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Cryoglobulins are abnormal immunoglobulins that precipitate or form a gel upon exposure to cold temperatures. Cryoglobulins consist of single immunoglobulins or complexes that may fix complement and initiate an inflammatory reaction similar to antigen-antibody complexes. Cryoglobulins are most commonly associated with lymphoproliferative, infectious, and autoimmune diseases. They have been classified as Type 1, 2 or 3 on the basis of their immunoglobulin composition.




Isolated monoclonal IgM or IgG


Monoclonal IgM reactive with polyclonal IgG


Two or more polyclonal immunoglobulins of multiple isotypes

Type 1 cryoglobulinemia is often associated with a monoclonal gammopathy such as a lympho- proliferative or plasma cell disorder. Because Type 1 cryoglobulins do not readily activate complement, patients may remain asymptomatic until the cryoglobulin reaches a high enough concentration to induce hyperviscosity.

Types 2 and 3 are called mixed cryoglobulins because they are composed of more than one immunoglobulin type, one of which has rheumatoid factor activity. A triad of palpable purpura, arthralgia, and weakness characterizes mixed cryoglobulinemia clinically. Other features include Raynaud’s phenomena, renal disease, sensory motor neuropathy, splenomegaly and anemia. CH50 is usually decreased along with a significant depression of C4 and slight depression of C3. Type 2 is the most common cryoglobulinemia and is usually associated with hepatitis C infection. It may also be associated with infections, lymphoproliferative disorders, plasma cell dyscrasias and autoimmune diseases. Type 3 is often associated with liver disease (especially hepatitis C), autoimmune diseases and chronic infections.

Type 1 cryoglobulin generally produces large precipitates within 24 hours of placing the serum at 4oC. Type 2 cryoglobulin often forms small precipitates within 1 to 7 days after refrigeration. The serum concentration of the monoclonal IgM is sometimes too low to be detected by serum protein electrophoresis. Type 3 cryoglobulin usually produces very small precipitates that may not be detected for up to 7 days.

Results are reported as present or absent. If present in sufficient quantity, cryoglobulins can be semi-quantitated by measuring a cryocrit. Immunoglobulin class can be determined by electrophoresis and immunofixation. Failure to detect a cryoglobulin may be due to (1) allowing blood to clot at a temperature below 37 degrees, (2) not incubating in the cold for a sufficient length of time, or (3) binding to serum lipids.

A related condition is cyrofibrinogenemia, which forms complexes of fibrinogen and fibrin in the cold. It is rare, but can also cause vasculitis. Cryo- fibrinogen forms a precipitate in plasma, but not in serum, because fibrinogen is consumed during clotting and is not present in serum specimens.

Phlebotomy should be performed using prewarmed 37 degree into a 10 mL plain red top tube. The tubes should be transported to the laboratory immediately in a thermos filled with 37-degree water.

Reference value is absent.

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