Defects of contact activation system (CAS) and kallikrein/kinin system (KKS)

Stable Identifier
Homo sapiens
Defects of Formation of Fibrin Clot (Clotting Cascade)
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The contact activation system (CAS) is a plasma protease cascade initiated by factor XII (FXII) that activates the pro-inflammatory kallikrein‐kinin system (KKS) and the pro-coagulant intrinsic coagulation pathway (Renne T 2012; Renne T et al. 2012; Maas C et al. 2011; Schmaier AH 2016; Long AT et al. 2016). The CAS is initiated by the auto‐activation of factor XII (FXII) on charged or neutral surfaces with conversion of plasma prekallikrein (PK) to plasma kallikrein (Samuel M et al. 1992; Ivanov I et al. 2017). These events are followed by reciprocal activation of FXII by kallikrein and amplification of each other's activation. Two branches of the CAS have been identified: (i) the inflammatory branch activates contact factors FXII and PK on the surface of endothelial cells resulting in release of the peptide bradykinin (BK) and (ii) the plasma coagulation branch activates FXII and FXI on the surface of platelets. The CAS is thought to be central to crosstalk between coagulation and inflammation and the underlying cause for various disorders affecting the cardiovascular system (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). HAE caused by defective function of SERPING1 is also covered here. 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. This module also describes elevation of FIX activity associated with thrombophilia. 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).

Literature References
PubMed ID Title Journal Year
11836440 Haemophilia A and haemophilia B: molecular insights

Bowen, DJ

MP, Mol. Pathol. 2002
27273087 Complement, Kinins, and Hereditary Angioedema: Mechanisms of Plasma Instability when C1 Inhibitor is Absent

Joseph, K, Kaplan, AP

Clin Rev Allergy Immunol 2016
30591525 A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain

McCrae, K, Cheng, Q, Kundu, S, Verhamme, IM, Matafonov, A, Ivanov, I, Dickeson, SK, Sun, MF, Gailani, D, Mohammed, BM, Gruber, A

Blood 2019
Name Identifier Synonyms
C1 inhibitor deficiency DOID:0060002 Quincke edema
hereditary angioedema DOID:14735 HANE, Hereditary angioedema, Hereditary angioneurotic edema
thrombophilia DOID:2452 hypercoagulability state
factor VIII deficiency DOID:12134 Congenital factor VIII disorder, Subhemophilia, Hemophilia A
hemophilia B DOID:12259 factor IX deficiency, Congenital factor IX deficiency, deficiency, functional factor IX, Congenital factor IX disorder
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