Factor XII

Coagulation factor XII, also known as Hageman factor, is a plasma is_associated_with::protein. It is the is_associated_with::zymogen form of factor XIIa, an is_associated_with::enzyme of the is_associated_with::serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 is_associated_with::gene.

Structure
Human Factor XII is 596 is_associated_with::amino acids long and consists of two domains, the heavy chain (353 residues) and light chain (243 residues) held together by a is_associated_with::disulfide bond. It is 80,000 daltons. Its heavy chain contains two is_associated_with::fibronectin-type domains (type I and II), two is_associated_with::epidermal growth factor-like domains, a kringle domain, and a proline-rich region, and its light chain contains the protease domain. Recently, the structure of the FnI-EGF-like tandem domain of coagulation factor XII was solved by x-ray crystallography.

Function
Factor XII is part of the is_associated_with::coagulation cascade and activates is_associated_with::factor XI and is_associated_with::prekallikrein in vitro. Factor XII itself is activated to factor XIIa by negatively charged surfaces, such as glass. This is the starting point of the intrinsic pathway, which is now regarded as an obsolete term, because of the fact that there is no intrinsic pathway in vivo. Factor XII is only used to start coagulation cascades in laboratory studies and is considered to have little to no effect on coagulation in vivo.



In vivo, factor XII is activated by contact to polyanions. Activated platelets secrete inorganic polymers, is_associated_with::polyphosphates. Contact to polyphosphates activates factor XII and initiates is_associated_with::fibrin formation by the intrinsic pathway of coagulation with critical importance for is_associated_with::thrombus formation. Targeting polyphosphates with is_associated_with::phosphatases interfered with procoagulant activity of activated is_associated_with::platelets and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of is_associated_with::Hermansky-Pudlak syndrome patients, indicating that the inorganic polymer is the endogenous factor XII activator in vivo. Platelet polyphosphate-driven factor XII activation provides the link from primary hemostasis (formation of a platelet plug) to secondary hemostasis (fibrin meshwork formation).

Genetics
The is_associated_with::gene for factor XII is located on the tip of the long arm of the fifth is_associated_with::chromosome (5q33-qter).

Role in disease
Factor XII deficiency is a rare disorder that is inherited in an is_associated_with::autosomal recessive manner. Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding. Mice lacking the gene for factor XII, however, are less susceptible to is_associated_with::thrombosis. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall.

Factor XII does play an important role in clot formation during in vitro measurements of the is_associated_with::partial thromboplastin time, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor XI deficiency. As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result. All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen.

Excess levels of factor XII can predispose individuals towards greater risk of is_associated_with::venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of is_associated_with::plasmin.

Factor XII is also activated by is_associated_with::endotoxins, especially is_associated_with::lipid A.

History
Hageman factor was first discovered in 1955 when a routine preoperative blood sample of the 37-year-old railroad brakeman John Hageman (1918) was found to have prolonged clotting time in test tubes, even though he had no hemorrhagic symptoms. Hageman was then examined by Dr. Oscar Ratnoff, who found that Mr. Hageman lacked a previously unidentified clotting factor. Dr. Ratnoff later found that the Hageman factor deficiency is an is_associated_with::autosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically, is_associated_with::pulmonary embolism contributed to Hageman's death after an occupational accident. Since then, case studies and clinical studies identified an association between is_associated_with::thrombosis and Factor XII deficiency. is_associated_with::Hepatocytes express blood coagulation factor XII.