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. Contact system.svg
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]

Contents

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]

Related Research Articles

Platelet Component of blood aiding in coagulation

Platelets, also called thrombocytes, are a component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. Platelets have no cell nucleus; they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow or lung, which then enter the circulation. Circulating inactivated platelets are biconvex discoid (lens-shaped) structures, 2–3 µm in greatest diameter. Activated platelets have cell membrane projections covering their surface. Platelets are found only in mammals, whereas in other vertebrates, thrombocytes circulate as intact mononuclear cells.

Coagulation Process by which blood changes from a liquid to a gel, forming a blood clot

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

Disseminated intravascular coagulation Medical condition

Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.

Fibrinogen Soluble protein complex in blood plasma and involved in clot formation

Fibrinogen is a glycoprotein complex, made in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.

Bradykinin Chemical compound

Bradykinin is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids.

Factor XII

Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.

Factor VIII Blood-clotting protein

Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. Factor VIII is produced in liver sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.

Angioedema Disease characterized by the rapid swelling

Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.

High-molecular-weight kininogen is a circulating plasma protein which participates in the initiation of blood coagulation, and in the generation of the vasodilator bradykinin via the kallikrein-kinin system. HMWK is inactive until it either adheres to binding proteins beneath an endothelium disrupted by injury, thereby initiating coagulation; or it binds to intact endothelial cells or platelets for functions other than coagulation.

The kinin–kallikrein system or simply kinin system is a poorly understood hormonal system with limited available research. It consists of blood proteins that play a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. Clinical symptoms include marked weakness, tachycardia, fever, leukocytosis and acceleration of ESR.

Factor X

Factor X, also known by the eponym Stuart–Prower factor, is an enzyme of the coagulation cascade. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.

Factor V

Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations predispose for thrombosis.

Factor XI

Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene.

Tissue factor

Tissue factor, also called platelet tissue factor, factor III, or CD142, is a protein encoded by the F3 gene, present in subendothelial tissue and leukocytes. Its role in the clotting process is the initiation of thrombin formation from the zymogen prothrombin. Thromboplastin defines the cascade that leads to the activation of factor X—the tissue factor pathway. In doing so, it has replaced the previously named extrinsic pathway in order to eliminate ambiguity.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (KLKB1) has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to produce kallikrein by activated Factor XII.

Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.

KLKB1

Plasma kallikrein is a protein that in humans is encoded by the KLKB1 gene.

Kininogen 1

Kininogen-1 (KNG1), also known as alpha-2-thiol proteinase inhibitor, Williams-Fitzgerald-Flaujeac factor or the HMWK-kallikrein factor is a protein that in humans is encoded by the KNG1 gene. Kininogen-1 is the precursor protein to high-molecular-weight kininogen (HMWK), low-molecular-weight kininogen (LMWK), and bradykinin.

Factor XII deficiency is a deficiency in the production of factor XII (FXII), a plasma glycoprotein and clotting factor that participates in the coagulation cascade and activates factor XI. FXII appears to be not essential for blood clotting, as individuals with this condition are usually asymptomatic and form blood clots in vivo. FXII deficiency tends to be identified during presurgical laboratory screening for bleeding disorders.

References

  1. ↑ Schmaier, AH (May 2014). "Physiologic activities of the contact activation system". Thrombosis Research. 133 Suppl 1: S41–4. doi:10.1016/j.thromres.2014.03.018. PMC   4004333 . 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. PMC   5871670 . PMID   29619369.CS1 maint: multiple names: authors list (link)
  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. ↑ Røjkjær R, Schousboe I (1997). "Partial Identification of the Zn2+‐Binding Sites in Factor XII and its Activation Derivatives". European Journal of Biochemistry. 247 (2): 491–496. 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. 5 (5): 671–8. 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. ↑ Mattsson E, Herwald H, Cramer H, Persson K, Sjöbring U, Björck L (2001). "Staphylococcus aureus Induces Release of Bradykinin in Human Plasma". Infection and Immunity. 69 (6): 3877–3882. doi:10.1128/IAI.69.6.3877-3882.2001. PMC   98413 . PMID   11349054.
  13. ↑ Kalter ES, van Dijk WC, Timmerman A, Verhoef J, Bouma BN (1983). "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. doi:10.1093/infdis/148.4.682. PMID   6355312.
  14. ↑ Morrissey JH, Choi SH, and Smith SA (2012). "Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation". Blood. 119 (25): 5972–5979. doi:10.1182/blood-2012-03-306605. PMC   3383012 . 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. ↑ Fredenburgh JC, Gross PL, and Weitz JI (2017). "Emerging anticoagulant strategies" (PDF). Blood. 129 (2): 147–154. doi: 10.1182/blood-2016-09-692996 . PMID   27780803.
  21. ↑ Pierre-Emmanuel Morange; et al. (2011). "KNG1 Ile581Thr and susceptibility to venous thrombosis" (PDF). Blood. 117 (13): 3692–3694. doi:10.1182/blood-2010-11-319053. PMID   21270443.
  22. ↑ Revenko AS; et al. (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. PMC   4425441 . PMID   21821705.
  23. ↑ Yi Wu (2015). "Contact pathway of coagulation and inflammation". Thrombosis Journal. 13: 17. doi:10.1186/s12959-015-0048-y. PMC   4421925 . PMID   25949215.
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