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Cryoglobulins are circulating immunoglobulins found in both serum and plasma that reversibly precipitate or gel upon cold exposure. Cryofibrinogens result from precipitation of fibrinogens on cold exposure and are detectable only in plasma samples, not serum. This chapter focuses on conditions that lead to either microvascular occlusion (Type I cryoglobulinemia and cryofibrinogenemia) or small- and medium-sized vessel vasculitis (Type II and III cryoglobulinemia) with emphasis on lesion morphology and cutaneous manifestations.



  • Cryoglobulins are circulating immunoglobulin complexes found in plasma or serum that reversibly precipitate in cold temperatures.

  • Cryoglobulinemia may be asymptomatic or cause a clinical syndrome involving the skin: purpura at distal sites is the hallmark. Livedo reticularis, acrocyanosis, ulceration, or gangrene also may be seen.

  • Cryoglobulins are classified based on molecular properties into Types I, II, III (Brouet classification).

  • Type I cryoglobulins consist of a single monoclonal immunoglobulin (typically IgG) or light chain. They occur with hematologic malignancies such as multiple myeloma. If symptomatic, they present with a noninflammatory occlusive vasculopathy.

  • Type II cryoglobulins consist of a monoclonal immunoglobulin (typically IgM) complexed with a polyclonal immunoglobulin (typically IgG).

  • Type III cryoglobulins consist of purely polyclonal immunoglobulin complexes; Type II-III refers to an intermediate state with oligoclonal immunoglobulin.

  • Types II and III are also referred to as mixed cryoglobulinemias. They are caused by chronic hepatitis C virus (HCV) infection in >90% of cases, whereas in a minority of cases no etiology can be identified, designating them as “essential mixed” cryoglobulinemias. They present as the cryoglobulinemic vasculitis syndrome, an immune complex vasculitis involving the skin, neural, and renal tissues.

  • Therapy primarily consists of controlling the underlying disease. In addition, immunosuppressants, plasma exchange, or targeting of cryoglobulin-producing B-cell clones may alleviate the cryoglobulin burden.



In 1933, Wintrobe and Buell first noted the in vitro phenomenon of cryoprecipitation, the cold-induced precipitation of plasma or serum proteins that is reversible upon rewarming at 37°C (98.6°F).1 In 1947, Lerner and Watson described immunoglobulins and mixtures of immunoglobulins with other proteins that precipitate in the cold and called them cryoglobulins.2 In 1974, Brouet introduced the classification of cryoglobulins based on molecular properties that is widely used.2 Cryoglobulinemia describes the presence of cryoglobulins in a patient’s serum (Fig. 144-1). It can be asymptomatic, meaning that its presence usually goes clinically undetected, or it can cause occlusive vasculopathy or the so-called cryoglobulinemic syndrome, which is characterized by immune-complex deposition causing vasculitis that involves the skin and other tissues.

Figure 144-1

Whitish cryoprecipitates after keeping tube at 4°C (39.2°F) for 48 hours and centrifugation.

The classification scheme of Brouet, estimated frequency, and composition of cryoglobulins is depicted in Table 144-1. Type I cryoglobulins consist of a single monoclonal immunoglobulin (Ig), typically IgM, ...

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