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Contributors: Vivian Wong MD, PhD, Susan Burgin MD, Belinda Tan MD, PhD, Lowell A. Goldsmith MD, MPH
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The cryoglobulinemias are caused by circulating immunoglobulins that undergo reversible precipitation from plasma or serum upon cooling (temperatures less than 37°C [98.6ºF]). Cryoglobulinemia is associated with multiple systemic disorders as outlined below.

Three subtypes of cryoglobulins are characterized, according to immunoglobulin type:
  • Type I cryoglobulins (10%-15% of cases) are monoclonal cryoglobulins typically made of IgM and sometimes IgA or IgG. Type I cryoglobulinemia is associated with lymphoproliferative disorders (most commonly multiple myeloma and Waldenström macroglobulinemia). The monoclonal cryoglobulins precipitate at lower temperatures, leading to vascular occlusion and ischemic damage of tissues. Typically, acral areas are affected.
  • Type II (50%-60% of cases) and Type III (30%-40% of cases) cryoglobulins are mixed cryoglobulins that consist of a rheumatoid factor (IgM) complexed with either a monoclonal IgG (Type II) or a polyclonal IgG or non-immunoglobulin serum component (Type III). While mixed cryoglobulins are most commonly associated with infections (hepatitis B and C, Epstein-Barr virus, cytomegalovirus, leprosy, endocarditis, and more rarely parasitic infections) and rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome), lymphoproliferative diseases (such as chronic lymphocytic leukemia) have also been associated. These complexes cause a small and medium vessel vasculitis due to deposition of IgG/IgM and complement activation.


D89.1 – Cryoglobulinemia

30911005 – Cryoglobulinemia

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

Type I cryoglobulinemia:
Types II and III cryoglobulinemia:

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Management Pearls

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Drug Reaction Data

Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.

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Last Updated: 06/09/2016
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Cryoglobulinemia : Acral, Eschar, Retinal hemorrhage, Ecchymosis, Arthralgia
Clinical image of Cryoglobulinemia
Purpuric macules on the leg and an eschar overlying a purpuric plaque on the ankle.
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