Cryoglobulinemia is a systemic condition characterized by the presence of cryoglobulins -- immunoglobulins that reversibly precipitate at temperatures below 37C and redissolve upon warming. When these abnormal proteins precipitate in the cooler peripheral microcirculation (fingers, toes, ears, nose, skin of the lower extremities), they deposit in small vessel walls, activate the complement cascade, and trigger a small-vessel vasculitis that can damage the skin, kidneys, peripheral nerves, and other organs. Cryoglobulinemia is classified into three types based on the Brouet classification. Type I cryoglobulinemia consists of a single monoclonal immunoglobulin (usually IgM or IgG) and is associated with lymphoproliferative disorders such as Waldenstrom macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. The monoclonal protein precipitates in the cold, causing hyperviscosity and vascular occlusion rather than immune complex-mediated inflammation. Type II cryoglobulinemia (mixed cryoglobulinemia) consists of a monoclonal IgM with rheumatoid factor (RF) activity directed against polyclonal IgG. Type III cryoglobulinemia consists of polyclonal IgM with RF activity directed against polyclonal IgG. Types II and III are collectively called 'mixed cryoglobulinemia' because they contain more than one immunoglobulin class. Mixed cryoglobulinemia is the...