Cold Agglutinin Disease Clinical Presentation

Updated: Feb 07, 2022
  • Author: James Carson Collie, MD; Chief Editor: Michael A Kaliner, MD  more...
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A common complaint among patients with cold agglutinin disease is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months.

Cold agglutinin–mediated acrocyanosis differs from Raynaud phenomenon. In Raynaud phenomena, caused by vasospasm, a triphasic color change occurs, from white to blue to red, based on vasculature response. No evidence of such a response exists in cold agglutinin disease. [25]

Other symptoms of cold agglutinin disease include the following:

  • Respiratory symptoms - May be present in patients with Mycoplasma pneumoniae infection

  • Hemoglobinuria (the passage of dark urine that contains hemoglobin) - A rare symptom that results from hemolysis, this may be reported following prolonged exposure to cold; hemoglobinuria is more commonly seen in paroxysmal cold hemoglobinuria

  • Chronic fatigue - Due to anemia

Anemia in patients with cold agglutinin disease may be mild, moderate, or severe. Along with fatigue, symptoms of anemia include pallor, dyspnea, and poor feeding.

Other symptoms of cold agglutinin disease, such as a history of weight loss and adenopathy, can be related to the underlying disease state associated with the production of cold agglutinins.

The severity of the clinical manifestations of the cold agglutinins themselves varies from an inconsequential laboratory finding, in cases of the benign variety, to serious manifestations, such as acute hemolytic crises and Raynaud-type phenomena, in cases of the more malignant variety.


Physical Examination

Physical examination may reveal nothing unusual or only pallor, unless the patient is observed during or shortly after cold exposure. Purplish discoloration of the ears, forehead, tip of the nose, and digits may then be seen. Livedo reticularis has been observed as well. Ischemic necrosis can lead to pain, but skin ulceration secondary to ischemia is uncommon.

Splenomegaly and jaundice, characteristic of lymphoproliferative disorders or infectious mononucleosis, are usually absent, but they may sometimes be observed in patients with chronic cold agglutinin disease.

Lymphadenopathy, fever, or both may be present in patients with lymphoma, infectious mononucleosis, or other infections.

Pulmonary signs, such as rales and fever, may be found in patients with Mycoplasma pneumonia. [27, 15]  Other findings, including hepatomegaly, relate to the presence of underlying or associated disease states. Signs of congestive heart failure or shock are rare but may be present when anemia is severe.