Cryofibrinogenemia

Did You Know?

• Most asymptomatic cases have cryofibrinogen levels below 50 milligram/liter of fibrinogen.
• The precipitate resolubilizes when plasma returns to normal temperature.

Cryofibrinogen precipitation

The cause of cold-induced precipitation of the fibrinogen-containing complex, both in vitro and in vivo, remains unknown, and the fibrinogen involved appears structurally normal. This distinguishes cryofibrinogenemia from dysfibrinogenemia and hypodysfibrinogenemia, which involve abnormal fibrinogen. Three hypotheses based on in vitro studies have been proposed: a deficiency in fibrinolysis activity, supported by elevated levels of alpha-1 antitrypsin or alpha-2-macroglobulin in some patients; increased thrombin binding to fibrinogen promoting coagulation; and high levels of immunoglobulins or immune complexes interacting with fibronectin, suggested by improvement with immunosuppressive drugs in some cases. Further research is needed.

Associated disorders

Secondary cryofibrinogenemia can arise alongside infections in about 12% of cases, malignant or premalignant conditions in 21%, vasculitis in 25%, and autoimmune diseases in 42%. Acute bacterial and mycobacterium infections typically cause a short-lived form that clears up with antibiotic treatment. Viral infections like HIV/AIDS, Epstein-Barr, cytomegalovirus, varicella zoster, herpes simplex, and hepatitis viruses can lead to longer-lasting elevations; with hepatitis C, 37% of patients had cryofibrinogenemia, 89% of those also had cryoglobulinemia, and antiviral therapy fully resolved it in only about half. Lymphoproliferative disorders such as B-cell and T-cell lymphomas, chronic lymphocytic leukemia, plasma cell dyscrasias, and various solid tumors have been linked to it. Vasculitis-related conditions include ANCA-associated vasculitides, giant cell arteritis, Behcet disease, polyarteritis nodosa, Henoch-Schonlein purpura, and cryoglobulinemic vasculitis.

Cryofibrinogenemic disease

Symptomatic cryofibrinogenemia typically begins in adults aged 40–50, with skin as the almost always affected organ. Cutaneous manifestations include cold-induced urticaria, Raynaud phenomena, cyanosis, palpable purpura (cryofibrinogenemic purpura), livedo reticularis, and non-healing ulcerations or gangrene, primarily on the lower extremities. Patients may also experience cold sensitivity, arthralgia, neuritis, myalgia, and overt thrombosis of arteries and veins, rarely involving major vessels. Renal involvement occurs in 4 to 25% of cases. Primary cryofibrinogenemia has a higher incidence of cutaneous lesions, arthralgia, and cold sensitivity but lower renal involvement than secondary forms. Pathological bleeding may occur due to consumption of clotting factors. Suggested diagnostic criteria include obligatory items such as cold sensitivity, cutaneous symptoms, thrombotic events, arthralgia or myalgia, neuritis, and renal disorder, plus additional criteria of typical biopsy findings and angiographic evidence of occlusion.