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SERPINC1  -  serpin peptidase inhibitor, clade C...

Homo sapiens

Synonyms: AT3, AT3D, ATIII, Antithrombin-III, MGC22579, ...
 
 
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Disease relevance of SERPINC1

  • In sepsis only ATIII is decreased [1].
  • Screening for PC, PS, and ATIII is advocated in young patients who have thromboembolic disease, especially when there is a positive family history of thrombosis [2].
  • Among chronic hepatitis cases, the active type showed a more significant decrease in ATIII alone than the inactive type [3].
  • Low levels of ATIII and PC are markers of and may be involved in the pathogenesis of MODS in BMT [4].
  • Multivariate analysis showed ATIII and PC levels were associated with single organ dysfunction independent of the type of transplant, the type of preparative regimen, and the presence of bacteremia [4].
 

Psychiatry related information on SERPINC1

 

High impact information on SERPINC1

  • Whereas AT3 regulates the proteolytic activity of thrombin in serum, PN may regulates the activity of serine proteases at and near the cell surface [6].
  • In several ways PN resembles antithrombin III (AT3), a prominent inhibitor of thrombin in serum: PN links thrombin, probably via an ester bond; PN does not link thrombin blocked at its catalytic site serine; PN has a high-affinity heparin-binding site; and heparin greatly accelerates the rate of linkage between soluble PN and thrombin [6].
  • Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice [7].
  • OBJECTIVE--To define the frequency and outcome of organ dysfunction in bone marrow transplantation (BMT) and to determine if patients with organ dysfunction have lower levels of protein C (PC) and/or antithrombin III (ATIII) than those without organ dysfunction [4].
  • The genes of seven structural mutants of antithrombin III (ATIII), presenting either defective serine protease reactivity or abnormal heparin binding, were analyzed [8].
 

Chemical compound and disease context of SERPINC1

 

Biological context of SERPINC1

  • CONCLUSIONS: Fibrinolysis is strongly activated and ATIII is utilized in sepsis [1].
  • Initial and sequential levels of ATIII (activity), PC (antigen and activity), PS (total and free), and C4b binding protein (C4bBP) were compared according to the outcome in patients with DIC [14].
  • The positions of introns in the ATIII gene were compared with other members of the serine protease inhibitor family which share 17-31% amino acid homology [15].
  • ATIII Geneva was found to have a G to A transition in Exon IIIa leading to an Arg-129 to Gln mutation [16].
  • Analysis of both total genomic DNAs and an ATIII gene cloned in a bacteriophage Charon 4A showed that the ATIII gene is present once per haploid genome and is distributed over 10-16 kilobases of DNA [17].
 

Anatomical context of SERPINC1

 

Associations of SERPINC1 with chemical compounds

  • Levels of fibrinogen, Factor VIII: C (VIII:C) and von Wildebrand antigen (vWf:Ag), and activities of ATIII and plasminogen (Plg) were significantly decreased in the group with physical training (p less than 0.05), while values were unchanged in the control group [21].
  • Although all patients were given heparin, a decrease in antithrombin III (ATIII) and progressive increase in thrombin-ATIII complex (TAT) and fibrinopeptide A (FPA) levels were noted during cardiopulmonary bypass, which indicated that heparinization did not completely inhibit the formation of thrombin and its function [22].
  • PC, PS and ATIII values were mostly lower in the 2nd group but this difference only became significant after at least 2 years of warfarin usage [23].
  • On the basis of database and in vitro glycosylation studies suggesting that N-X-S CSs are utilized less efficiently than N-X-T CSs, we hypothesized that the beta-ATIII isoform might result from inefficient core glycosylation of the N135 N-X-S CS due to the presence of a serine, rather than a threonine, in the third position [24].
  • Proline-407 is located 14 amino acids C-terminal to the reactive site arginine of ATIII in a core region of the molecule that has been highly conserved during evolution of the serine protease inhibitor (serpin) gene family [25].
 

Physical interactions of SERPINC1

  • The dissociation equilibrium constant for heparin binding to antithrombin III (ATIII) is a measure of the cofactor's binding to and activation of the proteinase inhibitor, and its salt dependence indicates that ionic and non-ionic interactions contribute approximately 40 and approximately 60% of the binding free energy, respectively [26].
  • Stored whole blood showed a significant decrease in ATIII activity by the second week with a significant decrease in thrombin-antithrombin complex by the fourth week. alpha 2-antiplasmin and plasminogen decreased significantly by the first and second week, respectively, accompanied by a significant increase in D-dimer level by the fourth week [27].
  • Consequently, the ratio of thrombin bound to ATIII over thrombin bound to alpha 2M was significantly lower in neonatal (less than 2.5) than in adult plasma (greater than 4.5; p less than 0.0001) [28].
  • Most notably, fibronectin contains six active binding sites for heparin which may interfere with the subsequent binding of heparin with ATIII or thrombin [29].
  • The purpose of this pilot study was to determine the effect of recombinant hirudin (r-hirudin) on coagulopathy and the relationship between concentrations of thrombin-antithrombin III (ATIII) complex (TAT) and thrombin-hirudin complex (THC) in patients with disseminated intravascular coagulation (DIC) [30].
 

Regulatory relationships of SERPINC1

  • As ATIII in plasma also inhibits protein C activation by a thrombin-thrombomodulin complex, we studied whether GAG-UTM accelerates protein C activation in plasma [31].
  • Also inclusion of human TM at increasing concentration suppressed the thrombin inhibitory activity of ATIII [32].
  • The ATIII/heparin regimen was well tolerated with no increase in bleeding or significant prolongation of the activated partial thromboplastin time [33].
  • This agent activates HC-II through inhibiting the thrombin generation but not inhibiting ATIII [34].
 

Other interactions of SERPINC1

  • Although much is known about the function, structure, and inhibitory mechanism of circulating serpins such as alpha(1)-antitrypsin (SERPINA1) and antithrombin III (SERPINC1), relatively little is known about the function of the vertebrate intracellular (clade B) serpins [35].
  • We conclude that these variations in ATIII and protein C with age and sex are important considerations in the determination of reference ranges for these proteins [36].
  • Sequential ATIII, PC, and PS measurements were consistent with prolonged consumption or inhibition that might account for a sustained procoagulant state and inhibition of fibrinolysis [14].
  • In contrast, in severe sepsis and mainly in septic shock plasminogen and the main coagulation inhibitors (i.e., ATIII, PrC) are depleted, indicating exhaustion of fibrinolysis and coagulation inhibitors [1].
  • With the exception of a decrease in ATIII and an increase in tPA and PAI-1, coagulation inhibitors and factors of fibrinolysis were not changed in sepsis [1].
 

Analytical, diagnostic and therapeutic context of SERPINC1

References

  1. Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock. Mavrommatis, A.C., Theodoridis, T., Economou, M., Kotanidou, A., El Ali, M., Christopoulou-Kokkinou, V., Zakynthinos, S.G. Intensive care medicine. (2001) [Pubmed]
  2. Hereditary thrombophilia among 217 consecutive patients with thromboembolic disease in Jordan. Awidi, A.S., Abu-Khalaf, M., Herzallah, U., Abu-Rajab, A., Shannak, M.M., Abu-Obeid, T., al-Taher, I., Anshasi, B. Am. J. Hematol. (1993) [Pubmed]
  3. Plasma antithrombin III, alpha 2-plasmin inhibitor and plasminogen activities in cases of various liver diseases. Ito, K., Niwa, M., Kawada, T., Tanaka, Y. Tokai J. Exp. Clin. Med. (1986) [Pubmed]
  4. Multiple organ dysfunction syndrome in bone marrow transplantation. Haire, W.D., Ruby, E.I., Gordon, B.G., Patil, K.D., Stephens, L.C., Kotulak, G.D., Reed, E.C., Vose, J.M., Bierman, P.J., Kessinger, A. JAMA (1995) [Pubmed]
  5. Serine protease inhibitor antithrombin III and its messenger RNA in the pathogenesis of Alzheimer's disease. Kalaria, R.N., Golde, T., Kroon, S.N., Perry, G. Am. J. Pathol. (1993) [Pubmed]
  6. Protease-nexin: a cellular component that links thrombin and plasminogen activator and mediates their binding to cells. Baker, J.B., Low, D.A., Simmer, R.L., Cunningham, D.D. Cell (1980) [Pubmed]
  7. Generation of C5a in the absence of C3: a new complement activation pathway. Huber-Lang, M., Sarma, J.V., Zetoune, F.S., Rittirsch, D., Neff, T.A., McGuire, S.R., Lambris, J.D., Warner, R.L., Flierl, M.A., Hoesel, L.M., Gebhard, F., Younger, J.G., Drouin, S.M., Wetsel, R.A., Ward, P.A. Nat. Med. (2006) [Pubmed]
  8. Molecular characterization of antithrombin III (ATIII) variants using polymerase chain reaction. Identification of the ATIII Charleville as an Ala 384 Pro mutation. Molho-Sabatier, P., Aiach, M., Gaillard, I., Fiessinger, J.N., Fischer, A.M., Chadeuf, G., Clauser, E. J. Clin. Invest. (1989) [Pubmed]
  9. Cloning and expression of the cDNA for human antithrombin III. Bock, S.C., Wion, K.L., Vehar, G.A., Lawn, R.M. Nucleic Acids Res. (1982) [Pubmed]
  10. Oxymetholone therapy in patients with familial antithrombin III deficiency. Shibuya, A., Ninomiya, H., Nakazawa, M., Nagasawa, T., Yoda, Y., Abe, T. Thromb. Haemost. (1988) [Pubmed]
  11. The quick machine--a mathematical model for the extrinsic activation of coagulation. Pohl, B., Beringer, C., Bomhard, M., Keller, F. Haemostasis (1994) [Pubmed]
  12. The MDA-180 coagulation analyser: a laboratory evaluation. Mohammed, A., Mehrabani, P.A., Coombs, R., Molesworth, L., Favaloro, E.J. Pathology. (1997) [Pubmed]
  13. Effect of glycosidase inhibitors on the biosynthesis of alpha 2-plasmin inhibitor and antithrombin III in Hep G2 cells. Mori, K., Wada, Y., Mimuro, J., Matsuda, M., Yoshikuni, Y., Kimura, K., Sakata, Y. Biochim. Biophys. Acta (1994) [Pubmed]
  14. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Fourrier, F., Chopin, C., Goudemand, J., Hendrycx, S., Caron, C., Rime, A., Marey, A., Lestavel, P. Chest (1992) [Pubmed]
  15. Intron structure of the human antithrombin III gene differs from that of other members of the serine protease inhibitor superfamily. Prochownik, E.V., Bock, S.C., Orkin, S.H. J. Biol. Chem. (1985) [Pubmed]
  16. Important role of arginine 129 in heparin-binding site of antithrombin III. Identification of a novel mutation arginine 129 to glutamine. Gandrille, S., Aiach, M., Lane, D.A., Vidaud, D., Molho-Sabatier, P., Caso, R., de Moerloose, P., Fiessinger, J.N., Clauser, E. J. Biol. Chem. (1990) [Pubmed]
  17. Isolation of a cDNA clone for human antithrombin III. Prochownik, E.V., Markham, A.F., Orkin, S.H. J. Biol. Chem. (1983) [Pubmed]
  18. Natural anticoagulant pathways in normal and transplanted human hearts. Labarrere, C.A., Pitts, D., Halbrook, H., Faulk, W.P. J. Heart Lung Transplant. (1992) [Pubmed]
  19. Successful detection by in situ cDNA hybridization of three members of the serpin family: angiotensinogen, alpha 1 protease inhibitor, and antithrombin III in human hepatocytes. Gaillard-Sanchez, I., Bruneval, P., Clauser, E., Belair, M.F., Da Silva, J.L., Bariety, J., Camilleri, J.P., Corvol, P. Mod. Pathol. (1990) [Pubmed]
  20. Maternal and cord blood hemostasis at delivery. Schneider, D.M., von Tempelhoff, G.F., Herrle, B., Heilmann, L. Journal of perinatal medicine. (1997) [Pubmed]
  21. Blood coagulability and fibrinolytic activity before and after physical training during the recovery phase of acute myocardial infarction. Suzuki, T., Yamauchi, K., Yamada, Y., Furumichi, T., Furui, H., Tsuzuki, J., Hayashi, H., Sotobata, I., Saito, H. Clinical cardiology. (1992) [Pubmed]
  22. The role of the protein C-thrombomodulin system in physiologic anticoagulation during cardiopulmonary bypass. Tanaka, K., Wada, K., Morimoto, T., Shomura, S., Satoh, T., Yada, I., Yuasa, H., Kusagawa, M., Deguchi, K. ASAIO transactions / American Society for Artificial Internal Organs. (1989) [Pubmed]
  23. Protein C, S and antithrombin III levels in patients with acute mechanical valve thrombosis. Tütün, U., Ulus, A.T., Aksöyek, A., Kaplan, S., Ayaz, S., Yilmaz, S., Birincioglu, L., Katircioglu, S.F. Panminerva medica. (2002) [Pubmed]
  24. Partial glycosylation of antithrombin III asparagine-135 is caused by the serine in the third position of its N-glycosylation consensus sequence and is responsible for production of the beta-antithrombin III isoform with enhanced heparin affinity. Picard, V., Ersdal-Badju, E., Bock, S.C. Biochemistry (1995) [Pubmed]
  25. Antithrombin III Utah: proline-407 to leucine mutation in a highly conserved region near the inhibitor reactive site. Bock, S.C., Marrinan, J.A., Radziejewska, E. Biochemistry (1988) [Pubmed]
  26. Antithrombin III phenylalanines 122 and 121 contribute to its high affinity for heparin and its conformational activation. Jairajpuri, M.A., Lu, A., Desai, U., Olson, S.T., Bjork, I., Bock, S.C. J. Biol. Chem. (2003) [Pubmed]
  27. Effect of cold storage on the haemostatic cascade systems. Omran, S., Hallouda, M., Essawi, F., el Attar, I., Aboul Enein, A., Gaafar, T., Afifi, N. Transfusion science. (1996) [Pubmed]
  28. Alpha-2-macroglobulin is an important progressive inhibitor of thrombin in neonatal and infant plasma. Schmidt, B., Mitchell, L., Ofosu, F.A., Andrew, M. Thromb. Haemost. (1989) [Pubmed]
  29. Effect of fibronectin on the binding of antithrombin III to immobilized heparin. Byun, Y., Jacobs, H.A., Feijen, J., Kim, S.W. J. Biomed. Mater. Res. (1996) [Pubmed]
  30. Recombinant hirudin for the treatment of disseminated intravascular coagulation in patients with haematological malignancy. Saito, M., Asakura, H., Jokaji, H., Uotani, C., Kumabashiri, I., Morishita, E., Yamazaki, M., Aoshima, K., Matsuda, T. Blood Coagul. Fibrinolysis (1995) [Pubmed]
  31. Protein C activation by recombinant thrombomodulin in plasma. Edano, T., Komine, N., Yoshizaki, H., Ohkuchi, M. Biol. Pharm. Bull. (1998) [Pubmed]
  32. The effect of human thrombomodulin on the inactivation of thrombin by human antithrombin III. Hirahara, K., Koyama, M., Matsuishi, T., Kurata, M. Thromb. Res. (1990) [Pubmed]
  33. Antithrombin III prophylaxis of venous thromboembolic disease after total hip or total knee replacement. Francis, C.W., Pellegrini, V.D., Harris, C.M., Marder, V.J. Am. J. Med. (1989) [Pubmed]
  34. Anticoagulant and antiprotease profiles of a novel natural heparinomimetic mannopentaose phosphate sulfate (PI-88). Demir, M., Iqbal, O., Hoppensteadt, D.A., Piccolo, P., Ahmad, S., Schultz, C.L., Linhardt, R.J., Fareed, J. Clin. Appl. Thromb. Hemost. (2001) [Pubmed]
  35. SRP-2 is a cross-class inhibitor that participates in postembryonic development of the nematode Caenorhabditis elegans: initial characterization of the clade L serpins. Pak, S.C., Kumar, V., Tsu, C., Luke, C.J., Askew, Y.S., Askew, D.J., Mills, D.R., Brömme, D., Silverman, G.A. J. Biol. Chem. (2004) [Pubmed]
  36. Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Dolan, G., Neal, K., Cooper, P., Brown, P., Preston, F.E. Br. J. Haematol. (1994) [Pubmed]
  37. Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor. Wuillemin, W.A., Minnema, M., Meijers, J.C., Roem, D., Eerenberg, A.J., Nuijens, J.H., ten Cate, H., Hack, C.E. Blood (1995) [Pubmed]
  38. Assignment of the human antithrombin III structural gene to chromosome 1q23-25. Bock, S.C., Harris, J.F., Balazs, I., Trent, J.M. Cytogenet. Cell Genet. (1985) [Pubmed]
  39. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L'Asparaginase-induced antithrombin III deficiency. Mitchell, L., Hoogendoorn, H., Giles, A.R., Vegh, P., Andrew, M. Blood (1994) [Pubmed]
 
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