Cryofibrinogenemia

Cryofibrinogenemia refers to a condition classified as a fibrinogen disorder in which the chilling of an individual's blood plasma from the normal body temperature of 37 °C to the near-freezing temperature of 4 °C causes the reversible precipitation of a complex containing fibrinogen, fibrin, fibronectin, and, occasionally, small amounts of fibrin split products, albumin, immunoglobulins and other plasma proteins. Returning this plasma to 37 °C resolubilizes the precipitate. Cryofibrinogenemia refers to a condition classified as a fibrinogen disorder in which the chilling of an individual's blood plasma from the normal body temperature of 37 °C to the near-freezing temperature of 4 °C causes the reversible precipitation of a complex containing fibrinogen, fibrin, fibronectin, and, occasionally, small amounts of fibrin split products, albumin, immunoglobulins and other plasma proteins. Returning this plasma to 37 °C resolubilizes the precipitate. Cryofibrinogenmia may occur as a laboratory finding in individuals that have no evidence of precipitate-induced tissue damage (i.e. asymptomatic cryofibrinogenemia) or in individuals suffering serious consequences of cryofibrinogen precipitation, particularly pathological blood clots in small and medium size arteries and veins. The clotting disease is commonly grouped with the asymptomatic condition in the term cryofibrinogenmia but is here termed cryofibrongemic disease for clarity purposes. When occurring in association with another serious disease, cryofibrinogenmic disease is referred as secondary cryofibrinogenmia; in the absence of such an association, it is referred to as primary cryofibrinogenmia. The reasons for the cold temperature-induced in vitro as well as the in vivo precipitation of the fibrinogen-containing complex is unknown. The fibrinogen involved in precipitate formation appears to have a normal structure. This separates cryofibrinogenemia from two pathological blood-clotting/bleeding diseases that can mimic cryofibrinogenemia but are due to structurally abnormal fibrinogen viz., dysfibrinogenemia and hypodysfibrinogenemia. Based on in vitro studies, three causes have been hypothesized for the precipitate formed in cryofibrinogenemia. 1) The blood and plasma of individuals with cryofibrinogenemia lack the fibrinolysis activity that normally degrades and thereby resolubilizes the precipitate. This hypothesis is based on the findings that some but not all individuals with the disorder have abnormally high levels of one or two of the agents, alpha-1 antitrypsin and alpha-2-macroglobulin, which inhibit the naturally occurring fibrinolytic agent, plasmin. 2) The blood of individuals has an increased ability of the pro-coagulant thrombin to bind fibrinogen and thereby promote coagulation. 3) The blood of individuals, particularly those with cryofibriognemic disease associated with other severe disorders, has high levels of immunological elements such as immunoglobulins or immune complexes that interact with fibronectin to promote blood clotting. This hypothesis is base on findings that some patients with cyrofibrinogenemic disease improve when treated with immunosuppressive drugs. Further basic research into this area is required. The occurrence of cryofibrinogenemia as defined by a 4 °C-induced formation of fibrinogen-based precipitation in plasma occurs in 2% to 9% of asymptomatic individuals and 8% to 13% of hospitalized patients without symptoms attributable to this precipitation. Most of these cases have relatively low levels of cold temperature-induced fibrinogen precipitate levels (<50 milligram/liter of fibrinogen) and do not have a disorder associated with the development of cryofibrinogenmia. Cryoglobulinemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulinemia. Secondary cryofibrinogenemia can develop in individuals suffering infection (~12% of cases), malignant or premalignant disorders (21%), vasculitis (25%), and autoimmune diseases (42%). In these cases of the secondary disorder, cryofibrinogenemia may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenemia is unclear. Cryofibrinogenemia can also occur in association with the intake of certain drugs. Acute bacterial and mycobacterium infections are sometimes associated with cryofibriongenemia. In these cases, cryofibrinogenemia is usually transient and rapidly resolves after appropriate anti-bacterial treatment. In HIV/AIDS virus, Epstein–Barr virus, Cytomegalovirus, varicella zoster virus, herpes simplex virus, and hepatitis virus infections any rise in circulating cryofibrinogen is more sustained and potentially symptomatic. For example, one large study of the most thoroughly study example of viral infection-associated cryofibrinogenmia, Hepatitis C infection, found that cryofibrinogenemia occurred in 37% of cases, was associated with concurrent cryoglobulinemia in 89% of cases, and led to significantly increased vascular disruption. Antiviral therapy resulted in complete resolution of the cryofibrinogenemia in only ~50% of these cases. Lymphoproliferative disorders such as B cell lymphomas, T cell lymphomas, chronic lymphocytic leukemia, and various plasma cell dyscrasias (e.g. multiple myeloma, Waldenström's macroglobulinemia, and the premalignant precursors to these two diseases, MGUS, smoldering multiple myeloma, IgM MGUS, and smoldering Waldenström's macroglobulinemia as well as adenocarcinomas of the stomach, liver, lung, colon, and other solid tumor cancers have been reported to be associated with symptomatic or asymptomatic cryfibrinogenemia. Cryofibrinogenemia is often associated with inflammatory disease of the arteries and/or veins. These vasculitis-associated diseases include ANCA-associated vasculitides, giant cell arteritis, Behcet disease, polyarteritis nodosa, and Henoch-Schonlein purpura. Cryofibrinogenemia is also often associated with the inflammatory vasculitis that accompanies mixed Cryoglobulinemia#Classification, i.e. cryoglobulinemic vasculitis, particularly but not exclusively in instances where hepatitis C virus is an underlining disease. A broad range of autoimmune diseases have been reported to be associated with cryofibrinogenemia. These diseases include systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, mixed connective tissue disease, polymyositis, dermatomyositis, systemic sclerosis, antiphospholipid antibody syndrome, Hashimoto disease, Graves disease, sarcoidosis, pyoderma gangrenosum, spondyloarthropathy, Crohn disease, and ulcerative colitis.