C27-07 Experimental Invasive Pulmonary Aspergillosis Results in Coagulopathy Associated With Fvii Deficiency and Impaired Host Defense

Rationale Invasive pulmonary aspergillosis is a deadly disease caused by the opportunistic mold Aspergillus. As the mold grows in the lungs, fungal hyphae penetrate the epithelium, resulting in lung injury and hemorrhage. We previously reported that this hemorrhage and the consequent release of extracellular heme accelerates fungal growth and worsens the outcome of the infection. However, the host response and attempts to control hemorrhage during aspergillosis remain understudied. We hypothesize that the hemostatic system is protective in host defense during invasive aspergillosis. Methods C57Bl/6J mice were partially neutrophil-depleted using a monoclonal antibody, and challenged with Aspergillus conidia via the trachea. We performed serial thromboelastography on the blood of infected mice and control mice, sampled the alveolar lumen by bronchoalveolar lavage (BAL), and assessed lung fungal burden. We also performed ELISAs for coagulation factor X and Thrombin-antithrombin complex on BAL fluid samples. We used mathematical modeling to map coagulation factors to thromboelastography curves and predict coagulation factors that explain observed thromboelastogram patterns. In some experiments, infected mice were treated with clinical drugs that inhibit factor Xa (apixaban), recombinant FVII, and drugs that prevent fibrinolysis (tranexamic acid), and compared them to controls. Results Infected mice had higher levels of thrombin-antithrombin complex in BAL, as well as higher maximum amplitudes in thromboelastography as compared to uninfected mice, indicating appropriate activation of the coagulation cascade. Unexpectedly, infected animals had an elongated time to clot formation on thromboelastography, suggesting coagulopathy. Our mathematical model predicted a potential depletion of factors X or VII. We found a partial depletion of factor VII but not factor X in the blood during infection. Treatment with apixaban increased fungal burden. Treatment with the anti-fibrinolytic drug tranexamic acid resulted in a pronounced reduction in fungal burden in female mice but had no effect on male mice. Lastly, administration of recombinant FVII resulted in decreased levels of fungal burden in the lung. Conclusions Our preliminary studies suggest that coagulopathy is an important component of invasive aspergillosis and that treatment with anticoagulants during infection might lead to worse outcomes in mice. Treatment with FVII resulted in decreased fungal burden, indicating a link between coagulation and host defense during invasive aspergillosis. Acknowledgements: University of Florida’s Research Opportunity Seed Fund, NIAID K25AI175668, NHLBI R01HL169974 This abstract is funded by: National Institutes of Health