Investigating the extrinsic pathway of coagulation as a therapeutic target for severe malaria
Bracken, Tara Catherine
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Malaria poses a serious threat to global health, with 3.2 billion people in 95 countries at risk of infection. Pregnant women and young children in malaria-endemic areas bear the heaviest burden of malaria infection due to two severe clinical manifestations of malaria, placental (PM) and cerebral malaria (CM) resulting from sequestration of infected erythrocytes in the maternal blood space of the placenta or the brain. The use of adjunctive therapies to specifically target pathogenic processes known to occur during PM and CM hold great promise to prevent the more serious outcomes of malaria infection. However, to date, therapies targeting the best-understood contributor to malaria pathogenesis — inflammation — have so far been unsuccessful. Previous experiments in our lab and evidence in the clinical literature have shown that a potently procoagulant state exists during PM and CM, and that suppression of that state with a research-grade low molecular weight heparin could mitigate mid-gestational pregnancy loss during murine placental malaria infection. These studies indicated activated coagulation was an important contributor to malaria pathogenesis, but which components of the coagulation cascade were relevant to the observed pathologies remained unclear. This dissertation, therefore, sought to build upon that work by identifying members of the extrinsic pathway of coagulation contributing to malaria pathogenesis and by assessing the potential of anticoagulant therapy to mitigate severe clinical outcomes of malaria. We began using Cre-lox technology to induce tissue-specific deletions of Tissue Factor, the initiator of the extrinsic pathway of coagulation, to identify tissue types contributing to this damaging procoagulant state. We then tested two anticoagulants currently approved for clinical use in humans — the low molecular weight heparin, Dalteparin, and the coagulation FXa inhibitor, Fondaparinux — to assess how blocking the coagulation cascade affects disease progression and outcome. This dissertation also includes an assessment of naturally acquired Helicobacter infection in laboratory mouse colonies and how such infections may interfere with mouse models of disease in pregnancy. The results here presented provide compelling evidence that anticoagulant drugs have the potential to serve as useful adjunctive therapies for the treatment of both placental and cerebral malaria.