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Woman With Recent Respiratory Tract Infection and Anemia


A 50-year-old woman presents to the emergency department with severe dizziness, weakness, and dyspnea of 1 week’s duration. Ten days earlier, an upper respiratory tract infection (URTI) was diagnosed; over-the-counter cough syrup and acetaminophen were prescribed. However, the patient’s condition has steadily deteriorated since then. In addition, her urine has darkened over the past few days.

A 50-year-old woman presents to the emergency department with severe dizziness, weakness, and dyspnea of 1 week’s duration. Ten days earlier, an upper respiratory tract infection (URTI) was diagnosed; over-the-counter cough syrup and acetaminophen were prescribed. However, the patient’s condition has steadily deteriorated since then. In addition, her urine has darkened over the past few days.


The patient is obese and has hypertension and depression. She takes enalapril, hydrochlorothiazide, and a selective serotonin reuptake inhibitor.


Vital signs are stable and normal, except for a heart rate of 108 beats per minute. Conjunctivae are pale and mucous membranes are moist; no oropharyngeal lesions are evident. Chest is clear, and heart is normal. An abdominal examination reveals no masses or organomegaly; bowel sounds are normal. Lymph nodes at all sites are nonpalpable, and skin is normal.


On admission, a complete blood cell count reveals a hemoglobin level of 4.9 g/dL, a hematocrit of 15.4%, a white blood cell count of 17,400/μL, and a platelet count of 404,000/μL. A chemistry profile reveals a slightly elevated serum creatinine level of 1.8 mg/dL and a blood urea nitrogen level of 26 mg/dL. Lactate dehydrogenase level is elevated at 386 U/L, and haptoglobin level is low at 8 mg/dL. Total bilirubin level is normal. Results of a direct antiglobulin test (Coombs test) are positive +2 for C3 and negative for IgG.

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This patient has acute hemolysis secondary to the URTI. The results of her direct antiglobulin test are consistent with the presence of cold agglutinins. In addition, red blood cell agglutination was seen on the peripheral blood smear.

Pathophysiology of cold agglutinin hemolysis. Most cases (up to 90%) of cold agglutinin hemolysis are mediated by IgM antibody. Hemolysis in patients with IgM antibodies is carried out via the complement pathway. IgM antibodies can be transient polyclonal antibodies, as they typically are in postinfectious disease, or they can be persistent monoclonal antibodies, as is usually the case in primary cold agglutinin disease.

The antibodies target primarily I/i blood antigens on the surface of erythrocytes; rarely, they also target anti-Pr and anti-P. When the blood cools, antibody- antigen complex is formed; this in turn induces complement activation via the classic pathway.

The conditions under which agglutination can occur are determined by the antibodies’ thermal amplitude, which is defined as the highest temperature at which the antibody will bind to the antigen. Erythrocyte agglutination caused by cold agglutinins always occurs at temperatures below 4°C (39.2ºF)1 but is rare at core temperature. Cold agglutinins can be found in serum of healthy volunteers; however, these immunoglobulins lack any clinical significance because their thermal amplitude typically does not exceed 15°C to 20°C (59ºF to 68ºF). The thermal amplitude of cold agglutinins in patients with cold agglutinin disease, on the other hand, usually exceeds 25°C (77ºF).2

When blood in which agglutination has occurred is subsequently warmed to 37°C (98.6ºF) (which in vivo occurs in the central parts of the body), the antibody-antigen complex breaks. However, the complement remains bound to the red blood cell, and erythrocytes that are covered by complement are destroyed by macrophages in the reticular endothelial system, mainly in the liver. The extent of hemolysis is determined mainly by the antibody titers and, more important, by the antibodies’ thermal amplitude.

Diseases associated with cold agglutinin hemolytic anemia. Cold agglutinin hemolysis has been described in a number of infections, most notably mycoplasmal infection. Affected patients typically present with signs of hemolysis 2 to 3 weeks after infection onset. The hemolysis is usually mild and self-limited, although it can be fatal. Cold agglutinins seen with mycoplasmal infection are polyclonal IgM anti-I antibodies.

Another self-limited infection associated with cold agglutinins is Epstein- Barr virus (EBV)-related infectious mononucleosis. The IgM antibodies associated with EBV mononucleosis are usually anti-i and transient, and the hemolysis resolves when the infection subsides. Occasionally, corticosteroid therapy is required when the hemolysis is severe.

Other infections associated with cold agglutinins include Cytomegalovirus infection, rubella, varicella zoster, Chlamydia psittaci infection, and parvovirus B19 infection. Persistent polyclonal cold agglutinins have also been reported in patients with HIV infection.3

Patients in whom no underlying infectious cause is identified require further evaluation to rule out a monoclonal disorder. Monoclonal cold agglutinins have been associated with lymphoproliferative diseases. In those settings, the immunoglobulins are products of the malignant clone rather than a reactive process involving normal lymphocytes. Most commonly, monoclonal cold agglutinins are anti-i.

The explosive onset of this patient’s condition, in association with a significant URTI, make a mycoplasmal infection a far more likely cause than the clinically more chronic monoclonal forms of cold agglutinin hemolysis (which are suggested by choices A and C).

Clinical and laboratory findings. Patients with cold agglutinin–mediated hemolysis can present with acrocyanosis and Raynaud phenomenon. Bilirubin and lactate dehydrogenase levels are elevated. Hallmarks of intravascular hemolysis (such as a low haptoglobin level and an elevated plasma free hemoglobin level) can be found in patients with severe hemolysis. A peripheral blood smear will show red blood cell agglutination and an increased number of reticulocytes. Results of a direct antiglobulin test are always positive- most commonly for C3.

Treatment. Most patients with cold agglutinin hemolysis require transfusion. Matching of blood units and ABO identification may be challenging in the presence of the antibodies involved. In polyclonal, postinfectious cold agglutinin hemolysis, treatment is aimed at the underlying cause. In mycoplasmal infection, antibiotics can shorten the duration of ongoing hemolysis. Intravenous immunoglobulin has been used to inhibit ongoing hemolysis until the infection resolves and the immunoglobulins spontaneously clear.4

The management of monoclonal cold agglutinin disease is more challenging and involves treatment to suppress immunoglobulin production. Agents used include corticosteroids, alkalating agents, azathioprine, interferon, purine analogues and, most recently, the monoclonal anti-CD20 antibody, rituximab.

Splenectomy (choice D) has on occasion been used successfully in warm IgG autoimmune hemolysis. However, its track record in cold agglutinin hemolysis is poor.

Outcome of this case. The patient had postinfectious cold agglutinin hemolysis. Azithromycin was started. After transfusion of 4 units of packed red blood cells and several days of antibiotic therapy, the hemolytic process began to subside. Subsequently, serology for Mycoplasma was positive. Her hemolysis continued to abate over the next week, and after 3 weeks she was fully recovered.




. Gertz MA. Management of cold haemolytic syndrome.

Br J Haematol.



. Berentsen S, Beiske K, Tjønnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy.


. 2007;12:361-370.


. McNicholl FP. Clinical syndromes associated with cold agglutinins.

Transfus Sci

. 2000;22:125-133.


. Gertz MA. Cold hemolytic syndrome.

Hematology Am Soc Hematol Educ Program

. 2006:19-23.

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