To the Editor:
We read with great interest the intriguing study by Walker et al.1 involving 14 adult patients receiving extracorporeal life support (ECLS) who were transitioned to bivalirudin as alternative systemic anticoagulation in the context of heparin-induced thrombocytopenia (HIT), heparin resistance, persistent clotting or bleeding while on heparin. We commend the authors for their work in this important area and share their passion and enthusiasm for caring for ECLS patients.
Walker et al.1 reported favorable outcomes with 64% surviving to successful ECLS decannulation and 50% surviving to hospital discharge in this high-risk population. The majority of the patients reported by Walker et al.1 received bivalirudin secondary to suspicion for or confirmed HIT and as such additional attention to this indication is warranted. Although uncommon, HIT during ECLS remains a recognized entity with one study reporting its diagnosis in three of nine acute respiratory distress syndrome patients.2 It should be noted that the diagnosis of HIT in patients treated with ECLS is challenged by the multitude of factors that can precipitate a drop in platelet count including sepsis, disseminated intravascular coagulation, activation by artificial surfaces, and various medical disorders thereby necessitating laboratory testing (heparin-platelet factor 4 enzyme-linked immunosorbent assay [ELISA] and confirmatory heparin-induced platelet aggregation or serotonin release assay).3 However, despite negative test results HIT may still be present.4 Reinforcing this clinical challenge, Walker et al.1 reported positive HIT ELISAs in eight of the 11 cases with a suspicion for HIT. Among the remaining three patients with negative HIT ELISAs, two experienced a 50% decrease in platelets without thrombosis and one patient developed thrombotic complications despite therapeutic heparinization.
Given the necessity of systemic anticoagulation during ECLS and the nontrivial reported incidence and complications of HIT, alternative strategies for achieving therapeutic anticoagulation are necessary. Bivalirudin is a semisynthetic bivalent inhibitor of thrombin that produces transient reversal of thrombin with a short half-life of 25 minutes. Although its clearance is largely organ independent (blood proteases), the kidneys provide approximately 20% of its clearance necessitating dose adjustments with moderate renal insufficiency and its molecular properties facilitate clearance with hemodialysis.5 Unlike the heparin–antithrombin III complex, bivalirudin exerts its effect by directly attaching to and inhibiting both free and fibrin-bound thrombin.6 Potential advantages over unfractionated heparin include the inhibition of fibrin (clot)-bound thrombin, a lack of binding to other plasma proteins yielding a more predictable anticoagulant response, no effect on platelet factor 4, and independence of antithrombin as cofactors producing a cleaner and more consistent anticoagulant effect.7
In addition to the importance of renal clearance well outlined by Walker et al.,1 bivalirudin carries other unique risks that are relevant to the ECLS population. Owing to its pharmacological profile, bivalirudin is rapidly cleaved by proteolytic enzymes with a short elimination half-life. In areas of stagnant blood flow where bivalirudin concentrations cannot be maintained by continuous systemic infusion of the drug, thrombus formation may be experienced because of the rapid cleavage of bivalirudin (such as during cardiac surgery with cardiopulmonary bypass, pericardial and pleural spaces, hard-shell cardiotomy reservoir, and stagnant atrial or ventricular blood flow).8 To avoid this condition, at our center in cases of intracardiac stasis bivalirudin is avoided. If ongoing bivalirudin therapy is necessary then maintenance of partial extracorporeal membrane oxygenation (ECMO) support is provided thereby maintaining a minimal degree of intracardiac blood flow. Given the risks associated with reduced circuit flow when employing bivalirudin, a protocol for anticoagulation management during ECLS weaning is essential to avoid thrombus formation during low-flow states.
The authors should be applauded for describing well the impact of renal function and renal replacement therapy on bivalirudin dosing during ECLS. However, the approach as described is reactionary rather than anticipatory in that dosing was guided by activated partial thromboplastin time (aPTT) levels that fluctuated in part because of changes in renal clearance (native or through dialysis). Evidence of the limitations of this approach includes the wide variation in initial infusion rate (0.02–0.26 mg/kg/h) and median time to target aPTT (0.4–13.7 hours) that Walker et al.1 reported. In addition, the median maintenance infusion rates of bivalirudin for all patients regardless of their renal function and for those patients who received CRRT were reported in the study. However, drawing conclusions from the data and applying the maintenance dosing in clinical practice is limited because of the small sample size (n = 14) and the limited number of patients within each creatinine clearance ranges. In contrast, our center developed an algorithmic-based approach that determines initial starting dose and dose adjustments based on estimated creatinine clearance. It is possible that this approach may accelerate the time to therapeutic anticoagulation while minimizing the number of titration steps necessary to achieve therapeutic dose particularly during rapidly changing effective renal function. This approach may also be easily adopted and applied by other ECMO centers.
We would like to congratulate the authors for their shrewd observation that in some patients, there is limited aPTT response at times despite notable increases in the bivalirudin infusion rates. It is in line with our center’s experience. The plausible explanations behind this phenomenon are likely twofold in addition to what might be attributed to intra- and interpatient variability. First of all, it is a known conundrum that all parenteral direct thrombin inhibitors (DTI) experience flattening of the dose response curve with a loss of linearity of DTI concentration and aPTT values at high dose ranges.9 This is an inherent limitation of using aPTT to monitor DTIs. Second, the less well-known phenomenon of the so-called apparent DTI resistance has started to gain recognition and understanding among the medical professionals with the increased widespread use of DTIs.10,11 Apparent DTI resistance refers to the presence of elevated factor VIII levels that interfere with the laboratory aPTT assays, which makes the aPTT value artificially low and seemingly disproportionate to the degree of the increase in DTI doses. Elevated factor VIII levels are widely prevalent in the critically ill patient population as one of the acute phase reactants.12 This is similar to what has been recognized and described in cases of elevated factor VIII levels contributing to apparent heparin resistance (an inadequate aPTT response in vitro despite appropriate in vivo antithrombotic efficacy of heparin as measured by anti-Xa levels).13 This phenomenon has significant clinical implications in terms of its recognition and management. At our center, if this phenomenon is suspected in setting of a confirmed elevated factor VIII level, alternate laboratory tests including thrombin time and activated clotting time have been pursued as an adjunct to monitor bivalirudin effect (Ecarin clotting time is not readily available). In addition to the dose capping as alluded to by Walker et al.1, the most important measure is to use clinical indicators including ECMO circuit patency and potential thrombotic and bleeding complications as our ultimate guidance for anticoagulation titration rather than solely relying on the number of aPTT values.
Although the available evidence for the use of bivalirudin as first line for systemic anticoagulation (i.e., not as salvage therapy because of refractory hemorrhage, thrombosis, HIT, or heparin resistance) remains limited, bivalirudin has been demonstrated to have potential advantages in post cardiotomy ECMO patients including a substantial reduction in aPTT variability, a reduction in blood loss, a decrease in allogeneic blood product transfusions, and a reduction in total patient cost versus heparin-based anticoagulation.14,15 The largest case series to date describing the use of bivalirudin in pediatric patients on ECMO found it viable as a potential option in patients who develop heparin resistance, heparin-induced thrombocytopenia, or significant thrombosis while on heparin.16 Although we concede that it is premature to recommend bivalirudin as first line during ECLS, based on the available published evidence it is time that larger well-conceived retrospective, or ideally randomized prospective, studies be undertaken to clarify the indication and role of bivalirudin in ECLS. Furthermore, a better understanding of the optimal dosing, monitoring, and the unique considerations of bivalirudin in ECLS patients is crucial given the relatively high rates of thrombotic and hemorrhagic complications in this complex patient population.
Troy G. Seelhammer
John K. Bohman
Devon O. Aganga
Department of Anesthesiology and Perioperative Medicine
Mayo Clinic College of Medicine
Department of Cardiovascular Surgery
Mayo Clinic College of Medicine
Department of Pharmacy
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