The Effects of Tranexamic Acid on Bleed Control, Coagulopathy and Survival with Trauma in Anemic Mice

Abstract

Clinical evidence suggests that anemia increases surgical bleeding and is associated with poor outcomes. Globally, ~ 50% of anemia is attributed to iron deficiency as the most common nutritional disorder. To study the effects of iron deficiency anemia (IDA) on traumatic bleeding we developed a mouse model of IDA and traumatic injury, and tested the effects of prophylactic tranexamic acid (TXA), on blood loss, coagulopathy and survival. Materials and Methods C57BL/6J mice, both male and female, were fed with usual laboratory ("control mice") or iron deficient (4ppm iron) chow ("IDA mice") starting at 3 weeks of age. After 6 weeks, IDA was documented by blood count, red cell indices and liver iron content. Mice then were subjected to an established liver laceration model causing severe bleeding. Blood loss (weighing blood-soaked sponges in the abdominal cavity), seven-day survival and coagulation parameters (APTT, activity levels of Factor (F) V, FVIII, Fibrinogen) were determined at 15 and 60 minutes after liver laceration for "IDA" and "control mice", treated or not treated five minutes prior to injury with TXA (10mg/kg). All data were expressed as median and were compared using Mann-Whitney test. Results Compared to "control" mice, "IDA mice" developed hypochromic and microcytic anemia with a significantly lower mean hematocrit (32±1.7% vs 49±1.2%, p≤0.0001) and hepatic iron content (75.9±19.8µg/g vs 22.4±9.4 µg/g, p≤0.0001). "IDA mice" demonstrated significantly more bleeding after liver laceration compared to "control mice." Most of the bleeding had occurred at 15 minutes after injury with little incremental bleeding at 60 minutes. The blood loss in "IDA mice" was greater at both time points compared to "control mice" (15 minutes: 21.5±2.3µl/g vs 15.9±2.6µl/g, p≤0.0001; 60 minutes: 24.5±1.6µl/g vs 20.7±1.9µl/g, p≤0.0001). TXA reduced bleeding significantly in "IDA mice" at 15 and 60 min to ~15µl/g. In "control mice", bleed improvement was only present at 60 min (also reduced to ~15µl/g), without improvement below the ~15µl/g baseline threshold at 15 min. Coagulopathy developed in both groups over 60 min, with similar prolongation of the APTT from baseline (23.9±1.5s to 36.0±4.9s in "IDA mice"; 22.8±1.3s 35.0±3.8s in "control mice"), substantial depletion of FV and FVIII activity levels and partial reduction of fibrinogen. TXA administration normalized the APTT only in "control mice" at 60 minutes, but not in "IDA mice", although TXA reconstituted FV and fibrinogen to ~100% activity, with FVIII activity of ~50% in both groups. Survival of "IDA mice" was lower compared to "control mice" (50% vs 75%), but increased significantly with TXA (80%, p=0.04). Conclusion Enhanced bleeding and poorer survival was observed in "IDA mice" compared to "control mice" after liver laceration at similar degrees of coagulopathy. Prophylactic TXA corrected bleeding and reduced mortality in "IDA mice" to values similar to those observed for "control mice" despite incomplete correction of the coagulopathy in "IDA mice". This suggests that TXA may be of particular importance in the face of anemia, by mechanisms that may go beyond hemostasis correction alone, warranting further investigation. Disclosures von Drygalski: CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: Statistical analysis plan for the WOMAN-2 trial: an international, randomised, placebo-controlled trial

“…Red blood cells also appear to shield fibrin strands from lysis by plasmin, a process known as steric hindrance 14 . Animal studies comparing the effects of TXA on bleeding in anaemic and non-anaemic mice show that TXA is more effective in the presence of anaemia 15 . Cohort studies in pregnant women recruited in the last trimester of pregnancy and followed until after childbirth support these laboratory observations 16 .…”