Cryofibrinogenemia refers to a condition classified as a fibrinogen disorder in which a person's blood plasma is allowed to cool substantially (i.e. from its normal temperature of 37 °C to the near-freezing temperature of 4 °C), causing the (reversible) precipitation of a complex containing fibrinogen, fibrin, fibronectin, and, occasionally, small amounts of fibrin split products, albumin, immunoglobulins and other plasma proteins. Return of plasma to more normal temperature resolubilizes the precipitate. Cryofibrinogenemia may occur in individuals that have no obvious evidence of precipitate-induced tissue damage (asymptomatic cryofibrinogenemia), or in consequence of cryofibrinogen precipitation resulting in blood clots in small and medium size arteries and veins. When occurring in association with another causual disease, cryofibrinogenemic disease is referred as secondary cryofibrinogenemia; in the absence of such an association, it is referred to as primary cryofibrinogenemia. Cryofibrinogen precipitation 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. Asymptomatic cryofibrinogenemia 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