Hematology · Medical Literature
Biological clocks and blood clots in space: circadian disruption-induced modulation of thrombosis risk.
Abstract
Long-duration space missions expose astronauts to microgravity, radiation, confinement, fluid redistribution, and circadian disruption, which together induce physiological adaptations, including cardiovascular hemodynamics. Emerging evidence suggests that spaceflight may modulate hemostasis and potentially increase thrombotic risk in the head/neck; however, the association of circadian disruption and hemostasis in space, and its ground-based analogs, has yet to be systematically evaluated. This systematic review aimed to synthesize evidence from real-spaceflight missions and ground-based analogs to (i) characterize thrombosis-related and hemostatic adaptations, (ii) evaluate circadian remodeling under altered gravitational conditions, and (iii) identify mechanistic and methodological gaps linking biological timing to coagulation regulation in space. A systematic search of PubMed, Scopus, and Web of Science was conducted from January 2016 to January 2026. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, studies investigating circadian rhythms, clock-gene regulation, autonomic chronobiology, hemostasis, thrombosis, platelet biology, and coagulation pathways, in spaceflight or spaceflight analogs were systematically screened and analyzed. Thirty-eight studies met inclusion criteria, of which 20 (52.6%) primarily examined hemostasis and thrombosis outcomes and 18 (47.4%) focused on circadian regulation. Thrombosis-related investigations demonstrated dynamic modulation of coagulation cascades, platelet activation pathways, fibrinogen levels, endothelial markers, and complement components across dry immersion, head-down bed rest, animal unloading models, radiation exposure, hypergravity, and real astronaut missions. However, most hemostatic studies relied on end point or milestone-based sampling without circadian-phase resolution. In contrast, circadian-focused studies used dense temporal sampling and revealed phase shifts, altered autonomic rhythmicity, and disruption of molecular clock regulators under simulated and real space conditions, yet rarely assessed direct thrombotic end points. Importantly, no included study simultaneously assessed circadian-phase regulation and hemostatic outcomes, highlighting a critical lack of mechanistic evidence linking biological timing to thrombotic regulation in spaceflight environments. The absence of circadian phase-resolved hemostatic assessment represents a fundamental mechanistic gap. Future integrative chronothrombotic study designs are required to determine whether disrupted biological timing directly contributes to thrombotic vulnerability during spaceflight.
Clinical relevance
Does circadian disruption during spaceflight and its ground-based analogs modulate hemostasis and increase thrombotic risk, and what are the mechanistic and methodological gaps linking biological timing to coagulation regulation in space? __SNAPSHOT__ {"studyDesign":"Systematic review (PRISMA-compliant; not a meta-analysis — quantitative pooling not described in the abstract)","setting":"Multinational; synthesizes evidence from real-spaceflight missions and ground-based spaceflight analogs (specific institutions not reported in the abstract); databases searched: PubMed, Scopus, and Web of Science","sampleSize":"Not reported in the abstract (number of included studies not specified in the truncated text)","population":"Astronauts on real-spaceflight missions and individuals in ground-based spaceflight analogs (e.g., head-down tilt bed rest, dry immersion); studies investigating circadian rhythms, clock-gene regulation, autonomic chronobiology, hemostasis, thrombosis, platelet biology, and coagulation","intervention":"Exposure to spaceflight-associated conditions — microgravity, radiation, confinement, fluid redistribution, and circadian disruption — and ground-based analogs of these conditions","comparator":"Not applicable as a primary comparator; studies may use pre-spaceflight baselines or terrestrial controls (not explicitly defined in the abstract)","primaryOutcome":"Three co-primary aims: (i) characterization of thrombosis-related and hemostatic adaptations in altered gravity; (ii) evaluation of circadian remodeling under altered gravitational conditions; (iii) identification of mechanistic and methodological gaps linking biological timing to coagulation regulation in space","followUp":"Literature search window: January 2016 to January 2026 (10 years); individual study follow-up durations not reported in the abstract","fundingSource":"Not reported"}
Key findings
The abstract, as provided, is truncated and does not report quantitative results (effect sizes, p-values, confidence intervals, or NNT/NNH). The review characterizes the conceptual landscape rather than synthesizing pooled numerical outcomes. Based on the abstract's stated aims and the broader literature this review engages, the study synthesizes evidence that spaceflight may modulate hemostasis — particularly in the cephalad venous system — and that circadian disruption may represent an under-recognized, mechanistically plausible contributor to this risk. Prior systematic reviews of microgravity and coagulation (e.g., Kim et al., 2021, Exp Physiol) identified cephalad venous dilation, elevated fibrinogen levels, thrombin generation markers, and endothelial damage during spaceflight, but noted that whether these changes precipitate clinically significant VTE risk remains unresolved. Circadian-hemostasis coupling is biologically well-established in ground-based research: clock genes (BMAL1, CLOCK, CRY, Rev-erbα) directly regulate platelet activation, PAI-1 expression, fibrinogen levels, and fibrinolysis, with morning peaks in prothrombotic activity documented in healthy humans independent of sleep-wake behavior. The contribution of circadian disruption — as a distinct and additive mechanism — to spaceflight thrombotic risk was the novel and as-yet unsystematically evaluated focus of this review. No specific effect sizes are calculable from the abstract as provided.
Practice implications
This systematic review addresses an important mechanistic gap: while spaceflight-associated thrombotic risk (particularly jugular venous thrombosis) has been recognized clinically since a sentinel case report in 2019, and prior reviews have documented hemostatic perturbations in microgravity, the role of circadian disruption as an independent or synergistic modulator of thrombosis risk in space has not been systematically evaluated before this publication. The study does not appear to establish a definitive causal link or produce quantitative risk estimates; rather, it maps the mechanistic plausibility and identifies knowledge gaps. Findings are applicable primarily to astronaut populations and healthy analog subjects, not to general clinical thrombosis patients. Patients with pre-existing thrombophilia, cardiovascular disease, or other comorbidities were not represented in the spaceflight literature reviewed. Clinicians managing astronauts, commercial space travelers, or designing countermeasure protocols for long-duration missions should be aware that circadian disruption may add a biologically plausible, currently unquantified layer of thrombotic risk on top of stasis and fluid redistribution. This review is available only as an abstract to this summary, which limits the ability to evaluate methodological quality, included study count, heterogeneity, and the strength of specific conclusions. __LIMITATIONS__ Abstract truncated: the full results, included study count, risk-of-bias assessment, and specific conclusions are unavailable for evaluation.,Spaceflight studies are inherently limited by very small sample sizes (astronaut cohorts are typically n<20), lack of blinding, absence of randomization, and inability to isolate individual stressors (microgravity, circadian disruption, radiation, confinement act simultaneously).,Ground-based analogs (head-down tilt bed rest, dry immersion) incompletely replicate true microgravity; stagnant or retrograde jugular venous flow observed in actual spaceflight has not been reproduced in any ground analog.,Circadian disruption and hemostasis have largely been studied in isolation; mechanistic studies linking clock-gene dysregulation specifically to coagulation in the space context are largely absent in the existing literature.,Systematic review without meta-analysis: formal quantitative pooling of effect sizes across studies is unlikely given marked heterogeneity in study designs, endpoints, and populations.,Publication bias cannot be excluded given the small number of institutions with access to spaceflight data.,Generalizability is severely limited: findings apply to a highly selected, medically screened population distinct from typical clinical thrombosis patients.,Ten-year search window (2016–2026) may exclude earlier foundational spaceflight hemostasis studies.,Funding source not reported, limiting assessment of potential conflicts of interest. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This PRISMA-compliant systematic review is the first to explicitly synthesize the intersection of circadian disruption and hemostatic risk in spaceflight and its ground-based analogs, addressing a recognized gap as NASA and ESA formalize VTE risk protocols for long-duration missions. No quantitative effect estimates are available from the abstract, and the body of evidence in this domain remains small, heterogeneous, and mechanistically incomplete. At this time, findings are not sufficient to change clinical thromboprophylaxis practice but should inform research prioritization and mission planning discussions for space medicine programs.