Direct thrombin inhibitors (DTIs) such as bivalirudin and argatroban have a predictable anticoagulant response, the ability to inhibit thrombin bound to fibrin, and efficacy in thrombotic environments. These properties make them a valuable tool to manage patients at risk of thrombotic events. DTIs require less frequent monitoring and dose adjustments than heparin. Due to poor correlation of activated partial thromboplastin time with DTI concentration, diluted thrombin time is widely used for monitoring bivalirudin anticoagulation. Emerging monitoring methods are promising and reflect the evolution of precision medicine toward more personalized, real-time monitoring techniques that can guide anticoagulation therapy in complex cases.

Venous thromboembolism (VTE) is rare in pediatric patients, and spontaneous thrombosis in otherwise healthy children presents unique diagnostic and therapeutic challenges. We describe a 15-year-old male who presented with abrupt right leg pain and swelling. Imaging revealed extensive deep venous thrombosis (DVT) involving the right iliac, femoral, and popliteal systems, along with bilateral pulmonary emboli (PEs). He was started on an unfractionated heparin (UFH) infusion but therapeutic anticoagulation was never achieved despite escalating doses, consistent with heparin resistance. During hospitalization, the patient developed worsening clot burden and limb swelling. His hospital course was complicated by worsening clot burden requiring two mechanical thrombectomies. Given failure of UFH, anticoagulation was transitioned to bivalirudin, which stabilized his clinical course and improved perfusion and clot burden on follow-up imaging. He was discharged on enoxaparin, though repeat evaluation at 3 months showed recurrent thrombosis and persistent pulmonary emboli. He was subsequently transitioned to oral dabigatran, after which follow-up ultrasound demonstrated improvement. This case highlights the importance of recognizing heparin resistance in pediatric patients with persistently subtherapeutic anticoagulation, considering mechanical thrombectomy for extensive or limb-threatening thrombosis, and using direct thrombin inhibitors such as bivalirudin when UFH fails. Although experience outside extracorporeal support is limited, bivalirudin may be a safe and effective alternative for pediatric VTE management. This case demonstrates successful use of bivalirudin after heparin resistance and thrombectomy in a pediatric patient without cardiac disease or extracorporeal support, highlighting a novel application of direct thrombin inhibition and the need for further studies to define standardized pediatric dosing, monitoring, and safety outcomes.

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.

IntroductionDirect thrombin inhibitors (DTIs) are an alternative to unfractionated heparin during pediatric ECMO. We aimed to describe their use and limitations across Europe.MethodsFifty-two pediatric EuroELSO centers were surveyed from July to December 2025. Thirty-seven respondents were analyzed across 11 countries.ResultsMost centers (n = 30, 81.1%) were referral sites for pediatric cardiothoracic surgery and 20 (54.1%) also provided non-ECMO mechanical support (i.e., ventricular assist devices [VADs]). Seventeen (45.9%) centers reported having used DTIs for the maintenance of systemic anticoagulation during ECMO at least once over the last years. Of these 17 centers, only 3 (17.6%) use DTIs as a first-line anticoagulant for pediatric ECMO. Most centers (n = 11/17, 64.7%) reserve DTIs for specific situations, such as VAD patients or suspected heparin-induced thrombocytopenia. Among the 17 respondents who reported using DTIs, bivalirudin (BIV) was identified as the preferred agent by 16 (94.1%). Dedicated protocols for DTIs management are implemented in 12 (70.6%) out of these 17 centers. Activated partial prothrombin time is the primary assay for monitoring BIV anticoagulation. From the 16 centers using BIV, only 4 (25.0%) reported having specific assays available. The main reported barrier for DTIs implementation was the lack of guidelines and published protocols (n = 14/20, 70.0%).ConclusionAlthough recent studies have discussed the interest in DTIs, their adoption as first-line anticoagulant during pediatric ECMO remains limited. Findings from this survey indicate the need for more evidence of DTIs clinical benefit, as well as robust guidelines regarding their protocolized use during pediatric ECMO.