Factor XII congenital deficiency (FXII CD) is a rare trait characterised by low or immeasurable FXII activity. As FXII CD does not manifest in a clinical phenotype, it is typically diagnosed as an incidental finding. Thus, the true prevalence of FXII CD is unknown. FXII is produced in the liver as an inactive enzyme and then secreted into the plasma. Contact with negatively charged surfaces, such as a thrombus, activates FXII to the serine protease FXIIa. FXIIa cleaves and activates plasma prekallikrein to plasma kallikrein (PK). PK then activates the inactive FXII still bound to the negatively charged surface in a positive feedback loop. FXIIa also activates FXI in the coagulation cascade as a response to contact activation with negatively charged surfaces, though this interaction may have little physiological importance. Individuals with FXII CD have prolonged clotting times in routine one-stage activated partial thromboplastin time (aPTT) assays, but even those with very low or absent FXII activity generally exhibit normal haemostasis and no abnormal bleeding symptoms. Hence, FXII CD is usually discovered incidentally during routine coagulation screens or prior to surgery.1-4
Experiments in mice have shown that a FXII knockout confers resistance to models of thromboembolism. However, a link between FXII CD and resistance to thrombosis has not been established in humans. A single study performed in Austria showed that decreased (10%–70% of normal activity) FXII levels are associated with an increased risk of cardiovascular mortality.5 However, mortality in individuals with very low levels of FXII (<10% of normal activity) was comparable to the general population. Furthermore, recent evidence suggests that people in the lower tertile of FXII activity have a lower risk of haemorrhagic but not ischemic stroke.3,6,7
FXII CD is caused by mutations of the F12 gene on chromosome 5. Most characterised mutations result in a loss of FXII activity, as opposed to loss of protein expression. Mutations in the F12 gene appear to have no effect on coagulation or haemostasis. However, rare point mutations have been linked to hereditary angioedema (HAE). HAE is a rare and life-threatening disorder usually caused by diminished C1INH expression or function. However, HAE type III has been linked to point mutations in the F12 gene.1,6
Patients with FXII CD have normal haemostasis. Thus, FXII CD is often revealed during routine laboratory tests by a prolonged aPTT clotting time. Lower levels of FXII have been associated with higher mortality and higher cardiovascular mortality. However, mortality is normal in patients with <10% FXII.1-3,6
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4. Schmaier AH. The elusive physiologic role of Factor XII. J Clin Invest 2008;118:3006-9.
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7. Johansson K, Jansson JH, Johansson L, et al. Factor XII as a Risk Marker for Hemorrhagic Stroke: A Prospective Cohort Study. Cerebrovasc Dis Extra 2017;7:84-94.