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 temperature – 37 degrees Celsius (99 degrees Fahrenheit) – and 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.
The monoclonal IgM involved in Type I cryoglobulinemic diseases lacks rheumatoid factor activity.More recent high resolution protein electrophoresis methods have detected a small monoclonal immunoglobulin component in type III cryoglobulins and/or a micro-heterogeneous composition of oligo-clonal (i.e., more than one monoclonal) immunoglobulin components or immunoglobulins with structures that do not fit into any classifications in the cryoglobulins of ≈10% of type II and III disease cases. It has been proposed that these cases be termed an intermediate type II-III variant of cryoglobulinemic disease and that some of the type III cases associated with the expression of low levels of a one or more isotypes of circulating monoclonal immunoglobulin(s) are in transition to type II disease. Signs and symptoms
The clinical features of cryoglobulinemic disease can reflect those due not only to the circulation of cryoglobulins but also to any underlying hematological premalignant or malignant disorder, infectious disease, or autoimmune syndrome. The following sections of clinical features focuses on those attributed to the cryoglobulins.