Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia (AIHA) characterized by immunoglobulin M (IgM)-mediated red blood cell agglutination and hemolysis due to activation of the classical pathway of complement system.1 CAD usually occurs in the seventh decade of life, more frequently in women.2 The mean age of patients is between 67 and 72 years, with a wide range of 30 to 92 years.2,3 However, CAD that develops before the age of 50 years is very rare.4
Hemolysis mediated by cold agglutinins results in mild to moderate chronic anemia. Besides hemolysis, clinical features of CAD include cold-induced circulatory conditions such as Raynaud disease, acrocyanosis, livedo reticularis, and cutaneous necrosis in rare cases.2
Cold Agglutinin-Mediated Hemolysis
AIHA is associated with CAD in 15% to 25% of cases. The characteristic feature of CAD is red cell lysis mediated by cold agglutinins, which are IgM autoantibodies that cause erythrocyte agglutination, usually at 0°C to 4°C. The autoantibodies bind to erythrocyte surface antigen 1, activating the classical pathway of the complement system via the C1 complex; this process eventually results in a series of events that cause primarily extravascular hemolysis and to a lesser extent intravascular hemolysis.5 The hemolysis may vary in severity from compensated hemolysis without anemia to a severe form of hemolytic anemia necessitating transfusions.6 Case reports have described seasonal hemolysis due to weather changes and paradoxical hemolysis due to febrile or other acute illnesses.7
Cold-induced symptoms, which range from mild acrocyanosis to disabling Raynaud phenomena,8 are documented in more than 90% of cases.3 Other cold-induced circulatory features include livedo reticularis and cutaneous ulceration or necrosis. Affected individuals experience discomfort and pain on swallowing cold liquids and food. Acrocyanosis is characterized by a violaceous, dusky discoloration of the acral regions of the body, such as the fingertips, nose, toes, and ears. Raynaud phenomenon is a common condition characterized by vasospasms in the digits, which cause sharply demarcated color changes of the skin. The exaggerated vasoconstriction induced by cold is a reflex response to cooling mediated by the sympathetic nervous system and by the activation of ɑ2C adrenoceptors locally.6,9
Thromboembolic Risk and Mortality
Patients with many different types of hemolysis have been found to have a higher incidence of episodes of venous and arterial thromboembolic episodes that ffect quality of life and lead to premature mortality.10 Few studies in the literature have described thrombotic events in patients with CAD. In a longitudinal analysis of 29 cases, 17% of the patients had at least one thrombotic event.11 In a small cohort of 13 patients with CAD enrolled in a phase 2 trial, 31% of the patients had had 7 thrombotic events before the start of treatment.12 In a review of 72 Danish patients, the incidence of venous thromboembolism was higher in those with CAD than in age- and sex-matched controls; however, these differences were not statistically significant. The authors recognized that the difference may have been due to the small sample size. Subgroup analysis revealed that the patients with severe hemolysis were at increased risk for venous thromboembolism.5 A retrospective study of 608 patients with CAD showed a clear association, reporting that 29.6% of patients with CAD experienced at least one venous thromboembolism event vs 17.6% of patients without CAD (adjusted hazard ratio, 1.94; 95% CI, 1.64‐2.30).10
Secondary Cold Agglutinin Syndrome
Cold agglutinin production is precipitated by infection, resulting in secondary cold agglutinin syndrome (CAS). Secondary CAS has been seen in association with Mycoplasma pneumoniae infection and viral infections with Epstein–Barr virus, influenza virus, and varicella virus.13
B-Cell Lymphoproliferative Disease
The association of CAD with plasma cell, B-cell, and lymphoproliferative diseases has been documented in various studies. In a study conducted in 1982 of 78 patients (average age, >60 years) with persistent cold agglutination, associated lymphoid malignancies were seen in approximately 65%, including lymphomas in 40%, Waldenström macroglobulinemia in 17%, and chronic lymphocytic leukemia (CLL) in 8%.14
A case series performed in 2013 enrolled 89 patients with CAD (median age, 65 years). Lymphoid disorders were noted in approximately 78% of cases, including monoclonal gammopathy of undetermined significance (MGUS) in 61%, other lymphomas in 12%, unspecified lymphoproliferative disorders in 12%, macroglobulinemia in 9%, and CLL in 6%.2
The probability of transformation of a CAD-associated lymphoproliferative disorder to aggressive lymphoma is approximately 3.5% over 10 years.3 Common late-onset hematologic malignancies include diffuse large B-cell lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndrome. Late-onset solid tumors also develop in some patients.15
- Hill QA, Punekar R, Morales Arias J, Broome CM, Su J. Mortality among patients with cold agglutinin disease in the United States: an electronic health record (EHR)-based analysis. Blood. 2019;134 (Suppl 1):4790. doi:10.1182/blood-2019-122140
- Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114–1121. doi:10.1182/blood-2013-02-474437
- Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population-based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.
- Hansen DL, Berentsen S, Fattizzo B, Hansen PL, Barcellini W, Frederiksen H. Seasonal variation in the incidence of cold agglutinin disease in Norway, Denmark, and Italy. Am J Hematol. 2021;96(7):E262-E265. doi:10.1002/ajh.26196
- Bylsma LC, Ording AG, Rosenthal A, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980–2985. doi:10.1182/bloodadvances/2019000476
- Brugnara C, Berentsen S. Cold agglutinin disease. UpToDate. Updated April 22, 2021. Accessed September 12, 2021.
- Lyckholm LJ, Edmond MB. Seasonal hemolysis due to cold-agglutinin syndrome. N Engl J Med. 1996;334(7):437. doi:10.1056/NEJM19902153340705
- Berentsen S. Cold agglutinin disease. Hematology Am Soc Hematol Educ Program. 2016;2016(1):226-231. doi:10.1182/asheducation-2016.1.226
- Fardoun MM, Nassif J, Issa K, Baydoun E, Eid AH. Raynaud’s phenomenon: a brief review of the underlying mechanisms. Front Pharmacol. 2016;7:438. doi:10.3389/fphar.2016.00438
- Broome CM, Cunningham JM, Mullins M, et al. Increased risk of thrombotic events in cold agglutinin disease: a 10-year retrospective analysis. Res Pract Thromb Haemost. 2020;4:628-635. doi:10.1002/rth2.12333
- Mullins M, Jiang X, Bylsma LC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization. Blood Adv. 2017;1(13):839-848. doi:10.1182/bloodadvances.2017004390
- Röth A, Bommer M, Hüttmann A, et al. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018;2(19):2543-2549. doi:10.1182/bloodadvances.2018024190
- Jensen CE, Wilson S, Thombare A, Weiss S, Ma A. Cold agglutinin syndrome as a complication of Covid-19 in two cases. Clin Infect Pract. 2020;7-8:100041. doi:10.1016/j.clinpr.2020.100041
- Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med. 1982;72(6):915-922. doi:10.1016/0002-9343(82)90852-x
- Berentsen S, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488. doi:10.1182/blood.2020005674
Reviewed by Kyle Habet, MD, on 9/14/2021.