By Gary M. White, MD

Cryoglobulins are immunoglobulins that precipitate at or below normal body temperature. The may form naturally presumably through loss of sialic acid residues. When overproduced or if the liver which normally clears them rapidly is damaged, they may accumulate. They have been divided into type I) single monoclonal, II) mixed monoclonal and polyclonal and III) mixed polyclonal. When a significant amount of monoclonal cryoglogulins accumulate in the serum, vascular occlusion may occur. It typically occurs in the cutaneous vessels, but those of internal organs may occasionally be affected. In patients with mixed or polyclonal cryoglobulinemia, the symptoms are the result of circulating immune complexes.

I) Single monoclonal IgG, IgM, IgA or (rarely) light chain

Associated with lymphoproliferative disorders, e.g. multiple myeloma, Waldenstrom's macroglobulinemia, lymphoma and lymphocytic leukemia and in some cases, idiopathic.

II) Mixed monoclonal and polyclonal

One monoclonal (IgM usually, but also IgG) and the rest polyclonal (IgG usually, but also IgM). It may be associated with connective tissue disease, viral hepatitis B or C, other infections and occasionally with lymphoproliferative diseases.

III) Mixed polyclonal

Polyclonal IgG or IgM. This may be associated with Hepatitis C.


Necrosis, purpura (may be reticulate), leg ulcers, livedo reticulatis, cold urticaria and Raynaud's phenomenon are presenting features in two thirds of patients with cryoglobulinemia. Palpable purpura, arthralgias and a glomerulonephritis may occur. The term cryocrit has been coined to describe the amount of cryoglobulin present. A reticulate pattern of purpura may develop on the legs in a patient with cryoglobulinemia. The cryoglobulins preferentially precipitate in the border areas between the blood-dispersing arterial cones where the blood flow is slow and the temperature, cool [BJD 1993;129;319].


Referral to a hematologist is in order. Bed rest, NSAIDs avoiding cold, trauma and prolonged standing may be enough for mild disease. For more significant disease, immune suppressive agents (e.g. prednisone, azathioprine, chlorambucil, or cyclophosphamide) may be used. There has been some success in treating HCV and mixed cryoglobulinemia with interferon alfa. Plasmapheresis has been done [AD 1996;132;498] and can be very effective.


Purpura of the legs, cutaneous ulcers, and livedo reticularis. Clinical and Developmental Immunology Volume 2012 (2012), 11 pages

Acronecrosis upon cold exposure.
Reumatología Clínica Vol 08. Num 02. March 2012 - April 2012

Acral purpuric macules in cryoglobulinemic vasculitis. Actas Dermosifiliogr. 2012;103:179-91 - Vol. 103

Large necrotic lesion. Dermatol. Argent., 2014, 20 (4): 244-247


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