Hematocrit and Hemoglobin Levels of Nonhuman Apes at Moderate Altitudes: A Comparison with Humans

Abstract

Mortola, Jacopo P. and DeeAnn Wilfong. Hematocrit and hemoglobin levels of nonhuman apes at moderate altitudes: a comparison with humans. High Alt Med Biol. 17:323–335, 2016.—We asked to what extent the hematologic response (increase in hematocrit [Hct] and in blood hemoglobin concentration [Hb]) of humans to altitude hypoxia was shared by our closest relatives, the nonhuman apes. Data were collected from 29 specimens of 7 species of apes at 2073 m altitude (barometric pressure Pb = 598 mm Hg); additional data originated from apes located at a lower altitude (1493 m, Pb = 639 mm Hg). The human altitude profiles of Hct and Hb between sea level and 3000 m were constructed from a compilation of literature sources that (all combined) comprised data sets of 10,000–12,000 subjects for each gender. These human data were binned for 0–250 m altitude (sea level) and for each 500 m of progressively higher altitudes. Values of Hb and Hct of both men and women were significantly higher than at sea level at the 1500 bin (1250–1750 m); hence, the altitude threshold for the human hematological responses must be between 1000 and 1500 m. In the nonhuman apes, no increase in Hct or Hb was apparent at 1500 m; at 2000 m, the increase was significant only for the Hb of females. At either altitude in the group of nonhuman apes, the increase in Hct was much less than in humans, and that of Hb was significantly less at 1500 m. We conclude that lack of, or minimal, hematopoietic response to moderate altitude can occur in mammalian species that are not genetically adapted to high altitudes. Polycythemia is not a common response to altitude hypoxia and, at least at moderate altitudes, the degree of the human response may represent the exception among apes rather than the rule.

Introduction

One of the hallmarks of permanence at high altitudes in humans is the increase in red blood cells or hematocrit (Hct) and in hemoglobin concentration (Hb). This notion, originated by Viault (1890) and Muntz (1891) and expanded by Barcroft et al. (1923) and Hurtado et al. (1945), has found support in a myriad of observations and is comprehensively summarized in many book chapters (e.g., Winslow, 1984; Winslow and Monge, 1987; West, 1998). In fact, studies concerned with any form of human adaptation to high altitude usually include data on the subjects' Hct, Hb, or both as indicators of the polycythemic response to high altitude residence. By comparison with the rich information on humans, nothing is known regarding the closest relatives of our species, the nonhuman apes.

Apes (or Hominoidea) are a small group of primates with morphofunctional features very similar to humans. They consist of two families, the great and the lesser apes (or, respectively, Hominidae and Hylobatidae) with four genera each and, respectively, 6 and 17 species. Homo sapiens is one of the great apes and share an extremely high percentage of DNA base pairs with some members of this group (Hoyer et al., 1972; Britten, 2002; Fujiyama et al., 2002; Prüfer et al., 2012).

The lack of information regarding nonhuman apes at altitude is explained by the fact that humans have been the only apes to spread out and colonize high altitude regions for at least 10,000 years (Aldenderfer, 2003), from the Andean Altiplano of South America to the Tibetan Plateau in Asia and the Ethiopian Highlands in East Africa. Differently, most nonhuman apes have evolved and live at sea level or lowland regions. The only exception is one subspecies of the Eastern gorilla, the Eastern mountain gorilla (Gorilla beringei beringei), which totals less than 1000 individuals in the wild; a small group of these lives in the Virunga National Park of the Democratic Republic of Congo with a habitat range between 2900 and 3700 m altitude (Rothman et al., 2007).

The difference in habitat range between human and nonhuman apes can have multiple explanations, including differences in the physiological mechanisms that permit phenotypic adaptation to sustained hypoxia. The primary goal of this study was to examine to what extent the human hematologic response to altitude hypoxia (increase in Hct and Hb) is shared by nonhuman apes. From what we know mostly on domestic or high altitude species, not all mammals increase hematopoiesis at altitudes by similar amounts.

Earlier studies had shown that rabbits develop an extremely marked polycythemia, while domestic cats do not (Reeves et al., 1963). Steers did not show increased Hct during 2-month permanence at 3800 m (Grover et al., 1963). With respect to wild species, the South American camelids (alpacas, vicuna, llamas) and a few Andean rodents show no or minimal Hct increase at altitudes (Monge and León-Velarde, 1991). Rocky mountain deer mice have higher Hct and Hb than their lowland counterpart, a difference that is not genetically determined, but environmentally driven (Tufts et al., 2013). Other native high altitude rodents, such as the pocket gopher, have Hct and Hb values very similar to their low altitude varieties (Lechner, 1977).

Some species of apes are, or have been, part of the holdings at the Cheyenne Zoo in the outskirts of Colorado Springs (CO); at 2073 m, this zoo is the one most highly located in North America. These specimens offered us a unique opportunity to test the hematopoietic responses of nonhuman apes to altitude hypoxia and the degree of their similarity to humans. Additional data were collected in specimens of the same species resident at a lower location (1493 m) and compared with literature data pertinent to the sea level habitat.

With respect to humans, there is ample evidence that Hct and Hb increase as elevation progresses; in the Andes, Hct values can exceed 70% at 4540 m (Hurtado, 1932) and Hb can reach 20.8 g/dL at 4540 m (Berglund, 1992). What remains unclear is the altitude profile of the hematologic response to moderate altitudes (<3000 m) and whether or not an altitude threshold needs to be reached for Hct or Hb to rise (Beall, 2001; Rojas Jaramillo, 2002). Böning et al. (2001) remarked that despite the fact that the most densely populated HA regions are between 2000 and 3000 m, the threshold for erythropoietic stimulation has only been estimated by interpolation. In fact, the vast majority of human data typically originate from studies at altitudes above 3000 m so that the profile of the human response to moderate altitudes is not firmly established.

Hurtado et al. (1945) combined their own measurements of Hb with those made by four other research groups. As a first approximation, they fitted the data with an exponential function and concluded that Hb continuously increased with altitude since the lowest elevations. The exponential function, however, originated from only five data points above sea level, and only one of these values was below 3500 m. Weil et al. (1968) collected Hct data at 1600 and 3100 m and found that the values differed significantly from sea level at the higher of the two altitudes; from this, they concluded that the arterial oxygen pressure had to decrease below ∼70 mm Hg for a significant hematologic response. Torrance et al. (1970\/71) sampled native adult men at six altitude locations, two of which were below 3000 m; their data (table 2 in Torrance et al., 1970\/71) showed an increase in Hct at the lower of the two locations (1550 m), while Hb increased at the higher one (2240 m). Winslow and Monge (1987) combined their own results with those of other studies and fitted a quadratic equation to the Hb data (Hct was not reported). The equation (fig. 3.3 in Winslow and Monge, 1987) indicated a clear increase in Hb at, and above, 1500 m. None of these studies considered the hematological responses of women.

Winslow and Monge's correlation is the most complete to date; nevertheless, it had only three data points below 3000 m, which do not provide sufficient resolution of the Hct and Hb profiles. Because of the variability of Hct and Hb introduced by differences in age, gender, and duration of the high altitude permanence, definitive functions require a large sample size at numerous altitudes; such comprehensive data compilation is not available. In an attempt to fill this void, and for a meaningful comparison between human and nonhuman apes, the current study comprises two parts. The first presents the Hct and Hb data from specimens of seven species of apes at 2073 m altitude, with additional data from apes located at a lower altitude (1493 m). The second section gathers literature data from more than 50 reports, which, all combined, correspond to a sample size of many thousands of men and women, for the purpose of defining the altitude-Hct and altitude-Hb curves of humans between sea level and 3000 m altitude.

Methods

Nonhuman Apes

Data were obtained from 29 specimens of seven species of nonhuman apes (Fig. 1, species common names in bold fonts). All animals were adults and had been at the Cheyenne Mountain Zoo (Colorado Springs, CO; 2073 m altitude, average barometric pressure, Pb, 598 mm Hg) for many years, except for a female 13-year-old Sumatran orangutan resident at HA for only 3 months. The breakdown of the number of animals by species and gender is indicated in Table 1 (females) and Table 2 (males). Venous blood samples were collected as part of the animal periodic checkup. If the animal had any systemic disease or condition that may have interfered with its hematology profile, the data were disregarded. In some cases, blood was drawn with the animal under sedation or general anesthesia; in others (e.g., orangutan), the animals were trained to provide blood samples from the brachial vein during wakefulness. Only the samples collected during the last few years were collected by one of us (D.W.); all the others were gathered from the data filed over the years.

FIG. 1.

Cladogram of apes. In bold, the species that provided data for the current study.

Table 1.

Females: Hematologic Data of the Nonhuman Apes Studied at 2073 m

Species	N ♀	Age (years)	Weight (kg)	HA permanence (years)	Hct (%) (s.l.)		Hb (g/dL) (s.l.)		References for sea level data
Gibbon, white-handed (Lar) (Hylobates lar)	2	16	6.7	14.8	44.7	(44.0) [62]	14.7	(14.2) [55]	^1,7,9,10
Gibbon, northern white-cheeked (Nomascus leucogenys)	2	27	8.4	17.5	43.0	(43.4) [35]	14.5	(13.9) [27]	¹
Siamang (Hylobates syndactylus)	6	14	8.2	12.8	44.5	(39.1) [42]	12.9	(11.7) [37]	¹
Gorilla, lowland (Gorilla gorilla)	3	21	83.0	20.7	34.7	(37.5) [69]	12.4	(11.8) [58]	^1,3,6–8
Orangutan, Bornean (Pongo pygmaeus)	3	18	83.8	9.0	39.8	(37.6) [97]	11.8	(11.8) [86]	^1,3,5–7
Orangutan, Sumatran (Pongo abelii)	1	13	36	0.3	36.0	(37.6)^a	-	(11.8)^a	^1,3,5–7 ^a
Chimpanzee (Pan troglodytes)	3	20	36.4	12.7	44.0	(42.5) [221]	13.9	(13.8) [216]	^1–4,7,9,11

No sea level data are available for this species; hence, the value is assumed to be like the Orangutan, Bornean.

ISIS (2002); ²Hawkey (1975) and references therein; ³Riegel et al. (1966); ⁴Lee et al. (1995); ⁵McClure et al. (1972a); ⁶Clevenger et al. (1971); ⁷Sedgwick et al. (1967); ⁸McClure et al. (1972b); ⁹Parer (1968); ¹⁰Wu (1997); ¹¹Rhodes (1975).

Hb, hemoglobin; Hct, hematocrit; N, number of specimens; s.l., sea level (in square brackets, the number of specimens).

Table 2.

Males: Hematologic Data of the Nonhuman Apes Studied at 2073 m

Species	N ♂	Age (years)	Weight (kg)	HA permanence (years)	Hct (%) (s.l.)		Hb (g/dL) (s.l.)		References for sea level data
Gibbon, white-handed (Lar) (H. lar)	1	6	3.9	5.7	48.7	(44.1) [41]	17.9	(14.3) [34]	^1,7,9,10
Siamang (H. syndactylus)	3	12	13	9.4	40.3	(43.6) [34]	12.7	(12.8) [31]	¹
Gorilla, lowland (G. gorilla)	2	23	175.5	6.0	42.2	(41.7) [72]	14.8	(13.2) [64]	^1,3,6–8
Orangutan, Sumatran (P. abelii)	2	8	29.5	4.0	41.1	(39.9)^a	13.8	(12.4)^a	^1,5–7 ^a
Chimpanzee (P. troglodytes)	1	2	40.9	1.6	52.3	(42.5) [262]	20.0	(13.6) [257]	^{1,2,4,7,9,11–13}

No sea level data are available for this species; hence, the value is assumed to be that of the Orangutan, Bornean.

ISIS (2002); ²Hawkey (1975) and references therein; ³Riegel et al. (1966); ⁴Wintrobe (1934); ⁵McClure et al. (1972a); ⁶Clevenger et al. (1971); ⁷Sedgwick et al. (1967); ⁸McClure et al. (1972b); ⁹Parer (1968); ¹⁰Wu (1997); ¹¹Hodson et al. (1967); ¹²Lenfant and Aucutt (1969); ¹³Wisecup et al. (1968).

A separate set of data was obtained from the ABQ BioPark Zoo, located in Albuquerque, NM, at 1493 m (average Pb 639 mm Hg). It consisted of Hct and Hb data from 21 specimens of four of the seven species studied at the higher altitude (Table 3); all were adult residents at the altitude for several years.

Table 3.

Hematologic Data of the Species Studied at 1493 m

Species	Gender	N	Age (years)	Weight (kg)	HA permanence (years)	Hct (%)	Hb (g/dL)
Siamang (H. syndactylus)	♀	1	19	14.3	1.5	38.0	11.8
	♂	1	26	13.1	11.8	43.0	13.1
Gorilla, lowland (G. gorilla)	♀	3	18.5	99.5	14.3	34.0	11.1
	♂	4	13.0	120.7	11.3	37.9	11.9
Orangutan, Sumatran (P. abelii)	♀	3	25.8	46.9	18.1	37.4	11.7
	♂	1	31.5	95.7	21.3	38.0	11.6
Chimpanzee (P. troglodytes)	♀	6	15	41.1	6	40.6	13.3
	♂	2	14.8	58.5	6.5	42.5	13.6

Values of Hct and Hb were obtained by, respectively, microcentrifugation and spectrophotometric analysis through an automatic analyzer (Abaxis Vetscan HM5 Veterinary Hematology Blood analyzer, Union City, CA). The number of samples per animal varied from 1 to 6 (on average two/specimen); when more than one sample was available, the results were averaged.

The sea level values for the species investigated were taken from the literature. The primary source was the International Species Information System (2002), a collection of hematology data for veterinarians, separated by gender and age. Several other literature sources were combined (Tables 1 and 2) and a number-weighted average was calculated according to the number of samples provided by each source. For example, if sources 1, 2, …n provided, respectively, average values Avg₁, Avg₂, …Avg_n from sample numbers S₁, S₂, …S_n, the global average was [(Avg₁· S₁)+(Avg₂·S₂)+… (Avg_n·S_n)]/ (S₁+S₂+…S_n); hence, the contribution of the various sources to the final average value of a species was in direct proportion to the sample size of each source.

Humans

All data of Hct and Hb for humans originated from a literature search that targeted residents at altitudes between 0 and 3100 m (Table 4). For the data at sea level (0–250 m), preference was given to sources with large (>100 individuals) sample size or to those that also reported data at the higher altitudes of interest. The massive data set published by the National Center for Health Statistics (Fulwood et al., 1982) could not be used because it averaged data from 64 main collection centers at unspecified US locations and altitudes. Several hematology data date back to the late 19th century (e.g., Vergara, 1896); however, we excluded those before 1910 because of the large variability in methodology and standards (Haden, 1933). Sources that specifically reported on children and young teenagers, elderly, or subjects with less than 3-week permanence at HA were excluded. For all the other studies surveyed, in the absence of the individual ages of the subjects, we assume that the data refer to men and women of reproductive age (∼14 to 45 years of age for women); over this age span, hematologic differences between genders are clear and cannot be overlooked (Hawkins et al., 1954; Grover, 1997).

Table 4.

Literature Summary of Hematocrit and Hemoglobin in Humans at Moderate Altitudes

		Men (N)		Women (N)
Altitude, m (Pb)	Geographical region	Hct (%)	Hb (g/dL)	Hct (%)	Hb (g/dL)	Reference [or source]
−250 (783)	Jordan		14.6 (191)		12.1 (288)	Al-Sweedan and Alhaj (2012)
0 (760)	USA	45.4 (1683)	15.3 (711)			[Hurtado et al. (1945)¹]
0 (760)	USA	45.8 (12)	15.3 (12)			Schmidt et al. (2002)
0 (760)	USA	45.1 (15)				Weil et al. (1968)
0 (760)	Argentina		15.3 (1927)			[Hurtado et al. (1945)²]
0 (760)	Peru		15.7 (100)			Hurtado et al. (1945)
0 (760)	Peru		14.4 (22)			Cossio-Bolanos et al. (2015)
0 (760)	Canada		14.8 (148)		13.1 (143)	Hawkins et al. (1954)¹³
0 (760)	UK		14.9 (316)			[Hurtado et al. (1945)³]
0 (760)	Switzerland		15.0 (224)			[Hurtado et al. (1945)]
0 (760)	India	41.7 (246)	16.0 (121)			[Hurtado et al. (1945)⁴]
0 (760)	Hawaii	44.2 (137)	15.1 (137)			[Hurtado et al. (1945)]
0 (760)	Philippines	43.0 (104)	14.1 (104)			[Hurtado et al. (1945)]
23 (758)	Norway	45.4 (288)	15.5 (288)	41.6 (217)	14.0 (217)	Natvig et al. (1967)
44 (756)	USA				13.8 (83)	Gutowska and Ellms (1946)
47 (756)	Germany	45.9 (14)	15.3 (14)	37.6 (15)	12.9 (15)	Böning et al. (2001, 2004)
77 (753)	Canada				12.0 (1080)	Hawkins et al. (1947)
100 (751)	USA		14.6 (684)		12.4 (604)	Sheets and Barrentine (1944)
104 (751)	USA	46.2 (25)	15.9 (25)	40.4 (25)	13.5 (25)	Belk et al. (1936)
150 (747)	Peru			41.5 (150)	14.0 (150)	Picón-Reátegui et al. (1954)
152 (747)	USA	44.8 (259)	15.8 (153)	41.0 (106)	13.9 (152)	Osgood (1935)
155 (747)	Mexico	49.3 (75)	16.0 (75)	43.9 (128)	14.1 (128)	Ruíz-Argüelles et al. (1980)
183 (744)	USA		16.1 (139)		14.0 (396)	Mirone (1954)
200 (743)	Canada	45.0 (557)	15.3 (557)	40.0 (694)	13.3 (694)	Kelly and Munan (1977) ¹⁰
277 (736)	USA	46.6 (2)	14.9 (2)	40.1 (5)	13.0 (5)	Lewis et al. (1943)
358 (729)	USA	358 (728)			13.2 (150)	Chaloupka et al. (1951)¹⁶
375 (728)	Central America	45.1 (28)	15.05 (28)	41.1 (38)	14.05 (38)	Viteri et al. (1972)⁹
462 (720)	USA			40.9 (4550)	13.4 (4550)	Ohlson et al. (1944)¹⁷
484 (719)	Canada				13.8 (352)	Hawkins et al. (1948)
574 (711)	Austria	47.7 (8)	15.8 (8)			Humpeler et al. (1979)
900 (685)	Venezuela	40.5 (250)	13.7 (250)	39.8 (250)	15.0 (250)	Fernández et al. (2006)⁷
900 (685)	Central Asia	43.7 (77)	14.1 (86)			Fiori et al. (2000)
964 (680)	Colombia			40.6 (14)	13.1 (14)	Böning et al. (2004)
1000 (677)	Mexico	48.1 (122)	15.8 (122)	42.4 (91)	13.8 (91)	Ruíz-Argüelles et al. (1980)
1000 (677)	Columbia	49.0 (10)	16.9 (10)			Schmidt et al. (1990)
1000 (677)	Jordan		15.0 (475)		12.6 (512)	Al-Sweedan and Alhaj (2012)
1125 (667)	Central America	48.1 (9)	16.1 (9)	42.8 (27)	14.0 (27)	Viteri et al. (1972)⁹
1260 (657)	Argentina	47.9 (108)	15.8 (108)	43.2 (49)	14 (49)	Chiodi-Pozzi, (1961)
1524 (637)	USA	48.4 (40)	16.6 (40)	43.2 (40)	14.4 (40)	Andresen and Mugrage (1936)²⁰
1554 (635)	USA		17.5 (5)		13.6 (2)	FitzGerald (1913)
1600 (632)	USA	45.2 (19)				Weil et al. (1968)
1609 (631)	USA	47.8	15.8	43.8	14.5	Myers A, unpublished¹⁵
1609 (631)	USA	48.8 (2)	16.5 (2)	41.8 (5)	13.9 (5)	Lewis et al. (1943)
1609 (631)	Mexico	46.5 (60)	15.7 (60)	40.6 (60)	13.8 (60)	Rodríguez et al. (2007)
1615 (630)	USA	48.3 (95)	16.6 (95)	44.0 (100)	14.8 (100)	Okin et al. (1966)
1725 (622)	South Africa		16.1 (60)			Licknaitzky (1934)²¹
1740 (621)	Austria	47.7 (8)	16.1 (8)			Humpeler et al. (1979)
1750 (621)	South Africa	50.1 (30)	17.8 (30)	45.2 (30)	15.3 (30)	Lurie (1945)
1828 (615)	Ethiopia		14.4		13.2	ICNND (1959)¹⁴
1829 (615)	USA		16.6 (6)		13.8 (2)	FitzGerald (1913)
1860 (613)	Mexico	51.3 (105)	16.8 (105)	45.0 (110)	14.5 (110)	Ruíz-Argüelles et al. (1980)
2000 (603)	Andean		15.32			Frisancho (1988)⁸
2078 (598)	Argentina	50.8 (32)	16.9 (32)			Chiodi-Pozzi, (1961)
2100 (596)	Central Asia	48.1 (109)	16.1 (107)			Fiori et al. (2000)
2131 (594)	USA		18.0 (1)			FitzGerald (1913)
2220 (588)	Mexico	51.5 (75)	17.4 (75)	44.6 (71)	14.6 (71)	Ruíz-Argüelles et al. (1980)
2240 (586)	Mexico	51.3 (403)	16.5 (403)			Vélez-Orozco, (1968)¹¹
2240 (586)	Mexico	51.1 (115)	17.1			Loría et al. (1971)
2240 (586)	Mexico	51.2 (100)	17.7 (100)	45.4 (100)	15.2 (100)	Robles and González (1948)
2240 (586)	Mexico			47.0 (68)	15.9 (68)	Piedras and Loría (1978)
2273 (584)	Mexico		15.5			Ocaranza (1920)⁵
2320 (581)	Peru		16.2 (20)			Cossio-Bolanos et al. (2015)
2327 (581)	Peru	48.7 (90)	16.4 (90)	43.2 (80)	15.1 (80)	Torres and Campos, (1959)
2371 (578)	USA		18.1 (10)		15.8 (6)	FitzGerald (1913)
2400 (576)	Ethiopia	52.7 (25)	16.5 (25)	45.8 (28)	14.4 (28)	Hofvander (1968)²²
2400 (576)	Ethiopia		15.6 (42)			Areskog, unpublished²³
2400 (576)	Ethiopia		16.7 (11)			CNE¹²
2600 (563)	Columbia	49.3 (10)	16.7 (10)			Schmidt et al. (1990)
2600 (563)	USA	48.5 (12)	16.3 (12)			Schmidt et al. (2002)
2600 (563)	Colombia	49.8 (32)	16.6 (32)	43.2 (27)	14.4 (27)	Coy Velandia et al. (2007)
2600 (563)	Colombia	51.9 (15)	17.4 (15)	44.1 (16)	14.4 (16)	Böning et al. (2001, 2004)
2658 (549)	USA			45.1 (3)	15.3 (3)	Lewis et al. (1943)
2664 (558)	Tibet		15.6 (348)		14.0 (174)	Wu et al. (2005)¹⁸
2670 (558)	Mexico	53.0 (74)	17.6 (74)	46.9 (91)	15.3 (91)	Ruíz-Argüelles et al. (1980)
2704 (556)	USA		18.1 (2)			FitzGerald (1913)
2800 (550)	Ecuador	48.0 (1398)	16.6 (1398)	42.6 (1192)	14.5 (1192)	Sáenz et al. (2008)
2800 (550)	Ecuador	49.0 (1600)		44.0 (1600)		CRE (1984–1985)⁶
2896 (544)	USA		18.7 (7)			FitzGerald (1913)
2939 (541)	Argentina	51.1 (45)	16.8 (45)			Chiodi-Pozzi, (1961)
3000 (537)	Andean		16.28			Frisancho (1988)⁸
3075 (532)	USA		19.0 (9)			FitzGerald (1913)
3109 (530)	USA	50.2 (65)	17.7 (65)	45.5 (74)	15.8 (74)	Okin et al. (1966)

From Hurtado et al. (1945) literature summary (Table 1), average of the 11 US studies with at least 100 subjects. ²From Hurtado et al. (1945) literature summary (Table 1), average of five Argentinian studies with at least 100 subjects. ³From Hurtado et al. (1945) literature summary (Table 1), averages of three UK studies with at least 100 subjects. ⁴From Hurtado et al. (1945) literature summary (Table 1), averages of two Indian studies with at least 100 subjects. ⁵Data reported in Table 3 of the study by Robles and González, 1948. ⁶Cruz Roja Ecuatoriana (1984–195), quoted by Sáenz et al. (2008). ⁷Quoted by Sáenz et al. (2008). ⁸From Figure 1, linear equation for people not living in mining areas. ⁹Average of the two age groups 17–49-year-olds from table VI. ¹⁰Average of the 20–50-year-olds. ¹¹Quoted in Loría et al. (1971). ¹²Children's Nutrition Unit, data reported by Hofvander (1968) (table 6). ¹³Data refer to the 20–50-year-olds. ¹⁴ICNND, Ethiopia nutrition survey by the data Interdepartmental Committee on Nutrition for Natural Defense (June 1959) reported by Hofvander, 1968. ¹⁵Unpublished data from Denver, CO, quoted by Treger et al. (1965). ¹⁶Data originated from regions in Nebraska, the average elevation of which is 358 m. ¹⁷Elevation computed as the average of the States that provided data. ¹⁸Data refer to the 16–40-year-olds, a group of Han Chinese origin. ¹⁹Data selected for the 18–20-year-olds. ²⁰For hemoglobin, average of three methodologies. ²¹Data were given in percentage of sea level, which here is assumed to be the average of 0–500 m altitude. ²²Data of professional adults from the authors' table 5. ²³Data reported by Hofvander (1968).

In italics: N, number of subjects; Pb, barometric pressure (mm Hg).

In the end, the survey compiled 50 and 30 data sets for Hct, and 72 and 45 data sets for Hb, for men and women, respectively. The grand total of the number of subjects sampled by all the studies combined was about 10,000 and 12,000 subjects (Hct and Hb, respectively) for men and similar numbers for women (Table 4), and the overwhelming majority of them have been living at the altitude for many years or their entire life. When not specifically indicated by the original source, Pb (mm Hg) at a given altitude (m) was computed according to the formula proposed by Zuntz et al. (1906) for ambient temperature of 20°C, considered more accurate than the standard tables of the International Civil Aviation Organization (ICAO, 1955). At the moderate altitudes considered in this study, the errors introduced by differences in ambient temperature or latitude (West, 1996) have negligible effects on the estimate of Pb.

The data derived from the studies surveyed were averaged in bins for the following seven altitude ranges: 0–250 m (sea level), 250–750, 750–1250, 1250–1750, 1750–2250, 2250–2750, and 2750–3100. Then, the data of each bin were compared statistically with those of the sea level bin by analysis of variance (ANOVA), with post hoc Bonferroni correction. For the purpose of constructing the altitude-Hct and altitude-Hb functions, the data falling within any given bin were averaged; in this way, differences in the number of data points among altitude ranges did not unduly skew the best-fit function as each altitude bin had one single value. The resulting seven data points (one per bin) were fitted by linear regression.

Group data are presented as mean ± 1 SEM. Statistical evaluations of the correlation coefficients and differences between two groups of data (unpaired: humans vs. nonhuman apes at a given altitude; paired: altitude–sea level comparison for the seven species of nonhuman apes) were evaluated by two-tailed t-test. A difference was considered statistically significant at p < 0.05.

Results

Nonhuman apes at 2073 m altitude

Tables 1 and 2 summarize the results of the species studied at 2073 m. The average Hct values of six of the seven species exceeded the corresponding sea level values (Fig. 2, left panel, filled symbols); however, as a group (N = 7), the average difference (42.3% ± 1.3% at altitude versus 40.8% ± 1.0% at sea level) did not reach statistical significance (paired analysis, p = 0.07). Equally, no statistical difference emerged when the two genders were considered separately. The Hb value of the seven species averaged 14 g/dL ± 0.5, significantly higher than the sea level value (12.7 g/dL ± 0.4; paired analysis p < 0.02) (Fig. 2, right panel, filled symbols); the difference was statistically significant in the females (p < 0.05), but not in the males (p = 0.08).

FIG. 2.

Average values of hematocrit (%, left panel) and hemoglobin (g/dL, right panel) for the seven species of nonhuman apes studied at 2073 m (filled symbols) and the four studied at 1493 m (open symbols), plotted against the corresponding sea level values. The oblique lines are the lines of identity. At the lower altitude, the values did not differ significantly from sea level. At the higher altitude, the difference was statistically significant only for hemoglobin. BO, Bornean orangutan; C, Chimpanzee; G, Gorilla; NwG, Northern white-cheeked gibbon; S, Siamang; SO, Sumatran orangutan; WG, White-handed gibbon. The sea level values for the seven species of apes were from Burns et al. (1967); Clevenger et al. (1971); Hawkey (1975) and references therein; Hodson et al. (1967); ISIS (2002); Johnn et al. (1992); Lee et al. (1995); Lenfant and Aucutt (1969); McClure et al. (1972a); McClure et al. (1972b); Parer (1968); Rhodes (1975); Riegel et al. (1966); Sedgwick et al. (1967); Wintrobe (1934); Wisecup et al. (1968); and Wu (1997).

Three of the animals studied had been transferred at altitude after various years at sea level, hence they had Hct or Hb determinations both at sea level and at 2073 m. In the 10-year-old male Sumatran orangutan, the average Hct of 10 samples taken at sea level was 39.4% ± 0.6%; 2 to 4 years after its transfer at altitude the average Hct of five samples was 40.2% ± 1%, not statistically different from sea level. The Hct of a male gorilla resident for 4–5 years at 2073 m was 43.4%, slightly higher than its single value previously taken at sea level (42%). In a female chimpanzee, the two samples taken after 3 to 6 years at altitude (Hct: 44% and 43%, Hb 13 g/dL) were similar to, or lower than, those taken previously at sea level (Hct 42% and 48%, Hb 15.9 g/dL).

Nonhuman apes at 1493 m altitude

The data pertinent to the specimens studied at the lower altitude (1493 m) are summarized in Table 3. None of the Hct or Hb values differed significantly from sea level (paired analysis, p > 0.05), whether genders were considered separately or combined (Fig. 2, open symbols).

Humans

The average values of Hct and Hb of the studies surveyed regarding humans at altitudes up to 3100 m are given in Table 4. The left panels of Figure 3 present the data as a function of barometric pressure (Pb). The panels at the right give the seven data points of the binned data; the best-fit linear regressions for Hct and Hb (heavy lines) were Hct (%) = −0.026Pb +64.41 (♂, r = 0.89), Hct (%) = −0.0215Pb +56.69 (♀, r = 0.89), and Hb (g/dL) = −0.0105Pb +22.89 (♂, r = 0.94), Hb (g/dL) = −0.0087Pb +19.757 (♀, r = 0.99). Between genders, the functions did not differ in slope, while they differed significantly in intercept. Hence, according to these functions, as Pb decreased with altitude, Hct and Hb increased by about 2.5% (Hct) and 1 g/dL (Hb) for every 100 mm Hg drop in Pb, while the differences between genders (∼5% for Hct and 2 g/dL for Hb) remained approximately unaltered over the altitude range considered.

FIG. 3.

Left panels: Literature data (Table 1) of the values of hematocrit (top, %) and hemoglobin (bottom, g/dL) in men (circles, N = 47 and 70) and women (triangles, N = 34 and 47) plotted at the corresponding barometric pressures. Dashed vertical lines indicate altitudes (m) above sea level, at 500 m intervals. Right panels: The data at left were grouped in bins of 500-m progressive altitudes after the first 250 m (sea level). Symbols are bin averages, bars are 1 SEM. Continuous lines represent the best-fit linear regressions and 95% confidence intervals. *Significantly higher than the data points of the first bin (ANOVA, p < 0.05); bins at altitudes higher than the one marked * were significantly different from sea level, while those at lower altitudes were not. ANOVA, analysis of variance.

The linear regressions of Figure 3, although highly significant, did not mean necessarily that Hct and Hb increased progressively from sea level. In fact, by one-way ANOVA, the first bins with Hct or Hb values significantly higher than those at sea level (0–250 m) were the bins covering the 1250–1750 m altitude range (Pb = 658–621 mm Hg range) for both Hct and Hb (Fig. 3, right panels); all the bins at higher altitudes were significantly different from sea level and those at lower altitudes were not.

Comparison between humans and nonhuman apes

In the nonhuman apes, the difference in Hct and Hb between 1493 m and sea level was smaller (p < 0.001 and p < 0.015, respectively) than those of humans at comparable altitudes (∼1500 m, 1250–1750 altitude range) (Fig. 4). At 2073 m, the changes in Hb of the nonhuman apes were similar to those of humans at comparable altitudes (∼2000 m, 1750–2250 altitude range), while the changes in Hct were significantly smaller (p < 0.005). The results remained essentially unaltered whether the altitude–sea level differences were computed from the mean values of each species (Fig. 4, left panels) or from the values of the individual specimens (Fig. 4, right panels).

FIG. 4.

Differences in hematocrit (top panel) and hemoglobin (bottom panel) between the values measured at altitude (∼1500 or ∼2000 m) and at sea level in nonhuman apes (filled columns) and in humans (hatched columns). In the panels at left, the values of nonhuman apes are the averages of the species (4 species at 1500 m and 7 species at 2000 m). In the panels at right, the values of nonhuman apes are the averages of all the individual specimens (21 specimens at 1500 m and 28–29 specimens at 2000 m). Columns are group averages, bars represent 1 SEM. *Significant difference between nonhuman and human apes.

Discussion

The question posed at the onset of the study was whether or not the Hct and Hb responses to altitude hypoxia of our closest relatives, the nonhuman apes, were similar to those of humans. The captive animals at the Cheyenne Zoo, 2073 m altitude, offered a rare opportunity to seek an answer. The comparison with humans proved more difficult than originally anticipated because our information on the human hematologic response is based largely on studies at altitudes above 3000 m. Hence, the interpretation of the animal data required construction of the human altitude profiles for Hct and Hb between sea level and 3000 m. In the end, the data have shown that the average increases in Hct, and partly those in Hb, for the species of apes tested were significantly smaller than in humans.

Humans at moderate altitudes

The compilation of human data (Fig. 3) showed unequivocally that in both genders, Hct and Hb increase with altitude. However, whether the increase should be seen as a continuum from sea level or only from a Pb threshold is unresolved. As mentioned in the Introduction section, the precise definition of the altitude-Hct and altitude-Hb trajectories of previous attempts (Hurtado et al., 1945; Winslow and Monge, 1987) found difficulties in the paucity of data included at moderate altitudes (<3000 m), in addition to the known variability of Hct and Hb among subjects (Vanier et al., 1963; Grover, 1997). Variations in plasma volume (Sánchez et al., 1970), in the arterial oxygen partial pressure (PaO₂), and in the Hb-O₂ affinity are probably the main factors responsible for the intersubject variability in Hct and Hb values. Differences in age and ethnicity could be additional sources of variability, although the former possibility is controversial (Hawkins et al., 1954; Whittembury and Monge, 1972; Chiodi, 1978; Grover, 1997), and the latter, documented for some high altitude populations of Tibet and Ethiopia by comparison with the Andean populations (Monge and León-Velarde, 1991; Beall et al., 2002; Beall, 2007), has not been demonstrated to occur at moderate (<3000 m) altitudes.

If the hematopoietic system were activated by changes in PaO₂ (rather than by changes in O₂ content, CaO₂) (Morikawa and Takubo, 2016), even small drops in Pb should initiate red cell production. However, the overwhelming evidence is that erythropoietin production is activated by a fall in CaO₂, not in PaO₂ (Wenger and Kurtz, 2011). In this case, because of the shape of the hemoglobin-O₂ dissociation curve, the hematologic response to altitude hypoxia is expected to become obvious only with O₂ desaturation, which, in humans, begins at a PaO₂ around 75 mm Hg. What would be the corresponding values of inspired O₂ pressure and altitude depends on the ventilatory response to hypoxia in relation to the metabolic level. We found that the first bins statistically different from sea level were those at 1500 m, hence a Pb threshold could exist somewhere between this and the immediately preceding altitude bin, that is, between 1000 and 1500 m. It is of interest that the drop in birth weight with ascending altitudes, which, like the erythropoietin response, depends on the fall of CaO₂, begins to be apparent at a slightly higher altitude threshold, ∼2000 m (Mortola et al., 2000). The women Hct and Hb functions were remarkably parallel to those of men (Fig. 3, right panels); presumably, therefore, in women, the progesterone stimulation on pulmonary ventilation (Machida, 1981; Bayliss et al., 1987; Lefter et al., 2007) and its effect on PaO₂ and CaO₂ have no measurable impact on the Hct and Hb response to progressive altitudes.

Given the above, our linear fitting through all the Hct and Hb data without consideration of the altitude threshold (Fig. 3) is likely to be an inappropriate description of the altitude profile patterns. However, linear regressions that neglect the possibility of altitude thresholds have practical advantages for the comparison of the hematopoietic response among different groups (e.g., Frisancho, 1988), and for modest altitude ranges, the error would be small. In any case, for the comparison of the Hct and Hb values with the nonhuman apes, rather than the values obtained by extrapolation of the linear functions, we have preferred to consider the actual values at the corresponding altitude bins (1500 and 2000 m).

Nonhuman apes at altitudes

The general message that emerged from the data was that the hematologic response of the nonhuman apes is less compared with humans at the same altitude (Fig. 4). We could sample 31 specimens at 2073 m and 21 specimens at 1493 m altitude. These numbers would be an adequate sample size for most biological studies, but they may not be so for analysis of Hct and Hb, owing to the characteristically large variability of these parameters. However, the conclusion is substantiated by several considerations. Variability typically obfuscates differences between groups (the statistical type II error or failure to reject a false null hypothesis). Hence, had the sample size been too small, we would have expected to find lack of differences rather than differences between groups.

By necessity, within each species, we compared the results of the individuals at altitudes with the values collected on different individuals at sea level. This transversal approach reduced the power of the altitude–sea level comparison, but had the advantage that hematologic data for apes at sea level are abundant; in fact, the sea level values used in this study for the seven species originated from a total of 526 and 479 specimens (for Hct and Hb, respectively, Table 1). Hence, the sea level values, which the high altitude data were compared with, can be considered firmly established.

Finally, three animals studied at 2073 m had previous data at sea level, and the results of their comparison (no changes in two, only 1% increase in Hct in the third one) were qualitatively in line with the conclusions drawn from the whole group. In summary, we feel that the sample size was adequate to reach the general conclusion that the hematological response of the nonhuman apes, as a group, was less than in humans. Differently, the number of specimens was probably too small for meaningful conclusions regarding the individual species. Of the seven species, the one with the largest number of specimens at 2073 m, the Siamang (N = 9), had an average increase in Hb and Hct of, respectively, 0.6 g/dL and 2%; both values were less than half the average response of humans at 2000 m.

Polycythemia is often considered a hallmark of the response to chronic lifelong hypoxia in humans and it increases the blood O₂ capacity up to, or even above, the normoxic level (Winslow and Monge, 1987). However, the disadvantages of the high blood viscosity on cardiac function have been known for long time to the point that the polycythemic response to high altitude hypoxia has been considered maladaptive (Smith and Crowell, 1963; Monge and León Velarde, 1991; Lutz and Storey, 1997). Domestic mammals introduced to the high altitude regions have variable degree of polycythemia, while genotypically adapted mammals, such as Andean rodents and American camelids (alpaca, vicuña, llama), have modest or no increase in Hct (Monge and León Velarde, 1991). These animals do not have a particularly high ventilatory response to hypoxia, but present unusually high Hb affinity for O₂ (or low P50), a characteristic shared by burrowing animals living in conditions of hypoxia, some high altitude carnivores, and other genetically adapted rodents (Monge and León Velarde, 1991; León-Velarde et al., 1996; Ostojic et al., 2002; Storz et al., 2010a, b). No data are available on the hypoxic ventilatory response of the animal species here investigated.

With respect to the Hb affinity for O₂, the P50 values of the gibbon, chimpanzee, gorilla, and orangutan were found to be similar to that of humans, taking into account the body size (allometric) effect, and so were the variations caused by changes in pH (Bohr effect) (Riegel, et al., 1966; Parer and Moore, 1968; Lenfant and Aucutt, 1969; Bartels, 1970). Red cells have large differences in size (Wintrobe, 1934), hence, for the same Hct, small red cells could increase the total surface area for gas exchange and offer a potential form of adaptation to low O₂ availability. However, in all ape species investigated (orangutan, gorilla, chimpanzee, white-handed gibbon), red cell size was observed to be similar to that of humans (Sedgwick et al., 1967).

The only parameter for which we found an increase of almost similar magnitude between animal and human apes was Hb at ∼2000 m (Fig. 4); this could be interpreted as a trend for the hematologic response of the nonhuman apes to become similar to that of humans at altitudes higher than the ones here considered. Such possibility is unlikely to be resolved in the field because nonhuman apes resident at very high altitudes are almost nonexistent; nevertheless, the present data cannot differentiate between a blunted hematologic response and a response shifted at lower values of Pb.

Conclusions and perspective

These results expand on the common concept that a small hematological response to high altitude is a characteristic of genetically adapted animals. Rather, by indicating that also our closest relatives have minimal responses, they raise the question of why the human hematological adaptation is unusually marked among apes. At present, any answer can only be hypothetical. Humans are unique among Hominoidea to have colonized high altitude regions (with the sole exception of a small group of Eastern gorillas, mentioned in the Introduction section, for which no hematology data are available). Presumably, the increase in O₂-carrying capacity has been an advantage for the rapid, in evolutionary terms, colonization of the high altitude Andean, North American, and European regions.

However, some ethnic groups of humans (Ethiopians and Tibetans) do not show the same degree of polycythemia of the majority of highlanders (Beall et al., 2002; Beall, 2007); in addition, the variability apparent in Figure 2 indicates that many human residents at high altitudes increase Hct and Hb much less than the population average. This means that at least at moderate altitudes, polycythemia is one mechanism, but by no means a universal one, for altitude adaptation; in fact, among apes, its occurrence to the degree manifested by humans appears to be the exception rather than the rule.

Footnotes

Acknowledgments

Several people have made possible in various ways the gathering of the data of the nonhuman apes presented in this study. In particular, the authors wish to thank Brigitte Mercier and Marie-Josée Limoges (Valley Zoo Veterinary Hospital, Edmonton, AB, Canada) for valuable suggestions and Erminia Ricci, Gwen Dragoo, and the personnel of the ABQ Biopark (Albuquerque, NM) for their major contribution to data collection.

Author Disclosure Statement

No competing financial interests exist.

References

Aldenderfer

. (2003). Moving up in the world. Am Sci, 91:542–549.

Al-Sweedan

, and Alhaj

. (2012). The effect of low altitude on blood count parameters. Hematol Oncol Stem Cell Ther, 5:158–161.

Andresen

, and Mugrage

. (1936). Red blood cell values for normal men and women. Arch Int Med, 58:136–146.

Barcroft

, Binger

, Bock

, Doggart

, Forbes

, Harrop

, Meakins

and Redfield

. (1923). Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Cerro de Pasco. Philos Trans R Soc Lond B, 211:351–480.

Bartels

. (1970). The respiratory function of primate blood. Primate News, 8:4–7.

Bayliss

, Millhorn

, Gallman

, and Cidlowski

. (1987). Progesterone stimulates respiration through a central nervous system steroid receptor-mediated mechanism in cat. Proc Natl Acad Sci U S A, 84:7788–7792.

Beall

. (2001). Adaptations to altitude: A current assessment. Annu Rev Anthropol, 56:423–456.

Beall

. (2007). Two routes of functional adaptation: Tibetan and Andean high-altitude natives. Proc Nat Acad Sci, 104:8655–8660.

Beall

, Decker

, Brittenham

, Kushner

, Gebremedhin

, and Strohl

. (2002). An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Nat Acad Sci U S A, 99:17215–17218.

10.

Belk

, Curtis

, and Wilson

. (1936). Erythrocyte counts, hemoglobin, and erythrocyte volume in normal young men and women residing in the eastern United States. Am J Clin Path, 6:487–496.

11.

Berglund

. (1992). High-altitude training. Aspects of haematological adaptation. Sports Med, 14:289–303.

12.

Böning

, Cristancho

, Serrato

, Reyes

, Mora

, Coy

, and Rojas

. (2004). Hemoglobin mass and peak oxygen uptake in untrained and trained female altitude residents. Int J Sports Med, 25:561–568.

13.

Böning

, Rojas

, Serrato

, Ulloa

, Coy

, Mora

, Gomez

, and Hütler

. (2001). Hemoglobin mass and peak oxygen uptake in untrained and trained residents of moderate altitude. Int J Sports Med, 22:572–578.

14.

Britten

. (2002). Divergence between samples of chimpanzee and human DNA sequences is 5% counting indels. Proc Nat Acad Sci U S A, 99:13633–13635

15.

Burns

, Ferguson

, and Hampton

. (1967). Compendium of normal blood values for baboons, chimpanzees, and marmosets. Amer J Clin Pathol, 48:484–494.

16.

Chaloupka

, Leverton

, and Diedrichsen

. (1951). Serum iron and hemoglobin values of 275 healthy women. Proc Soc Exper Biol Med, 77:677–680.

17.

Chiodi

. (1978). Aging and high-altitude polycythemia. J Appl Physiol, 45:1019–1020.

18.

Chiodi

, and Pozzi

. (1961). Hematic values in residents at high altitudes between 1260 m and 4515 m above sea level. Acta Physiol Lat Am, 11:51–59.

19.

Clevenger

, Marsh

, and Peery

. (1971). Clinical laboratory studies of the gorilla, chimpanzee, and orangutan. Am J Clin Pathol, 55:479–488.

20.

Cossio-Bolanos

, Gómez-Campos

, Lee Andruske

, Olivares

, Santi-Maria

, Lazari

, Luarte Rocha

, and de Arruda

. (2015). Hemoglobin concentration and resilience of professional soccer players residing at sea level and moderate altitude regions. J Exerc Physiol Online, 18:76–84.

21.

Coy Velandia

, Castilo Bohórquez

, Mora

, Munevar

, and Peña

. (2007). Características hematológicas de donantes de sangre de Bogotá, D.C., Colombia (2600 m). Rev Med, 15:40–47.

22.

Fiori

, Facchini

, Ismagulov

, Ismagulova

, Tarazona-Santos

, and Pettener

. (2000). Lung volume, chest size, and hematological variation in low-, medium-, and high-altitude central Asian populations. Am J Phys Anthropol, 113:47–59.

23.

FitzGerald

. (1913) The changes in the breathing and the blood at various high altitudes. Phil Trans R Soc London B, 203:351–371.

24.

Frisancho

. (1988). Origins of differences in hemoglobin concentration between Himalayan and Andean populations. Respir Physiol, 72:13–18.

25.

Fujiyama

, Watanabe

, Toyoda

, Taylor

, Itoh

, Tsai

, Park

, Yaspo

, Lehrach

, Chen

, Fu

, Saitou

, Osoegawa

, de Jong

, Suto

, Hattori

, and Sakaki

. (2002). Construction and analysis of a human-chimpanzee comparative clone map. Science, 295:131–134.

26.

Fulwood

, Johnson

, Bryner

, et al. (1982). National Center for Health Statistics. Hematological and nutritional biochemistry reference data for persons 6 months-74 years of age: United States, 1976–1980. Viral and Health Statistics. Series 11-No. 232. Public Health Service. Washington. U.S. Government Printing Office, Library of Congress Cataloging in Publication Data, pp. 1–174.

27.

Grover

. (1997). Thick blood with thin air: Who needs it? In: Hypoxia–Women at Altitude. Houston

and Coates

, eds. Queen City Printers, Burlington, VT, Chapter 22. pp. 177–185.

28.

Grover

, Reeves

, Will

, and Blount

. (1963). Pulmonary vasoconstriction in steers at high altitude. J Appl Physiol, 18:567–574.

29.

Gutowska

, and Ellms

. (1946). Nutritional status of women students. J Am Diet Ass, 22:763–765.

30.

Haden

. (1933). Hemoglobin standards. Am J Clin Path, 3:85–95.

31.

Hawkey

. (1975). Comparative Mammalian Haematology. Cellular Components and Blood Coagulation of Captive Wild Animals. William Heinemann Medical Books, London, UK, p. 310.

32.

Hawkins

, Barsky

, and Collier

. (1948). Haemoglobin levels among Saskatchewan College women. Can Med Ass J, 58:161–162.

33.

Hawkins

, Leeson

, and McHenry

. (1947). Haemoglobin levels in Canadian population groups: Children and young women. Can Med Ass J, 56:502–505.

34.

Hawkins

, Speck

, and Leonard

. (1954). Variation of the haemoglobin level with age and sex. Blood, 9:999–1007.

35.

Hodson

, Lee

, Wisecup

, and Fineg

. (1967). Baseline blood values of the chimpanzee. I. The relationship of age and sex and hematological values. Folia Primat, 7:1–11.

36.

Hofvander

. (1968). Hematological values in healthy and apparently healthy subjects of different ages in Addis Ababa, 2400 m above sea level. Acta Med Scand, 494 (Suppl):17–34.

37.

Hoyer

, van de Velde

, Goodman

, and Roberts

. (1972). Examination of hominid evolution by DNA sequence homology. J Human Evol, 1:645–649.

38.

Humpeler

, Inama

, and Deetjen

.(1979). Improvement of tissue oxygenation during a 20 days-stay at moderate altitude in connection with mild exercise. Klin Wochenschr, 57:267–272.

39.

Hurtado

. (1932). Studies at high altitude. Blood observations on the Indian natives of the Peruvian Andes. Am J Physiol, 100:487–504.

40.

Hurtado

, Merino

, and Delgado

. (1945). Influence of anoxemia on the hemopoietic activity. Arch Int Med, 75:284–323.

41.

ICAO. (1955). Report 1235-Standard atmosphere-tables and data for altitudes to 65,800 feet International Civil Aviation Organization. Montreal, Canada, and Langley Aeronautical Laboratory, Langley Field, NACA (National Advisory Committee for Aeronautics) 41:719–834.

42.

ISIS (International Species Information System). (2002). Physiological data reference values. Teare

, ed., Apple Valley, MN 55124.

43.

Johnn

, Phipps

, Gascoyne

, Hawkey

, and Rampling

. (1992). A comparison of the viscometric properties of the blood from a wide range of mammals. Clin Hemorheol, 12:639–647.

44.

Kelly

, and Munan

. (1977). Haematologic profile of natural populations: Red cell parameters. Brit J Haematol, 35:153–160.

45.

Lechner

. (1977). Metabolic performance during hypoxia in native and acclimated pocket gophers. J Appl Physiol, 43:965–970.

46.

Lee

W-M

, Chou

S-R

, Shyu

C-L

, and Tung

K-C

. (1995). The hematology and blood-chemistry of orangutan under artificial feeding environment. J Chin Soc Vet Sci, 21:160–168.

47.

Lefter

, Morency

, and Joseph

. (2007). Progesterone increases hypoxic ventilatory response and reduces apneas in newborn rats. Respir Physiol Neurobiol, 156:9–16.

48.

Lenfant

, and Aucutt

. (1969). Respiratory properties of the blood of five species of monkeys. Respir Physiol, 6:284–291.

49.

León-Velarde

, de Muizon

, Palacios

, Clark

, and Monge-C

. (1996). Hemoglobin affinity and structure in high-altitude and sea-level carnivores from Peru. Comp Biochem Physiol A, 113:407–411.

50.

Lewis

, Iliff

, Duval

, and Kinsman

. (1943). The effect of change of altitude on the blood of human subjects. J Lab Clin Med, 28:860–866.

51.

Licknaitzky

. (1934). The red cell and haemoglobin content of the blood in young male adults living on the Witwatersrand. Quart J Exp Physiol, 24:161–167.

52.

Loría

, Piedras

, Labardini

, and Sánchez Medal

. (1971). Anemia nutricional. I. Valores de serie roja en varones adultos sanos residentes a 2240 metros sobre el nivel del mar. Rev Invest Clín, 23:3–9.

53.

Lurie

. (1945). Normal haematological standards at an altitude of 5740 feet (Witwatersrand, South Africa). Quart J Exp Physiol Cogn Med Sci, 33:91–105.

54.

Lutz

, and Storey

. (1997). Adaptations to variations in oxygen tension by vertebrates and invertebrates. In: Handbook of Physiology. Comparative Physiology. Dantzler

, ed. Oxford University Press, Oxford. pp. 1479–1522 [reprinted in Comprehensive Physiol. 2011].

55.

Machida

. (1981). Influence of progesterone on arterial blood and CSF acid-base balance in women. J Appl Physiol, 51:1433–1436.

56.

McClure

, Keeling

, and Guilloud

. (1972a). Hematologic and blood chemistry data for the orangutan (Pongo pygmaeus). Folia Primat, 18:284–299.

57.

McClure

, Keeling

, and Guilloud

. (1972b). Hematologic and blood chemistry data for the Gorilla (Gorilla gorilla). Folia Primat, 18:300–316.

58.

Mirone

. (1954). Hemoglobin level and dietary intake of adults. Am J Clin Nutr, 2:38–42.

59.

Monge

, and León-Velarde

. (1991). Physiological adaptation to high altitude: Oxygen transport in mammals and birds. Physiol Rev, 71:1135–1172.

60.

Morikawa

, and Takubo

. (2016). Hypoxia regulates the hematopoietic stem cell niche. Eur J Physiol, 468:13–22.

61.

Mortola

, Frappell

, Aguero

, and Armstrong

. (2000). Birth weight at altitude: A study in Peruvian communities. J Pediatr, 136:324–329.

62.

Muntz

. (1891). De l'enrichissement du sang en homoglobine, suivant les conditions d'existence. C R Acad Sci Paris, 112:298–301.

63.

Natvig

, Vellar

, and Andersen

. (1967). Studies on hemoglobin values in Norway. VII. Hemoglobin, hematocrit and MCHC values among boys and girls aged 7–20 years in elementary and grammar schools. Acta Med Scand, 182:183–191.

64.

Ohlson

, Cederquist

, Donelson

, Leverton

, Kinsman Lewis

, Armstrong Himwich

, and Reynolds

. (1944). Hemoglobin concentrations, red cell counts and erythrocyte volumes of college women of North Central states. Am J Physiol, 142:727–732.

65.

Okin

, Treger

, Overy

, Weil

, and Grover

. (1966). Hematologic response to medium altitude. Rocky Mount Med J, 63:44–47.

66.

Osgood

. (1935). Normal hematologic standards. Arch Int Med, 56:849–863.

67.

Ostojic

, Cifuentes

, and Monge

. (2002). Hemoglobin affinity in Andean rodents. Biol Res, 35:27–30.

68.

Parer

, and Moore

. (1968). Respiratory characteristics of the blood of the Baboon, Gibbon and Chimpanzee. Folia Primat, 9:154–159.

69.

Picón-Reátegui

, Merino

, Febres

, and Hurtado

. (1954). Etudios hematologicos en mujeres adultas sanas. Ann Fac Med Lima, 37:628–645.

70.

Piedras

, and Loría

. (1978). Anemia nutricional. VII. Valores de serie roja en mujer nuliparas sanas residentes a 2,240 metros sobre el nivel del mar. Rev Invest Clin (Mexico), 30:241–246.

71.

Prüfer

, Munch

, Hellmann

, Akagi

, Miller

, Walenz

, Koren

, Sutton

, Kodira

, Winer

, Knight

, Mullikin

, Meader

, Ponting

, Lunter

, Higashino

, Hobolth

, Dutheil

, Karakoc

, Alkan

, Sajjadian

, Catacchio

, Ventura

, Marques-Bonet

, Eichler

, Andre

, Atencia

, Mugisha

, Junhold

, Patterson

, Siebauer

, Good

, Fischer

, Ptak

, Lachmann

, Symer

, Mailund

, Schierup

, Andres

, Kelso

, and Paabo

. (2012). The bonobo genome compared with the chimpanzee and human genomes. Nature, 486:527–531.

72.

Reeves

, Grover

, and Grover

. (1963). Circulatory response to high altitude in the cat and rabbit. J Appl Physiol, 18:575–579.

73.

Rhodes

. (1975). Biochemical profiles in exotic captive animals. Proc Am Ass Zoo Vet. 81–111.

74.

Riegel

, Bartels

, Kleihauer

, and Lang

. (1966). Comparative studies of the respiratory function of mammalian blood. I. Gorilla, chimpanzee and orangutan. Respir Physiol, 1:138–144.

75.

Robles

, and González

. (1948). Determination of the number of erythrocytes, volume of packed red cells, hemoglobin and other hematologic standards in Mexico City (altitude 7457 feet). Study made on two hundred healthy persons. Blood, 3:660–681.

76.

Rodríguez

, Schlottfeldt

, Vela

, Inchaustegui

, Herrera

, and Rosales

. (2007). Intervalos de confianza de la fórmula eritrocítica en habitantes adultos de la ciudad de Comitán de Domínguez (Chiapas, México). Hig Sanid Ambient, 7:270–275.

77.

Rojas Jaramillo

. (2002). Aspectos fisiológicos en la adaptación a la hipoxia altitudinal. Acta Biol Colom, 7:5–16.

78.

Rothman

, Plumptre

, Dierenfeld

, and Pell

. (2007). Nutritional composition of the diet of the gorilla (Gorilla beringei): A comparison between two montane habitats. J Trop Ecol, 23:673–682.

79.

Ruíz-Argüelles

, Sánchez-Medal

, Loría

, Piedras

, and Córdova

. (1980). Red cell indices in normal adults residing at altitude from sea level to 2670 meters. Am J Hematol, 8:265–271.

80.

Sáenz

, Narváez

, and Cruz

. (2008). Valores de referencia hematológicos en población altoandina ecuatoriana. Rev Mex Patol Clin, 55:207–215.

81.

Sánchez

, Merino

, and Figallo

. (1970). Simultaneous measurement of plasma volume and cell mass in polycythemia of high altitude. J Appl Physiol, 28:775–778.

82.

Schmidt

, Dahnners

, Correa

, Ramírez

, Rojas

, and Böning

. (1990). Blood gas transport properties in endurance-trained athletes living at different altitudes. Int J Sports Med, 11:15–21.

83.

Schmidt

, Heinicke

, Rojas

, Gomez

, Serrato

, Mora

, Wolfarth

, Schmid

, and Keul

. (2002). Blood volume and hemoglobin mass in endurance athletes from moderate altitude. Med Sci Sports Exerc, 34:1934–1940.

84.

Sedgwick

, Simpson

, and Schalm

. (1967). Clinical hematology in zoo animals. I. Hemograms. Am J Vet Clin Path, 1:105–114.

85.

Sheets

, and Barrentine

. (1944). Hemoglobin concentration and erythrocyte counts of the blood of college men and women. J Am Diet Ass, 20:521–523.

86.

Smith

, and Crowell

. (1963). Influence of hematocrit ratio on survival of unacclimatized dogs at simulated high altitude. Am J Physiol, 205:1172–1174.

87.

Storz

, Runck

, Moriyama

, Weber

, and Fago

. (2010a). Genetic differences in hemoglobin function between highland and lowland deer mice. J Exp Biol, 213:2565–2574.

88.

Storz

, Scott

, and Cheviron

(2010b). Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. J Exp Biol, 213:4125–4136.

89.

Torrance

, Lenfant

, Cruz

, and Marticorena

. (1970/71). Oxygen transport mechanisms in residents at high altitude. Respir Physiol, 11:1–15.

90.

Torres

, and Campos

. (1959). Valores hematológicos en hombres y mujeres sanos residentes en Arequipa. An Fac Med, 41:38–61.

91.

Treger

, Shaw

, and Grover

. (1965). Secondary polycythemia in adolescents at high altitude. J Lab Clin Med, 66:304–314.

92.

Tufts

, Revsbech

, Cheviron

, Weber

, Fago

, and Storz

. (2013). Phenotypic plasticity in blood-oxygen transport in highland and lowland deer mice. J Exp Biol, 216:1167–1173.

93.

Vanier

, Dulfano

, Wu

, and Desforges

. (1963). Emphysema, hypoxia and the polycythemic response. N Engl J Med, 269:169–178.

94.

Vergara

. (1896). La hematolgia de las altitudes en sus relaciones con la clínica y la terapèutica. Rev Quinc Anat Patol Clin Med Quirurg, 1:23–53.

95.

Viault

. (1890). Sur l'augmentation considerable du nombre des globules rouges dans le sang chez les habitants des hauts plateaux de l'Amérique du Sud. C R S Acad Sci, 111:917–918.

96.

Viteri

, De Tuna

, and Guzmán

. (1972). Normal hematological values in the Central American population. Br J Haematol, 23:189–204.

97.

Weil

, Jamieson

, Brown

, Grover

, Balchum

, and Murray

. (1968). The red cell mass-arterial oxygen relationship in normal man—application to patients with chronic obstructive airway disease. J Clin Invest, 47:1627–1639.

98.

Wenger

, and Kurtz

. (2011). Erythropoietin. Compr Physiol, 1:1759–1794.

99.

West

. (1996). Prediction of barometric pressures at high altitudes with the use of model atmospheres. J Appl Physiol, 81:1850–1854.

100.

West

. (1998). High Life. A History of Haigh-Altitude Physiology and Medicine. Oxford University Press, New York, NY. p. 493.

101.

Whittembury

, and Monge

. (1972). High altitude, hematocrit, and age. Nature (London), 238:278–279.

102.

Winslow

. (1984). High altitude polycythemia. In: High Altitude and Man. West

, ed. Springer, New York. Chapter 14. pp. 163–172.

103.

Winslow

, and Monge

. (1987). Hypoxia, Polycythemia, and Chronic Mountain Sickness. Johns Hopkins University Press, Baltimore, MD. p. 255.

104.

Wintrobe

. (1934). Variation in the size and hemoglobin content of erythrocytes in the blood of various vertebrates. Folia Haemat, 51:32–49.

105.

Wisecup

, Hodson

, Lovett

, Prine

, and Hanly

. (1968). Anemia in chimpanzees (Pan troglodytes) resulting from serial collection of blood. Am J Vet Res, 29:1823–1830.

106.

, Wang

, Wei

, Cheng

, Wang

, Li

, Dong

, Zhao

, Young

, Li

, and Wang

. (2005). Hemoglobin levels in Qinghai-Tibet: Different effects of gender for Tibetans vs. Han. J Appl Physiol, 98:598–604.

107.

Y-H

. (1997). Preventive medical examinations and medical reference values of the gibbon. J Chin Soc Vet Sci, 23:350–367.

108.

Zuntz

., Loewy

., Müller

, and Caspari

. (1906). Höhenklima und Bergwanderungen in ihrer Wirkung auf den Menschen. Bong, Berlin. pp. 37–39.