Clinical Information

Cryoglobulins are immunoglobulins that precipitate when cooled and dissolve when heated. Because these proteins precipitate when cooled, patients may experience symptoms when exposed to the cold. Cryoglobulins may be associated with a variety of diseases including plasma cell disorders, autoimmune diseases, and infections. Cryoglobulins may also cause erroneous results with some automated hematology instruments.

Cryoglobulins may be classified as follows: Type I, Type II, and Type III. Type I is composed of a monoclonal immunoglobulin: IgG or IgM, or rarely IgA or free monoclonal light chains. Type II cryoglobulins consist of a monoclonal component and a polyclonal component. Finally, type III cryoglobulins are composed of only polyclonal immunoglobulins.

The majority of patients with cryoglobulins are asymptomatic. The type or quantity of cryoglobulin does not reliably predict whether or which symptoms will be present. The concentration of cryoglobulins tends to vary by type with the majority of cases: of type III, being less than 1 mg/mL; of type II, greater than 1 mg/mL; and of type I, greater than 5 mg/mL. Even though the type I cryoglobulin concentrations tend to be the highest, they are the least likely to cause symptoms. The thermal amplitude (temperature at which the cryoglobulin precipitates) is a better predictor of symptoms than quantity or type.

Symptoms of cryoglobulinemia include purpura, Raynaud phenomenon, cyanosis, skin ulceration, gangrene, kidney failure, peripheral neuropathy, fever, and malaise.

Type I cryoglobulinemia is associated with monoclonal gammopathy of undetermined significance, macroglobulinemia, or multiple myeloma.

Type II cryoglobulinemia is associated with autoimmune disorders such as vasculitis, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, and Sjogren syndrome. It may be seen in infections such as hepatitis, infectious mononucleosis, cytomegalovirus, and toxoplasmosis. Type II cryoglobulinemia may also be essential, ie, occurring in the absence of underlying disease.

Type III cryoglobulinemia usually demonstrates trace levels of cryoprecipitate, may take up to 7 days to appear, and is associated with the same disease spectrum as Type II cryoglobulinemia.

A cryoprecipitate that is seen in plasma but not in serum is caused by cryofibrinogen. Cryofibrinogens are extremely rare and can be associated with vasculitis. Patients with cryofibrinogenemia often present asymptomatically, but this disorder can also be secondary to numerous conditions that include, but are not limited to, malignancies, infection, inflammation, or thrombotic disorders. Of those with symptoms, primary or essential cryofibrinogenemia can present with systemic manifestations or with a more specific clinical picture that typically includes cold intolerance and thrombotic/hemorrhagic manifestations, such as purpura, necrosis, ulcers and gangrene. Due to the rarity of clinically significant cryofibrinogenemia, testing for cryoglobulins is usually sufficient for investigation of cryoproteins.