Review
An approach to the diagnosis and treatment of cryofibrinogenemia

https://doi.org/10.1016/j.amjmed.2003.09.033Get rights and content

Abstract

Cryofibrinogenemia is a rarely symptomatic disorder that is underrecognized due to the infrequency with which it causes symptoms. Although completely reversible, this disorder can be life threatening when untreated. In this review, the classification, pathophysiology, and clinical presentation of cryofibrinogenemia are described, based on case reports and prospective observational data. Diagnostic criteria are outlined, and therapies are assessed critically. This information should help clinicians in establishing a diagnosis of cryofibrinogenemia and initiating treatment.

Section snippets

Methods

Articles were obtained via a MEDLINE search, interview of two experts, and review of references obtained from articles. Searches were limited to human studies written in English. Search terms included cryofibrinogenemia, cryoprotein, plasmapheresis, and cryofiltration.

The search results yielded case reports, case series, and observational data. Due to the infrequency of symptomatic disease, there are no randomized trials. A total of 46 articles were obtained, 21 of which were eliminated due to

Classification

Cryofibrinogenemia has been classified into an essential (primary) and a secondary form. Clinically relevant essential cryofibrinogenemia is rare and its prevalence is not known, although one study reported a prevalence of 3% in 135 healthy residents in Oklahoma City, Oklahoma (1). Two epidemiological studies estimated the prevalence of secondary cryofibrinogenemia in patients without symptoms of cryofibrinogenemia who were hospitalized for another illness 1, 2. One study, which involved 36,000

Pathophysiology

Cryofibrinogen is the term that was used by Korst and Kratochvil in 1955 to describe an abnormal, cold, precipitable protein (6). The substance is a cold, insoluble complex of fibrin, fibrinogen, and fibrin split products with albumin, plasma proteins, and immunoglobulins. Cryofibrinogen clots with thrombin and reversibly precipitates in the plasma on cooling to 4°C, then redissolves on warming to 37°C. Serum is the fluid remaining after plasma is allowed to clot. The proteins consumed in the

Clinical presentation

Essential cryofibrinogenemia develops spontaneously in previously healthy persons. Too few cases have been reported, however, to determine the clinical presentation by patient characteristics. Secondary cryofibrinogenemia occurs with a female to male ratio of 1.4 to 1, but with no age or racial predilection (2). These patients suffer from an underlying inflammatory disease, such as a malignancy, diabetes mellitus, collagen vascular disease, or active infection. They live in colder climates and

Diagnosis

The diagnosis of cryofibrinogenemia should be considered in all previously healthy persons presenting with unexplained areas of tissue ischemia and gangrene. The differential diagnosis includes cryoglobulinemia, peripheral vascular disease, frostbite, thrombotic thrombocytopenia purpura, disseminated intravascular coagulation, coumarin necrosis, hereditary hypercoagulable states, antiphospholipid antibody syndrome, embolic diseases such as endocarditis or cholesterol emboli, vasculitis,

Treatment

The level of the evidence on which treatment decisions for cryofibrinogenemia are based is limited to case reports. Avoidance of cold exposure and placing the symptomatic patient in an environment of about 37°C is a reasonable, inexpensive measure that is without risk, and that has been found to be partially efficacious. Antiseptic wound care is imperative. Cutaneous lesions should be managed in the same way as for any gangrenous soft tissue injury or burn. All patients require lifelong

Conclusion

Cryofibrinogenemia is an underrecognized and unnecessarily life-threatening disease. The information provided in this paper should help clinicians to become more efficient at establishing a diagnosis and initiating treatment.

Acknowledgements

We would like to thank Robert Marcus, MD, for his expertise in rheumatology and special interest in cryofibrinogenemia; Sameer Bade, MD, whose images and posters brought clarity to this project's presentations; and Satish Chandra, MD, for his support with radiological studies.

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