Cold Agglutinins

Synonyms: Cold agglutinin disease (CAD), cold antibody disease, cold-induced autoimmune haemolytic anaemia

See also related article Haemolytic Anaemia.

Cold agglutinins are autoantibodies that react with antigens on the red blood cell surface. They may induce complement-mediated haemolysis and agglutination (clumping) of red cells (a cryopathic haemolytic syndrome). Cold agglutinins exert their pathological effects via haemolysis and red cell destruction in the reticuloendothelial system, predominantly in the liver, or by agglutination of red cells in peripheral cold-exposed vessels leading to vaso-occlusion.

Cold agglutinins derive their name from the fact that they show maximal activity at temperatures lower than normal body temperature. They are present in low titres in healthy individuals, but may be associated with a range of disease states.

• 'Physiological' cold agglutinins develop as a result of the change in expression of red cell antigens that occurs naturally after birth, and react maximally at about 4 ° C.
• 'Pathological' cold agglutinins are maximally reactive at around 28-31°C and tend to occur at very low titres. They are most commonly of the IgM class but can occur less commonly as IgG and IgA forms.

The cold agglutinin-induced diseases are classified into primary or idiopathic form, and secondary form, caused by the existence of an underlying disease state. Primary cold agglutinins are monoclonal, secondary ones may be either polyclonal or monoclonal.

• Cold agglutinin disease (CAD) is relatively rare. Annual incidence in USA is roughly 1 case per 300,000 population.¹
• Accounts for up to a quarter of all haemolytic anaemias which have an annual incidence in the US of approximately 10 in 300,000.¹
• There appear to have been no UK-based epidemiological studies of cold agglutinin disease.

Either primary (idiopathic) form, or secondary to the following conditions:

Symptoms

• Cold agglutinins may be detected when a routine sample is sent for red blood cells and the results indicate that agglutination is occurring, prompting further tests within the haematology lab. It is thought that many people who develop 'pathological' cold agglutinins remain asymptomatic or become only subclinically unwell.
• Where the illness is more severe and chronic it can cause discomfort and purplish discolouration affecting the fingers and toes and other extremities, such as the nose and earlobes. This usually occurs after being out in the cold and so tends to be worse during the winter.
• If haemolysis is significant enough to cause anaemia then non-specific symptoms such as fatigue and dyspnoea may occur. In patients with angina or cardiac failure, it may cause decompensation of these illnesses.
• If the disease occurs due to pulmonary mycoplasma infection then it may be associated with dyspnoea and cough.
• In severe cases marked intravascular haemolysis can cause haemoglobinuria and the passage of dark urine after cold-exposure.
• Raynaud's phenomenon is usually only a feature of severe cases.
• Non-specific weight loss, anergy and lymphadenopathy may occur in mild, chronic cases, or as a result of an underlying cause for the problem, e.g. lymphoma, infectious mononucleosis.
• A rare presentation of cold agglutinin disease can occur after blood cooling used with cardiopulmonary bypass for thoracic surgery.²

Signs

• Anaemia due to haemolysis may cause pallor affecting skin, mucous membranes, conjunctivae and palmar skin-creases.
• If the patient presents shortly after being out in the cold, then acrocyanosis (purplish discolouration of distal limbs, fingers and toes) may be found. The same is true for the earlobes, forehead and nose.
• Rarely, in severe cases, there is peripheral skin infarction and necrosis with ulcer formation.
• The presence of splenomegaly, hepatomegaly and/or jaundice is unusual in the primary form and suggests an underlying haematological disorder.
• Lymphadenopathy or fever suggest a haematological or infective precipitant.
• The chest should be examined to check for signs of pulmonary consolidation due to pulmonary mycoplasma infection.

• Warm antibody-mediated haemolytic anaemia and drug-induced haemolysis.
• Cryoglobulinaemia (may present with Raynaud's phenomenon but does not show haemolytic features).
• Paroxysmal cold haemoglobinuria (severe CAD can cause haemoglobinuria); PCH is primarily a disease of children and is usually very severe, whereas cold agglutinin disease is more commonly found in older adults and tends to be a mild or subclinical problem.
• Lymphoid neoplasm.
• Other causes of Raynaud's phenomenon, e.g. Rheumatoid arthritis, progressive systemic sclerosis.
• Severe thrombocytopenia, particularly heparin-induced (can present with sore fingers).
• Vasculitides.
• Severe sepsis without cold agglutinin-mediated haemolysis.

• Full blood count and peripheral smear with reticulocyte count (elevated in active haemolysis).
• Urinalysis and urine microscopy for red cells to distinguish haematuria from haemoglobinuria (sample must be fresh as decaying red cells will release haemoglobin).
• Serum globulins and serum protein electrophoresis/immunoelectrophoresis (N.B. Sample must be kept at 37 °C en-route to lab to avoid antibody agglutination and false-negative result).
• Plasma LDH (raised in haemolysis), total and direct bilirubin to confirm/refute haemolysis.
• Consider urine electrophoresis to detect Bence-Jones protein ± 24-hour urine collection for Ig light-chains. These tests usually needed only if abnormality in serum globulins.
• More specialised tests such as Coombs' test, cold-agglutinin titres, Donath-Landsteiner Ab, cryoglobulins etc. will usually be performed under haematological guidance and need expert interpretation; bone marrow/lymph-node biopsy may also be conducted in secondary care if necessary.
• Consider specific antibody titres to possible infective triggers, e.g. Mycoplasma, Influenza.
• If collagen-vascular disease possible perform autoantibody tests according to suspected underlying syndrome.
• Chest x-ray if mycoplasma is suspected.
• Abdominal US/CT if suspected hepato/splenomegaly or lymphadenopathy is detected.

Non-drug

• The vast majority of primary cases require no specific therapy other than wearing warm clothing and taking cold-weather precautions.
• Specialist anti-cold clothing may be needed in severe cases.
• If it is firmly established that there is no underlying cause then the patient should be reassured that the condition is benign and usually resolves, but may be prone to relapses.
• It is wise to follow up patients with idiopathic disease in the long-term in the haematology clinic, as some may later show evidence of a previously covert underlying cause.
• Underlying causes should be treated in conjunction with advice from a relevant specialist along with haematological input.
• Post-infective illness tends to resolve and not return.
• Anaemia need only be treated by transfusion in extreme, severe cases with very low haemoglobin.
• Plasmapheresis removes the offending antibodies from the circulation and may be used in life-threatening cases.¹

Drug

• Folic acid supplementation should be prescribed during active, symptomatic phases of the disease to ameliorate the effects of haemolysis, in an attempt to prevent significant anaemia.
• Steroids may be used under expert guidance in some cases but can mask evidence of some of the underlying causes so they must be given with caution.
• Rarely, chemotherapeutic or immunosuppressant agents are used in severe disease, but only under haematological guidance due to the high risk of adverse effects that could be worse than the agglutinin-associated disease.
• If an underlying haematological neoplasm is found it will usually require anti-neoplastic therapy according to current therapeutic guidelines. TNF-alpha monoclonal antibody modulators such as rituximab have been used on a small scale in refractive cases and may become more widely used following further trials.^3,4

All complications are rare but include:

• Haemolytic crisis following cold exposure or cardiopulmonary bypass
• Ischaemic necrosis of extremities following prolonged cold exposure
• Severe symptomatic anaemia
• Development of malignant disease in patient initially thought to have primary form

• Prognosis is very good for primary cases.
• Post-infective cases usually resolve without problems.
• Those with an underlying non-infective cause have a life expectancy determined by the nature of the disease in question.

• The effects of the cold on sufferers can be reduced through education, appropriate clothing and precautions.
• Folic acid supplementation for active haemolysis.
• Moving to a warmer climate may be advisable for patients who suffer prolonged, severe effects.