Cold agglutinins were first described by Landsteiner in 1903 [¹]. Their pathological action against red blood cells (haemolytic anaemia) and blood vessels (Raynaud's syndrome) was described some years later by Clough and Iwai [²,³]. In 1953 Schubothe coined the term: Cold Agglutinin Disease (CAD) [⁴].

CAD is characterized by an auto-antibody [⁵] which is able to agglutinate red blood cells (RBCs) at temperatures lower than that of the body, and subsequently to activate the complement system responsible for lysis of RBCs.

Patients show haemolytic anaemia of varying degrees of severity, as well as episodes of hemoglobinuria and acrocyanosis, which arise or worsen upon exposure to low temperatures.

Cold agglutinin antibodies are mainly specific for the I/i and H RBCs membrane systems [⁶], and their production can be stimulated by Mycoplasma pneumoniae or infection by the Epstein-Barr virus, as well as by lymphoproliferative disorders such as Waldenström's macroglobulinemia.

The auto-antibody involved is usually an IgM, less frequently an IgA or IgG, which is able to agglutinate RBCs at temperatures of between 0 and 5°C. Complement activation generally occurs between 20 and 25°C, but is also possible at normal body temperature. It is also important to note that agglutination is not necessary for complement activation, especially in patients with high levels of auto-antibodies (wide thermal range of cold agglutinins) [⁷,⁸]. This obviously has serious repercussions in a clinical setting.

A 48-year-old Caucasian man presented to the Accident and Emergency Department of our hospital with symptoms of extreme asthenia, but showed no evidence of Raynaud's syndrome. In the past few months, he had complained about a productive cough and post-prandial vomiting. At admission, he was evidently dehydrated and undernourished, very pale, dyspnoeic and tachycardiac (110 bpm) at rest. Heart sounds were soft but no other pathologic sign concerning his lungs and abdomen was noted. His blood pressure was 80 over 50 mmHg.

A blood cell count showed severe anaemia (haemoglobin = 3.8gr/dl) and the patient was prescribed an emergency transfusion of RBCs (0 Rh-positive), owing to the severe anaemia associated with dyspnoea and tachycardia at rest, and hypotension. Blood samples were also sent to our Blood Transfusion Service at this time. Previous data relating to our patient was not found in our records.

After centrifugation, samples showed low hematocrit and normal plasma appearance. The direct blood group test resulted in unequivocally A with Rh phenotype Ccddee, while the indirect test revealed agglutination of B cells and a strong agglutination of 0 cells. Antibody screening also showed strong agglutination (4+) of all panel cells.

The above-mentioned Accident and Emergency Department was immediately alerted to our patient's immunohaematological situation, and we advised urgent cessation of the transfusion of RBCs (0 Rh-positive), which the physician had already initiated as prescribed by the emergency guidelines in force. We also recommended our patient's transferral to the Haematology Department in Ferrara City Hospital, where he arrived in a state of severe cardiovascular shock.

Blood samples taken from him at this time showed dramatic haemolysis, which led to his death within a few hours.

Subsequent blood tests revealed the presence of cold agglutinin syndrome with very high levels of anti-H (1:65.600). He showed positive (3+) results for the direct antiglobulin test for complement fractions, which caused the intravascular haemolysis and consequent cardiovascular shock.

His death prevented further attempts to define the aetiology of his condition. However, an emergency ultrasonography had shown several enlarged lymph nodes (average diameter, 5 cm) along the iliac vessels and the thoracic and abdominal aorta, suggesting a lymphomatous pathology.

The dramatic clinical situation of our patient upon presentation led the physician to commence emergency transfusion of universal RBCs (0 Rh-positive) according to the guidelines which were designed to safeguard against major complications such as multi-organ failure due to severe anaemia.

However, the transfusion of 0 RBCs, expressing a large amount of H antigens, caused dramatic haemolysis, cardiovascular shock and our patient's death within a few hours.

We conclude that emergency transfusion of universal red blood cells (0 Rh-positive/negative) may be dangerous and the risks of the procedure should be assessed against the risks of delaying transfusion until the pre-transfusion tests are completed.

The authors declare that they have no competing interests.

GL and DR performed pre-transfusion evaluations and made the diagnosis; then they searched the literature for other similar reports. GL and RR drafted the manuscript. All authors read and approved the final manuscript.

Written consent was obtained from our patient's next-of-kin for publication of this case study. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

The authors greatly appreciate the technical assistance of Ms. Paola Bonauguro and Mr. Alberto Castellani.