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Thread: Factors in Thrombosis and Hemostasis

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    PharmD Year 1 TomHsiung's Avatar
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    Default Factors in Thrombosis and Hemostasis

    Factor XII (Hageman Factor, Contact Factor)

    Factor XII is the zymogen precursor of the serine protease factor XIIa. Factor XII is also known as contact factor for its role in the initiation of coagulation on contact with substances such as glass or kaolin. The contact pathway is the basis for the activated partial thromboplastin time clotting assay. Factor XII circulates in plasma at an average concentration of 40 ug/mL (500 nmol/L). Increased levels of factor XII are seen in postmenopausal women using estrogen replacement therapy and during pregnancy. Animal studies also demonstrate enhanced expression of factor XII by estrogen and prolactin. Since a deficiency of factor XII is not associated with any bleeding abnormality, its precise role in hemostasis is at present unknown. Studies show that mice lacking factor XII are protected against arterial thrombosis and stroke. This suggests that the intrinsic pathway of coagulation is essential for thrombus stability. The components of the contact pathway are also believed to provide a link between coagulation and inflammation, with the multifunctional cellular protein gC1-R/p33 postulated to play a central bridging role between these two processes. Misfolded protein aggregates have been implicated in activating factor XII.

    Biochemistry
    Human factor XII is synthesized as a precursor protein with a 19-residue signal peptide. The mature factor XII molecule is a 596-amino acid single-chian beta-globulin with a molecular weight of approximately 80 kDa. It circulates at a concentration of 40 ug/mL (500 nmol/L) with a half-life (t1/2) of 2 to 3 days. The factor XII molecule is composed of two domains: an NH2-terminal heavy chain and a COOH-terminal light chain. The heavy chain contains several domain structures: fibronectin type I and type II domains, two epidermal growth factor (EGF)-like domains, a kringle domain, and a proline-rich region (residues 277 to 330). The light chain contains the serine protease catalytic domain, a region homologous to the B-chain of the enzyme plasmin. The mature factor XII molecule contains approximately 17% carbohydrate. Zn2+ binding to factor XII likely induces a conformation change that promotes activation of factor XII associated with negatively charged surfaces.

    Activation
    Factor XII undergoes auto activation on interaction with negatively charged surfaces such as glass, kaolin, dextran sulfate, ellagic acid, elite, or bismuth subgallate, and on interaction with hydrophobic surfaces. This is likely only an in vitro event triggered by the artificial surfaces used in studies of the contact pathway, although research is ongoing. Although factor XII associates with many physiologically relevant anionic surfaces, including negatively charged phospholipids, the autoactivation of factor XII induced by these surfaces in vitro does not appear to represent the mechanism for factor XII activation in vivo. Instead, factor XII is most likely activated by a cell membrane-associated proteinase. When factor XII, prekallikrein, and HMWK form a complex on anionic phospholipids of the cell membrane, prekallikrein is cleaved, forming the enzyme kallikrein. Kallikrein then activates factor XII (plasmin activates factor XII as well) via a single cleavage at Arg-Val to generate an 80-kDa two-chain enzyme, alpha-factor XIIa (factor XIIa, alpha-HFa, or HFa). This cleavage is essential for exposure of the active site in factor XIIa. Factor XIIa can then bind negatively charged surface and activate factor XI and prekallikrein. Two secondary cleavages can also occur on factor XII: one outside the disulfide bond and one inside the disulfide loop, generating beta-factor XIIa. beta-Factor XIIa has no surface-binding capabilities but is able to activate prekallikrein.

    Function
    Factor XIIa is a serine protease that activates factor XI and prekalikrein by mechanisms dependent on anionic surfaces and the cofactor HMWK. Factor XIIa also activates the C1 component of the complement system. In addition, factor XIIa down-regulates the Fc receptor on monocytes and macrophages, induces release of IL-1 and IL-6 from monocytes and macrophages, and stimulates neutrophils. Although these roles have no apparent impact on normal coagulation, factor XII/XIIa may be an important link between coagulation and inflammation. Factor XIIa also activates plasminogen to plasmin, linking the contact pathway to fibrinolysis.

    Regulation
    C1 inhibitor is the major inhibitor of both factor XIIa and beta-factor XIIa and irreversibly inhibits both enzymes. Antithrombin and plasminogen activator inhibitor (PAI)-1 also inhibit factor XIIa. Endothelial cells and eosinophils are reported to produce proteins that inhibit factor XII activation but not factor XIIa activity. Amyloid precursor protein likewise is reported to inhibit factor XII activation but not factor XIIa.
    Last edited by TomHsiung; Tue 14th March '17 at 11:05am.
    B.S. Pharm, West China School of Pharmacy, Class of 2007, Health System Pharmacist, RPh. Hematology, Infectious Disease.

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