attributed to
haematological parameters return to normal about a week ageing per se until underlying disease has been excluded;
after delivery. however, a significant number of elderly subjects with anae-
mia have no identifiable clinical or nutritional causes.
The elderly
In healthy men and women, Hb, RBC, Hct and other red Exercise
cell indices remain remarkably constant until the sixth dec- Optimal athletic performance depends on proper function
ade. Anaemia becomes more common in those older than of many organs, including the blood. Several haemato-
70–75 years13 and is associated with poor clinical outcomes logical parameters can affect or be influenced by physi-
due to reduced cognition, increased frailty and an elevated cal activity, including blood cell counts and coagulation
risk of hospitalisation and of complications during hospi- mechanisms.14 For example, endurance athletes may de-
talisation. In the elderly, the difference in Hb between men velop so-called ‘sports anaemia’, which is thought to be
and women is 10 g/l or less compared with a difference the result of increased plasma volume. Increasing oxygen
of 20 g/l in younger age groups. Serum iron increases as delivery by raising the Hct is a simple acute method to
women age although serum ferritin levels remain higher improve athletic performance. Legal means of raising the
in elderly men than in women. Factors that contribute to Hct include altitude training and use of hypoxic tents.
the lower Hb in the elderly include renal insufficiency, in- Illegal means include blood doping and the administra-
flammation, testosterone deficiency, diminished erythro- tion of erythropoietin (EPO) (see Chapter 6).15 Endurance
poiesis, stem cell proliferative decline and myelodysplasia. athletes may also have decreased levels of serum iron and
ferritin, possibly associated with loss of iron in sweat. Leucocyte count

Conversely, in sprinters who require a short burst of very
strenuous muscular activity, there is a transient increase At birth, the total leucocyte count is high; neutrophils pre-
in RBC by 0.5 × 1012/l and in Hb by 15 g/l, largely because dominate, reaching a peak of ≈ 13.0 × 109/l within 6–8 h
of a reduction in plasma volume and to a lesser extent the for neonates of >28 weeks’ gestation and 24 h for those de-
re-entry into the circulation of cells previously sequestered in livered at <28 weeks.9 The count then falls to ≈ 4.0 × 109/l
the spleen. The effects of exercise must be distinguished from over the next few weeks and then stabilises (Tables 2-1,
a form of haemolysis known as ‘runner’s anaemia’ or ‘march 2-2 and 2-3). The lymphocytes decrease during the first
haemoglobinuria’, which occurs as a result of pounding of 3 days of life, often to a low level of ≈ 2.0–2.5 × 109/l, and
the feet on the ground.16 A similar phenomenon has been then rise up to the tenth day; after this time, they are the
reported in djembe drummers from repeated hand trauma. predominant cell (up to about 60%) until the fifth to sev-
enth year, when neutrophils predominate. From that age
Posture onwards, the levels are the same as those of adults. There
There is a small but significant alteration in the plasma vol- are also slight sex differences; the total leucocyte count
ume with an increase in Hb and Hct as the posture changes (WBC) and the neutrophil count may be slightly higher in
from lying to sitting, especially in women;17 conversely, girls than in boys, and in women than in men.21 After the
changing from walking to lying results in a 5–10% de- menopause, the counts fall in women so that they tend to
crease in the Hb and Hct. The difference in position of the become lower than in men of similar age.
arm during venous sampling, whether dependent or held People differ considerably in their leucocyte counts.
at atrial level, can also affect the Hct. Some tend to maintain a relatively constant level over long
These aspects highlight the relevance of using a stand- periods; others have counts that may vary by as much as
ardised method for blood collection, although this is not 100% at different times. In some subjects, there appears
necessarily practicable in routine practice. This is dis- to be a rhythm, occurring in cycles of 14–28 days, and
cussed in Chapter 1 and the differences between venous in women this may be related to the menstrual cycle or
and capillary blood are described on page 3. to the use of oral contraception. There is no clear-cut di-
urnal variation, but minimum counts are found in the
Diurnal and seasonal variation morning with the subject at rest and during the course
Changes in Hb and RBC during the course of the day are of a day there may be differences of 14% for the WBC,
usually slight, about 3%, with negligible changes in the 10% for neutrophils, 14% for lymphocytes and 20% for
MCV and MCH. However, variation of 20% occurs with eosinophils;18 in some cases this may result in a reversed
reticulocyte counts.18 Studies of diurnal variation of serum neutrophil:lymphocyte ratio. Random activity may raise
erythropoietin have shown conflicting results. Pronounced, the count slightly; strenuous exercise causes increases of
but variable, diurnal variations are seen in serum iron and up to 30 × 109/l, partly because of mobilization of mar-
ferritin and in patients taking iron-containing supple- ginated neutrophils and changes in cortisol levels.22 Large
ments.19 It has been suggested that minor seasonal vari- numbers of lymphocytes and monocytes also enter the
ations also occur, but the evidence for this is conflicting. bloodstream during strenuous exercise. However, there
have also been reports of neutropenia and lymphopenia in
Altitude athletes undergoing strenuous exercise.23
The effect of altitude is to reduce the plasma volume, in- Epinephrine (adrenaline) injection causes an increase in
crease the Hb and Hct and raise the number of circulat- the numbers of all types of leucocytes (and platelets), pos-
ing red cells with a lower MCV.20 The magnitude of the sibly reflecting the extent of the reservoir of mature blood
polycythaemia depends on the degree of hypoxaemia. At cells present not only in the bone marrow and spleen but
an altitude of 2000 m, Hb is ≈ 8–10 g/l and Hct is 0.025 also in other tissues and organs of the body. Emotion may
higher than at sea level; at 3000 m, Hb is ≈ 20 g/l and Hct possibly cause an increase in the leucocyte count in a sim-
is 0.060 higher; and at 4000 m, Hb is 35 g/l and Hct is ilar way. A transient lymphocytosis with a reversed neutro-
0.110 higher. Corresponding increases occur at interme- phil:lymphocyte ratio occurs in adults with physical stress
diate and at higher altitudes.20 These increases appear to or trauma. The effect of ingestion of food is uncertain.
be the result of enhanced erythropoiesis secondary to the Cigarette smoking has an effect on the leucocyte count
hypoxic stimulus, and the decrease in plasma volume that (see p. 16).
occurs at high altitudes. A moderate increase in the WBC, of up to 15 × 109/l,
is common during pregnancy, owing to an increase in the
Smoking neutrophil count, with the peak in the second trimester.
Cigarette smoking affects Hb, RBC, Hct and MCV (see The count returns to non-pregnancy levels about a week
p. 16). after delivery.24
In individuals of African ancestry there is a tendency TAB LE 2 -5

for the neutrophil:lymphocyte ratio to be reversed primar-
ily due to a reduction in neutrophil count. This is due EFFECTS OF CIGARETTE SMOKING*
to genetic rather than environmental factors. Significantly
Increased Decreased
lower WBC and neutrophil counts have also been observed
in Africans and Afro-Caribbeans living in Britain as well as Haemoglobin concentration (Hb) Plasma volume
in many African countries. ‘Benign ethnic neutropenia’ oc- Red blood cell count (RBC) Protein S
curs in up to 5% of African Americans and is defined as a Haematocrit (Hct)
neutrophil count <1.5 × 109/l without overt cause or com- Mean cell volume (MCV)
Mean cell haemoglobin (MCH)
plications.25 A Duffy null polymorphism is associated with White blood cell count (WBC)
the difference in WBC and neutrophil counts between Neutrophil count
African Americans and European Americans.26 Elderly Lymphocyte count
people receiving influenza vaccination show a lower total T cells (CD4-positive)
leucocyte count owing to a decrease in lymphocytes.27 Monocyte count
Carboxyhaemoglobin (>2%)
Platelet count (transient)
Platelet count Mean platelet volume
There is a slight diurnal variation in the platelet count Fibrinogen concentration
of about 5%;18 this occurs during the course of a day as β thromboglobulin concentration
von Willebrand factor
well as from day-to-day. Within the wide normal reference Red cell mass
range, there are some ethnic differences, and in healthy Haptoglobin concentration
Afro-Caribbeans and Africans platelet counts may on av- Plasma viscosity
erage be 10–20% lower than those in Europeans living in Whole blood viscosity
the same environment.28 There is also a gender difference; Erythrocyte sedimentation rate (ESR)
thus, in women, the platelet count is about 20% higher
than in men.29 A decrease in the platelet count may occur *Extent of change from normal reference values varies with individuals
and the amount smoked. Some effects may be transient or occur only
in women at about the time of menstruation. In the first during and immediately after smoking.
year after birth the reference range for the platelet count is
higher than the adult reference range. Strenuous exercise
causes a 30–40% increase in platelet count;22 the mecha- level increases by about 1%, and in heavy smokers the
nism is similar to that for leucocytes. carboxyhaemoglobin may constitute ≈ 4–5% of the to-
Further information. Detailed ranges related to age, tal haemoglobin. The WBC increases, largely as a result
gender, ethnic origin and pregnancy status are given in of an increase in the neutrophils; neutrophil function
reference 30. may also be affected. Smoking can cause an increase in
CD4-positive lymphocytes and total lymphocyte count.
Smokers tend to have higher platelet counts than non-
Other blood constituents smokers, but the counts decrease rapidly on cessation of
smoking. Studies of platelet aggregation and adhesiveness
As with the blood count, variations from usual values occur have given equivocal results, but there appears to be a
in relation to gender, age, exercise, stress, diurnal fluctua- consistent increase in platelet turnover with decreased
tion and so on. These are described in the relevant chapters. platelet survival and increased plasma β thromboglob-
ulin. Elevated fibrinogen concentration (with increased
plasma viscosity) and reduced protein S have been re-
EFFECTS OF SMOKING ON ported, but smoking does not seem to have any consist-
HAEMATOLOGICAL NORMAL ent effects on the fibrinolytic system.
REFERENCE VALUES
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2

Reference Ranges and

HAEMATOLOGICAL VALUES FOR NORMAL ADULTS (PREDOMINANTLY FROM EUROPE AND

*Approximations because wide variations have been reported in different studies.

possibly subclinical iron deficiency in women. The extent TAB LE 2 -4

ferritin, possibly associated with loss of iron in sweat. Leucocyte count

In individuals of African ancestry there is a tendency TAB LE 2 -5

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