Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia (AIHA).1 In this rare disease, exposure to cold temperatures leads to the production of cold agglutinins, which bind to red blood cells and cause them to agglutinate. The immune system then induces premature hemolysis of the red blood cells and the development of cold-induced autoimmune hemolytic anemia. CAD usually affects middle-aged or older individuals, and the incidence can be higher in women.2

Patient Education Overview

Differences in prevalence rates reported in recent studies may indicate that CAD is underdiagnosed. A misdiagnosis of CAD can delay the therapeutic course of action. Increasing patient and medical staff awareness of the clinical features of CAD may result in an adequate diagnosis.3

The symptoms associated with CAD reflect the reduced number of red blood cells and may vary according to the severity of the hemolytic anemia.2 The symptoms of anemia should be monitored. Patients with CAD need to learn how to identify signs of fatigue, palpitations, dyspnea, and pale or cold skin. In severe cases, anemia can lead to dizziness, chest pain, fainting, and heart failure.2,4 Patients should also be able to identify signs of hemolysis, such as jaundice and dark urine, and should be instructed to seek medical help if they observe these signs. To increase medical staff awareness, patients may wear ID bracelets alerting providers to the fact that they have CAD and informing them about how CAD should be managed in urgent medical situations.5

Other symptoms may develop when circulating blood is affected, such as a dark purple-gray discoloration on the hands and feet (acrocyanosis). Patients with Raynaud phenomenon will see distinct color changes on their fingers and toes, which are commonly painful.5 Patients with CAD need to be aware of the importance of keeping warm and avoiding cold, as hemolysis can be precipitated by exposure to colder temperatures.5 Educating patients to wear adequate clothing in cold environments, avoid cold foods, and control the temperature of their surroundings while working is therefore important.6 When patients are hospitalized or undergo surgery, intravenous fluids and blood products should be administered after they have been warmed to an adequate temperature. 

In addition to low temperatures, fever and acute illness may exacerbate hemolysis. Infections should be treated as soon as possible, and medication should be used to lower the body temperature rather than ice or cooling blankets.5 

Folic acid supplementation can be recommended for patients with CAD. It is important that they adhere to the recommended daily intake prescribed by the medical team because this supplement is required for patients with a chronic hemolytic disease to maintain red blood cell production.6 The recommended daily dose of folic acid is 1 mg.5 

Patient Education Material and Supporting Organizations

Several organizations provide information to patients with CAD, their caregivers, and family members. The Cold Agglutinin Disease Foundation (CADF) is a nonprofit organization formed in 2019 that is dedicated to educating patients with CAD, medical professionals, and care partners.7 The CADF provides access to resource pages with materials that help patients familiarize themselves with their disease and find information on clinical trials designed to assess possible treatments. Patients with a new diagnosis of CAD can also download information about CAD posted by other patients with the disease. Additionally, patients can register on a Members Page to connect with other persons affected by CAD and can use the Cold Agglutinin Disease Foundation Chat through Facebook to connect with other patients socially.

Patients with CAD can register with the Autoimmune Registry, a nonprofit entity that collects and compiles information on autoimmune disease research, statistics, and data.8 The Autoimmune Registry aims to deliver information on the prognosis and available treatments for many autoimmune diseases that patients can access easily. It is currently supporting research on CAD by collecting patient information.  

Additional organizations that help patients find information and provide general support include the American Autoimmune & Related Disease Association (AARDA),9 the Genetic and Rare Diseases (GARD) Information Center,10 the NIH National Heart, Lung, and Blood Institute (NHLBI),11 and the National Organization for Rare Disorders (NORD).12


1. What Is CAD? Cold Agglutinin Disease Foundation. Accessed September 11, 2021.

2. Cold agglutinin disease. National Organization for Rare Disorders. Accessed September 11, 2021.

3. Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and future prospects. J Blood Med. 2019;10:93-103. doi:10.2147/JBM.S177621

4. Anemia. eMedicineHealth. Reviewed September 26, 2019. Accessed September 11, 2021. 

5. Info for medical professionals. Cold Agglutinin Disease Foundation. Accessed September 11, 2021.

6. What is included in patient education about cold agglutinin disease? Medscape. Updated December 2, 2020. Accessed September 11, 2021.

7. CAD Foundation. Cold Agglutinin Disease Foundation. Accessed September 11, 2021.

8. About Autoimmune Registry, Inc. Autoimmune Registry. Accessed September 11, 2021.

9. Who we are. American Autoimmune Related Diseases Association (AARDA). Accessed September 11, 2021

10. Cold agglutinin disease. GARD Genetic and Rare Diseases Information Center. Accessed September 11, 2021

11. Hemolytic anemia. National Heart, Lung, and Blood Institute. Accessed September 11, 2021.12. Cold agglutinin disease.  NORD National Organization for Rare Disorders. Accessed September 11, 2021.

Reviewed by Debjyoti Talukdar, MD, on 9/21/2021.