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Other Resources UpToDate PubMed


Contributors: Casey P. Schukow DO, Vivian Wong MD, PhD, Susan Burgin MD
Other Resources UpToDate PubMed


Cryofibrinogenemia is an acquired vascular occlusive disease that results from the cold precipitation of cryofibrinogens. Cryofibrinogens are composed of a complex of fibrin, fibrinogen, fibrin split products, albumin, plasma proteins, and immunoglobulins that reversibly precipitate in the cold. These cryoproteins cause an occlusive vasculopathy of small- to medium-size blood vessels. While many patients are asymptomatic, cryofibrinogenemia can cause significant morbidity. The clinical examination and course is similar to type I cryoglobulinemia. Cryofibrinogenemia can be idiopathic (primary) or associated with malignancy (particularly prostatic cancer, other solid organ tumors, and lymphomas), viral infection, collagen vascular disease, thromboembolic disease, or oral contraceptive pills.

A familial autosomal dominant form has also been reported. In a 2020 study, cryofibrinogenemia was detected in two-thirds of 54 patients with COVID chilblains. More studies are needed to confirm that cryofibrinogenemia is implicated in the pathogenesis of chilblains in COVID-19 patients.

Cryofibrinogenemia may be treatable and reversible, with a relatively prompt resolution of skin lesions with immunosuppressive therapy.


D89.2 – Hypergammaglobulinemia, unspecified

10934005 – Cryofibrinogenemia

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

  • Cryoglobulinemia
  • Cholesterol emboli
  • Bacterial sepsis
  • Medium vessel vasculitides such as Granulomatosis with polyangiitis
  • Warfarin necrosis
  • Purpura fulminans
  • Ecthyma gangrenosum
  • Calciphylaxis
  • Cocaine levamisole toxicity
  • Raynaud phenomenon
  • Waldenström macroglobulinemia
  • Livedoid vasculopathy
  • Chilblains (perniosis)
  • Heparin-induced thrombocytopenia
  • Thrombotic thrombocytopenic purpura / Hemolytic uremic syndrome
  • Homocysteinemia
  • Protein C deficiency and Protein S deficiency deficiencies
  • Antithrombin deficiency
  • Prothrombin G202120A mutation
  • Factor V Leiden deficiency
  • Sickle cell disease

Best Tests

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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:02/23/2022
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A medical illustration showing key findings of Cryofibrinogenemia : Acral distribution, Cryofibrinogen increased, Gangrene, Palpable purpura, Skin ulcer, Ecchymosis, Cold intolerance, Painful skin lesion
Clinical image of Cryofibrinogenemia - imageId=4477923. Click to open in gallery.  caption: 'Erythematous and purpuric papules and plaques on the distal toes of a patient with lupus.'
Erythematous and purpuric papules and plaques on the distal toes of a patient with lupus.
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