148

REVIEW

Heights and haematology: the story of haemoglobin at

altitude
Jeremy S Windsor, George W Rodway
...................................................................................................................................

Postgrad Med J 2007;83:148–151. doi: 10.1136/pgmj.2006.049734

In order to compensate for the low partial pressure of oxygen at This, the first recorded description of a red blood
cell (erythrocyte), would provide the starting point
altitude, the human body undergoes a number of physiological for a clear description of the constituents of the cell
changes. A vital component in this process is the increase in the and finally, an understanding of its origins and
concentration of circulating haemoglobin. The role of HIF-1a, function. At the University of Bologna in 1747,
erythropoietin and red blood cells in this acclimatisation process Vincenzo Menghini demonstrated the presence of
iron in red cells by burning blood and showing
is described, together with the fall in plasma volume that that its ashes were attracted to a magnet.3 Later,
increases the concentration of haemoglobin in the early stages Jons Jacob Berzelius distinguished between the
of hypoxic exposure. protein ‘‘globulin’’ and the pigmented ‘‘haem’’
compound contained in the cell, before correctly
.............................................................................
identifying that the latter component carried the
iron moiety.4 Subsequent experiments conducted

A
lthough estimates vary, it is thought that by Johannes Mulder determined the composition
approximately 140 million people live above of the ‘‘haem’’ component and demonstrated that
2500 m, with the majority being found in the pigmented structure was responsible for
Central Asia, East Africa, Central and South carrying oxygen.5 By the middle of the nineteenth
America (table 1).1 century, Felix Hoppe Seyler was able to crystallise
The greatest challenge facing humans at altitude the molecule and finally named it ‘‘haemoglobin’’.
is the reduction in the partial pressure of oxygen Seyler would later go on to describe the formation
that results from a fall in barometric pressure. of ‘‘oxyhaemoglobin’’ following the reaction of
When faced with this hypoxic challenge, the body haemoglobin with oxygen.6 In 1865 Seyler pre-
responds in a number of different ways depending sented his results to his colleague Paul Bert (fig 1).
upon the rate and severity with which the stimulus By exposing animals to a range of different
is imposed. The acute hypoxia suffered by aviators barometric pressures, Bert was able to describe
in an unpressurised aircraft generates a very for the first time a rudimentary oxyhaemoglobin
different set of physiological responses than the dissociation curve.7
more chronic form experienced by mountaineers, Bert is considered by many to be the father of
who typically take several weeks to reach similar high altitude physiology. With the publication of
heights. It is striking to note that someone who La Presson Bariometrique in 1878, Bert was the first
ascends rapidly from sea level to the summit of Mt to make the connection between the problems
Everest (8850 m) will lose consciousness within humans faced at high altitude and the fall in
seconds, while those who have spent several weeks barometric pressure.8 This work had been
ascending can often function relatively well. The prompted in large part by fellow Frenchman and
physiological changes which allow this to occur are physician Denis Jourdanet.9 Jourdanet had spent
grouped together under the term ‘‘acclimatisa- almost 20 years practising medicine at high
tion’’, while change that occurs over many gen- altitudes in Mexico and had focused much of his
erations in high altitude populations is known as attention on the effects of high altitude on
‘‘adaptation’’. In order to cope with hypoxia, the humans. With Jourdanet’s subsequent encourage-
body attempts to maximise the delivery of oxygen ment and financial support, Bert was able to build
See end of article for to the tissues. Within minutes of arriving at one of the earliest pressure chambers in his
authors’ affiliations altitude this is manifest by an increase in cardiac laboratory and was able to demonstrate that by
........................ output and minute ventilation.2 Over time, addi- breathing supplemental oxygen in hypoxic condi-
Correspondence to: tional improvements occur in both the circulation tions, the symptoms of acute mountain sickness
Jeremy S Windsor, Centre and tissues that enhance the acclimatisation could be treated.
for Aviation, Space and process further. This review will focus upon During his time in Mexico, Jourdanet observed a
Extreme Environment perhaps the most widely known change seen on consistent increase in the viscosity of human blood
Medicine (CASE), University ascent to altitude, that is the increase in the
College London, Archway at high altitude. This would lead Bert to correctly
Campus, Whittington concentration of haemoglobin. hypothesise that such a change was due to an
Hospital, Archway, London increase in the concentration of red cells in the
N19 5NF, UK; jswindsor@ Early historical developments circulation. However, it would take another
doctors.org.uk In 1674 Anthony Von Leeuwenhoeck announced
Received 18 May 2006
to members of the Royal Society, ‘‘I have observed, Abbreviations: CMS, chronic mountain sickness; EPO,
Accepted taking some blood out of my hand, that it consists erythropoietin; HIF-1a, hypoxia inducible factor-1a; HVR,
13 November 2006 of small round globules driven through a crystal- hypoxic ventilatory response; VHL protein, Von Hippel
........................ line humidity of water’’.3 Lindau protein

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Height and haematology 149

Table 1 The five countries with the largest populations

living above 2500 m1
Estimated population
living above 2500 m Estimated percentage of
Country (millions) the total population (%)

India 26.82 3
China 22.09 2
Mexico 14.05 15
Pakistan 14.05 10
Ethiopia 13.76 25

Frenchman, Francois-Gilbert Viault to confirm this, when in

1890 he found that after 23 days at 4392 m, his own red cell
count had risen from 5 to 8 million per cubic millimetre.10 In
later studies on lowland Europeans and Peruvian high altitude
residents, Viault was able to confirm what is now commonly
known – haemoglobin concentrations rise on ascent to altitude.

Twentieth century and beyond

The response of lowlanders to hypoxia
In 1906 Carnot and Deflandre, two scientists at the University
of Paris, took the understanding of haemoglobin one step
further. By injecting the serum of bleeding rabbits into Figure 1 Paul Bert, considered by many to be the father of high altitude
otherwise healthy animals, they were able to demonstrate an physiology.
increase in the red cell concentrations of the transfused
animals. This, the authors felt, had shown ‘‘the presence of a
substance haemopoietin [erythropoietin] capable of activating concentration, despite EPO production remaining high.22 Once
haemopoiesis and of rapidly provoking in normal animals, a bound to the erythroid cells in the bone marrow, EPO triggers
high constant hyperglobulism’’.11 an increase in iron turnover and a doubling of nucleated red
Although it would take almost 50 years to demonstrate the cells within 7 days of exposure to moderate altitude.23 In a long
effect of erythropoietin (EPO) on erythroid cell lines in term study conducted over a year, the increase in red cell
humans, the structure and origins of the molecule would soon production has been shown to continue for up to 8 months and
follow. However, it was not until the discovery of hypoxia result in an increase in red cell mass of 50%.24
inducible factor-1a (HIF-1a), largely as a result of Greg Despite such an enormous change, the increase in haemo-
Semenza’s work in the 1990s, that the agent responsible for globin concentration appears to be even more dramatic during
EPO release was discovered.12 13 Under normoxic conditions, the first few weeks spent at altitude. The reason for this was
HIF-1a has one of the shortest half lives of any normal protein, first identified in 1952 by Lawrence et al who measured changes
binding to the Von Hippel Lindau (VHL) protein inside healthy in the circulation with autologous red cells labelled with
cells before rapidly degrading.14 However, under hypoxic radioactive phosphorous and found that plasma volume fell
conditions HIF-1a resists VHL and instead binds to HIF-1b to shortly after ascending to altitude.25 This was confirmed almost
form HIF.15 This molecule subsequently binds to the EPO gene a decade later by Pugh, the physiologist assigned to the first
on chromosome 7 and stimulates red cell production. In successful expedition to Mt Everest in 1953 and the scientific
Chuvash polycythaemia, a recessive condition common in parts leader of the landmark ‘‘Silver Hut’’ scientific expedition to the
of the former Soviet Union, abnormalities in the VHL protein Khumbu region of Nepal in 1960–126 (fig 2).
prevent HIF-1a from degrading under normoxic conditions.16
The consequences for those with this condition are the same as
those seen in individuals ascending to altitude – an increase in
HIF, EPO and red cell production.
As a protein that is being constantly being produced and
degraded in cells, HIF-1a responds to hypoxia rapidly. Within
an hour of exposure to hypoxia, HIF-1a concentrations peak
and trigger an almost immediate rise in the concentration of
circulating EPO.17 Increases in EPO are strongly related to the
altitude reached, with a rise of 30% at 1900 m compared to
300% at 4500 m.18 Interestingly, absolute values can vary by as
much as +400% to 240% among individuals exposed to 3000 m
over a period of 24 h.19 The reasons for this variation are
unclear, although it is thought that subtle polymorphisms in
the EPO gene may make a significant contribution.20 During a
prolonged stay at altitude, EPO levels continue to rise for up to
3 days before eventually returning to normal after 3 weeks.21
Recently, it has been suggested that this fall may be relative,
with production of EPO remaining high throughout and the
consumption of EPO gradually increasing over the first month Figure 2 The ‘‘Silver Hut’’ expedition, a landmark in high altitude
of exposure. This would result in an apparent fall in EPO research. Photograph courtesy of JB West.

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150 Windsor, Rodway

55 18

Hgb (g/dl)
50 17
Hct (%)
45 16

40 15
0 5 10 15 0 5 10 15
Elapsed time (days) Elapsed time (days)

Figure 3 The mean values of haematocrit (Hct) seen in four mountaineers Figure 4 The mean values of haemoglobin (Hgb) concentration seen in
ascending from 1530 m to advanced base camp (5700 m) on Cho Oyu four mountaineers ascending from 1530 m to advanced base camp
(8201 m). (5700 m) on Cho Oyu (8201 m).

Following 18 weeks above 4000 m, Pugh identified a 21% illnesses, dietary deficiencies, occupation, cigarette smoking
reduction in the plasma volume of four healthy expedition and exposure to fossil fuel smoke. This subsequently allowed
members. However over the following 3 months this deficit the authors to demonstrate that genetic factors accounted for
narrowed and resulted in just a 10% reduction by the end of the more than 85% of the difference between the two groups and
expedition.26 This transient fall in plasma volume has the led them to conclude that the difference was due to Tibetans
potential to provide mountaineers with an important boost undergoing a much longer period of adaptation. Although high
during the first few weeks at altitude. Although volumes of altitude residents have been present in the Altiplano regions of
haemoglobin are only just starting to rise, a sudden reduction the Andes for approximately 9000–12 000 years, the Himalayan
in plasma volume can rapidly increase the concentration of plateau has been populated by humans for more than
haemoglobin and therefore enhance the carriage of oxygen for 50 000 years and it is this difference that has provided
any given volume of blood. Tibetans with a longer period to adapt to hypoxia and
Previously unpublished data from the 2005 Xtreme Everest subsequently develop a lower concentration of haemoglobin.
Expedition to Cho Oyu (8201 m) demonstrate that large A normal haemoglobin concentration is vital for longevity
increases in haematocrit and haemoglobin concentration and is well demonstrated by the huge variance in life
occurred during the 15 day journey from Kathmandu expectancy (42 v 70 years) between those with Chuvash
(,1530 m) to advanced base camp (,5700 m) (figs 3 and 4). polycythaemia and matched controls.16 This enormous differ-
A rapid increase in the concentration of haemoglobin
ence is largely due to the increase in viscosity caused by the
provides mountaineers with a means to compensate for the
high concentration of red cells in the circulation that results in
dramatic fall in arterial oxygen saturation seen at altitude
an increased incidence of heart failure and thrombo-embolic
(table 2).
disease. Over the course of 50 000 years, Tibetan residents have
Although a small increase in haemoglobin would normally be
undergone considerable natural selection that has discouraged
expected over the first few weeks at altitude, the increase in
the survival and reproductive success of those with high
concentration seen here (approximately 2 g/dl) is largely due to
haemoglobin concentrations. By comparison, the Andean
a redistribution of total body water, with fluid being shifted
natives, whose ancestors moved to high altitude relatively
from the circulation and deposited into the interstitial space.
recently, have not yet achieved an equivalent level of adapta-
Unfortunately, the factors responsible for this shift are unclear
tion. This is compounded by the widespread colonisation of
and despite a number of different studies that have examined
the behaviour of the sympathetic nervous system and a range of Andean communities which has led to out-breeding with low
different hormones at altitude, we are still no closer to altitude residents.
explaining this phenomenon. In order to maintain low levels of haemoglobin and still
deliver adequate amounts of oxygen to the tissues, Tibetan
The response of high altitude residents to hypoxia residents have made a unique adaptation. Following exposure
As Viault demonstrated more than a century ago, sea level and to low partial pressures of oxygen, humans respond by
high altitude residents both experience an increase in haemo- increasing the rate and depth of their breathing in order to
globin on ascending to higher altitudes. Although the final ensure adequate oxygenation. Although this hypoxic ventila-
concentration can vary, the increase is largely dependent upon tory response (HVR) varies considerably between humans, a
the altitude reached and the individual’s arterial oxygen pattern has emerged. In a comparison between Tibetan and
saturation.27 Underlying this similarity is the knowledge that Andean high altitude residents, Tibetans have been found to
the structure and function of haemoglobin molecules vary little have a higher HVR and as a consequence an increase in resting
between different ethnic groups. Although the incidence of minute ventilation.32 This would suggest that the blunted HVR
haemoglobinopathies (such as sickle cell disease and b-
thalassaemia) may vary between populations, the behaviour Table 2 Content of oxygen in the blood at 1530 m and at
of HIF, EPO and red cells when exposed to hypoxia is broadly Cho Oyu advanced base camp (5700 m)
similar.1 Despite this, considerable variation exists in the final Day 1: Day 14:
concentration of haemoglobin between different ethnic groups 1530 m 5700 m
resident at moderate altitude. Over the last two decades
Arterial oxygen saturation (SaO2) 95 82
Cynthia Beall and her colleagues have conducted a number of
Haemoglobin concentration (g/dl) 15.2 17.5
meticulous studies comparing the haemoglobin concentrations Oxygen delivered by haemoglobin 19.3 19.2
of residents in Bolivia, Tibet and Ethiopia living at altitudes of to the tissues (ml/100 ml blood)
3500–4000 m29–32 (table 3).
In a comparison between Bolivian and Tibetan residents, Despite a fall in arterial oxygen saturation, the content of oxygen in the
blood remains unchanged at Cho Oyu advanced base camp (5700 m) due
Beale and her colleagues were able to control for a range of to a significant increase in haemoglobin concentration.
potential conflicting factors including concurrent medical

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Height and haematology 151

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Authors’ affiliations 30 Beall CM, Decker MJ, Brittenham GM, et al. An Ethiopian pattern of human
Jeremy S Windsor, Centre for Aviation, Space and Extreme Environment adaptation to high altitude hypoxia. Proc Natl Acad Sci U S A
Medicine (CASE), University College London, London, UK 2002;99(26):17215–8.
George W Rodway, Center for Sleep and Respiratory Neurobiology, 31 Beall CM, Brittenham GM, Strohl KP, et al. Hemoglobin concentration of high-
University of Pennsylvania Schools of Medicine and Nursing, Philadelphia, altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol
USA 1998;106:385–400.
32 Beall CM, Strohl KP, Blangero J, et al. Ventilation and hypoxic ventilatory
Competing interests: None. response of Tibetan and Aymara high altitude natives. Am J Phys Anthrop
1997;104:427–47.
33 Severinghaus JW, Bainton CK, Carcelen C. Respiratory insensitivity to hypoxia in
chronically hypoxic man. Respir Physiol 1966;1:308–34.
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