Cold agglutinin dieaseD59.1

Autoimmune hemolytic anemia due to cold agglutinins of the IgM type.

Chronic cold agglugtinin syndrome is classified as follows:

• Idiopathic: Age > 50 yrs (very rare)
• Secondary: Mostly in B-cell lymphomas or autoimmunological diseases. Patients with MGKS/MGUs type IgM kappa produce increased IgM through clonal B-cells and are often the trigger for cold agglutinin disease.

Cold agglutinins are complement-activating autoantibodies that agglutinate strongly at 0-50 C. IgM antibodies already bind to erythrocytes at approx. 30oC (this temperature is the temperature of the acres at normal outside temperature) with complement activation. Pseudagglutination during storage of the blood sample disappears immediately after warming. The clumping of the erythrocytes leads to ischemia of the downstream end-stream pathways. The bound IgM antibodies are recognized and marked by the complement factor C1q. This leads to activation of the complement cascade via the classic pathway and to the formation of a C3 convertase. This in turn cleaves C3 into C3a and C3b, which is further cleaved into C3c and C3d. In addition, C3b forms C5 convertase when it attaches to C4bC2a. In further steps, this forms the membrane-attacking complex, which leads to direct lysis of the cell. This leads to intra- or extravascular hemolysis. The latter mainly takes place in the liver.

Men at an advanced age. Chronic cold agglugtinin syndrome is often a sign of malignant lymphoproliferative diseases.

Leading symptom: acrocyanosis on exposure to cold - reversible after warming (DD: in Raynaud's syndrome); anemia, acute intravascular hemolysis with hemoglobinuria after exposure to cold. Clinically, the disease is characterized by pallor of the affected person's skin in the cold. It is also characterized by cold acres and a livedo appearance of the extremities.

Blood count: polychromasia, spherocytes

Autoagglutination of the blood at room temperature

High-titer monoclonal IgM antibodies (mostly against the I/i antigen complex, a blood group system on erythrocytes)

Direct monospecific Coombs test shows strong complement loading (C3d, C3c) Di:  Indirect evidence: difficulties in blood collection (agglutination of red cells in the puncture cannula), MCV incorrectly high due to agglutination, difficulties in counting red cells, in preparing a smooth blood smear, in cross-matching.

ESR strongly accelerated at room temperature, at 37°C (incubator) normal ESR!

Determination of the cold agglutinin titer at 4°C and avidity/thermal amplitude:

Important for the laboratory: either immediately desalinate the blood while warm (the serum may then cool down) or send it warm to the laboratory. Clinically relevant are usually titers > 1: 1,000 and Ak with high avidity (the closer to body temperature, the more relevant).

Cold agglutinins of the anti-I type are found in mycoplasma infections and benign monoclonal gammopathy.

Furthermore, cold agglutinins of the anti-i type are found in mononucleosis and malignant lymphomas.

In a larger collective (n=534) of patients with monoclonal IgM disorders, IgM cryoglobulinemia was identified in around 25%. Of these, 76% had Waldenström's macroglobulinemia (WM), 5% had another non-Hodgkin's lymphoma (NHL) and 19% had a monoclonal IgM gammopathy of undetermined significance(MGUS).

Clinically, IgM-associated disorders (including cold agglutinin disease/CAD, amyloidosis and Schnitzler syndrome) were found in 31% of patients, more frequently in MGUS than in Waldenström's macroglobulinemia or non-Hodgkin's lymphoma.

Half of all patients were found to have active manifestations at cryoglobulin diagnosis: vasomotor (22%), cutaneous (16% - acroyanosis, livedo images of the skin), peripheral neuropathy (22%) and hyperviscosity (9%). Age was the only predictor of overall survival. Predictors of cryoglobulinemic treatment/cryoglobulinemic death were hyperviscosity (Khwaja J et al. 2024).

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2. Fukushima H et al (2023) Cold agglutinin syndrome. N Engl J Med 389:642.
3. Jochums F et al. (2024) A blue face. JDDG22: 1685-1688
4. Khwaja J et al. (2024) Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia. Br J Haematol 204:177-185.
5. Läuchli S et al. (2001) Cold agglutinin disease--the importance of cutaneous signs. Dermatology 202:356-358.
6. Rottem M et al. (2006) Autoimmune hemolytic anaemia in the antiphospholipid syndrome. Lupus. 15:473-477.