Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is a rare disease characterized by hemolytic anemia. It is caused by autoantibodies or cold agglutinins (CAs), primarily immunoglobulin M antibodies, which bind to red blood cells (RBCs) when exposed to cold temperatures. The temperature below which the CAs bind to the RBCs is called the thermal amplitude of the CAs.1,2 

Presence of CAs means that any surgical procedure that requires cooling in these patients poses several challenges. Lower temperatures may lead to CA activation that may eventually lead to hemolysis and ischemic complications. To reduce the risks involved in surgical operations, the titer of CAs in CAD patients needs to be reduced prior to the surgery so as to lower the effective thermal amplitude of CAs. This can be done temporarily by using a combination of plasmapheresis2,3 and hemodilution4,5 performed prior to the surgery.

In addition, the temperature range at which CAs are activated to bind to the RBC surface should be quantified prior to the surgical procedure so as to avoid activation of CAs during surgery. Therefore, the patient’s core body temperature should be closely monitored intraoperatively to avoid cooling and prevent hemolysis.6

Surgical techniques including normothermic cardiopulmonary bypass and continuous warm blood cardioplegia have been successfully used for CAD patients undergoing cardiac surgery.

The surrounding temperature in the surgery room should also be monitored and kept warm before, during, and after surgery to avoid cooling. Similarly, fluids and blood should be warmed appropriately prior to infusion at all times. Thus, multidisciplinary cooperation and planning are required, with inputs from the consulting hematologist, laboratory testing service, anesthesiologist, operative room staff, and the surgical team to ensure a safe and successful surgery.

A study reviewed management of CAD patients over 8 years (2002 to 2010) at the Mayo Clinic, where 10 patients with high levels of CAs and 6 patients with CAD underwent cardiac surgery. The study found that patients with CAD could be safely operated on using warm blood cardioplegia (​​temporary cessation of cardiac activity), provided they undergo laboratory testing (including tests to assess CA titers and thermal amplitude) as well as hematology consultation before cardiac surgery. A patient required preoperative plasma exchange. Another patient experienced CA-related postoperative hemolysis requiring transfusion, which was resolved with active warming.8

A case study reported the prophylactic use of eculizumab (anti-C5 monoclonal antibody) for the prevention of severe hemolysis following cardiac surgery in a patient with CAD prone to exacerbation of hemolysis.9

In another case study, an 85-year-old male with bladder cancer, who was diagnosed with CAD during preoperative evaluation, safely underwent radical cystectomy. The surgical team followed several preventive measures to reduce hemolysis including conducting plasmapheresis, keeping the patient warm using warming devices, and warming all intravenous fluids and blood products. The patient required blood transfusion after surgery, and rituximab therapy was started for long-term management.10

In surgeries such as organ transplantation, the organs are infused with a warm perfusate, which is otherwise cold to preserve organ function. In a case study of an older female with CAD, large-volume plasma exchange prior to transplant and infusion of warm saline resulted in successful kidney transplantation.11

General Recommendations for Surgery

Prior to Surgery

CAD patients should undergo hematology and anesthesiology consultations. Plasmapheresis should be performed to reduce the titer of CAs. The patient should be kept warm by adjusting the operative room temperature. Blood products or fluids should be appropriately warmed.10

During Surgery

Cross-matched, warmed blood products should be available during the surgery in case transfusions are needed for severe anemia. A patient’s body temperature and hemoglobin levels should be closely monitored. All intravenous and surgical fluids should be warm.10

After Surgery

The patient’s surrounding temperature should continue to be warm. Plasmapheresis should be considered if needed. Blood tests should be performed, such as basic metabolic panel, complete blood count, comprehensive metabolic panel, haptoglobin test, and lactate dehydrogenase test. Hematology consultation should be provided, and the patient should be followed up. Pharmacologic therapy such as rituximab should be initiated for long-term management if needed.10


  1. Cold agglutinin disease. Genetic and Rare Diseases Information Center (GARD). Accessed September 21, 2021.
  2. Agarwal SK, Ghosh PK, Gupta D. Cardiac surgery and cold-reactive proteins. Ann Thorac Surg. 1995;60(4):1143-1150. doi:10.1016/0003-4975(95)00501-b
  3. Park JV, Weiss CI. Cardiopulmonary bypass and myocardial protection: management problems in cardiac surgical patients with cold autoimmune disease. Anesth Analg. 1988;67(1):75-78.
  4. Gallimore KS, Maurer WG. The effect of hemodilution on cold agglutinins. J Extra-Corpor Technol. 1987;19(3):290-296.
  5. Oliver WC, Nuttall GA. Chapter 18 – Uncommon cardiac diseases. In: Kaplan JA, ed. Essentials of Cardiac Anesthesia. Elsevier; 2008:chap 18. Accessed September 22, 2021.
  6. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437
  7. Atkinson VP, Soeding P, Horne G, Tatoulis J. Cold agglutinins in cardiac surgery: management of myocardial protection and cardiopulmonary bypass. Ann Thorac Surg. 2008;85(1):310-311. doi:10.1016/j.athoracsur.2007.02.002
  8. Barbara DW, Mauermann WJ, Neal JR, Abel MD, Schaff HV, Winters JL. Cold agglutinins in patients undergoing cardiac surgery requiring cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2013;146(3):668-680. doi:10.1016/j.jtcvs.2013.03.009
  9. Tjønnfjord E, Vengen ØA, Berentsen S, Tjønnfjord GE. Prophylactic use of eculizumab during surgery in chronic cold agglutinin disease. BMJ Case Rep. 2017;2017:bcr2016219066. doi:10.1136/bcr-2016-219066
  10. Southern JB, Bhattacharya P, Clifton MM, Park A, Meissner MA, Mori RL. Perioperative management of cold agglutinin autoimmune hemolytic anemia in an older adult undergoing radical cystectomy for bladder cancer. Urol Case Rep. 2019;27:100998. doi:10.1016/j.eucr.2019.100998
  11. Vilayur E, Trevillian P, Heer M. Successful renal transplantation in a patient with cold agglutinin disease. J Clin Apher. 2017;32(1):56-58. doi:10.1002/jca.21460

Reviewed by Debjyoti Talukdar, MD, on 9/23/2021.