In Interdisciplinary CardioVascular and Thoracic Surgery, clinicians presented the rare case of a pediatric patient with cold agglutinin disease (CAD) undergoing cardiac surgery. 

Cold agglutinins can cause hemoagglutination and microvascular thrombosis in cold temperatures; if untreated, they may cause complement fixation and hemolysis. Although this phenomenon has been previously described in cardiac surgery, the incidence is extremely low—less than 1%. 

Case Details

The case study details an infant who was scheduled for cardiac surgery and was known preoperatively to have CAD. The main congenital cardiac anomalies that the 11-month-old patient had were atrial septal defect and pulmonary stenosis. Upon chest auscultation, her physicians detected a systolic ejection murmur III/VI and fixed splitting of the second heart sound at the left second intercostal space. The baby was known to have had cardiac catheterization for percutaneous balloon pulmonary valvuloplasty at 6 months of age; it was effective for valvular but not supravalvular pulmonary stenosis. 

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An echocardiogram was performed, allowing the infant’s physicians to visualize a secundum atrial septal defect measuring 12 mm × 8 mm with left-to-right shunt. Valvular and supravalvular pulmonary stenosis were also observed. A further Doppler ultrasound examination revealed a velocity of 3.8 m/s across the pulmonary valve; this corresponded to a peak systolic pressure gradient of 68 mm Hg. 

Read more about CAD etiology

Upon admission, the infant’s physicians found that she had a preoperative blood testing revealing elevated cold agglutinin titers at 4oC and 25oC. Because information of the cold agglutinins was limited, the clinical team decided to perform an open heart surgery with normothermic cardiac bypass surgery using electrical fibrillation for added safety. 

The surgery was successfully performed—the atrial septal defect was closed and the supravalvular pulmonary stenosis released. No evidence of complications related to cold agglutinins was recorded. An echocardiogram taken 7 days later showed that the atrial septal defect was fully repaired and that the supravalvular pulmonary stenosis improved. The patient was discharged on day 8. 

“In summary, we experienced a case of pediatric cardiac surgery in a patient with cold agglutinins,” the authors of the report wrote. “We recommend preoperative evaluation of cold agglutinin titre and temperature in the cold agglutinin activation, which can give us an individualized surgical planning to prevent cold agglutinin-related complications.”

Precautions for Heart Surgery in a Patient With CAD 

“The optimal guidelines of patients with cold agglutinins undergoing cardiac bypass surgery operation remain controversial because of the limited number of case reports,” Dr Ogawa wrote in BMJ Case Reports.  “Some physicians believe that patients with low titres and low thermal amplitude antibodies may undergo cardiac bypass surgery operation without any change in the routine management plan.” 

Like may rare diseases, the sheer lack of case reports makes it difficult for like-for-like comparisons; randomized controlled trials are also restricted due to ethical reasons. Anecdotal evidence suggests that the biggest risk of conducting cardiac surgery on patients with CAD is that there is a notable risk of complications. 

Based on an aggregate of surgeons’ feedback, there is some consensus that physicians should determine if antigen-negative red blood cells should be used in the event that cold agglutinins are incidentally detected. However, because the benefit of this approach is minimal at best, many physicians choose to forgo any examinations regarding a patient’s cold agglutinin status.

Read more about CAD treatment

Another issue of importance is the temperature that surgeons should maintain when conducting cardiac bypass surgery. Research has concluded that the best temperature for this procedure is less than 37°C to avoid cerebral hyperthermia. In addition, the temperature gradients between arterial output and venous inflow should not be more than 10oC; this is to minimize the risk of gaseous ennobling. However, the presence of cold agglutinins may complicate proceedings.

“The presence of cold agglutinins presents more complicated problems in optimal temperature management during cardiopulmonary bypass,” Ogawa wrote. “According to the experts’ opinion, normothermic cardiopulmonary bypass operation with warm cardioplegia can be safely performed without any complications in patients with cold agglutinins.” 

There is a caveat: in the event that a patient’s background is not readily known, or if the physician lacks experience dealing with patients with CAD, maximum caution is advised. Inexperienced physicians should preoperatively test for antibody titers and thermal amplitudes in close coordination with other medical professionals, working together in a multidisciplinary setting.

“A continuous retrograde hyperkalemic infusion and intermittent antegrade infusion of warm cardioplegia with normothermic cardiopulmonary bypass is one of the best measures for patients with unknown background characteristics and for physicians without much experience in treating this condition,” Ogawa wrote. 

It is worth remembering that the lack of protocol with regard to the specific scenario in the case study is driven by its extraordinary rarity. Nonetheless, a surgeon worth his salt should be well prepared for every eventuality, especially if a wrong move may negatively impact prognosis. As the medical literature around patients with CAD undergoing cardiac surgery increases, we can have every confidence that future guidelines issued will be further finetuned based on best available evidence. 


Hasegawa T, Oshima Y, Maruo A, Matsuhisa H. Paediatric cardiac surgery in a patient with cold agglutininsInteract Cardiovasc Thorac Surg. 2012;14(3):333-334. doi:10.1093/icvts/ivr117

Ogawa T. Cold agglutinins in a patient undergoing normothermic cardiac operation with warm cardioplegia. BMJ Case Rep. 2017;2017:bcr2017221888. doi:10.1136/bcr-2017-221888