In thecontact activation system orCAS, three proteins in the blood,factor XII (FXII),prekallikrein (PK) andhigh molecular weight kininogen (HK), bind to a surface and causeblood coagulation andinflammation. FXII and PK areproteases and HK is a non-enzymatic co-factor. The CAS can activate thekinin–kallikrein system andblood coagulation through its ability to activate multiple downstream proteins. The CAS is initiated when FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. FXIIa can initiate thecoagulation cascade by cleaving and activatingfactor XI (FXI), which leads to formation of a blood clot. Additionally, the CAS can activate the kinin–kallikrein system when PKa cleaves HK to form cHK, releasing a peptide known asbradykinin (BK). BK and its derivatives bind to bradykinin receptorsB1 andB2 to mediateinflammation.^[1][2][3]

Artificial negatively charged substances that activate FXII include L-homocysteine,heparan sulfates,chondroitin sulfates,dermatan sulfate,uric acid crystals,lipoproteins,ferritin andporphyrins. However, the physiological substances or surfaces that activate FXII are still under debate. These may include proteins, such as gC1q-R, aggregated proteins,amyloid,collagen,nucleic acids, andpolyphosphates.^[4][5][6] The ability of FXII to bind to negatively charged surfaces and activate coagulation forms the basis of theaPTT test, in which artificial materials act as a surface for contact activation. This test is used to measure the contact activation pathway (intrinsic pathway) and the common pathway of clotting.^[7] FXII is azymogen, which means that it requires processing to attain its catalytic protease activity. Upon binding to surfaces, FXII alters in its conformation, giving it low-level protease activity. This change in conformation also promotes its cleavage by PKa and cleavage by FXIIa itself. FXIIa can cleave PK producing PKa, producing a positive feed-back to activate both enzymes. HK binds to PK and is required to locate PK at the surface for activation by FXII.^[8]

Zinc has been reportedly demonstrated to be crucial in inducing aconformational change in both FXII and HK as it is required for assembly of FXII and HK bound PK on some negatively charged surfaces. Zinc is suggested to mediate binding of FXII and HK to negatively charged surfaces including gC1q-R and Polyphosphates.^[9][10][11]

Although contact factors FXII and HK bound PK have been reported to interact withendothelial cells (via gC1q-R),platelets (via Polyphosphate) andLeukocytes;bacteria (Streptococcus pyogenes,Salmonella, andEscherichia coli) andviruses (Hantavirus andHerpes simplex 1 virus) have also been demonstrated to bind to contact factors.^[12] Negatively chargedlipopolysaccharide (LPS) or surface associated negatively chargedteichoic acids fromS. aureus^[13] and long chainPolyphosphate have all been shown to induce contact activation andbradykinin release thereby contributing to the host-defense reactions^[14] by activating thecomplement cascade.^[15]

Although the contact system can activate FXI and the subsequent clotting cascade, and it is routinely observed to activate coagulation in the presence of medical devices,^[16] the actual role of the contact system in normal physiological coagulation remains contentious. This is primarily due to the fact that deficiencies in the contact system proteins FXII, PK and HK do not produce bleeding disorders.^[17]

The contact activation system's physiological role in the kinin-kallikrein system is more clear. Here, after activation of PK to PKa by FXIIa, PKa cleaves HK. This produces cleaved HK (cHK), releasing a small peptide known as bradykinin. This peptide binds to bradykinin receptor B2 and its derivative, Des-Arg9-bradykinin binds to bradykinin receptor B1. Upon ligand binding, these receptors mediate inflammatory responses.^[18] PK can also lead to fibrinolysis by converting plasminogen to plasmin.^[19]

FXII can also lead to complement activation by directly targetingC1r andC1s.^[19]C1INH inhibits the action of PK, FXIIa, and FXIa, in addition to its classical inhibitory role for C1r and C1s.^[19]

Activation of the CAS is associated withhereditary angioedema, a disorder characterised by episodes of swelling.^[20]Genetic knockout studies in murine models ofcardiovascular disease andgenetic linkage studies in humans have implicated the contact factors in contributing to diversecardiovascular disease processes includingthrombosis^[21][22][23] andstroke.^[24]

• Coagulation system
• Blood
• Protein methods

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