| Summary: | Treatment of occlusive clots (thrombi) is important for proper health yet systemic bleeding remains a major complication of thrombolytic therapy. Thus, the utility of agents such as alteplase, the current thrombolytic approved to rapidly lyse thrombi, is limited. As an alternative, our laboratory has found that cleavage products of clotting factor Xa (FXa) can enhance the generation of localized plasmin, the enzyme that degrades and solubilizes clots. This function is stabilized by blocking or chemically modifying the active site of FXa such that FXaβ, the first resulting fragment, persists.
In recent years, direct oral anticoagulants (DOACs) have been approved for the treatment and prevention of venous thromboembolism and stroke in patients with atrial fibrillation. Two agents in this class of drugs, rivaroxaban and apixaban, are direct inhibitors of FXa. This dissertation addresses the effect these two DOACs have on fibrinolysis and FXa fragmentation due to their ability to block the active site of FXa. Results presented in Chapter 3 demonstrate that in normal pooled plasma, rivaroxaban and apixaban enhance clot lysis in a FX- and dose-dependent manner. Downstream effects caused by a potential reduction in thrombin generation were not the basis for the enhancement. Instead, FXaβ persisted in plasma. In purified protein experiments, FXaβ, generated in the presence of rivaroxaban and apixaban, enhanced plasmin generation by binding plasminogen.
Results in chapter 4 showed persistence of FXaβ in rivaroxaban-treated patient samples but not in samples from non-anticoagulated patients and those treated with a thrombin-specific DOAC. A strong correlation between increasing FXaβ amounts and faster fibrinolysis time was shown in rivaroxaban-treated patients with atrial fibrillation, the approved indication in which thrombosis is the least provoked. Fibrinolysis was not, however, dose-dependently enhanced. There was also no statistical difference in fibrinolysis times between rivaroxaban-treated and non-anticoagulated atrial fibrillation patients; an observation attributed to the involvement of potential confounders. Findings in this dissertation may have implications in the use of FXa-specific DOACs as thrombolytic adjuncts and as the anticoagulants of choice in preventing post-thrombotic syndrome, a common long-term morbidity in patients with deep vein thrombosis that may result from delayed or impaired clot dissolution. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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