Development of A Directed Acyclic Graph for Venous Thromboembolism During Spaceflight

Introduction: Recent studies have reported the development of venous blood flow stasis in
astronauts and an occlusive venous thrombosis during spaceflight. Subsequent investigations
revealed approximately one quarter of surveilled crew members had some degree of blood flow
stasis in the left internal jugular vein. Therefore, NASA’s Human System Risk Board now
formally tracks venous thromboembolism (VTE) as a “concern” for human spaceflight. To
investigate potential mechanisms by which exposures concomitant with spaceflight (e.g.,
microgravity, radiation) may contribute to VTE, we developed a causal diagram in the form of a
directed acyclic graph (DAG).

Methods: The mechanisms by which spaceflight exposures may elevate the risk of VTE and
the downstream effects on mission outcomes were critically analyzed, taking into account
scientific literature and subject matter expertise consultation, and a DAG was generated. A
Level-of-Evidence score for each causal relationship was assigned based on assessing the
literature against a set of criteria derived from the A. Bradford Hill Causal Guidelines.

Results: The set of three main factors that predispose people to VTE (hypercoagulability,
endothelial damage, and blood stasis) is known as Virchow’s Triad. In constructing the DAG for
VTE we articulated various mechanisms by which the principal spaceflight hazards
(microgravity, radiation, closed hostile environment, isolation and confinement, distance from
Earth) are thought to interact with or cause the components in Virchow’s triad. We found
sufficient evidence to at least speculate that fluid shifts from microgravity, compensatory
alterations in hematologic indices, spaceflight atmospheric conditions, and oxidative
stress/inflammation from radiation may be potential contributors to VTE development.

Discussion: Developing the DAG entailed a systematic and repeatable approach for visualizing
relationships between contributing factors that may lead to VTE in spaceflight. Articulating
pathways linking spaceflight exposures to VTE risk factors and possible VTE development
enables subject matter experts from different domains to construct a shared mental model.
Assignment of levels of evidence scores to the relationships helps identify knowledge and
capability gaps that should be considered for further investigation. Furthermore, the DAG
highlights modifiable variables and may therefore facilitate the development of new VTE risk
mitigation strategies.