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Venous stasis-induced fibrinolysis prevents thrombosis in mice: role of ?2-antiplasmin.

ABSTRACT: Stasis of venous blood triggers deep vein thrombosis by activating coagulation, yet its effects on the fibrinolytic system are not fully understood. We examined the relationship between stasis, fibrinolysis, and the development of experimental venous thrombosis. Effects of stasis-induced deep vein thrombosis and fibrinolysis on thrombosis were examined by inferior vena cava ligation in congenic mice with and without ?2-antiplasmin (?2AP), the primary inhibitor of plasmin. Venous thrombus weights were measured and thrombus composition was determined by Martius scarlet blue and immunofluorescence staining. Venous thrombi from ?2AP+/+ mice contained plasminogen activators, plasminogen activator inhibitor-1, plasminogen, and ?2AP, which changed with thrombus age. Normal, ?2AP+/+ mice developed large, occlusive thrombi within 5 hours after ligation; thrombi were even larger in plasminogen-deficient mice (P < .001). No significant thrombus formation was seen in ?2AP-/- mice (P < .0001) or in ?2AP+/+ mice treated with an ?2AP-inactivating antibody (P < .001). Venous stasis activated fibrinolysis, measured by D-dimer levels, in ?2AP-/- mice vs ?2AP+/+ mice (P < .05). Inhibition of fibrinolysis by the indirect plasmin inhibitor ?-aminocaproic acid or by ?2AP restored thrombosis in ?2AP-/- mice. In addition to its effects on acute thrombosis, thrombus formation was also markedly suppressed in ?2AP-/- mice vs ?2AP+/+ mice (P < .0001) 1, 7, and 14 days after ligation. We conclude that experimental venous stasis activates the fibrinolytic system to block the development of venous thrombosis. Suppression of fibrinolysis by ?2AP appears essential for stasis-induced thrombus development, which suggests that targeting ?2AP may prove useful for preventing venous thrombosis.

SUBMITTER: Singh S

PROVIDER: S-EPMC6753621 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Venous stasis-induced fibrinolysis prevents thrombosis in mice: role of α2-antiplasmin.

Singh Satish S Houng Aiilyan K AK Reed Guy L GL

Blood 20190808 12

Stasis of venous blood triggers deep vein thrombosis by activating coagulation, yet its effects on the fibrinolytic system are not fully understood. We examined the relationship between stasis, fibrinolysis, and the development of experimental venous thrombosis. Effects of stasis-induced deep vein thrombosis and fibrinolysis on thrombosis were examined by inferior vena cava ligation in congenic mice with and without α2-antiplasmin (α2AP), the primary inhibitor of plasmin. Venous thrombus weights ...[more]

PMID: 31395599

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Project description:Importance:Exposure to a weightless environment during spaceflight results in a chronic headward blood and tissue fluid shift compared with the upright posture on Earth, with unknown consequences to cerebral venous outflow. Objectives:To assess internal jugular vein (IJV) flow and morphology during spaceflight and to investigate if lower body negative pressure is associated with reversing the headward fluid shift experienced during spaceflight. Design, Setting, and Participants:This prospective cohort study included 11 International Space Station crew members participating in long-duration spaceflight missions . Internal jugular vein measurements from before launch and approximately 40 days after landing were acquired in 3 positions: seated, supine, and 15° head-down tilt. In-flight IJV measurements were acquired at approximately 50 days and 150 days into spaceflight during normal spaceflight conditions as well as during use of lower body negative pressure. Data were analyzed in June 2019. Exposures:Posture changes on Earth, spaceflight, and lower body negative pressure. Main Outcomes and Measures:Ultrasonographic assessments of IJV cross-sectional area, pressure, blood flow, and thrombus formation. Results:The 11 healthy crew members included in the study (mean [SD] age, 46.9 [6.3] years, 9 [82%] men) spent a mean (SD) of 210 (76) days in space. Mean IJV area increased from 9.8 (95% CI, -1.2 to 20.7) mm2 in the preflight seated position to 70.3 (95% CI, 59.3-81.2) mm2 during spaceflight (P < .001). Mean IJV pressure increased from the preflight seated position measurement of 5.1 (95% CI, 2.5-7.8) mm Hg to 21.1 (95% CI, 18.5-23.7) mm Hg during spaceflight (P < .001). Furthermore, stagnant or reverse flow in the IJV was observed in 6 crew members (55%) on approximate flight day 50. Notably, 1 crew member was found to have an occlusive IJV thrombus, and a potential partial IJV thrombus was identified in another crew member retrospectively. Lower body negative pressure was associated with improved blood flow in 10 of 17 sessions (59%) during spaceflight. Conclusions and Relevance:This cohort study found stagnant and retrograde blood flow associated with spaceflight in the IJVs of astronauts and IJV thrombosis in at least 1 astronaut, a newly discovered risk associated with spaceflight. Lower body negative pressure may be a promising countermeasure to enhance venous blood flow in the upper body during spaceflight.

Dataset Information

Venous stasis-induced fibrinolysis prevents thrombosis in mice: role of ?2-antiplasmin.

Publications

Venous stasis-induced fibrinolysis prevents thrombosis in mice: role of α2-antiplasmin.

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