Waldenström's macroglobulinemia and the pre-malignant precursors to this cancer, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenstrom's macroglobulinemia. Monoclonal IgG or, rarely, IgA, κ light chain, or λ light chain cryoglobulins occur in cases of multiple myeloma and the pre-malignant precursors to this cancer, non-IgM monoclonal gammopathy of undetermined significance and non-IgM smoldering multiple myeloma. Non-IgM monoclonal immunoglobulin-based cases of cryoglobulinemic disease are less commonly associated with other B-cell lymphocytic diseases viz., Non-Hodgkin lymphoma, Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and Castleman disease; they occur rarely in non-B cell hematological disorders such as myelodysplastic syndromes and chronic myelogenous leukemia. Among these purely monoclonal immunoglobulin causes of cryoglobulinemic disease, Waldenström macroglobulinemia and multiple myeloma together account for ≈40% of cases; their pre-malignant precursors account for ≈44% of cases; and the other cited hematological diseases account for ≈16% of cases. Mixtures of monoclonal or polyclonal IgM, IgG, and/or IgA along with blood complement proteins such as C4 are the cryoglobulins associated with cases of infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection, and, less commonly or rarely, with cases of other infectious diseases such as hepatitis B infection, hepatitis A infection, cytomegalovirus infection, Epstein–Barr virus infection, Lyme disease, syphilis, lepromatous leprosy, Q fever, poststreptococcal nephritis, subacute bacterial endocarditis, coccidioidomycosis, malaria, schistosomiasis, echinococcosis, toxoplasmosis, and Kala-azar. These mixed-protein cryoglobulins are also associated with autoimmune diseases, particularly Sjögren syndrome, less commonly systemic lupus erythematosus and rheumatoid arthritis, and rarely polyarteritis nodosa, systemic sclerosis, temporal arteritis, polymyositis, Henoch–Schönlein purpura, pemphigus vulgaris, sarcoidosis, inflammatory bowel diseases, and others. In these mixed-protein depositions, the monoclonal or polyclonal IgM typically possesses rheumatoid factor activity and therefore binds to the Fc region of polyclonal IgG antibodies, activates the blood complement system, and complexes with complement components to form precipitates composed of IgM, IgG or IgG, and complement components, particularly complement component 4 (C4). Diagnosis Cryoglobulinemia and cryoglobulinemic disease must be distinguished from cryofibrinogenemia or cryofibrinogenemic disease, conditions which involve the cold-induced intravascular deposition of circulating native fibrinogens. These molecules precipitate at lower temperatures (e.g., 4 °C). Since cryofibrinogens are present in plasma but greatly depleted in serum, precipitation tests for them are positive in plasma but negative in serum. Cryofibrinogenemia is occasionally found in cases of cryoglobulinemic disease. Cryoglobulinemic disease must also be distinguished from frostbite as well as numerous other conditions that have a clinical (particularly cutaneous) presentation similar to cryoglobulinemic