Received: 15 January 2021 Accepted: 1 March 2021

DOI: 10.1113/EP089409

REVIEW ARTICLE

The effect of microgravity on the human venous system and

blood coagulation: a systematic review

David S. Kim1,2 Sergi Vaquer1,3 Lucia Mazzolai4 Lara N. Roberts5

James Pavela6 Manabu Watanabe7 Guillaume Weerts1 David A. Green1,3,8

1
Space Medicine Team, European Astronaut
Centre, European Space Agency (ESA), Abstract
Cologne, Germany
Recently, an internal jugular venous thrombus was identified during spaceflight,
2
Department of Emergency Medicine,
but whether microgravity induces venous and/or coagulation pathophysiology, and
University of British ColumbiaBritish
Columbia, Vancouver, Canada thus, an increased risk of venous thromboembolism (VTE) is unclear. Therefore,
3
KBR, WyleLabs GmbH, Cologne, Germany a systematic (Cochrane compliant) review was performed of venous system or
4
Angiology division, Heart and Vessel coagulation parameters in actual spaceflight (microgravity) or ground-based analogues
Department, Lausanne University Hospital
(CHUV), Lausanne, Switzerland in PubMed, MEDLINE, Ovid EMBASE, Cochrane Library, European Space Agency,
5
Department of Haematological Medicine, National Aeronautics and Space Administration, and Deutsches Zentrum für Luft-
King’s Thrombosis Centre, King’s College und Raumfahrt databases. Seven-hundred and eight articles were retrieved, of which
Hospital NHS Foundation Trust, London, UK
6
26 were included for evaluation with 21 evaluating venous, and five coagulation
Department of Preventive Medicine and
Population Health, University of Texas Medical parameters. Nine articles contained spaceflight data, whereas the rest reported
Branch, Galveston, TX, USA
ground-based analogue data. There is substantial variability in study design, objectives
7
Japan Aerospace Exploration Agency,
and outcomes. Yet, data suggested cephalad venous system dilatation, increased
Tsukuba, Japan
8
Centre of Human and Applied Physiological
venous pressures and decreased/reversed flow in microgravity. Increased fibrinogen
Sciences, King’s College London, London, UK levels, presence of thrombin generation markers and endothelial damage were also
reported. Limited human venous and coagulation system data exist in spaceflight, or its
Correspondence
David Andrew Green, European Astronaut analogues. Nevertheless, data suggest spaceflight may induce an enhanced coagulation
Centre, European Space Agency, Cologne,
state in the cephalad venous system, as a consequence of changes in venous
D-51147, Germany
Email: david.green@esa.int flow, distension, pressures, endothelial damage and possibly hypercoagulability.
Whether such changes precipitate an increased VTE risk in spaceflight remains to be
Edited by: Jeremy Ward
determined.

KEYWORDS
coagulation, microgravity, spaceflight, thromboembolism, venous system

1 INTRODUCTION case was reported following retrospective analysis of the other 10

A recent research study performing ultrasonic evaluation of jugular
venous flow reported the incidental finding of an obstructive left
internal jugular venous thrombus in an astronaut during spaceflight
(Marshall-Goebel et al., 2019). Furthermore, an additional suspected
crew members who participated in the study. The potential for a fatal
venous thromboembolism (VTE) in such a highly selected low-risk
population (due to intensive medical screening of crew members) led
to the re-evaluation of the current risk management protocols, and to
an international initiative to better understand the pathophysiology

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2021 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

Experimental Physiology. 2021;106:1149–1158. wileyonlinelibrary.com/journal/eph 1149

1150
of this potentially ‘new’ hazard of spaceflight and its implications for
future exploration of space.
Terrestrially, the three factors that contribute to VTE development
are summarized by the Triad of Virchow: hypercoagulability, blood
stasis and vessel wall injury (Kumar et al., 2010). Any congenital
or acquired state that induces vessel wall injury or a reduced
blood flow state can promote thrombosis. As normal haemostasis is
characterized by a balance between pro- and anti-coagulant pathways,
any haemostatic imbalance towards hypercoagulability may result in
thrombotic disease.
However, it is unclear how the space environment affects
the components of Virchow’s Triad, and whether physiological
adaptations that occur in spaceflight (i.e., microgravity) modulate
the pathophysiology of VTE (Arbeille et al., 2015; Foldager et al.,
1996; Fortrat et al., 2017) since no single study has defined this, or
even the relative risk of VTE (Arbeille et al., 2015; Foldager et al.,
1996; Fortrat et al., 2017). Furthermore, given the inability to provide
rapid gold-standard terrestrial medical care in space, it is imperative
to understand potential pathophysiological changes that may pre-
cipitate elevated VTE risk in spaceflight in order to devise preventive,
diagnostic and/or mitigation strategies (Longo et al., 2019).
Thus, the aim of this systematic review was to evaluate the available
literature investigating venous physiology and coagulation in ground-
based analogues and actual microgravity in order to provide an over-
view of potential pathophysiological processes that may underlie VTE
in spaceflight.
2 METHODS
We performed a systematic search of available published literature in
accordance with the Cochrane guidelines (Higgins & Thomas, 2019).
Databases used in the search were PubMed, MEDLINE, Ovid EMBASE,
Cochrane Library and three space agency databases (Internal research
archives for European Space Agency (ESA), National Aeronautics and
Space Administration (NASA) and Deutsches Zentrum für Luft- und
Raumfahrt (DLR)). Standard methods for searching were employed
using keywords with Boolean operators (AND, OR, NOT, *, “”), MeSH
terms and combination of search terms (e.g., #1 AND #2), the main
ones being ‘venous system’ or ‘coagulation’ in combination with ‘micro-
gravity’. The search was performed in August 2020 according to the
strategy defined in Table 1. A modified search strategy was utilized
using main keywords from each of the categories from ‘Reduced
gravity’, ‘Venous system’ and ‘Coagulation’ for its query as it was not
possible to employ Boolean logic when searching the space agencies’
databases.
2.1 Study selection, data extraction and reporting
The standard PICO (population, intervention, control, outcomes)
eligibility criteria were employed (P: humans; I: microgravity or micro-
gravity analogues; C: same population without the intervention; O:
KIM ET AL .
New Findings
∙ What is the central question of this study?
Recently, an internal jugular venous thrombus
was identified during spaceflight: does micro-
gravity induce venous and/or coagulation
pathophysiology, and thus an increased risk of
venous thromboembolism (VTE)?
∙ What is the main finding and its importance?
Whilst data are limited, this systematic review
suggests that microgravity and its analogues may
induce an enhanced coagulation state due to
venous changes most prominent in the cephalad
venous system, as a consequence of changes in
venous flow, distension, pressures, endothelial
damage and possibly hypercoagulability in micro-
gravity and its analogues. However, whether such
changes precipitate an increased VTE risk in
spaceflight remains to be determined.
molecular/biochemical/cellular or clinical responses with respect to
venous or coagulation physiology) (Schardt et al., 2007). Studies
assessing molecular/biochemical/cellular or clinical responses with
respect to venous system or coagulation on humans or animals, and
in microgravity or microgravity analogues were selected. All studies
were then imported into the open-source Rayyan software (Web
Rayyan QCRI) and screened using the defined PICO criteria (Ouzzani
et al., 2016). Following exclusion based on title and abstract of any
non-relevant studies, a full text version of all remaining articles was
obtained and assessed.
For the final included articles, relevant data were extracted using
a modified version of Cochrane’s Effective Practice and Organisation
of Care (EPOC). Articles were categorized into either microgravity or
its ground-based analogue (head down tilt (HDT), head down bedrest
(HDBR) and dry immersion (DI)) based articles, and then further sub-
divided into venous system or coagulation outcomes. In addition,
the bibliographies of the final articles were screened to identify any
potential studies that may not have been included in the original
search.
3 RESULTS
The results of the search yielded 708 articles, of which 20 were
duplicates (Figure 1). The remaining 688 articles were screened using
the title and abstract, leading to the exclusion of 595. Following full
text retrieval and subsequent screening of the remaining 93 articles,
26 were selected for final data evaluation and synthesis. Upon review
KIM ET AL . 1151

TA B L E 1 Boolean search terms and search strategy

Main category Specific category Keywords in Boolean search format Search number Search mask
reduced gravity Microgravity ‘microgravity’ OR ‘spaceflight’ OR ‘hypogravity’ OR ‘reduced 1 Abstract/title
gravity’ OR ‘zero gravity’ OR ‘weightlessness’ OR ‘micro-G’
OR ‘space analogue’ OR ‘low gravity’ OR ‘bedrest’ OR
‘zero-G’ OR ‘neutral buoyancy’ OR ‘water immersion’ OR
‘head down tilt’ OR ‘microgravity analogue’
Responses Venous system ‘venous system’ OR ‘venous physiology’ OR ‘venous 2 Abstract/title
pathology’ OR ‘venous function’ OR ‘venous flow’ OR
‘venous pathology’ OR ‘venous pathophysiology’ OR
‘venous disease’ OR ‘venous pressure’ OR ‘venous
circulation’ OR ‘venous hemodynamics’ OR ‘vessel damage’
OR ‘vessel injury’
Coagulation ‘coagulation’ OR ‘clotting’ OR ‘coagulation cascade’ OR 3 Abstract/title
‘hemostasis’ OR ‘haemostasis’ OR ‘thrombosis’ OR
‘thrombus’ OR ‘coagulopathy’ OR ‘thromboembolism’
#2 OR #3 4
Population Inclusion criteria ‘humans’ OR ‘human’ OR ‘animals’ OR ‘animal’ OR ‘mammals’ 5 all fields
OR ‘mammal’ OR ‘mammalian’ OR ‘vertebrate’ OR
‘vertebra’ OR ‘astronauts’ OR ‘subjects’ OR ‘participants’
Excluded ‘plants’ OR ‘plantae’ OR ‘prokaryotes’ OR ‘botany’ 6 All fields
#5 NOT #6 7
#1 AND #4 AND #7 8

FIGURE 1 CONSORT flow diagram

of the bibliography of the selected studies, no additional article was
deemed eligible for inclusion. All 26 final articles were based on
studies involving astronauts/cosmonauts or research volunteers. Of
the final 26 articles, 21 investigated the venous system, and five
investigated aspects of coagulation. Nine articles contained spaceflight
data, with the remainder reporting data from ground-based analogues.
There was a high degree of variability in study design, outcomes
assessed and presented data across the final articles. In a significant
number of articles, authors presented subjective or qualitative
assessments, dimensionless parameters without quantifiable results
and/or reported heterogeneous data. As a result, no meta-analysis
could be performed.
1152 KIM ET AL .

TA B L E 2 Venous system changes in microgravity and ground-based analogues

Study Method Outcome

Microgravity studies
Martin et al. (2016) Parabolic flight (n = 11) Increased JV pressure
Herault et al. (2000) Spaceflight (n = 6) Increased JV CSA
Increased FV CSA
Arbeille et al. (2015) Spaceflight (n = 10) Increased JV CSA
Increased portal vein CSA
Fortrat et al. (2017) Spaceflight (n = 24) Increased venous compliance
Decreased venous emptying
Marshall-Goebel et al. (2019) Spaceflight (n = 11) Increased JV CSA
Increased JV pressure
Stagnant or reverse flow
Ground-based analogue studies
Moreva (2008) Dry immersion ×7 days (n = 8) Decreased linear blood velocity
Navasiolava et al. (2010) Dry immersion ×7 days (n = 8) Decreased basal venous blood velocity
Increased circulating endothelial microparticles
Marshall-Goebel et al. (2016) Head-down tilt at −12o (n = 9) Decreased venous outflow
Increased JV CSA
Arbeille et al. (2001) −6o head-down bed rest ×42 days (n = 8) Increased JV CSA
Decreased FV CSA
Bleeker et al. (2004) −6o head down bed rest ×18 days (n = 11) Increased leg venous flow resistance
Ogoh et al. (2020) −6 head down bed rest ×60 days (n = 10)
o
Decreased JV blood flow
a
All results are statistically significant (P < 0.05) unless indicated. Abbreviations: CSA, cross-sectional area; FV, femoral vein; JV, jugular vein.

3.1 Ground-based analogue effects on the venous
system
Across the six articles from ground-based analogues, changes in
parameters related to venous flow and distension were observed
indicative of increased venous stasis and wall stress (Table 2).
A decrease in blood velocity was observed in two DI articles, with
increased levels of endothelial microparticles reported in one (Moreva,
2008; Navasiolava et al., 2010). Moreva (2008) showed that 7-day
DI in eight participants induced decreased venous basal flow rates
in both the head and the lower extremity. Blood velocity decreased
in all vessel types, but a greater decrease was observed in the veins.
Similarly, Navasiolava et al. (2010) reported decreased basal flow rates
in calf veins using laser Doppler (that has limited tissue penetration),
and increased circulating endothelial microparticles and endothelial
dysfunction (as measured by plasma levels of microparticles and
soluble endothelial factors) that was significant from day 3 onwards
within 7 days of DI study. Microparticles from other cell types were,
however, unchanged, suggestive of isolated microvascular impairment
and disturbance of endothelial function as a result of reduced venous
flow.
Marshall-Goebel et al. (2016) reported an increased cross-sectional
area of the internal jugular vein and decreased cerebral outflow in
nine participants during −12o HDT, suggesting a degree of venous
distension and decreased venous flow rates. Similarly, three long-term
HDBR articles reported decreased venous flow, increased resistance
and increased jugular vein cross-sectional area. Arbeille et al. (2001)
found that 42 day −6o HDBR increased jugular vein cross-sectional
area by 40%, and decreased femoral vein cross-sectional area by
35%. Similarly, Bleeker et al. (2004) observed increased leg venous
flow resistance via venous plethysmography after 18 days of −6o
HDBR in 11 subjects (from mean ± SD 1.73 ± 1.08 to 3.10 ±
1.00 mmHg/ml⋅100 ml min). They also reported reduced leg venous
compliance, whereas arm venous compliance was unchanged post-
HDBR. More recently, Ogoh et al. (2020) reported reduced jugular
vein blood flow (via ultrasonography) on day 30 of −6o HDBR in
10 heathy volunteers. The same article also reported both arterial
and venous cerebral blood flow parameters and found differential
flow states between the anterior and posterior vasculature systems.
Specifically, posterior cerebral arterial and venous circulations were
maintained, whereas significantly reduced flow was reported in the
anterior cerebral circulatory system.
3.2 Microgravity effects on the venous system
Five articles reported data from microgravity, with one from parabolic
flight, and four from actual spaceflight (Table 2). Overall, increases
in jugular venous pressure, cross-sectional area and evidence of
decreased/reversed flow states in the upper body venous systems
were reported.
Martin et al. (2016) observed in parabolic flight (vs. 1 g) an increase
in internal jugular venous pressures when measured via compression
sonography (from 9.9 ± 5.1 to 23.9 ± 5.6 mmHg), consistent with
KIM ET AL . 1153

venous distension and increased wall stress. In addition, jugular venous TA B L E 3 Coagulation system changes in microgravity and
pressure increases were observed in simulated lunar (1/6 g), and ground-based analogues
Martian gravity (1/3 g) parabolas (vs. 1 g). Outcome on re-entry or
In all four spaceflight articles, increased jugular vein cross-sectional Study Method re-ambulation
area, increased venous pressure and decreased venous emptying/flow Microgravity studies
were reported. Herault et al. (2000) reported increased jugular Stein & Schluter Spaceflight Increased fibrinogen
(23−30%) and femoral (33−70%) vein cross-sectional areas at 1– (2006) (n = 5) synthesis rate
5 months during six long-duration MIR space station cosmonauts. In a Kuzichkin et al. Spaceflight Increased fibrinogen
study of 10 International Space Station (ISS) astronauts, Arbeille et al. (2010) (n = 5) INR b
(2015) observed increased jugular vein cross-sectional area at flight D-Dimer b

day 15 (+178%) that was even greater at 5 months (+225%) compared Larina et al. Spaceflight Increased fibrinogen
(2017) (n = 18) αchains
to prefight. Portal vein cross-sectional areas were also increased by
+36% at flight day 15, and +45% at 5 months. The same study also Ground-based analogue studies

reported decreased calf vein cross-sectional area during spaceflight,
consistent with that observed during HDBR (Arbeille et al., 2015).
Fortrat et al. (2017) observed lower limb venous compliance that
increased significantly inflight from 0.09 ± 0.005 to 0.12 ± 0.007
(arbitrary units), which returned to baseline 8 days after landing in
24 ISS cosmonauts. In addition, there was a significant decrease in
lower limb venous emptying from −0.004 ± 0.022 to −0.212 ± 0.033
(arbitrary units) during spaceflight, suggesting decreased venous flow
and increased compliance (Fortrat et al., 2017).
In the most recent spaceflight study evaluating 11 ISS
crew members during ISS long-duration missions, jugular vein
measurements using ultrasound were acquired before launch, in flight
and following landing (Marshall-Goebel et al., 2019). Data showed an
increase in jugular vein cross-sectional area during spaceflight of 70.3
mm2 at flight day 150, compared to 9.8 mm2 pre-flight. Additionally,
jugular venous pressure increased from 5.1 to 21.1 mmHg during
spaceflight. Critically, this study showed for the first time both
stagnant and reversed jugular venous flow in more than half (55%)
of crew members. Furthermore, in one crew member, an occlusive
thrombus in the internal jugular vein was observed, with retrospective
review of all ultrasonographic data suggesting a potential partial
occlusive thrombus in another crew member.
3.3 Ground-based analogue effects on the
coagulation system
Only two HDBR articles were identified that investigated coagulation
via thromboelastometry (TEM), thrombin generation or standard
laboratory markers with varying durations of bedrest and cohorts.
Furthermore, all the participants in these studies were male and
screened for any genetic or medical conditions prior to study
enrolment (Table 3).
Cvirn et al. (2015) reported increased clotting times and decreased
alpha angles during 21-day HDBR versus baseline in 11 participants
(Table 3). Thrombin generation was also evaluated, identifying
reduced peak thrombin and velocity index at day 2, with subsequent
normalisation for the remaining 19 days. There was evidence of
shortened lag time, time-to-peak and increased peak thrombin and
Cvirn et al. Bedrest x21 Increased TEM CT
(2015) days (n = 11) Decreased TEM alpha
angle
Haider et al. Bedrest x60 Increased D-Dimer/TAT/PT
(2013) days (n = 9) F1+F2
Decreased EXTEM CFT
Increased EXTEM alpha
angle
Increased FIBTEM MCF
a
All results are statistically significant (P < 0.05) unless indicated. b Non-
significant results. Abbreviations: CFT, clot formation time; CT, clotting
time; EXTEM, extrinsic pathway thromboelastometry; FIBTEM, fibrinogen
thromboelastometry; INR, international normalized ratio; MCF, maximal
clot firmness; PT F1+F2, prothrombin fragment F1+2; TAT, thrombin–
antithrombin III complex; TEM, thromboelastometry.
velocity index, upon re-ambulation when compared to baseline.
Thrombin–antithrombin complexes and prothrombin fragments were
also significantly increased on re-ambulation, suggesting enhanced in
vivo thrombin generation, in addition to in vitro thrombin generating
capacity.
Haider et al. (2013) studied 24 participants who underwent 60-
day HDBR with, or without performance of exercise. No significant
changes to any of the TEM values of coagulation were reported
between groups. In the control group that underwent HDBR
without exercise (n = 9), however, there was significant extrinsic
pathway thromboelastometry tissue-factor activated shortening
of the clot time, increased alpha angle and increased fibrinogen
thromboelastometry fibrinogen based maximum clot firmness during
HDBR, which was even more pronounced post- (i.e., during re-
ambulation) compared to pre-HDBR values. In addition, D-dimer
increased during HDBR along with progressive incremental increases
of thrombin–antithrombin III complex and prothrombin fragment
F1+2.
3.4 Microgravity effects on the coagulation
system
Three articles reported the effect of microgravity upon aspects of
coagulation; however, no study reported on flight data (Table 3).
1154
Stein & Schluter (2006) investigated various plasma protein synthesis
rates in five astronauts, pre and post a 16-day Space Shuttle mission.
They observed a significant increase in the fractional protein synthesis
rate of fibrinogen post- (29.6 ± 4.7%) compared to pre-flight (19.6 ±
3.5%). Similarly, Kuzichkin et al. (2010) reported a significant increase
in fibrinogen following short duration (10–11 day) spaceflight in five
cosmonauts. There was a (non-significant) trend toward shortening
of thrombin time, activated partial thromboplastin time and reduced
antithrombin, suggestive of hypercoagulablity. However, no difference
in D-dimer, international normalized ratio or plasminogen activity
was observed (Kuzichkin et al., 2010). Larina et al. (2017) performed
proteomic blood analysis 30 days prior to launch, on the day of return,
and 7 days following long duration ISS missions in 18 cosmonauts. They
observed a significant increase in fibrinogen alpha-chain levels on the
day of return (7651 ± 1350 fmol/μl) and 7 days after return (7727
± 1492 fmol/μl) compared to prefight levels (6782 ± 2899 fmol/μl).
However, no significant differences in factors VII, IX, X, XI, XII, other
fibrinogen chains, prothrombin and plasminogen were observed.
4 DISCUSSION
4.1 Stasis: altered venous flow in spaceflight
(microgravity)
In microgravity, humans experience a headward fluid shift as a product
of the loss of gravity-driven hydrostatic gradient in the +Gz direction.
The absence of significant musculo-venous pump activity and a limited
number of venous valves in the upper body impede adequate cephalad
blood drainage (Thiranagama et al., 1989). Studies including ones in this
systematic review report increased cross-sectional areas of cephalad
veins in microgravity and its ground-based analogues. Distension has
been further attributed to increased venous pressures in microgravity,
with a parabolic flight (Martin et al., 2016) study and spaceflight
studies showing increased jugular venous pressures during micro-
gravity (Fortrat et al., 2017; Marshall-Goebel et al., 2019). These
changes may help explain the upper extremity, facial and neck oedema
observed in astronauts upon exposure to microgravity (Norsk et al.,
2015; Videbaek & Norsk, 1997).
Furthermore, ground-based analogues have also been shown
to induce decreased venous flow, including DI (Moreva, 2008;
Navasiolava et al., 2010), HDT (Marshall-Goebel et al., 2016) and
HDBR (Arbeille et al., 2001; Bleeker et al., 2004; Ogoh et al., 2020).
Such findings are consistent with recent observations in spaceflight.
In the study by Marshall-Goebel et al. (2019) performed during long
duration spaceflight, all 11 crew members exhibited some form of
altered venous flow at the level of the internal jugular vein, with more
than half (55%) demonstrating signs of stagnant flow or retrograde
flow. Interestingly, to date, stagnant or reversed venous flow has never
been demonstrated in ground-based analogues (including supine and
head-down tilt up to −18o ), suggesting that such changes may be
limited to actual spaceflight (Marshall-Goebel et al., 2016, 2019).
KIM ET AL .
Reduced flow states in the venous system on Earth can trigger
various signalling cascades and endothelial activation that promotes
thrombosis formation (Previtali et al., 2011). Furthermore, prolonged
immobility and venous insufficiency, both causing venous stasis,
distension and elevated venous pressures, are major VTE risk factors
(Byrnes & Wolberg, 2017; Nicolaides, 2000; Tenna et al., 2012). Thus,
a shift towards cephalad venous stasis, combined with associated
distension and increased venous pressure, and in some cases even
reversed flow, has the potential to increase VTE risk in space.
4.2 Hypercoagulability: altered coagulation
system in microgravity
Based on the limited available data, the effect of spaceflight upon
the human coagulation system is unclear. Studies included in this
review were limited, both in number and in study design, which
contributed to substantial data heterogeneity rendering interpretation
and synthesis challenging. It should also be noted that there were
no studies evaluating coagulation during actual spaceflight, as all
three spaceflight studies evaluated pre- and post-flight data only
(Kuzichkin et al., 2010; Larina et al., 2017; Stein & Schluter, 2006).
The only relevant common finding was increased levels of fibrinogen
following spaceflight observed in two of the three studies, which
could be a marker of an acute phase reactant or hypercoagulability,
but this warrants further study (Kuzichkin et al., 2010; Larina
et al., 2017).
Interestingly, two HDBR studies separately reported increased
markers of in vivo thrombin generation (increased D-dimer, thrombin-
antithrombin complexes and prothrombin F1+F2) and increased
coagulation factors (factor VII and VIII) upon re-ambulation (Cvirn
et al., 2015). Similarly, thrombin generation showed a trend towards
hypercoagulability upon re-ambulation, including increased velocity
index, increased peak thrombin (Cvirn et al., 2015; Haider et al.,
2013) and decreased time to peak (calibrated automated thrombogram
time to peak and start tail values) (Cvirn et al., 2015). Unfortunately,
no study has evaluated these coagulation parameters during, or in
response to, spaceflight. Such knowledge is critical to understand
the mechanisms that may underlie the development of a hyper-
coagulability state upon re-exposure to a gravitational environment
following spaceflight.
In contrast, results obtained using TEM during the actual bedrest
period in HDBR studies are equivocal, with one study suggesting
hypocoagulability and the other hypercoagulability. Cvirn et al. (2015)
found some evidence of a hypocoagulability during HDBR, with
increased TEM clotting times and decreased alpha angles. In contrast,
Haider et al. (2013) reported increased alpha angles and maximal clot
firmness along with shortened clot formation times. Thus, research is
urgently needed to better understand human coagulation dynamics
during microgravity, and in particular the influence of factors such
as disturbed flow, vessel distention and endothelial impairment. It
should also be noted that other factors that may potentially affect
KIM ET AL .
TA B L E 4 Endothelial stress via decreased/disturbed flow and
increased distension of vessels
High cyclical stretch
Low and disturbed shear stress(increased
stress(decreased flow) distension/pressure)
∙ Increased pro-inflammatory ∙ Venous wall remodelling
changes (via MCP-1, ICAM-1, ∙ Increased pro-inflammatory
VCAM-1, TGF, TNF, Nox-4 and changes
TF) ∙ Increased extracellular matrix
∙ Increased extracellular matrix changes
remodelling ∙ Increased procoagulant
∙ LDL uptake and lipid synthesis molecule expression (vWF, TF,
∙ Increased atherogenesis thrombin, platelets)
∙ Increased thrombotic markers
(END1 and PDGFB)
Abbreviations: END1, endothelin 1; ICAM-1, intercellular adhesion
molecule-1; LDL, low-density lipoproteins; MCP-1, monocyte chemo-
attractant protein-1; NOX-4, NADPH oxidase 4; PDGFB, platelet-derived
growth factor β; TF, tissue factor; TGF, transforming growth factor; TNF,
tumour necrosis factor; VCAM-1, vascular cell adhesion molecule-1; vWF,
von Willebrand factor.
coagulability such as blood volume reductions and increases to
haematocrit (Kunz et al., 2017), which has been observed in spaceflight,
warrant further investigation.
4.3 Vessel injury: altered endothelial function in
microgravity
In normal physiological states, laminar flow and high wall shear stress
(normal venous flow velocities) induce vessel protective signalling that
promotes endothelial health (Chiu & Chien, 2011a). However, in stasis
or reduced flow (and thus low shear stress), there is an increased
risk of vessel inflammation, oxidative stress, thrombosis and stenosis
(López & Dong, 2005). These occur mostly as flow disturbances cause
activation of various modulators (mechanotransducers, mitogen-
activated protein kinases and effector molecules) that lead to a pro-
thrombotic state via expression of both inflammatory (via tumour
necrosis factor and endothelial cells) and thrombotic (via endothelin
1 and platelet-derived growth factor β) markers (Berk et al., 2008;
Passerini et al., 2003; Traub & Berk, 1998). Low shear stress associated
with physical inactivity or disturbed flow correlates with increased
endothelial dysfunction and endothelial–leukocytic interactions that
can promote thrombotic pathways (Chiu & Chien, 2011b). Such end-
othelial dysfunction can also lead to increases in growth promoting
agents, wall damage, inflammation via monocyte chemoattractant
protein-1 and vascular cell adhesion molecule-1 signalling, and an even
more pronounced pro-thrombotic state (Paszkowiak & Dardik, 2003)
(Table 4).
It is also proposed that increased venous pressures causes vascular
wall remodelling via disruption of smooth muscle cells and elastin
fibres (Porto et al., 1998; Travers et al., 1996), increasing inflammatory
stresses and local tissue injury (Bergan et al., 2006; Takase et al.,
1155
2002). Terrestrially, venous insufficiency associated with venous
hypertension is a known contributor to various pathologies including
VTE (Bergan et al., 2006). In both animal and human terrestrial
studies, chronically high venous cyclical stretching causes venous
wall remodelling, activates pro-inflammatory pathways and instigates
changes to the extracellular matrix (Nicolaides, 2000). This endothelial
dysfunction promotes coagulation via increased local expression of
pro-coagulant factors such as von Willebrand factor and tissue factor
as well as enhanced thrombin generation, promotion of platelet
aggregation/adhesion and fibrin deposition (Chiu & Chien, 2011a;
Cunningham & Gotlieb, 2005) (Table 4). Interestingly, one DI study
reported increased endothelial microparticles associated with vascular
distension (Navasiolava et al., 2010), which might be indicative of
enhanced endothelial damage.
All studies in the present systematic review reported increased
venous distension (venous cross-sectional area), increased venous
pressure and decreased or even retrograde venous flow states, in
cephalad regions of the body, both in microgravity (Arbeille et al.,
2015; Fortrat et al., 2017; Herault et al., 2000; Marshall-Goebel et al.,
2019; Martin et al., 2016) and in ground-based analogues (Arbeille
et al., 2001; Bleeker et al., 2004; Marshall-Goebel et al., 2016; Moreva,
2008; Navasiolava et al., 2010; Ogoh et al., 2020). These findings
may be associated with increased cyclical stretch forces and reduced
shear forces, which may lead to a pro-thrombotic state, and thus
increased VTE risk in spaceflight. However, this hypothesis remains to
be demonstrated in spaceflight.
4.4 Limitations
Several limitations should be considered when interpreting the
results of this systematic review. First, the articles included were
heterogeneous in terms of study design and outcomes assessed.
For instance, four types of ground-based analogues were analysed,
each with different study protocols, outcome variables and exposure
durations. This prevents meta-analysis and thus interpretation.
Second, there were limited spaceflight studies, which were generally
underpowered. Additionally, ground-based analogues are imperfect
simulations of microgravity and the space environment – rendering
extrapolation of data to actual spaceflight suspect (Hargens &
Vico, 2016). Third, a significant selection bias existed in the
populations included in this systematic review. In both spaceflight
and ground-based analogue studies, there is active selection of healthy
participants, leading to the severe under-representation of individuals
with elevated VTE risk profiles. Fourth, it should be noted that in all
but one analogue study, all participants were male, thereby excluding
identification or evaluation of female-specific risk factors (such as
the use of oral contraceptives for menstrual suppression during
spaceflight) that may affect coagulation and orthostasis (Goswami
et al., 2013; Jain et al., 2020) in addition to failing to reflect the
composition of the international astronaut corps (Jain & Wotring,
2016).
1156
FIGURE 2 Changes in Virchow’s Triad in microgravity
5 CONCLUSION
This systematic review highlights a paucity of data regarding the
risk of, and changes to, the human venous and coagulation systems
in spaceflight (microgravity) or its analogues that may underlie
VTE. Nevertheless, the data suggest astronauts may be exposed
to an enhanced coagulation state in the cephalad venous systems
in spaceflight, due to altered venous flow, venous distension,
venous pressure, endothelial damage and possibly hypercoagulability
(Figure 2). However, whether such changes explain the recent finding of
an internal jugular VTE in spaceflight and thereby reflect an increased
risk of VTE in microgravity remains to be determined. This is critical
as a VTE in spaceflight could be potentially catastrophic, particularly
in deep space beyond the ISS where medical and communication
capabilities will be even more constrained in addition to an inability
to rapidly return crew back to Earth. Thus, more research is urgently
needed to evaluate the pathophysiological processes that occur in
actual spaceflight to guide risk assessment and appropriate pre-
ventive, diagnostic, treatment and countermeasure strategies for VTE
in space.
COMPETING INTERESTS
The authors declare no competing interests.
AUTHOR CONTRIBUTIONS
D.K., S.V. and D.A.G. wrote the main manuscript text and D.K. pre-
pared the figures and tables. All authors reviewed the manuscript. All
authors have read and approved the final version of this manuscript
and agree to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved. All persons designated as
KIM ET AL .
authors qualify for authorship, and all those who qualify for authorship
are listed.
DATA AVAILABILITY STATEMENT
Supplementary data presenting the Boolean search terms and search
strategy is provided, but no other supporting data were generated as
part of this systematic review as no meta-analysis was possible.
ORCID
David A. Green https://orcid.org/0000-0001-8634-8769
REFERENCES
Arbeille, P., Fomina, G., Roumy, J., Alferova, I., Tobal, N., & Herault, S.
(2001). Adaptation of the left heart, cerebral and femoral arteries, and
jugular and femoral veins during short- and long-term head-down tilt
and spaceflights. European Journal of Applied Physiology, 86(2), 157–
168.
Arbeille, P., Provost, R., Zuj, K., & Vincent, N. (2015). Measurements
of jugular, portal, femoral, and calf vein cross-sectional area for the
assessment of venous blood redistribution with long duration spaceflight
(Vessel Imaging Experiment). European Journal of Applied Physiology,
115(10), 2099–2106.
Bergan, J. J., Schmid-Schönbein, G. W., Smith, P. D. C., Nicolaides, A. N.,
Boisseau, M. R., & Eklof, B. (2006). Chronic venous disease. New England
Journal of Medicine, 355(5), 488–498.
Berk, B. C., Abe, J.-I., Min, W., Surapisitchat, J., & Yan, C. (2008). Endothelial
atheroprotective and anti-inflammatory mechanisms. Annals of the New
York Academy of Sciences, 947(1), 93–111.
Bleeker, M. W. P., De Groot, P. C. E., Pawelczyk, J. A., Hopman, M. T. E., &
Levine, B. D. (2004). Effects of 18 days of bed rest on leg and arm venous
properties. Journal of Applied Physiology, 96(3), 840–847.
Byrnes, J. R., & Wolberg, A. S. (2017). New findings on venous
thrombogenesis. Hamostaseologie, 37(1), 25–35.
Chiu, J.-J., & Chien, S. (2011a). Effects of disturbed flow on vascular
endothelium: Pathophysiological basis and clinical perspectives. Physio-
logical Reviews, 91(1), 327–387.
Chiu, J.-J., & Chien, S. (2011b). Effects of disturbed flow on vascular
endothelium: Pathophysiological basis and clinical perspectives. Physio-
logical Reviews, 91(1), 327–387.
KIM ET AL .
Cunningham, K. S., & Gotlieb, A. I. (2005). The role of shear stress in the
pathogenesis of atherosclerosis. Laboratory Investigation, 85, 9–23.
Cvirn, G., Waha, J. E., Ledinski, G., Schlagenhauf, A., Leschnik, B.,
Koestenberger, M., Tafeit, E., Hinghofer-Szalkay, H., & Goswami, N.
(2015). Bed rest does not induce hypercoagulability. European Journal of
Clinical Investigation, 45(1), 63–69.
Foldager, N., Andersen, T. A., Jessen, F. B., Ellegaard, P., Stadeager, C.,
Videbaek, R., & Norsk, P. (1996). Central venous pressure in humans
during microgravity. Journal of Applied Physiology, 81(1), 408–412.
Fortrat, J. O., de Holanda, A., Zuj, K., Gauquelin-Koch, G., & Gharib, C. (2017).
Altered venous function during long-duration spaceflights. Frontiers in
Physiology, 8, 694.
Goswami, N., Gorur, P., Pilsl, U., Anyaehie, B., Green, D. A., Bondarenko, A.
I., Roessler, A., & Hinghofer-Szalkay, H. G. (2013). Effect of orthostasis
on endothelial function: A gender comparative study. PLoS One, 8(8),
71655.
Haider, T., Gunga, H.-C., Matteucci-Gothe, R., Sottara, E., Griesmacher, A.,
Belavý, D. L., Felsenberg, D., Werner, A., & Schobersberger, W. (2013).
Effects of long-term head-down-tilt bed rest and different training
regimes on the coagulation system of healthy men. Physiological Reports,
1(6), e00135.
Hargens, A. R., & Vico, L. (2016). Long-duration bed rest as an analog to
microgravity. Journal of Applied Physiology, 120, 891–903.
Herault, S., Fomina, G., Alferova, I., Kotovskaya, A., Poliakov, V., & Arbeille, P.
(2000). Cardiac, arterial and venous adaptation to weightlessness during
6-month MIR spaceflights with and without thigh cuffs (bracelets).
European Journal of Applied Physiology, 81(5), 384–390.
Higgins, J., & Thomas, J. (2019). Cochrane Handbook for Systematic
Reviews of Interventions. London: Cochrane Collaboration. https:
//training.cochrane.org/handbook/current
Jain, V., Ploutz-Snyder, R., Young, M., Charvat, J. M., & Wotring, V. E. (2020).
Potential venous thromboembolism risk in female astronauts. Aerospace
Medicine and Human Performance, 91(5), 432–439.
Jain, V., & Wotring, V. E. (2016). Medically induced amenorrhea in female
astronauts. NPJ Microgravity, 2, 16008.
Kumar, D. R., Hanlin, E., Glurich, I., Mazza, J. J., & Yale, S. H. (2010). Virchow’s
contribution to the understanding of thrombosis and cellular biology.
Clinical Medicine & Research, 8(3–4), 168–172.
Kunz, H., Quiriarte, H., Simpson, R. J., Ploutz-Snyder, R., McMonigal, K.,
Sams, C., & Crucian, B. (2017). Alterations in hematologic indices during
long-duration spaceflight. BMC Hematology, 17(1), 12.
Kuzichkin, D. S., Morukov, B. V., Markin, A. A., Juravlyova, O. A.,
Zabolotskaya, I. V., & Vostrikova, L. V. (2010). Hemostasis system
indices after short-term space flights and during 7-day “dry” immersion
experiment. Human Physiology, 36(4), 478–482.
Larina, I. M., Percy, A. J., Yang, J., Borchers, C. H., Nosovsky, A. M., Grigoriev,
A. I., & Nikolaev, E. N. (2017). Protein expression changes caused by
spaceflight as measured for 18 Russian cosmonauts. Scientific Reports,
7(1), 8142.
Longo, D. L., Stepanek, J., Blue, R. S., & Parazynski, S. (2019). Space medicine
in the era of civilian spaceflight. New England Journal of Medicine, 11,
1053–1060.
López, J. A., & Dong, J. (2005). Shear stress and the role of high molecular
weight von Willebrand factor multimers in thrombus formation. Blood
Coagulation & Fibrinolysis, 16(Suppl 1), S11–S16.
Marshall-Goebel, K., Ambarki, K., Eklund, A., Malm, J., Mulder, E., Gerlach,
D., Bershad, E., & Rittweger, J. (2016). Effects of short-term exposure to
head-down tilt on cerebral hemodynamics: A prospective evaluation of
a spaceflight analog using phase-contrast MRI. Journal of Applied Physio-
logy, 120(12), 1466–1473.
Marshall-Goebel, K., Laurie, S. S., Alferova, I. V., Arbeille, P., Auñón-
Chancellor, S. M., Ebert, D. J., Lee, S. M. C., Macias, B. R., Martin,
D. S., Pattarini, J. M., Ploutz-Snyder, R., Ribeiro, L. C., Tarver, W. J.,
Dulchavsky, S. A., Hargens, A. R., & Stenger, M. B. (2019). Assessment
1157
of jugular venous blood flow stasis and thrombosis during spaceflight.
JAMA Network Open, 2(11), e1915011.
Martin, D. S., Lee, S. M. C., Matz, T. P., Westby, C. M., Scott, J. M., Stenger,
M. B., & Platts, S. H. (2016). Internal jugular pressure increases during
parabolic flight. Physiological Reports, 4(24), e13068.
Moreva, T. I. (2008). [Investigation of peripheral hemodynamics with
the use of ultrasonic dopplerography under the conditions of 7-day
immersion.]. Aviakosmicheskaia i Ekologicheskaia Meditsina – Aerospace and
Environmental Medicine, 42(5), 35–40.
Navasiolava, N. M., Dignat-George, F., Sabatier, F., Larina, I. M., Demiot, C.,
Fortrat, J.-O., Gauquelin-Koch, G., Kozlovskaya, I. B., & Custaud, M.-A.
(2010). Enforced physical inactivity increases endothelial microparticle
levels in healthy volunteers. American Journal of Physiology. Heart and
Circulatory Physiology, 299(2), H248–H256.
Nicolaides, A. N. (2000). Investigation of chronic venous insufficiency: A
consensus statement. Circulation, 102(20), E126–E163.
Norsk, P., Asmar, A., Damgaard, M., & Christensen, N. J. (2015). Fluid shifts,
vasodilatation and ambulatory blood pressure reduction during long
duration spaceflight. Journal of Physiology, 593(3), 573–584.
Ogoh, S., Sato, K., Abreu, S., Denise, P., & Normand, H. (2020). Arterial and
venous cerebral blood flow responses to long-term head-down bed rest
in male volunteers. Experimental Physiology, 105, 44–52.
Ouzzani, M., Hammady, H., Fedorowicz, Z., & Elmagarmid, A. (2016).
Rayyan—A web and mobile app for systematic reviews. Systematic
Reviews, 5(1), 210.
Passerini, A. G., Milsted, A., & Rittgers, S. E. (2003). Shear stress magnitude
and directionality modulate growth factor gene expression in pre-
conditioned vascular endothelial cells. Journal of Vascular Surgery, 37(1),
182–190.
Paszkowiak, J. J., & Dardik, A. (2003). Arterial wall shear stress:
Observations from the bench to the bedside. Vascular and Endovascular
Surgery, 37(1), 47–57.
Porto, L. C., Ferreira, M. A. P., Costa, A. M. A., & Da Silveira, P. R. M. (1998).
Immunolabeling of type IV collagen, laminin, and α-smooth muscle actin
cells in the intima of normal and varicose saphenous veins. Angiology,
49(5), 391–398.
Previtali, E., Bucciarelli, P., Passamonti, S. M., & Martinelli, I. (2011). Risk
factors for venous and arterial thrombosis. Blood Transfusion, 9, 120–138.
Schardt, C., Adams, M. B., Owens, T., Keitz, S., & Fontelo, P. (2007). Utilization
of the PICO framework to improve searching PubMed for clinical
questions. BMC Medical Informatics and Decision Making, 7, 16.
Stein, T. P., & Schluter, M. D. (2006). Plasma protein synthesis after
spaceflight. Aviation, Space, and Environmental Medicine, 77(7), 745–
748.
Takase, S., Lerond, L., Bergan, J. J., & Schmid-Schönbein, G. W. (2002).
Enhancement of reperfusion injury by elevation of microvascular pre-
ssures. American Journal of Physiology. Heart and Circulatory Physiology,
282(4), H51–H54.
Tenna, A. M. S., Kappadath, S., & Stansby, G. (2012). Diagnostic tests and
strategies in venous thromboembolism. Phlebology, 27(Suppl 2), 43–52.
Thiranagama, R., Chamberlain, A. T., & Wood, B. A. (1989). Valves in super-
ficial limb veins of humans and nonhuman primates. Clinical Anatomy,
2(3), 135–145.
Traub, O., & Berk, B. C. (1998). Laminar shear stress: Mechanisms by which
endothelial cells transduce an atheroprotective force. Arteriosclerosis,
Thrombosis, and Vascular Biology, 18, 677–685.
Travers, J. P., Brookes, C. E., Evans, J., Baker, D. M., Kent, C., Makin, G. S.,
& Mayhew, T. M. (1996). Assessment of wall structure and composition
of varicose veins with reference to collagen, elastin and smooth muscle
content. European Journal of Vascular and Endovascular Surgery, 11(2),
230–237.
Videbaek, R., & Norsk, P. (1997). Atrial distension in humans during micro-
gravity induced by parabolic flights. Journal of Applied Physiology, 83(6),
1862–1866.
1158 KIM ET AL .

AUTHOR BIOGRAPHY
How to cite this article: Kim, DS, Vaquer, S, Mazzolai, L, et al.
The effect of microgravity on the human venous system and
David Kim received his Medical Degree
blood coagulation: a systematic review. Experimental
from the University of British Columbia
Physiology. 2021;106: 1149–1158.
and specialization training in Emergency
https://doi.org/10.1113/EP089409
Medicine at the Vancouver General
Hospital. He also has subspecialty training
in Aerospace Medicine from the Royal
Air Force, King’s College London, and
the European Space Agency. He also holds an MSc in Aerospace
Medicine from King’s College London and a Diploma in Aviation
Medicine from the UK Faculty of Occupational Medicine. He is also
the co-founder and director of the Canadian Society of Aerospace
Medicine and is interested in advancing Aerospace Medicine
capabilities and research.