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.

Figure 1. ( 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.