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- Springer Journals
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- Copyright © The Author(s) 2023
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- 10.1038/s41526-023-00260-9
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Abstract
www.nature.com/npjmgrav REVIEW ARTICLE OPEN Pathophysiology, risk, diagnosis, and management of venous thrombosis in space: where are we now? 1 2 3 4,5✉ 4,5,6✉ 7 Katie M. Harris , Roopen Arya , Antoine Elias , Tobias Weber , David A. Green , Danielle K. Greaves , 8,9 2 10 11 12 4,13 Lonnie G. Petersen , Lara Roberts , Tovy Haber Kamine , Lucia Mazzolai , Andrej Bergauer , David S. Kim , 14,15 16 17 17 17 18 Rik H. Olde Engberink , Peter zu Eulenberg , Bruno Grassi , Lucrezia Zuccarelli , Giovanni Baldassarre , Kevin Tabury , 18 19 20 21 21,22 23,24 Sarah Baatout , Jens Jordan , Andrew P. Blaber , Alexander Choukér , Thais Russomano and Nandu Goswami The recent incidental discovery of an asymptomatic venous thrombosis (VT) in the internal jugular vein of an astronaut on the International Space Station prompted a necessary, immediate response from the space medicine community. The European Space Agency formed a topical team to review the pathophysiology, risk and clinical presentation of venous thrombosis and the evaluation of its prevention, diagnosis, mitigation, and management strategies in spaceflight. In this article, we discuss the findings of the ESA VT Topical Team over its 2-year term, report the key gaps as we see them in the above areas which are hindering understanding VT in space. We provide research recommendations in a stepwise manner that build upon existing resources, and highlight the initial steps required to enable further evaluation of this newly identified pertinent medical risk. npj Microgravity (2023) 9:17 ; https://doi.org/10.1038/s41526-023-00260-9 INTRODUCTION presentation, its risk (and the factors that may affect risk), whilst proposing evaluation of candidate diagnostic, mitigation, and A recent study investigating astronaut jugular venous flow inflight management strategies compatible with human spaceflight. The on the International Space Station (ISS) reported the incidental team was supported by individuals familiar with Human Space- finding of a persistent asymptomatic obstructive left internal flight medical operations to identify relevant knowledge gaps. jugular (IJV) venous thrombosis (VT) in a single crewmember . The objectives of the team were to: Furthermore, an additional suspected case was reported following retrospective analysis of the images from the other 11 crew 1. Identify key knowledge gaps and technological/procedural members who participated in the study . Venous thrombi can lead development needs in the (proposed) domains of: to localised pain, redness, distal swelling, venous ischaemia, skin necrosis and even organ dysfunction . However, the most 11. Venous system status, hemodynamics and coagulation significant complication is lung embolization of thrombotic cascade in microgravity (Pathophysiology working fragments, termed pulmonary embolism (PE) that can lead to group); cardiorespiratory insufficiency, which can be fatal. Thus, the 12. Risk of VT and its clinical presentation in microgravity potential identification of VT, a mission-critical medical condition, (Risk working group); in such a highly selected, previously considered low-risk popula- 13. VT diagnostic systems compatible with the constraints of tion is concerning and warrants urgent investigation. spaceflight (Operational Diagnostic working group); As a result, the European Space Agency (ESA) supported the 14. Management of VT in microgravity (Operational Manage- creation in 2020 of a ‘Topical Team’ comprising of international ment working group). subject matter experts in coagulation, venous thrombosis, 2. To determine a cohesive and appropriate operationally driven prophylaxis, and treatment of thrombo-embolic events. The research and technological/procedural evaluation strategy creation of this team was additionally supported by the that addresses the identified gaps, needs, risks and risk factors, Cardiovascular, Pulmonary, Renal and Lymphatic Working Group whilst also proposing evaluation pathways of candidate of the ESA SciSpacE roadmap. An operationally focused research diagnostic, mitigation and management strategies compatible strategy is required to define the pathophysiological processes with future long duration/exploration space missions. leading to VT presentation in spaceflight, potential clinical 1 2 3 Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Canada. Kings College Hospital, NHS Foundation Trust, London, UK. Vascular Medicine, Toulon Hospital 4 5 6 Centre, Toulon, France. Space Medicine Team, European Astronaut Centre, European Space Agency, Cologne, Germany. KBR, Cologne, Germany. Centre for Human and 7 8 Applied Physiological Sciences, King’s College London, London, UK. Faculty of Health, University of Waterloo, Waterloo, Canada. Department of Biomedical Sciences, University 9 10 of Copenhagen, Copenhagen, Denmark. Department of Aeronautics and Astronautics, Massachusetts Institute of Technology, Cambridge, USA. Division of Trauma, Acute Care 11 12 Surgery, and Surgical Critical Care, Baystate Medical Center, Springfield, MA, USA. Department of Angiology, Lausanne University, Lausanne, Switzerland. Surgery, LKH 13 14 Südsteiermark, Wagna, Austria. Department Emergency Medicine, University British Columbia, Vancouver, Canada. Amsterdam UMC location University of Amsterdam, Department of Internal Medicine, Section of Nephrology, Amsterdam, The Netherlands. Amsterdam Cardiovascular Sciences, Microcirculation, Amsterdam, The Netherlands. 16 17 18 Institute for Neuroradiology, Ludwig-Maximilians-University Munich, Munich, Germany. Department of Medicine, University of Udine, Udine, Italy. Radiobiology Unit, Belgian 19 20 Nuclear Research Centre, SCK CEN, Mol, Belgium. Institute of Aerospace Medicine, German Aerospace Center and University of Cologne, Köln, Germany. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada. Translational Research Stress & Immunity, Klinik für Anästhesiologie/Forschungslabors, 22 23 LMU Klinikum, München, Germany. InnovaSpace UK, London, UK. Division of Physiology, Otto Löwi Research Center for Vascular Biology, Immunity and Inflammation, Medical University of Graz, Graz, Austria. Mohammed Bin Rashid University of Medicine and Applied Health Sciences, Dubai, United Arab Emirates. email: tobias.weber@ext.esa.int; david.green@ext.esa.int Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; K.M. Harris et al. Initially four working groups were formed to address the Virchow’s Triad may be modulated but the data is not conclusive . specific domains, however during monthly full group meetings While unexplored by Kim et al. , the radiation environment in Low where ongoing research and key findings of the subgroups were Earth Orbit (LEO) may also have an effect, particularly as discussed, working groups I & II were combined. This paper will radiotherapy is associated with a significant increase in the risk of discuss the findings of the topical team, key knowledge gaps, and VT, including cerebral bleeding . However, whether such changes provide recommendations for future research along European and precipitate an actual increased VT risk in spaceflight remains to be international space research goals. determined, given the lack of VT in ground-based analogues and limited sample of VT in spaceflight. Additionally, the association of radiotherapy with VT on the ground is often within the context of VENOUS THROMBUS IN SPACE: WHAT DO WE KNOW? malignancy, which may be a risk. VT Pathophysiology and risk factors (working group I) Following spaceflight, a return to activity in a 1 G gravitational field may also constitute a VT risk factor. Indeed, changes in G-loading To date, no symptomatic cases of VT have been identified in 609 have been demonstrated to be high risk periods, with brief periods of astronauts that have undertaken space travel (https:// hypergravity activating haemostasis in healthy volunteers . However, www.worldspaceflight.com/bios/stats.php). In 2019, a cohort the only documented VT to date in spaceflight was undetectable study of 11 ISS crew members showed 6 individuals with apparent upon landing, and was discovered months after the hypergravity of stagnant or retrograde IJV flow on approximately flight day 50, launch .While areturnto1Gafter prolonged exposure to 0 G may with one developing occlusive IJV thrombosis , the management induce haemostasis due to the relative hypergravity of the changed of which is discussed separately by Aunon-Chancellor et al .An gravitational field, this has not been thoroughly explored. additional potential partial IJV thrombus was identified in another 1,2 One set of VT risk factors of increasing relevance are those crew member retrospectively . 17,18 related to sex given that whilst to date (as of March 2022), These findings suggest that the underlying VT incidence in space only 67 women have flown into space , representing <10% of the may not be dissimilar to that in the general population. For instance, astronaut population . This situation is evolving, with 50% (9/18) the average rate of venous thrombus in the United States is 1–2per of those selected by NASA in 2020 to prepare for the Artemis 1000 people . A calculation of the 95%CI of the proportion states programme (NASA Artemis. at https://www.nasa.gov/specials/ that a symptomatic VT rate of 0/609 astronauts places the upper artemis/) being females. Indeed, whilst there are some physiolo- bound of the 95%CI at 0.6%, similar to the symptomatic VT rate in postoperative patients (at 0.3–0.7%) . Concerningly, VT in neck veins gical differences that should be considered , females may also may be associated with relatively poor outcomes , yet are rare on present operational physiological advantages for extended space- flight due to decreased (on average) body size and energy Earthinthe absenceof specificriskfactors , accounting for 4–10% 22 23 consumption compared to their male counterparts . Sex-based of overall VT or ~4–10 per 100,000 persons per year . Currently, risks include the optional but frequent use of hormonal contra- astronauts are a carefully selected cohort that lack many classical VT 17,18,24,25 ception in female astronauts to suppress menstruation . risk factors (detailed in Table 1), however, studies suggest that up to The elevated risk is highest during the first months but remains 50% of VT on Earth have no identifiable risk factors . significantly increased compared to non-users, depending on the There may be space- or microgravity-specific risk factors, such type of hormonal contraceptive prescribed (ie. 1st or 2nd as the removal of tissue compressive forces along with cephalad generation, (2–3x risk), versus 3rd or 4th generation (2–5x fluid shifting that may also cause pathologies such as Spaceflight 10,11 18,26,27 risk)) . Moreover, increased risk persists up to 3 months Associated Neuro-ocular Syndrome (SANS) , which is sug- following discontinuation . The presence of thrombophilia gested by the finding of flow abnormalities in the aforementioned further increases VT risk. There is currently no indication for studies. However, whether IJV flow was correctly identified as stagnant or retrograde in the initial cohort study, considering the hereditary or acquired thrombophilia screening in astronauts technological limitations and the relative inexperience of crew as without a personal or family history of VT or without any other sonographers, is unknown . However, a recent update by Pavela comorbidity. Whether this needs to be re-considered remains to et al. also documented retrograde IJV flow in 2/11 astronauts be determined—particularly as thrombophilia testing has little 28,29 undergoing routine venous ultrasound surveillance in flight. relevance for terrestrial VT management . A recent systematic review reported that microgravity and its Finally, as space travel is opening to a wider population, ground-based analogues, chiefly 6° head down tilted bed rest conventional risk factors associated with VTs may become more (HDTBR), may induce an enhanced coagulation state, most relevant to the practice of aerospace medicine. While the medical prominently in the venous system due to cephalad fluid shifting requirements for private spaceflight participants are currently less 14 30 during gravitational unloading . Some evidence of changes in stringent than space agency crews, they will evolve . Considera- venous flow, distension, pressures, endothelial damage, and tion of pre-existing conditions and comorbidities such as age, possibly hypercoagulability exists, suggesting that all aspects of obesity, personal history of VT (VT or PE), family history of Table 1. VT risk factors on Earth. Categorized as strong (OR > = 10); moderate (OR 2–9) or weak (OR < 2) Adapted from Table 3, Ortel et al. . Weak risk factors Moderate risk factors Strong risk factors Bed rest/immobility Combined hormonal contraception/hormone Prior VT replacement therapy Age Inflammatory/autoimmune diseases Recent major surgery/major trauma Varicose veins/venous Infections Antiphospholipid syndrome/ Antithrombin deficiency insufficiency Superficial vein thrombosis Congestive heart or respiratory failure Active cancer Obesity Venous catheters Recent hospitalisation or more than a 3-day immobilisation for acute medical conditions Pregnancy or postpartum period Neurological disease with extremity paresis Genetic thrombophilia npj Microgravity (2023) 17 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; K.M. Harris et al. unprovoked VT and cancer (and its treatment) will become even qualitatively to determine the presence of turbulent, slow, stagnant more important for longer duration spaceflight participants. or retrograde venous flow is intended to be applied to the high velocities associated with arterial flow . That said, discerning the presence or absence of flow is sufficient in most cases, if the pressure VT diagnosis applied at the probe is appropriate and consistent. Given the limited resources and absence of clinical presentation, Hence, whilst the compression ultrasound (CUS) test can rule-out VT diagnostic testing is not performed in space. However, in the diagnosis of thrombosis in a peripheral vein if it is compressible, symptomatic patients a range of approaches are taken. it may lack specificity if the vein segment is not compressible in On Earth, B-mode compression ultrasound (CUS) is reported to spaceflight. This lack of specificity due to higher pressures needed be a sensitive and specific diagnostic method for acute VT in the to compress, and thus collapse a vein may potentially be alleviated peripheral veins of both the lower and upper limbs in addition to by simply using an adjacent artery as a visual ‘pressure gauge’.For 32–35 the jugular veins . The technique relies on venous compres- instance, by increasing the pressure applied at the ultrasound sibility to ‘rule-out’ the presence of VT, with non-compressibility probe to that required to almost close the adjacent artery, the combined with the direct imaging of the thrombus confirming a 37 visualised vein segment should be completely compressed . VT diagnosis. Colour Doppler Ultrasound is an adjunct to B-mode It must be noted however that manual control of applied pressure CUS. By evaluating venous blood flow, it helps to delineate the in microgravity is difficult even if combined with the use of the Crew thrombus if it is partially obstructing the vein, or show no flow Medical Restraint System (CMRS). Currently, safety concerns relating 32,34,35 when the thrombus is completely occlusive . to pressure control preclude the use of autonomous probes. Thus, Slow, stagnant, or retrograde venous flow may be important even with remote guidance (from ground-based sonographers), the clues to understanding if a clot is formed, in the process of crew, despite being inexperienced sonographers, must generate forming or even predict where one may in the future. The application pressure and thus significantly affect image acquisition. combination of Colour Doppler Ultrasound for the direct This is particularly important in, and around the neck as inadvertent investigation of central vein thromboses (abdominal, pelvic and activation of the carotid sinus baroreceptors could precipitate intrathoracic veins) with the Doppler signal patterns at the level of hypotension and bradycardia in individuals with carotid sinus the peripheral veins appears to provide high diagnostic accuracy, hypersensitivity . Thus, poor technique and image quality could although this technique has not been subject to the same level of translate into flow measurement error, particularly in the case of no- 32,33 validation compared to peripheral veins in the legs . flow characterisation. In spaceflight, the diagnostic accuracy of conventional B-mode Furthermore, ultrasonic flow evaluation requires several assump- US/ CUS/ Colour Doppler US/ Doppler US is unknown. Furthermore, tions including linear flow with respect to the vessel lumen and probe reduced, stagnant and/or retrograde venous flow may occur not due positioning . This, assumption is in fact known to be violated in the to VT, but rather—particularly in the upper-limb and jugular veins— IJV . However, angle-independent methods are being developed in due to volume overload and elevated venous pressures secondary to addition to technologies such as ultra-fast US and vector projectile the classic cephalad fluid shift . In fact, the ultrasound used to imaging that show promise in facilitating more accurate evaluation of measure venous blood flow velocity on ISS, and subsequently turbulent, slow, stagnant, and retrograde flow . Table 2. Pathophysiology/Risk—Gap Analysis and Recommendations. Gap Recommendation We do not know the specific VT risk associated with spaceflight, or the Establish the relative risk profile of VT during spaceflight, together with modulating factors of spaceflight that affect risk (ie. length of flight). anatomical predilection sites (due to headward fluid shift and other changes). A comprehensive investigation of the whole venous network (peripheral and central vein segments) is essential to clearly distinguish between thrombosis and stasis in spaceflight and to identify potential sites of thrombosis and key areas to screen during future flights. We do not know the utility of screening potential astronauts for Evaluate the use of test specifically aimed at evaluating endothelial/ thrombophilia’s or terrestrial VT risk factors. microvascular function (e.g., the increase in blood flow in the common femoral artery, determined by Eco-Doppler, during passive leg movements) in the selection of astronauts. Consider routine screening for VT in future travellers. Significant effort must be made to develop state-of-the-art technologies to individualize direct imaging of the thrombus at the level of the peripheral veins (lower and upper limbs) and the central veins (abdomen, pelvis, and thorax). The group recommends that ESA creates a Request for Proposal to further investigate high frame rate ultrasound and 3D motorized probes as next generation diagnostic technology for quantifying blood flow characteristics and possibly predicting a circulation environment where clots might occur. Consider the feasibility of spaceflight for individuals with specific known risk factors (i.e., Factor C/S deficiency, genetic risks). We do not know the risks or benefits of hormone therapy in female Further assess potential prothrombotic effects of sex hormones during astronauts. space travel. We do not know the pathophysiological processes that may underlie Further assess microgravity-specific potential risk factors. symptomatic and asymptomatic VT risk. Build a database of standard measures (biomarkers and ultrasound flow) to track changes and timeline of changes during analogue trials and in- flight missions. We do not know the normal range of values in- and immediately post- Assess prothrombotic biomarkers during spaceflight and in ground-based flight of candidate Earth-based coagulation tests. analogues. Spaceflight testing of coagulation markers and coagulation times is necessary to recommend treatment protocols. Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 17 K.M. Harris et al. Table 3. Prevention—Gap Analysis and Recommendations. Gap Recommendation We do not know which measures could be taken to 1. Assess the role of countermeasures and potential adverse effects of those prevent VT in space. countermeasures for prevention of VT, including: We do not know the adverse effects of potential a. LBNP in VT prevention during space travel and in ground-based analogues countermeasures. b. Assess effectiveness of whole-body vibration (WBV) and RVE interventions to prevent VT during spaceflight and in ground-based analogues c. Assess role of anticoagulant and antiplatelet therapy for VT prevention during spaceflight and in ground-based analogues d. Assess the role of nitric oxide (NO) precursors (nitrites and nitrates) as a way to increase NO bioavailability, induce vasodilation, and prevent inappropriate aggregation / coagulation. e. Assess role of mechanical measures (e.g., compression stockings) to reduce stasis during spaceflight and in ground-based analogues f. Assess the role of exercise (type of exercise, intensity, duration, time of the day) as a way to increase prevent muscle atrophy (and the associated decreased muscle pump), induce shear stress, improve endothelial function, prevent venous stasis, inappropriate aggregation and coagulation. Table 4. Diagnosis - Gap Analysis and Recommendations. Gap Recommendation We do not understand the effects of microgravity on conventional coagulation/ Further assess coagulation parameters in microgravity and their role in diagnosing VT. clotting tests. We do not have any means of measuring coagulation activity in spaceflight to date, nor Determine how microgravity affects the validity/standards of the tests of coagulation systems have we identified alternative devices that could be useful during spaceflight to assess and function. Investigate the potential utility of viscoelastic tests such as TEG, TEM, or coagulation function. Sonoclot, which are cartridge based and easy to use, and capable of assessing the entirety of the clotting cascade. Baseline values of TEG/TEM in spaceflight participants would be required. We do not have a valid spaceflight compatible imaging diagnosis pathway. Determination of a gold-standard diagnostic algorithm/pathway (biomarkers and imaging). This involves progressing existing work on diagnostic methods (U/S and biomarkers) for VT during spaceflight . The ultrasound criteria to rule-out and rule-in the diagnosis of VT in spaceflight must be established. The group recommends that ESA directs its resources to procuring the highest-quality and cutting-edge technology in ultrasound devices for use on Artemis and longer duration missions. Create a diagnostic flowchart based on pre-test and post-test probability. Progress existing ultrasound technologies available to crew for diagnosis and prediction of VT based on turbulent flow patterns or changes to flow patterns with fluid shifts. D-dimer (product of fibrin, a protein fragment present in anticoagulants such as low molecular weight heparins or fondapar- blood following fibrinolytic clot degradation) is a test used inux are approved for VT management. Current international 3 42 terrestrially to rule out lower limb VT and PE although it is less guidelines or consensus documents recommend direct oral antic- established for the diagnosis of upper-limb VT. The key utility is oagulants (DOACs) as the first line treatment in the absence of that a low D-dimer in conjunction with a low Wells score can be contraindications. used to exclude lower limb VT/PE without further imaging . Furthermore, antidotes are available for rivaroxaban and However, given the lack of clarity regarding sensitivity to VT in apixaban (andexanet alfa), dabigatran (idarucizumab) and warfarin the upper body and the ‘normal range’ in spaceflight it is (vitamin K and prothrombin complex concentrate) but not for unclearwhether D-dimerassessmentwouldbeavalid LMWH, though there is partial efficacy of protamine for this diagnostic approach. Additionally, D-dimer is not currently purpose . The availability of an antidote is a key advantage as available or validated for the spaceflight context, nor is the rapid reversibility may be required in the case of traumatic injury Wells score, and therefore is of limited interest for future and may reduce the need for monitoring. However, costs in diagnosis of VT during spaceflight. replacing medications with limited shelf life may be prohibitive and impractical in the face of the low likelihood of VT and Management subsequent anticoagulant-related bleeding. On Earth, anticoagulation medication is usually prescribed for Thus far, the experience in managing IJV thrombosis in space is 3 months in patients with proximal VT if the risk of recurrence is limited to the single asymptomatic individual. The astronaut was low (i.e., major transient/reversible risk factors) . Longer term anticoagulated with once daily enoxaparin (1.5 mg/kg, then 1 mg/ anticoagulation medication can be considered for those with low kg to extend supplies) transitioning to apixaban 5 mg twice daily bleeding risk and high recurrence rate (i.e., major thrombophilia, at 42 days, with dose reduction at 3 months. To negate the risk of persistent or non-identified risk factors). A further important excessive bleeding due to traumatic injury on re-entry treatment, consideration is the risk of embolization from VT in spaceflight. On the anticoagulant was stopped 4 days prior to return to Earth . Thought was also given to the provision of an antidote in the Earth, upper extremity VT is associated with a significantly (5–8%) event of anticoagulation-related bleeding . lower embolization risk than lower extremity VT . However, On Earth, oral anticoagulants including direct factor Xa inhibitors theoretically, IJV VTs could propagate to more proximal vein (rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (dabi- segments and cause superior vena cava thrombosis and cannot gatran), vitamin K antagonists (warfarin), and subcutaneous be simply extrapolated from Earth to space. npj Microgravity (2023) 17 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA K.M. Harris et al. Table 5. Management—Gap Analysis and Recommendations. Gap Recommendation We do not know potency or efficacy of traditional anticoagulant The risks of anticoagulation in space and optimal reversal strategies for anticoagulants therapies in the microgravity environment. during space flight must be determined, specifically the role of DOACs and their reversal agents. Characterize the anticoagulant drug levels and pharmacokinetics we can expect in space travellers and the haemodynamic effects of anticoagulants in microgravity. We do not know if follow-up from a VT event should be conducted Access existing longitudinal health data from astronauts to assess long term in space or on the ground post mission. cardiovascular health including sequelae of VT to determine if existing long term follow up is suitable. Fig. 1 Suggested areas of research based on ESA Topical Team gap analysis. Each box contains a research focus that will build towards better characterization of risk and/or management. The dependencies between the different research foci are shown by the arrows. GAP ANALYSIS AND RECOMMENDATIONS findings, a visual representation of the above recommendations and the pathways in which they enable the primary prevention Over the course of the topical team’s tenure, we have published on and management of VT in space is shown in Fig. 1, considering the the likelihood of flow abnormalities in contributing to VT forma- 12 46 recommendations which must be addressed first to enable the tion , endothelial disruption related risks of VT ,and diagnostic implementation of the other recommendations. modalities for VT in space (in review). We found that current tools on board the ISS are insufficient to characterize blood flow patterns that may contribute to clot formation and that there are no validated DISCUSSION biomarkers that reliably predict increased likelihood of VT formation There continue to be many unknowns regarding the pathophy- in otherwise healthy people. Based upon these publications and siology, risk, prevention, diagnosis, management, and follow up through the meetings of the topical team, knowledge gaps in each of VT occurrences during spaceflight. With upcoming missions of the working group areas were identified. These key knowledge to the Moon and Mars, differences in medical resources and gaps are shown in Tables 2–5, along with recommendations for crew autonomy will further complicate the priority of each of future research to address said gaps. While the topical team was subdivided into four initial the above recommendations. For example, advanced diagnos- subgroups, the main objective of the team, and space medicine, tics that require from-ground input are unlikely to be under- is to prevent medical emergencies from occurring, and developing taken for missions with significant communication delays, while a reasonable management plan for the rare instances they do initial investigation into the nature of clotting in microgravity occur. To capture this goal and show the interdependencies of our may be undertaken preferentially in the low Earth orbit Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 17 K.M. Harris et al. environment. The VT Topical Team suggest that space agencies 21. Mark, S. et al. The impact of sex and gender on adaptation to space: executive summary. J. Women’sHeal 23, 941–947 (2014). and commercial operators consider the recommendations of 22. Scott, J. P. R., Green, D. A., Weerts, G. & Cheuvront, S. N. 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Chest 133, 143–148 (2008). 20. Smith, M. G., Kelley, M. & Basner, M. A brief history of spaceflight from 1961 to 46. Harris, K. et al. Search for venous endothelial biomarkers heralding venous 2020: an analysis of missions and astronaut demographics. Acta Astronaut. 175, thromboembolism in space: a qualitative systematic review of terrestrial studies. 290–299 (2020). Front. Physiol. 13,1–10 (2022). npj Microgravity (2023) 17 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA K.M. Harris et al. ACKNOWLEDGEMENTS COMPETING INTERESTS The authors would like to acknowledge the members of the topical team who The authors declare no competing interests. contributed to the ideas and recommendations provided in this manuscript: ESA VT Topical Team Members. A.B. A.P.B. Andrew Winnard. Angelique Van Ombergen. A.E. ADDITIONAL INFORMATION Bianca Brix. B.G. D.K.G. D.A.G. D.S.K. Gerhard Cvirn. Giovanni Baldasarre. Guy Meyer. Hanns-Christian Gunga. James Pavela. J.J. Jens Tank. Jutta Gärtner. K.M.H. Kristina Supplementary information The online version contains supplementary material Kofler. L.R. L.G.P. L.M. L.Z. Myles George Harris. Patrick De Boever. P.z.E. Rado Pišot. available at https://doi.org/10.1038/s41526-023-00260-9. Robert Riddell. Roopen Arya. Sargsyan Ashot. Sergi Vaquer. Setfan Du Plessis. T.W. Correspondence and requests for materials should be addressed to Tobias Weber or T.H.K. Ulrich Limper. We are thankful to the European Space Agency and NASA for David A. Green. financial support of this project. The European Space Agency provided funding to cover the open access cost of this publication. Publication costs were covered Reprints and permission information is available at http://www.nature.com/ specifically from the ESA-sponsored Topical Team on “Pathophysiology, risk and reprints clinical presentation of venous thromboembolism (VTE) and its evaluation of its prevention, diagnosis, mitigation and management strategies in spaceflight” (Grant Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims number 4000131108/20/NL/PG/pt) and NASA Grant number 80NSSC19K0020, PI. The in published maps and institutional affiliations. project was funded by the European Space Agency and KBR GmbH. The funder (KBR GmbH) provided support in the form of salaries for the authors T.W. and D.A.G. but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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D.A.G., A.P.B., A.C., R.A., regulation or exceeds the permitted use, you will need to obtain permission directly D.K.G., L.G.P., P.z.E, L.Z., L.M., A.E. edited the written manuscript and generated the from the copyright holder. To view a copy of this license, visit http:// tables. K.M.H., R.A., T.W., D.A.G., D.K.G, L.G.P., A.E., L.R., T.H.K., L.M., A.P.B., D.S.K., creativecommons.org/licenses/by/4.0/. R.H.O.E., P.z.E., B.G., L.Z., G.B., K.T., S.B., JJ, A.P.B., A.C., T.R., N.G. contributed to the initial literature reviews, the writing of the sections, the generation of the recommenda- tions and gaps, and reviewed the final manuscript. © The Author(s) 2023 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2023) 17
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