EXPLANATION


Bivalirudin is a direct thrombin inhibitor (DTI) that exerts its anticoagulant effect by binding both circulating and clot-bound thrombin, thus preventing cleavage of fibrinogen to fibrin. It is metabolized via proteolytic cleavage (80%) and renal excretion (20%), and its half-life is age-dependent, ranging from 15-18 minutes in children to 25 minutes in healthy adults. There are no reversal agents. While bivalirudin has been recently FDA-approved in adults in the setting of percutaneous coronary angioplasty, there are no approved indications in the pediatric population. It is, however, increasingly used in patients on mechanical circulatory support (MCS), including extracorporeal membrane oxygenation (ECMO). In most ICUs, bivalirudin is usually started at 0.3 mg/kg/h and titrated for an aPTT value of 1.5-2.5x normal. In contrast to unfractionated heparin (UFH), it does not depend on the action of antithrombin III (ATIII), thereby providing more stable levels of anticoagulation, which is particularly relevant in a population with highly variable ATIII levels. A study by Freniere et al. compared bivalirudin to UFH in children with Berlin Heart ventricular assist devices (VAD). Similar to other studies, they found there were no differences in thrombotic or hemorrhagic complications between both groups, but chest tube output was reduced in the bivalirudin group. Patients in the aPTT-monitored bivalirudin group had a shorter time to reach the therapeutic range (5.7 vs. 69.5 hours) and a greater percentage of test results and time in the therapeutic range compared to the anti-Xa-monitored UFH group. Interestingly, when anticoagulation was measured with aPTT for both drugs, the time to reach therapeutic levels was no longer statistically different, thus highlighting the importance of how anticoagulation is measured.


APTT is an assay that classically measures the activity of the tissue factor/ extrinsic pathway. However, it is sensitive to a plethora of factors, including contact activation from artificial surfaces, inflammation, and variations in factor VIII levels. Moreover, anticoagulation with DTIs does not exhibit a linear correlation with commonly used tests, including aPTT, ACT, and kaolin-activated TEG, particularly at higher plasma concentrations. This may lead to erroneous dosing of bivalirudin, especially during MCS with ECMO or cardiopulmonary bypass (CPB). More recently, dilute thrombin time (dTT) has emerged as a more precise assay, as it provides a better correlation with bivalirudin plasma levels. A study by Engel et al. looked at several aPTT, dTT, and experimental bivalirudin-specific dTT assays in children on ECMO and with VADs who were anticoagulated with bivalirudin. They found the experimental and conventional dTT assays all correlated with the bivalirudin dosing but poorly correlated with aPTT. This supports the idea that while aPTT is widely used to measure bivalirudin anticoagulation due to its history and availability, it remains a suboptimal assay.


UFH may also be monitored with a PTT, with a similar level of imprecision. The anti-Xa assay is used to measure UFH and low-molecular-weight heparin (LMWH) and is more sensitive than aPTT, leading to faster achievement of target anticoagulation and lower dose requirement. However, it cannot be used for bivalirudin monitoring as the latter does not exert its effect on factor X. The activated clotting time (ACT) is widely used to measure heparin anticoagulation during vascular or cardiac surgical procedures. It remains non-specific to any type of anticoagulant drug or physiologic disturbance and is unreliable to measure bivalirudin anticoagulation, even when used for CPB.


The correct answer is B. aPTT is the most commonly used test to monitor patients on bivalirudin. ACT and anti-Xa are used to monitor anticoagulation with UFH and LMWH.


REFERENCES


Faraoni D, DiNardo JA. Bivalirudin: The misunderstood alternative to heparin. Paediatr Anaesth. 2024;34(5):394-395. doi:10.1111/pan.14868


Freniere V, Salerno DM, Corbo H, et al. Bivalirudin Compared to Heparin as the Primary Anticoagulant in Pediatric Berlin Heart Recipients. ASAIO J. 2023;69(5):e205-e211. doi:10.1097/MAT.0000000000001921


Engel ER, Perry T, Block M, Palumbo JS, Lorts A, Luchtman-Jones L. Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018-2022. Pediatr Crit Care Med. 2024;25(7):e328-e337. doi:10.1097/PCC.0000000000003527


Zaleski KL, DiNardo JA, Eaton MP. Bivalirudin: Are kids just adults to the ¾ power? Paediatr Anaesth. 2021;31(6):628-630. doi:10.1111/pan.14168