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Contributors: Amy E. Blum MD, Vivian Wong MD, PhD, Belinda Tan MD, PhD, Susan Burgin MD
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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.

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 B-cell 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). Mixed cryoglobulinemias are caused by chronic B-cell activation that leads to immune complex formation (IgM / IgG) and deposition in small and medium vessels, resulting in vasculitis. The majority of cases (80%-90%) are associated with chronic hepatitis C virus (HCV) infection. Other infections (hepatitis B virus, HIV, Epstein-Barr virus, cytomegalovirus, leprosy, and, more rarely, other viral, bacterial, and parasitic infections) and rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome) have also been associated. Due to chronic B-cell stimulation, cryoglobulinemia is associated with the development of malignant B-cell lymphoproliferative disease, in particular non-Hodgkin lymphoma (35 times higher risk than the general population). When no underlying cause is identified, it is designated as essential mixed cryoglobulinemia.
Cryoglobulinemia is rare, with an estimate of fewer than 5 cases per 10 000 individuals in Europe and North America. It is more common in Southern Europe than in Northern Europe or North America. The time course is most often chronic but varies depending on the underlying condition and response to treatment. Overall survival in HCV-associated cryoglobulinemic vasculitis was found to be 75% at 5 years and 63% at 10 years in a cohort of 151 patients. Liver fibrosis, renal involvement, and severe vasculitis are associated with worse prognosis. Cryoglobulinemic vasculitis is sometimes associated with somatic mutations in the CARD11 or KLHL6 genes.


D89.1 – Cryoglobulinemia

30911005 – Cryoglobulinemia

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

Type I cryoglobulinemia:
  • Cryofibrinogenemia – Cold precipitable proteins are found in plasma but not in serum.
  • Cholesterol emboli – Associated with a recent history of vascular intervention or thrombolytic therapy. Most often affects toes and feet.
  • Disseminated intravascular coagulation (DIC) – Presents as diffuse cyanotic lesions, palpable purpura, bullae, or petechiae often associated with bacterial sepsis. Also associated with thrombosis and bleeding.
  • Warfarin necrosis – Typically occurs 3-5 days after warfarin initiation.
  • Purpura fulminans – Associated with DIC and bacterial sepsis.
  • Cocaine levamisole toxicity – Look for purpura on the helix of the ear.
  • Raynaud phenomenon – Presents as reversible white or blue discoloration of distal digits triggered by cold exposure or stress.
  • Waldenström macroglobulinemia – Associated with cryoglobulinemia. May also cause amyloidosis and cutaneous macroglobulinosis (skin-colored to red papules).
  • Livedoid vasculopathy – Presents as ulcers on the lower extremities that resolve as stellate scars. Associated with autoimmune connective tissue disease and coagulopathy.
  • Chilblains (perniosis) – Look for symmetric, erythematous papules in an acral distribution 12-24 hours after cold exposure. Most common in children and middle-aged women.
  • Heparin-induced thrombocytopenia – Typically occurs 5-14 days after starting heparin. Thrombocytopenia is indicative.
  • Thrombotic thrombocytopenic purpura / Hemolytic uremic syndrome – Presents with microangiopathic anemia and thrombocytopenia. Schistocytes may be seen on peripheral blood smear.
  • Homocysteinemia – Look for developmental delay, ectopia lentis, and marfanoid body habitus.
  • Thrombophilia (Protein C deficiency and Protein S deficiency, Antithrombin deficiency, prothrombin G202120A mutation, factor V Leiden deficiency) – Characterized by recurrent venous thromboembolism.
  • Sickle cell disease – Look for anemia on CBC. Hemoglobin electrophoresis and sickling test are diagnostic.
Types II and III cryoglobulinemia:
  • Leukocytoclastic vasculitis caused by infection, medications, or connective tissue diseases – Typically a symmetric eruption of palpable purpura on the shins 7-10 days after a trigger.
  • Granulomatosis with polyangiitis – Look for constitutional and respiratory tract symptoms.

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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 Reviewed:04/13/2020
Last Updated:01/12/2023
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A medical illustration showing key findings of Cryoglobulinemia (Type I) : Blurred vision, Dizziness, Acral distribution, Cyanosis, Eschar, Ecchymosis, Retiform purpura
Clinical image of Cryoglobulinemia - imageId=43785. Click to open in gallery.  caption: 'Purpuric macules on the leg and an eschar overlying a purpuric plaque on the ankle.'
Purpuric macules on the leg and an eschar overlying a purpuric plaque on the ankle.
Copyright © 2024 VisualDx®. All rights reserved.