Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells. Cryoglobulins typically precipitate (clumps together) at temperatures below normal body temperatureand will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become gangrenous. While this disease is commonly referred to as cryoglobulinemia in the medical literature, it is better termed cryoglobulinemic disease for two reasons: 1) cryoglobulinemia is also used to indicate the circulation of (usually low levels of) cryoglobulins in the absence of any symptoms or disease and 2) healthy individuals can develop transient asymptomatic cryoglobulinemia following certain infections. In contrast to these benign instances of circulating cryoglobulins, cryoglobulinemic disease involves the signs and symptoms of precipitating cryoglobulins and is commonly associated with various pre-malignant, malignant, infectious, or autoimmune diseases that are the underlying cause for production of the cryoglobulins. Classification Since the first description of cryoglobulinemia in association with the clinical triad of skin purpura, joint pain, and weakness by Meltzer et al. in 1967, the percentage of cryoglobulinemic diseases described as essential cryoglobulinemia or idiopathic cryoglobulinemia, that is cryoglobulinemic disease that is unassociated with an underlying disorder, has fallen. Currently most cases of this disease are found to be associated with premalignant, malignant, infectious, or autoimmune disorders that are the known or presumed causes for the production of cryoglobulins. This form of non-essential or non-idiopathic cryoglobulinemic disease is classically grouped into three types according to the Brouet classification. The classification distinguishes three subtypes of cryoglobulinemic diseases based on two factors, the class of immunoglobulins in the cryoglobulin and the association of the cryoglobulinemic disease with other disorder. The following table lists these three types of cryoglobulinemic disease, characterized on the monoclonal immunoglobulin(s) comprising the involved cryoglobulin, percentage of total cryoglobulinemic disease cases, and class of disorders associated for each type. The monoclonal or polyclonal IgM proteins involved in Types II and III cryoglobulinemic disease have rheumatoid factor activity. That is, they bind to polyclonal immunoglobulins, activate the blood complement system, and thereby form tissue deposits that contain IgM, IgG (or, rarely, IgA), and components of the complement system, including in particular complement component 4. The vascular deposition of these types of cryoglobulin-containing