Cold Agglutinin Disease (CAD)

Most patients with cold agglutinin disease (CAD) are unaware of their condition, especially if living in a region with a warm climate. There is a 4-fold difference between the incidence and prevalence of CAD in colder and warmer climates.1

Common complications of CAD include hemolytic anemia and cold-induced symptoms, which range from mild to severe. Cold agglutinin syndrome (CAS) has been recently reported in the setting of coronavirus disease 2019 (COVID-19).2  CAD can be associated with underlying malignancy and is referred to as secondary CAD in this instance.3 Primary CAD-associated lymphoproliferative disorder is the term used to describe a series of bone marrow abnormalities, including gains of chromosome 3, 12, or 18 and lymphoid infiltration of nodular B-cell aggregates found in some patients with CAD.4,5 This entity is distinct from lymphoplasmacytic lymphoma (LPL) and is not associated with extramedullary lymphoma.6 

Hemolytic Anemia

The largest observational study of CAD reported that the mean baseline hemoglobin level was 9.3 mg/dL, with 27% of patients possessing levels below 8 mg/dL. Ninety percent of patients with CAD have abnormal hemolytic biomarkers (elevated LDH and bilirubin and decreased haptoglobin). The associated elevated complement levels and decreased hemoglobin concentration contribute to the fatigue experienced by patients with CAD.1  

Cases of devastating hemolysis with microvascular occlusion and subsequent organ failure have been reported during cardiopulmonary bypass surgery involving hypothermia.7

Cold-Induced Symptoms

Acrocyanosis, livedo reticularis, mild to severe Raynaud’s phenomenon, and odynophagia to cold liquids are common cold-induced manifestations of CAD. They are more common in patients inhabiting regions with cold climates.1  

Cold Agglutinin Syndrome (CAS)

Production of autoantibodies to erythrocytes can be triggered by certain viral and bacterial infections including Mycoplasma pneumoniae, Epstein-Barr virus, varicella, and influenza virus. This process is denominated cold agglutinin syndrome. Recently, CAS in the setting of COVID-19 has been described, which resulted in 1 death.2 

Severe Raynaud’s Phenomenon

Raynaud’s phenomenon is an exaggerated vasoconstrictor response to cold that affects the acral regions of the body. It is mediated by the sympathetic nervous system and is usually painful. It is clinically evident by pallor and cyanosis of the digits following exposure to the cold.8 The abnormal vasoconstrictor response in patients with CAD may be so exaggerated that it leads to ulceration, necrosis, or gangrene of the affected digits.9,10

Venous Thromboembolism

There is conflicting evidence on whether CAD is associated with an increased risk of venous thromboembolism (VTE). A review of 72 Danish patients found that the incidence of VTE was increased in patients with CAD compared to age- and sex-matched controls, however, these differences did not achieve statistical significance. The authors recognized that this may have been due to a small sample size. Subgroup analysis revealed that patients with severe hemolysis were at increased risk for VTE.11 A retrospective study of 608 patients with CAD showed a clear association, reporting that 29.6% of affected patients experienced at least 1 VTE vs 17.6% of patients without CAD (adjusted hazard ratio: 1.94; 95% CI: 1.64‐2.30).12  

Primary CAD-Associated Lymphoproliferative Disorder

Previously, LPL was described as the underlying cause of CAD in up to 75% of cases. Using immunohistochemistry, flow cytometry, and gene sequencing analysis, it was revealed that biopsy specimens of patients with CAD have unique characteristics; this condition is now categorized as a distinct entity named primary CAD-associated lymphoproliferative disorder. Furthermore, testing for the MYD88 L265P mutation, which is commonly seen in LPL, was negative in the tested samples.4 

Late-Onset Malignancies

The probability of transformation of CAD-associated lymphoproliferative disorder to aggressive lymphoma is approximately 3.5% over 10 years.13 Common late-onset hematologic malignancies include diffuse large B-cell lymphoma, acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndrome. Some patients also develop late-onset solid tumors.1 


1. 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

2. 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

3. 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

4. Randen U, Trøen G, Tierens A, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014;99(3):497-504. doi:10.3324/haematol.2013.091702

5. Małecka A, Delabie J, Østlie I, et al. Cold agglutinin-associated B-cell lymphoproliferative disease shows highly recurrent gains of chromosome 3 and 12 or 18. Blood Adv. 2020;4(6):993-996. doi:10.1182/bloodadvances.2020001608

6. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121. doi:10.1182/blood-2013-02-474437

7. Findlater RR, Schnell-Hoehn KN. When blood runs cold: cold agglutinins and cardiac surgery. Can J Cardiovasc Nurs. 2011;21(2):30-34; quiz 35-36.

8. 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

9. Oh SH, Kim DS, Ryu DJ, Lee KH. Extensive cutaneous necrosis associated with low titres of cold agglutinins. Clin Exp Dermatol. 2009;34(7):e229-230. doi:10.1111/j.1365-2230.2008.03078.x

10. Iwasaki H. Acronecrosis with cold agglutinin disease mimics diabetic gangrene. Intern Med. 2013;52(7):837-838. doi:10.2169/internalmedicine.52.9313

11. Bylsma LC, Gulbech Ording A, 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

12. 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(4):628-635. doi:10.1002/rth2.12333

13. 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.

Reviewed by Harshi Dhingra, MD, on 9/7/2021.