Contact activation system

Artificial negatively charged substances that activate FXII include L-homocysteine, heparan sulfates, chondroitin sulfates, dermatan sulfate, uric acid crystals, lipoproteins, ferritin and porphyrins. 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, and polyphosphates.{{cite journal |last1=Ghebrehiwet |first1=B |last2=Kaplan |first2=AP |last3=Joseph |first3=K |last4=Peerschke |first4=EI |title=The complement and contact activation systems: partnership in pathogenesis beyond angioedema |journal=Immunological Reviews |date=November 2016 |volume=274 |issue=1 |pages=281–289 |doi=10.1111/imr.12469 |pmid=27782339|s2cid=2787614 }}{{cite journal |last1=Naudin |first1=C |last2=Burillo |first2=E |last3=Blankenberg |first3=S |last4=Butler |first4=L |last5=Renné |first5=T |title=Factor XII Contact Activation |journal=Seminars in Thrombosis and Hemostasis |date=November 2017 |volume=43 |issue=8 |pages=814–826 |doi=10.1055/s-0036-1598003 |pmid=28346966|s2cid=22844127 }}{{cite journal |last1=Schmaier |first1=AH |title=The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities |journal=Journal of Thrombosis and Haemostasis |date=January 2016 |volume=14 |issue=1 |pages=28–39 |doi=10.1111/jth.13194 |pmid=26565070|doi-access=free }} The ability of FXII to bind to negatively charged surfaces and activate coagulation forms the basis of the aPTT 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.{{cite journal |last1=Naudin |first1=C |last2=Burillo |first2=E |last3=Blankenberg |first3=S |last4=Butler |first4=L |last5=Renné |first5=T |title=Factor XII Contact Activation |journal=Seminars in Thrombosis and Hemostasis |date=November 2017 |volume=43 |issue=8 |pages=814–826 |doi=10.1055/s-0036-1598003 |pmid=28346966|s2cid=22844127 }} FXII is a zymogen, 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.{{cite journal |last1=de Maat |first1=S |last2=Tersteeg |first2=C |last3=Herczenik |first3=E |last4=Maas |first4=C |title=Tracking down contact activation - from coagulation in vitro to inflammation in vivo |journal=International Journal of Laboratory Hematology |date=June 2014 |volume=36 |issue=3 |pages=374–81 |doi=10.1111/ijlh.12222 |pmid=24750684|doi-access=free }}

Zinc has been reportedly demonstrated to be crucial in inducing a conformational 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.{{cite journal |vauthors=Røjkjær R, Schousboe I|title=Partial Identification of the Zn2+-Binding Sites in Factor XII and its Activation Derivatives |journal=European Journal of Biochemistry |date=1997 |volume=247 |issue=2 |pages=491–496 |doi=10.1111/j.1432-1033.1997.00491.x|pmid=9266689 |doi-access=free }}{{cite journal |last1=Schousboe I |title=Contact activation in human plasma is triggered by zinc ion modulation of factor XII (Hageman factor) |journal=Blood Coagul Fibrinolysis |date=1993 |volume=4 |issue=5 |pages=671–8 |doi=10.1097/00001721-199310000-00002 |pmid=7507361}}{{cite journal |last1=Rasmus KBJKJER and Inger SCHOUSBOE |title=The surface-dependent autoactivation mechanism of factor XII |journal=Eur. J. Biochem. |date=1997 |volume=243 |issue=1–2 |pages=160–166|doi=10.1111/j.1432-1033.1997.0160a.x |pmid=9030735 |doi-access=free }}

Although contact factors FXII and HK bound PK have been reported to interact with endothelial cells (via gC1q-R), platelets (via Polyphosphate) and Leukocytes; bacteria (Streptococcus pyogenes, Salmonella, and Escherichia coli) and viruses (Hantavirus and Herpes simplex 1 virus) have also been demonstrated to bind to contact factors.{{cite journal |vauthors=Mattsson E, Herwald H, Cramer H, Persson K, Sjöbring U, Björck L|title=Staphylococcus aureus Induces Release of Bradykinin in Human Plasma |journal=Infection and Immunity |date=2001 |volume=69 |issue=6 |pages=3877–3882 |doi=10.1128/IAI.69.6.3877-3882.2001 |pmid=11349054 |pmc=98413 |url=}} Negatively charged lipopolysaccharide (LPS) or surface associated negatively charged teichoic acids from S. aureus{{cite journal |vauthors=Kalter ES, van Dijk WC, Timmerman A, Verhoef J, Bouma BN|title=Activation of purified human plasma prekallikrein triggered by cell wall fractions of Escherichia coli and Staphylococcus aureus |journal=The Journal of Infectious Diseases |date=1983 |volume=148 |issue=4 |pages=682–691 |pmid=6355312 |doi=10.1093/infdis/148.4.682}} and long chain Polyphosphate have all been shown to induce contact activation and bradykinin release thereby contributing to the host-defense reactions{{cite journal |vauthors=Morrissey JH, Choi SH, and Smith SA|title=Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation |journal=Blood |date=2012 |volume=119 |issue=25 |pages=5972–5979 |doi=10.1182/blood-2012-03-306605 |pmid=22517894 |pmc=3383012 |url=}} by activating the complement cascade.{{cite journal |last1=Nickel|first1=KF |last2=Renné|first2=T |title=Crosstalk of the plasma contact system with bacteria |journal=Thrombosis Research |date=2012 |volume=130 |pages=S78–S83 |doi=10.1016/j.thromres.2012.08.284 |pmid=23026673 }}

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,{{cite journal |last1=Jaffer |first1=IH |last2=Fredenburgh |first2=JC |last3=Hirsh |first3=J |last4=Weitz |first4=JI |title=Medical device-induced thrombosis: what causes it and how can we prevent it? |journal=Journal of Thrombosis and Haemostasis |date=June 2015 |volume=13 |issue=Suppl 1 |pages=S72–81 |doi=10.1111/jth.12961 |pmid=26149053|doi-access=free }} 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.{{cite journal |last1=de Maat |first1=S |last2=Tersteeg |first2=C |last3=Herczenik |first3=E |last4=Maas |first4=C |title=Tracking down contact activation - from coagulation in vitro to inflammation in vivo |journal=International Journal of Laboratory Hematology |date=June 2014 |volume=36 |issue=3 |pages=374–81 |doi=10.1111/ijlh.12222 |pmid=24750684|doi-access=free }}

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.{{cite journal |last1=Schmaier |first1=AH |title=The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities |journal=Journal of Thrombosis and Haemostasis |date=January 2016 |volume=14 |issue=1 |pages=28–39 |doi=10.1111/jth.13194 |pmid=26565070|doi-access=free }} PK can also lead to fibrinolysis by converting plasminogen to plasmin.{{cite journal | vauthors = Long AT, Kenne E, Jung R, Fuchs TA, Renné T | title = Contact system revisited: an interface between inflammation, coagulation, and innate immunity | journal = Journal of Thrombosis and Haemostasis | volume = 14 | issue = 3 | pages = 427–437 | date = March 2016 | pmid = 26707513 | doi = 10.1111/jth.13235 | doi-access = free }}

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

Activation of the CAS is associated with hereditary angioedema, a disorder characterised by episodes of swelling.{{cite journal |last1=De Maat |first1=S |last2=Hofman |first2=ZLM |last3=Maas |first3=C |title=Hereditary angioedema: the plasma contact system out of control |journal=Journal of Thrombosis and Haemostasis |volume=16 |issue=9 |pages=1674–1685 |date=19 June 2018 |doi=10.1111/jth.14209 |pmid=29920929|doi-access=free }}

Genetic knockout studies in murine models of cardiovascular disease and genetic linkage studies in humans have implicated the contact factors in contributing to diverse cardiovascular disease processes including thrombosis{{cite journal |vauthors=Fredenburgh JC, Gross PL, and Weitz JI|title=Emerging anticoagulant strategies |journal=Blood |date=2017 |volume=129 |issue=2 |pages=147–154 |doi=10.1182/blood-2016-09-692996 |pmid=27780803 |url=http://www.bloodjournal.org/content/bloodjournal/129/2/147.full.pdf|doi-access=free }}{{cite journal |last1=Pierre-Emmanuel Morange|display-authors=et al |title=KNG1 Ile581Thr and susceptibility to venous thrombosis |journal=Blood |date=2011 |volume=117 |issue=13 |pages=3692–3694 |doi=10.1182/blood-2010-11-319053 |pmid=21270443 |s2cid=39069970 |url=http://www.bloodjournal.org/content/bloodjournal/117/13/3692.full.pdf}}{{cite journal |last1=Revenko AS|display-authors=et al |title=Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding |journal=Blood |date=2011 |volume=118 |issue=19 |pages=5302–5311 |doi=10.1182/blood-2011-05-355248 |pmid=21821705 |pmc=4425441 |url=}} and stroke.{{cite journal |last1=Yi Wu |title=Contact pathway of coagulation and inflammation |journal=Thrombosis Journal|date=2015 |volume=13 |pages=17 |doi=10.1186/s12959-015-0048-y |pmid=25949215 |pmc=4421925 |doi-access=free }}

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