|Coagulation factor XII (Hageman factor)|
|Symbols||; HAE3; HAEX; HAF|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 184.108.40.206) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.
Human Factor XII is 596 amino acids long and consists of two domains, the heavy chain (353 residues) and light chain (243 residues) held together by a disulfide bond. It is 80,000 daltons. Its heavy chain contains two fibronectin-type domains (type I and II), two 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.
Factor XII is part of the coagulation cascade and activates factor XI and 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, polyphosphates. Contact to polyphosphates activates factor XII and initiates fibrin formation by the intrinsic pathway of coagulation with critical importance for thrombus formation. Targeting polyphosphates with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of 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).
Role in disease
Factor XII deficiency is a rare disorder that is inherited in an 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 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 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 venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of plasmin.
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 autosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically, pulmonary embolism contributed to Hageman's death after an occupational accident. Since then, case studies and clinical studies identified an association between thrombosis and Factor XII deficiency. Hepatocytes express blood coagulation factor XII.
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- de Grouchy J, Turleau C (1975). "Tentative localization of a Hageman (Factor XII) locus on 7q, probably the 7q35 band". Humangenetik 24 (3): 197–200. doi:10.1007/bf00283584. PMID 4140832.
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- Hovinga JK, Schaller J, Stricker H et al. (1994). "Coagulation factor XII Locarno: the functional defect is caused by the amino acid substitution Arg 353-->Pro leading to loss of a kallikrein cleavage site". Blood 84 (4): 1173–81. PMID 8049433.
- Schloesser M, Hofferbert S, Bartz U et al. (1996). "The novel acceptor splice site mutation 11396(G-->A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients". Hum. Mol. Genet. 4 (7): 1235–7. doi:10.1093/hmg/4.7.1235. PMID 8528215.
- Hofferbert S, Müller J, Köstering H et al. (1996). "A novel 5'-upstream mutation in the factor XII gene is associated with a TaqI restriction site in an Alu repeat in factor XII-deficient patients". Hum. Genet. 97 (6): 838–41. doi:10.1007/BF02346200. PMID 8641707.
- The MEROPS online database for peptidases and their inhibitors: S01.211
- Factor XII at the US National Library of Medicine Medical Subject Headings (MeSH)