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Introduction: Protein C (PC) deficiency results in dysregulated thrombin generation and increases thrombosis risk., Methods: In order to investigate the potential effects of anticoagulant drugs in PC deficiency, we evaluated the pharmacodynamic effect of selective direct factor (F) IIa inhibitors (dabigatran and argatroban), selective direct FXa inhibitors (rivaroxaban and apixaban) and an indirect FXa/FIIa inhibitor (enoxaparin) in commercial PC-deficient plasma using thrombin generation and viscoelastometry assays modified to reflect PC anticoagulant activity., Results: Endogenous thrombin potential (ETP) and peak thrombin concentration (PTC) were increased in PC-deficient plasma but this corrected completely with PC concentrate. Inhibition of FIIa and FXa with the selective inhibitors also corrected the increased ETP and PTC but required high drug concentrations. There was sustained low-level thrombin generation in PC-deficient plasma with FXa inhibitors but not with FIIa inhibitors. Adding PC concentrate to PC-deficient plasma anticoagulated with dabigatran had little additional effect on ETP or PTC. In contrast, addition of even small quantities of PC concentrate to PC-deficient plasma anticoagulated with rivaroxaban further diminished ETP, primarily by abolishing sustained thrombin generation. In the viscoelastometry assay, the coagulation time was shortened and α-angle increased in PC-deficient plasma. These abnormalities reversed with both dabigatran and rivaroxaban., Conclusion: The selective direct FXa and FIIa inhibitors at high concentrations both counteracted the abnormal thrombin generation and clot formation observed in PC-deficient plasma, but with qualitative differences in their effects., (© 2019 John Wiley & Sons Ltd.)