Thrombin generation and the pharmacodynamics of parenteral anticoagulants

Parenteral anticoagulants are mainstay therapies in critical care and perioperative settings because of their unique pharmacological properties, but they have a narrow therapeutic window. This emphasizes the need to thoroughly understand their pharmacodynamics effects on hemostasis. Thrombin generation assays provide a comprehensive measure of coagulation and can characterize class-specific anticoagulant effects. We reviewed the literature with a focus on parenteral anticoagulants to define the role of thrombin generation as a pharmacodynamic measure of anticoagulation status. We contextualize these results in light of findings from a prior review on the effects of oral anticoagulants on thrombin generation and consider our findings in view of results stemming from comparative anticoagulation-focused epidemiologic research. This review provides proof of principle that, from a pharmacodynamics perspective, not all anticoagulants are the same. They exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects, such as unfractionated or low-molecular-weight heparins, are better able to suppress thrombin generation than selective direct inhibitors, such as bivalirudin, argatroban, direct oral anticoagulants, or factor XI(a) inhibitors. We propose a conceptually valid theoretical framework, grounded in mechanistic rationale, supported by experimentation, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants. The knowledge reviewed herein may support the future development of more personalized approaches to anticoagulation treatment. Our findings contribute a foundation upon which future anticoagulation research can be based and warrant further investigation. SIGNIFICANCE STATEMENT: From a pharmacodynamic perspective, not all anticoagulants are the same. Oral and parenteral anticoagulants exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects are better able to suppress thrombin generation than selective direct inhibitors. This review proposes a theoretical framework, grounded in mechanistic rationale, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants.