[16] and [17] The association between cold hemagglutination and hemolysis was first reported in 1937.18 CA can be determined semi-quantitatively by the titer, based on their ability to agglutinate erythrocytes at 4 °C.4 Screening for CA

have shown that a high proportion of the adult population has CA in serum without any evidence of hemolysis or other disease.[5] and [15] These normally occurring CA are polyclonal and are found in low titers, usually below 64 and rarely exceeding 256.5 On the contrary, in 172 consecutive individuals with monoclonal IgM in serum, significant CA activity was found in 8.5% with titers between 512 and 65,500, and all individuals learn more with detectable CA had hemolysis.19 Thus, monoclonal CA are generally far more pathogenic than polyclonal CA. The thermal amplitude is defined as the highest temperature at which the CA will react with the antigen.[4] and [20] In general, the pathogenicity of CA is more dependent on the thermal amplitude than on the titer.[20] and [21] The normally occurring CA have low thermal amplitudes. If the thermal amplitude exceeds 28–30 °C, erythrocytes will agglutinate in

the circulation in acral parts of the body even at mild ambient temperatures and, often, complement fixation and complement-mediated hemolysis will ensue. CA should not be confused with cryoglobulins. Occasionally, BAY 73-4506 in vivo however, patients have been reported in whom the cryoprotein had both CA and cryoglobulin properties.[8], [22] and [23] CA are most often directed against

the Ii blood group system.[4] and [24] About 90% of CA are anti-I specific while most of the remaining ones show specificity for i.[3] and [5] The I and i antigens are carbohydrate macromolecules and the densities of these antigens on the erythrocyte surface are inversely proportional. Neonatal red blood cells almost exclusively express the i antigen, while the I antigen predominates in individuals of 18 months of age and older.25 Hence, CA with anti-I specificity are generally more pathogenic in children and adults than those specific for the i antigen.[5], [25] and [26] Occasionally, CA show specificity against the erythrocyte surface protein antigen designated Pr and such CA can be highly pathogenic.[26] and [27] Galeterone Several other specificities have been reported but are probably very rare. Cooling of blood during passage through acral parts of the circulation allows CA to bind to erythrocytes and cause agglutination (Fig. 1). Antigen-bound IgM-CA is more prone than IgG to bind complement protein C1 and thereby initiate the classical complement pathway.[28], [29], [30] and [31] C1 esterase activates C4 and C2, generating C3 convertase which leads to the formation of C3b. Upon returning to central parts of the body with a temperature of 37 °C, IgM-CA detaches from the cell surface, allowing agglutinated erythrocytes to separate from each other, while C3b remains bound.