Human Factor XII is 596amino acids long and consists of two chains, the heavy chain (353residues) and light chain (243 residues) held together by adisulfide bond. It is 80,000 daltons in molecular weight. The heavy chain contains twofibronectin-type domains (type I and II), twoepidermal growth factor-like domains, a kringle domain, and a proline-rich region, while the light chain contains the protease domain. FXII can be cleaved sequentially at two sites, Arg353 and Arg334, with the second cleavage liberating the light chain and forming β-FXIIa.[6]
The structure of the FnI-EGF-like tandemdomain of coagulation factor XII has been solved byX-ray crystallography.[7][8] Crystal structures of the FXII light chain have also been determined, both unbound (β-FXII) and bound (β-FXIIa) toinhibitors.[9][10][11]
Factor XII (FXII, Hageman factor) is a plasma glycoprotein of approximately 90 kDa and is part of thecoagulation cascade. It activatesfactor XI andprekallikrein in vitro. FXII is activated to FXIIa by negatively charged surfaces such as glass, initiating the intrinsic pathway.[12] FXII also plays a role in diagnostic coagulation assays called activated partial thromboplastin times (aPTT).[13]
In vivo, FXII is activated by binding topolyanions in a process termed contact activation. Various polymers, such as kaolin and glass, act as non-physiological activators of FXII. Activated platelets release inorganicpolyphosphates, which activate FXII, initiating the intrinsic pathway and contributing tofibrin formation and thrombus development.[14] Polyphosphates also accelerate thrombin-induced activation of factor XI.[15]
Polyphosphate forms calcium-richnanoparticles in vivo, which accumulate on platelets and activate FXII. The regulation of platelet polyphosphates is still not fully understood, but the phosphate-exporter XPR1 has been identified as a key regulator.[16] Targeting XPR1 increases polyphosphate levels, accelerating thrombosis in mouse models.[17]
Given FXII’s role in thrombosis while sparing hemostasis, it has become a target for anticoagulant drug development. Inhibitors targeting FXII are in clinical trials.[18]
Factor XII deficiency is a rare disorder that is inherited in anautosomal recessive manner.[19] Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding.[19] Mice lacking the gene for factor XII, however, are less susceptible tothrombosis. 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.[20]
Factor XII does play an important role in clot formation duringin vitro measurements of thepartial 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.[19] 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.[19] All of this, including the mechanism of inheritance, also holds true for the other contact factors,prekallikrein (Fletcher factor) and high molecular weightkininogen.[19]
Excess levels of factor XII can predispose individuals towards greater risk ofvenous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form ofplasmin.[21]
Factor XII is also activated byendotoxins, especiallylipid A in vitro. Experimental mouse models have suggested a role of FXII in multiple sclerosis.[22]
Hageman factor was first discovered in 1955 when a routine preoperativeblood 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 nohemorrhagic symptoms. Hageman was then examined by hematologistOscar Ratnoff, who found that Hageman lacked a previously unidentified clotting factor.[23] Ratnoff later found that the Hageman factor deficiency is anautosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically,pulmonary embolism contributed to Hageman's death after an occupational accident in 1968. Since then, case studies and clinical studies identified an association betweenthrombosis and Factor XII deficiency.Hepatocytes express blood coagulation factor XII.[24]
Currently producedQuikClot products, produced and marketed primarily for use inbattlefield medicine to treat penetrating trauma (such asgunshot wounds andstab wounds), and other injuries that are known to commonly causeexsanguination (such asblast injury), are used with the overarching goal of increasing the time between the blood loss occurring, and the patient succumbing to the blood loss. The purpose of increasing this time is so that the patient may reach a higher level of medical care before succumbing from their injuries. These products use aKaolinite-based coating, applied to the bandages by the manufacturer before packaging and sale. This coating, when applied to an open wound via the application of the bandages, directly promotes blood clotting by activating Factor XII in the coagulation cascade.[25] Also, due to the active ingredient nature ofKaolinite, the activation of the Factor XII occurs in both an earlier amount of time than it otherwise would, and at an increased, more rapid rate than it otherwise would.[26][27] This coating is widely considered amongstcombat medics to be vastly superior to the olderQuikClot powder formulation, which was poured into wounds, due to the fact that the older formulation used bead-formZeolite, a mineral which promotes the coagulation cascade, due to the fact that the reaction between the Zeolite powder and the blood inside the wound site was anExothermic one, sometimes so intensely that it caused cases ofsecond degree burns on the inside surface of the wound. This, obviously, caused extreme pain to the patient, often more-so than the initial injury was causing them at the time (assuming the patient was still conscious at the time of the application of the powder).[28] This effect is often seen in movies and TV programs, with the QuikClot powder being poured into wounds, and the patient screaming out in pain as their wounds were violently burned on the inside surface of the wounds. This created a common misconception, which persists to this day, that commonly used QuikClot products still use this method of clot promotion (Zeolite powder) to this day. However, Zeolite-based clotting products are no longer widely used by militaries and police departments throughout the western world, as they have been widely supplanted by the Kaolinite-based bandage products, which do not cause any exothermic reaction whatsoever, nor do they have the absolute-requirement of the application of the product exclusively to the inside-surface of the wound.
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^Dee KC, Puleo DA, Bizios R, Madhavan G (2002).Tissue-biomaterial interactions. Hoboken: Wiley & Sons.ISBN978-0-471-46112-8.
^Trabattoni D, Montorsi P, Fabbiocchi F, Lualdi A, Gatto P, Bartorelli AL (August 2011). "A new kaolin-based haemostatic bandage compared with manual compression for bleeding control after percutaneous coronary procedures".European Radiology.21 (8):1687–1691.doi:10.1007/s00330-011-2117-3.PMID21476127.S2CID11755594.
^Politi L, Aprile A, Paganelli C, Amato A, Zoccai GB, Sgura F, et al. (February 2011). "Randomized clinical trial on short-time compression with Kaolin-filled pad: a new strategy to avoid early bleeding and subacute radial artery occlusion after percutaneous coronary intervention".Journal of Interventional Cardiology.24 (1):65–72.doi:10.1111/j.1540-8183.2010.00584.x.hdl:11380/649198.PMID20807305.
^Wright JK, Kalns J, Wolf EA, Traweek F, Schwarz S, Loeffler CK, et al. (August 2004). "Thermal injury resulting from application of a granular mineral hemostatic agent".The Journal of Trauma.57 (2):224–230.doi:10.1097/01.ta.0000105916.30158.06.PMID15345965.
Girolami A, Randi ML, Gavasso S, Lombardi AM, Spiezia F (April 2004). "The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature".Journal of Thrombosis and Thrombolysis.17 (2):139–143.doi:10.1023/B:THRO.0000037670.42776.cd.PMID15306750.S2CID19336633.
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