Biology:Contact activation system

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The two arms of the contact system. PKa's cleavage of HK liberates BK and promotes inflammation. FXIIa's cleavage of FXI initiates coagulation.

In the contact activation system or CAS, three proteins in the blood, factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK), bind to a surface and cause blood coagulation and inflammation. FXII and PK are proteases and HK is a non-enzymatic co-factor. The CAS can activate the kinin–kallikrein system and blood 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 the coagulation cascade by cleaving and activating factor 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 as bradykinin (BK). BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate inflammation.[1][2][3]

Surfaces and activation

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.[4][5][6] 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.[7] 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.[8]

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.[9][10][11]

Contact factors binding to bacteria and viruses

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.[12] Negatively charged lipopolysaccharide (LPS) or surface associated negatively charged teichoic acids from S. aureus[13] and long chain Polyphosphate have all been shown to induce contact activation and bradykinin release thereby contributing to the host-defense reactions[14] by activating the complement cascade.[15]

Physiological roles

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]

Roles in disease

Activation of the CAS is associated with hereditary angioedema, a disorder characterised by episodes of swelling.[19] 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[20][21][22] and stroke.[23]


References

  1. ↑ Schmaier, AH (May 2014). "Physiologic activities of the contact activation system". Thrombosis Research 133 Suppl 1 (1): S41–4. doi:10.1016/j.thromres.2014.03.018. PMID 24759141. 
  2. ↑ de Maat, S; Tersteeg, C; Herczenik, E; Maas, C (June 2014). "Tracking down contact activation - from coagulation in vitro to inflammation in vivo". International Journal of Laboratory Hematology 36 (3): 374–81. doi:10.1111/ijlh.12222. PMID 24750684. 
  3. ↑ Monika Pathak, Bubacarr Gibril Kaira, Alexandre Slater and Jonas Emsley (2018). "Cell Receptor and Cofactor Interactions of the Contact Activation System and Factor XI". Frontiers in Medicine 5: 66. doi:10.3389/fmed.2018.00066. PMID 29619369. 
  4. ↑ Ghebrehiwet, B; Kaplan, AP; Joseph, K; Peerschke, EI (November 2016). "The complement and contact activation systems: partnership in pathogenesis beyond angioedema". Immunological Reviews 274 (1): 281–289. doi:10.1111/imr.12469. PMID 27782339. 
  5. ↑ Naudin, C; Burillo, E; Blankenberg, S; Butler, L; Renné, T (November 2017). "Factor XII Contact Activation". Seminars in Thrombosis and Hemostasis 43 (8): 814–826. doi:10.1055/s-0036-1598003. PMID 28346966. 
  6. ↑ Schmaier, AH (January 2016). "The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities". Journal of Thrombosis and Haemostasis 14 (1): 28–39. doi:10.1111/jth.13194. PMID 26565070. 
  7. ↑ Naudin, C; Burillo, E; Blankenberg, S; Butler, L; Renné, T (November 2017). "Factor XII Contact Activation". Seminars in Thrombosis and Hemostasis 43 (8): 814–826. doi:10.1055/s-0036-1598003. PMID 28346966. 
  8. ↑ de Maat, S; Tersteeg, C; Herczenik, E; Maas, C (June 2014). "Tracking down contact activation - from coagulation in vitro to inflammation in vivo". International Journal of Laboratory Hematology 36 (3): 374–81. doi:10.1111/ijlh.12222. PMID 24750684. 
  9. ↑ "Partial Identification of the Zn2+‐Binding Sites in Factor XII and its Activation Derivatives". European Journal of Biochemistry 247 (2): 491–496. 1997. doi:10.1111/j.1432-1033.1997.00491.x. PMID 9266689. 
  10. ↑ Schousboe I (1993). "Contact activation in human plasma is triggered by zinc ion modulation of factor XII (Hageman factor)". Blood Coagul Fibrinolysis 4 (5): 671–8. doi:10.1097/00001721-199310000-00002. PMID 7507361. 
  11. ↑ Rasmus KBJKJER and Inger SCHOUSBOE (1997). "The surface-dependent autoactivation mechanism of factor XII". Eur. J. Biochem. 243 (1–2): 160–166. doi:10.1111/j.1432-1033.1997.0160a.x. PMID 9030735. 
  12. ↑ "Staphylococcus aureus Induces Release of Bradykinin in Human Plasma". Infection and Immunity 69 (6): 3877–3882. 2001. doi:10.1128/IAI.69.6.3877-3882.2001. PMID 11349054. 
  13. ↑ "Activation of purified human plasma prekallikrein triggered by cell wall fractions of Escherichia coli and Staphylococcus aureus". The Journal of Infectious Diseases 148 (4): 682–691. 1983. doi:10.1093/infdis/148.4.682. PMID 6355312. 
  14. ↑ "Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation". Blood 119 (25): 5972–5979. 2012. doi:10.1182/blood-2012-03-306605. PMID 22517894. 
  15. ↑ Nickel, KF; Renné, T (2012). "Crosstalk of the plasma contact system with bacteria". Thrombosis Research 130: S78–S83. doi:10.1016/j.thromres.2012.08.284. PMID 23026673. 
  16. ↑ Jaffer, IH; Fredenburgh, JC; Hirsh, J; Weitz, JI (June 2015). "Medical device-induced thrombosis: what causes it and how can we prevent it?". Journal of Thrombosis and Haemostasis 13 (Suppl 1): S72–81. doi:10.1111/jth.12961. PMID 26149053. 
  17. ↑ de Maat, S; Tersteeg, C; Herczenik, E; Maas, C (June 2014). "Tracking down contact activation - from coagulation in vitro to inflammation in vivo". International Journal of Laboratory Hematology 36 (3): 374–81. doi:10.1111/ijlh.12222. PMID 24750684. 
  18. ↑ Schmaier, AH (January 2016). "The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities". Journal of Thrombosis and Haemostasis 14 (1): 28–39. doi:10.1111/jth.13194. PMID 26565070. 
  19. ↑ De Maat, S; Hofman, ZLM; Maas, C (19 June 2018). "Hereditary angioedema: the plasma contact system out of control". Journal of Thrombosis and Haemostasis 16 (9): 1674–1685. doi:10.1111/jth.14209. PMID 29920929. 
  20. ↑ "Emerging anticoagulant strategies". Blood 129 (2): 147–154. 2017. doi:10.1182/blood-2016-09-692996. PMID 27780803. http://www.bloodjournal.org/content/bloodjournal/129/2/147.full.pdf. 
  21. ↑ Pierre-Emmanuel Morange (2011). "KNG1 Ile581Thr and susceptibility to venous thrombosis". Blood 117 (13): 3692–3694. doi:10.1182/blood-2010-11-319053. PMID 21270443. http://www.bloodjournal.org/content/bloodjournal/117/13/3692.full.pdf. 
  22. ↑ Revenko AS (2011). "Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding". Blood 118 (19): 5302–5311. doi:10.1182/blood-2011-05-355248. PMID 21821705. 
  23. ↑ Yi Wu (2015). "Contact pathway of coagulation and inflammation". Thrombosis Journal 13: 17. doi:10.1186/s12959-015-0048-y. PMID 25949215. 



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