Cold Agglutinin Disease (CAD)

The treatment of cold agglutinin disease (CAD) depends on the severity of the clinical symptoms, as determined by the characteristics of the antibody, and the presence of associated diseases.1

Avoidance of Cold

Mild CAD symptoms can be managed by simply avoiding exposure to cold temperatures by avoiding cold food and water, using room heaters, and wearing warm clothing (warm shoes, scarves, gloves, ear muffs, warm inners, and stockings).2

In case of hospitalized patients, all of the previously mentioned precautions should be taken to avoid cold temperatures. In addition, intravenous fluids and blood products should be appropriately warmed prior to infusion.3

Treatment for Anemia


Plasmapheresis is a temporary but effective method to remove cold agglutinins (CAs), primarily immunoglobulin (Ig) M autoantibodies, from the plasma. This procedure is performed only in case of emergencies when it is inappropriate to wait for the immunosuppressive drugs to produce an effect. Plasmapheresis can also be performed 1 to 2 days prior to hypothermic surgical procedures to avoid reaccumulation of CAs. Care should be taken to perform plasmapheresis under warm conditions.1

There have been case reports that described a reduction of hemolysis and, in one case, improvement in severe acrocyanosis (a peripheral vascular disorder).4,5

However, this procedure is a temporary relief since it does not treat the cause of anemia, so therapy to address the underlying cause should be initiated concomitantly. 

An alternative form of plasmapheresis called the cryofiltration apheresis (CFA) allows the removal of CAs without removal of other plasma proteins and therefore does not require a replacement fluid such as donor plasma or albumin.6


Blood transfusions may be required in emergency cases with severe hemolysis precipitated by infection or cold during the winter months. As with plasmapheresis, transfused red blood cells (RBCs) provide significant improvement in critical patients but the response is often temporary. The procedure should be performed with special care so that patient samples are kept warm during pretransfusion testing and crossmatching (compatibility testing). An in-line blood warmer is used to appropriately warm blood or any coadministered solutions.7

Therapy to Reduce Antibody Production

Treatment with drugs is indicated only for those patients who have significant symptomatic hemolytic anemia or cold-induced ischemic symptoms that pose challenges to a normal life.1

Corticosteroids and splenectomy are not effective therapies in the majority of patients with CAD. However, response to corticosteroids or splenectomy may be observed in some cases, such as those with a high thermal amplitude CAs or IgG-mediated disease.3

Anti-B-Cell Therapy

This therapy targets the pathogenic B-cell clones in the bone marrow, which produces monoclonal CAs. Rituximab is often used as a first-line therapy. If patients do not respond to rituximab, it can be combined with other drugs such as bendamustine. For those with inadequate or no response to rituximab-containing regimens, bortezomib can be used.8

Therapy is monitored by measuring hemoglobin levels, markers of hemolysis (lactate dehydrogenase, bilirubin, haptoglobin, reticulocyte count), and IgM levels.


Rituximab is an anti-CD20 monoclonal antibody that depletes B-lymphocytes, thereby inhibiting the production of CAs. It may be used alone or in combination with other agents depending on the severity of the disease and the side effects involved.8

Rituximab monotherapy has been shown to be effective in about 50% of patients, with a major reduction in CAs (but not complete removal), a response duration of approximately 1 year, and low toxicity. Rituximab monotherapy is the treatment of choice for patients who are less fit to tolerate combination treatments. The First International Consensus Group on diagnosis and therapy of autoimmune hemolytic anemia recommends rituximab as a first-line treatment, with or without bendamustine, for patients with CAD requiring treatment.9,10

Rituximab-Containing Regimens

The combination of rituximab with bendamustine has been found to be more efficient than rituximab alone and sufficiently safe, with 76% of patients responding to the treatment and a longer response duration. A complete removal of CAs was observed in about 40% of patients.11

Rituximab plus fludarabine combination therapy is approximately as efficient as the combination of rituximab plus bendamustine, however, the combination of rituximab plus fludarabine is more toxic. This combination can be used as a second-line therapy only if the benefits of the therapy outweigh the risks.12


Bortezomib, a proteasome inhibitor used in lymphoid (B-cell) malignancies, can also be used as a second-line therapy if rituximab-containing regimens are ineffective. A study demonstrated the efficacy of 1 cycle of bortezomib monotherapy in one-third of patients who failed previous treatments, with acceptable toxicity and long-lasting benefits.13

Therapy Targeting Complement Proteins

These investigational therapies target the classical complement pathway components responsible for extravascular hemolysis in CAD.


Sutimlimab (also known as BIVV009 or TNT009) is a humanized monoclonal antibody that targets the complement protein C1s, which is an upstream enzyme in the complement pathway that has the potential to reduce extravascular hemolysis mediated by C3b. 

In a recent phase 1b trial in 10 patients with CAD, sutimlimab therapy administered weekly as intravenous infusions rapidly abrogated extravascular hemolysis, significantly increasing hemoglobin levels, normalizing bilirubin levels, and making the patients transfusion-free.14


Eculizumab is a monoclonal antibody that inhibits the complement protein C5, which is a part of the terminal complement complex that mediates cell lysis intravascularly. Although eculizumab inhibits only intravascular hemolysis, it has been found to be effective in severely affected patients with transfusion-dependent CAD refractory to rituximab. It is also used as a prophylactic measure before heart surgery to avoid exacerbation of hemolysis.

In a prospective phase 2 trial, eculizumab inhibited intravascular hemolysis, precluding the need for transfusions. However, anemia and quality of life did not improve.15,16


Pegcetacoplan (previously called APL-2) is a pegylated cyclic peptide inhibitor of C3 administered subcutaneously. Since C3 is at the point of convergence between all 3 complement-activating pathways and the initiation of the terminal lytic pathway, its inhibition is expected to block the entire complement system (including the C3b-mediated opsonization of RBCs in CAD) and may also pose a higher risk of infections.

Interim results from a phase 2 clinical trial have demonstrated pegcetacoplan to be safe and effective in patients with CAD.17 Thus, this anti-C3 therapy seems promising in patients with CAD and further studies are needed.


  1. Cold agglutinin disease. Genetic and Rare Diseases Information Center. Updated May 26, 2016. Accessed September 13, 2021.
  2. Cold agglutinin disease. National Organization for Rare Disorders. Accessed September 13, 2021.
  3. Berentsen S. How I manage patients with cold agglutinin disease. Br J Haematol. 2018;181(3):320-330. doi:10.1111/bjh.15109
  4. Pereira A, Mazzara R, Escoda L, Alcorta I, Nomdedeu B, Roelcke D. Anti-Sa cold agglutinin of IgA class requiring plasma-exchange therapy as early manifestation of multiple myeloma. Ann Hematol. 1993;66(6):315-318. doi:10.1007/BF01695974
  5. Zoppi M, Oppliger R, Althaus U, Nydegger U. Reduction of plasma cold agglutinin titers by means of plasmapheresis to prepare a patient for coronary bypass surgery. Infusionsther Transfusionsmed. 1993;20(1-2):19-22. doi:10.1159/000222800
  6. Siami FS, Siami GA. A last resort modality using cryofiltration apheresis for the treatment of cold hemagglutinin disease in a Veterans Administration hospital. Ther Apher Dial. 2004;8(5):398-403. doi:10.1111/j.1526-0968.2004.00182.x
  7. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012;26(3):107-115. doi:10.1016/j.blre.2012.01.002
  8. Berentsen S, Hill A, Hill QA, Tvedt THA, Michel M. Novel insights into the treatment of complement-mediated hemolytic anemias. Ther Adv Hematol. 2019;10:2040620719873321. doi:10.1177/2040620719873321
  9. Berentsen S, Ulvestad E, Gjertsen BT, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004;103(8):2925-2928. doi:10.1182/blood-2003-10-3597
  10. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648. doi:10.1016/j.blre.2019.100648
  11. Berentsen S, Randen U, Oksman M, et al. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017;130(4):537-541. doi:10.1182/blood-2017-04-778175
  12. Berentsen S, Randen U, Vågan AM, et al. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010;116(17):3180-3184. doi:10.1182/blood-2010-06-288647
  13. Rossi G, Gramegna D, Paoloni F, et al. Short course of bortezomib in anemic patients with relapsed cold agglutinin disease: a phase 2 prospective GIMEMA study. Blood. 2018;132(5):547-550. doi:10.1182/blood-2018-03-835413
  14. Jäger U, D’Sa S, Schörgenhofer C, et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019;133(9):893-901. doi:10.1182/blood-2018-06-856930
  15. Therapy of chronic cold agglutinin disease with eculizumab (DECADE). February 25, 2011. Updated July 19, 2017. Accessed September 13, 2021.
  16. 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
  17. Grossi F, Shum MK, Gertz MA, et al. Inhibition of C3 with APL-2 results in normalisation of markers of intravascular and extravascular hemolysis in patients with autoimmune hemolytic anemia (AIHA). Blood. 2018;132(Suppl 1):3623. doi:10.1182/blood-2018-99-119468

Reviewed by Debjyoti Talukdar, MD, on 9/14/2021.