Introduction
Tacrolimus is the standard immunosuppressant used in paediatric orthotopic heart transplantation. Tacrolimus-associated haemolytic anaemia is a rare and life-threatening side effect seen in patients after haematopoietic stem cell transplant or solid organ transplant, and it can present with different phenotypes with complement activation as a common pathway. Reference Wong1,Reference Jodele2 We present a case of a 6-year-old patient with a history of orthotopic heart transplant on tacrolimus immunosuppression who developed life-threatening and refractory haemolysis. He recovered fully following treatment with eculizumab, a monoclonal antibody directed towards complement C5. This is the first reported case describing the use of eculizumab in a paediatric orthotopic heart transplant recipient to treat severe haemolytic anaemia associated with tacrolimus immunosuppression.
Case description
The patient is a 6-year-old with Noonan syndrome with prenatally diagnosed double outlet right ventricle and hypoplastic aortic arch that was repaired in infancy. At one year of life, he had worsening subaortic stenosis leading to a cardiac arrest requiring veno-arterial extracorporeal membrane oxygenation support, and he ultimately received an orthotopic heart transplant. Following transplant, his immunosuppression was maintained with tacrolimus and azathioprine.
Four years after transplant, he presented to his local institution with emesis and was found to be anaemic, with a haemoglobin of 5.0 g/dL. Laboratory workup demonstrated significant haemolysis, coagulopathy, and an acute kidney injury. An echocardiogram demonstrated new mild to moderate tricuspid regurgitation and elevated right ventricular systolic pressures. He received 5 mL/kg packed red blood cells and was transported to our institution for further management.
Rapid ex vivo haemolysis in our patient’s samples suggested that cold haemolysis was driving his condition. However, direct antiglobulin test suggested warm and cold haemolysis, as both IgG autoantibodies and C3 were detected. Therefore, methylprednisolone was initiated to treat warm haemolysis in addition to rituximab for cold agglutinin-mediated haemolysis. Tacrolimus trough was 18.7 ng/mL (goal trough 5–8 ng/mL) and subsequently replaced with sirolimus. He also received doxycycline for presumed M. pneumoniae infection, as IgG and IgM antibodies reactive to Mycoplasma pneumoniae were detected in his serum—IgM M. pneumoniae antibodies are classically associated with cold haemolysis.
Soon after arrival, the patient decompensated, requiring vasoactives, intubation, chest tube placement, and continuous renal replacement therapy. The patient’s haemolysis persisted, and he also developed microangiopathy with thrombocytopenia and schistocytes. He was initiated on plasma exchange therapy in attempt to remove the antibodies contributing to his haemolysis. A summary of the patient’s course can be seen in Figure 1A. Because of the patient’s continued critical illness and ongoing need for transfusions despite systemic steroids, rituximab, and plasma exchange, the decision was made to treat with eculizumab with four weekly doses. Following the initial dose of eculizumab, the patient’s haemoglobin stabilised; and after the second dose of eculizumab, his clinical status, transfusion requirement (Figure 1B), and haemolysis improved.
( a ) A timeline of the patient’s hospitalisation by hospital day. Shown in dark grey is the time spent at the patient’s local hospital prior to being transferred to our institution. Pertinent clinical events and initiation of treatments are labelled. Days are not shown to scale. PLEX (plasma exchange therapy). Epi (epinephrine). CRRT (continuous renal replacement therapy). HD (haemodialysis). ( b ) Number of transfusions of RBCs (red blood cells) administered per day of hospitalisation. Units are approximately 250 mL – 300 mL in volume. A 5 mL/kg transfusion of RBC was given at the local hospital prior to transfer.
After three weeks of continuous renal replacement, he was transitioned to intermittent haemodialysis before his kidney function recovered sufficiently. He developed hypertension attributed to his kidney injury necessitating amlodipine and metoprolol. He was initiated on an erythropoietin-stimulating agent and a steroid wean while continuing sirolimus and azathioprine. Due to his treatment with rituximab and eculizumab, he was started on antimicrobial prophylaxis of sulfamethoxazole-trimethoprim and amoxicillin. He ultimately required 27 units of blood, but his haemoglobin has remained stable as of eight months following discharge. Direct antiglobulin test has remained negative. Pertinent laboratory values are listed in Supplementary Table S1.
Discussion
Tacrolimus contributes to the initial immunosuppressant regimen of almost ninety per cent of paediatric heart transplant patients. Reference Colvin3 Haemolytic anaemia is a rare complication of chronic tacrolimus immunosuppression in transplant patients; it can present as either a thrombotic microangiopathy or autoantibody-mediated autoimmune haemolysis, both involving complement activation. Reference Jodele4,Reference Berentsen5 While the exact pathophysiological mechanism of tacrolimus-induced microangiopathy is unknown, it is hypothesised that calcineurin inhibitors, including cyclosporine, can, in a dose-dependent manner, directly damage endothelial cells and form immune complexes, leading to haemolysis. Reference Munjal6,Reference Dhakal7 Patients who develop tacrolimus-associated haemolysis are typically transitioned to alternative immunosuppressive agents, such as sirolimus, as was the case with our patient. Reference Munjal6 Eculizumab is a monoclonal antibody targeted to complement component C5 and can treat complement-induced haemolytic anaemias and microangiopathies. Our patient represents the first documented case of eculizumab treating tacrolimus-associated autoimmune haemolytic anaemia in a paediatric patient after orthotopic heart transplant.
In addition to tacrolimus use, our patient had IgM antibodies to M pneumoniae, which is classically associated with cold haemolysis. However, this is typically self-limiting and only rarely requires intervention. Reference Berentsen8 Given the severity of the presentation, we hypothesise that tacrolimus played a multifactorial role in our patient’s haemolysis. Tacrolimus likely contributed to a dysregulated humoral response, leading to a severe case of infection-associated autoimmune haemolysis, as has been described in other cases. Reference Kanellopoulou9 Furthermore, since the patient did not improve following humoral response-directed treatment, his tacrolimus trough was supra-therapeutic, and there was evidence of a microangiopathic process exacerbating his multisystem organ failure, we hypothesise that direct endothelial toxicity from tacrolimus was also driving our patient’s haemolysis. While there are reported patient-specific factors predisposing to haemolysis, there are no reports associating Noonan syndrome with haemolysis. Reference Valoti10
Eculizumab prevents the cleavage product formation of C5b, a necessary component of the membrane attack complex, and it has been used with success in paediatric stem cell and adult solid organ transplant recipients to acutely treat tacrolimus-associated haemolysis, as well as haemolysis from alternative aetiologies that sometimes require chronic treatment. Reference Jodele2,Reference Dhakal7,Reference Gill and Meghrajani11 Reported use of eculizumab in paediatric orthotopic heart transplant recipients to date has been limited to treatment of antibody-mediated rejection or prevention in high-risk recipients. Reference Law12 Our use of eculizumab in this patient population to treat refractory complement-mediated haemolysis is unique. Our case highlights several important aspects of the care of paediatric patients after heart transplantation. The first is to have a high index of suspicion for haemolysis in a patient presenting with anaemia, as it can rapidly develop into multi-system organ failure. The second is the ability of eculizumab to acutely stabilise a patient with refractory haemolysis.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S1047951125101339
Acknowledgements
Thank you to Dr Dave Wilson for assistance in editing this manuscript.
Financial support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Competing interests
The authors of this manuscript have no conflicts of interest to disclose.
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