ReviewAn approach to the diagnosis and treatment of cryofibrinogenemia
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.
References (25)
- et al.
Familial primary cryofibrinogenemia
J Eur Acad Dermatol Venereol
(1999) - et al.
Cryofibrinogen formation in case of lung neoplasm associated with thrombophlebitis migrans
Blood
(1955) - et al.
Thrombotic vasculopathy associated with cryofibrinogenemia
J Am Acad Dermatol
(1991) - et al.
Stanozolol causes rapid pain relief and healing of cutaneous ulcers caused by cryofibrinogenemia
J Am Acad Dermatol
(1993) - et al.
Spontaneous necrosis of the skin associated with cryofibrinogenemia, cryoglobulinemia, and homocystinuria
Ann Vasc Surg
(1996) - et al.
Intravascular coagulation necrosis of the skin associated with cryofibrinogenemia, diabetes mellitus, and cardiolipin autoantibodies
J Am Acad Dermatol
(1991) - et al.
Cryofibrinogenemiaan addition to the differential diagnosis of calciphylaxis in end-stage renal disease
Am J Kidney Dis
(1998) - et al.
Incidence and significance of cryofibrinogenemia
J Lab Clin Med
(1963) - et al.
Cryofibrinogenemiaincidence, clinical correlations, and a review of the literature
Am J Clin Pathol
(1972) - et al.
Familial presence of primary cryofibrinogenaemia, a report of three cases
Br J Rheumatol
(1996)