接触激活系统(CAS)是由因子XII (FXII)启动的血浆蛋白酶级联,可激活促炎激肽酶‐激肽系统(KKS)和促凝内源性凝血途径(Renne T 2012;Renne T et al. 2012;Maas C et al. 2011;Schmaier啊2016;Long AT et al. 2016)。CAS是通过在带电或中性表面上的XII因子(FXII)的自动激活,将等离子体前激肽酶(PK)转化为等离子体激肽酶(Samuel M et al. 1992;Ivanov I et al. 2017)。这些事件之后,FXII通过激肽酶相互激活,并相互放大对方的激活。CAS有两个分支:(i)炎症分支激活内皮细胞表面的接触因子FXII和PK,导致肽缓激肽(BK)的释放;(ii)血浆凝血分支激活血小板表面的FXII和FXI。CAS被认为是凝血和炎症之间的相互作用的中心,以及影响心血管系统的各种疾病的潜在原因(Wu Y 2015; Long AT et al. 2016). Physiologically, a fine balance is normally maintained between blood flow and blood clotting, the dysfunction of which yields either hemorrhage or thrombosis. Defects in the intrinsic pathway coagulation factors (FVIII, FIX, and FXI) are associated with a significant bleeding tendency. The X-linked recessive disorders, hemophilia A (FVIII deficiency) and B (FIX deficiency), are associated with spontaneous and excessive hemorrhage, especially hemarthroses and muscle hematomas (Bowen DJ 2002; Goodeve AC 2015). A deficiency in FXI, which is encoded by a gene on chromosome 4, generally results in a less severe, but still significant, bleeding tendency (James P et al. 2014; Puy C et al. 2016). Although PK and FXIIa are recognized as upstream triggers for the intrinsic coagulation system, the clinical significance of these factors on thrombosis and hemorrhage is not fully understood. The CAS blockade results in prolonged coagulation times in the activated partial thromboplastin time (aPTT) assay. However, the absence of thrombotic and hemostatic abnormalities in individuals with genetic deficiencies of PK or FXII has suggested that the CAS plays a minimal role in physiological coagulation (Müller F et al. 2011). At the same time, excessive formation of bradykinin due to abnormal FXII-dependent KKS activation causes increased vascular permeability at the level of the post capillary venule and results in hereditary angioedema (HAE). HAE initiated by bradykinin is usually associated with SERPING1 (C1-INH) deficiency (Suffritti C et al. 2014). More rarely, HAE occurs in individuals with normal SERPING1 activity, and has been linked to mutations in other proteins, including FXII, plasminogen, and angiopoietin (Cichon S et al. 2006; Magerl M et al. 2017; Zuraw BL 2016; Ivanov I et al. 2019). This Reactome module describes abnormal FXII-dependent KKS activation that leads to an excessive formation of bradykinin causing increased vascular permeability at the level of the post capillary venule and results in hereditary angioedema (HAE). The module also includes disorders that can cause abnormal bleeding due to a shortage (deficiency) of coagulation factor proteins, which are involved in blood clotting. Genetic variants are named following Human Genome Variation Society (HGVS) nomenclature with sequence numbering starting from the first methionine of the protein as +1.(Goodeve AC et al.2011).