Abstract
Factor XIa is a plasma protease that, by activating Factor IX, plays an important role in the early phase of the intrinsic pathway of blood coagulation. Four plasma protease inhibitors, α1-protease inhibitor, antithrombin III, C1-inhibitor, and α2-plasmin inhibitor, have been reported to inactivate human Factor XIa, but their quantitative contribution to the inactivation of Factor XIa in plasma has not been fully assessed. Using purified systems, we observed that the second-order rate constants for the reaction of Factor XIa with α1-protease inhibitor, antithrombin III, and CI-inhibitor were 4.08, 10, and 14.6 M−1 min−1 × 103, respectively. The pseudo-first-order rate constants, at plasma concentration of the inhibitors, were 1.86 × 10−1, 4.68 × 10−2, and 2.4 × 10−2 min−1, respectively. These kinetic data predict that α1-protease inhibitor should account for 68%, antithrombin III for 16%, and C1-inhibitor and the equipotent α2-plasmin inhibitor each for 8% of the total inhibitory activity of plasma against Factor XIa. The rate of inactivation of Factor XIa in various plasma samples specifically deficient in inhibitors was consistent with these predictions.
Factor XI, the zymogen form of Factor XIa, circulates in plasma associated with the contact system cofactor, high molecular weight kininogen (HMW kininogen). Kinetic analysis indicated the existence of a reversible bimolecular Factor XIa-HMW kininogen complex with a dissociation constant (Kd) = 0.17 μM. The light chain derived from HMW kininogen decreased the inactivation rate of Factor XIa by C1-inhibitor with a Kd of 0.08 μM for a complex of Factor XIa and the light chain derived from HMW kininogen. The protective effect of HMW kininogen was confirmed by the finding that the inactivation rate of Factor XIa in kininogen-deficient plasma was increased over normal plasma.
The present study confirms that α1-protease inhibitor is the major inhibitor of Factor XIa in plasma, and that the formation of a reversible complex between Factor XIa and HMW kininogen decreases the rate of inactivation of the enzyme by its inhibitors.
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Selected References
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- Bolton A. E., Hunter W. M. The labelling of proteins to high specific radioactivities by conjugation to a 125I-containing acylating agent. Biochem J. 1973 Jul;133(3):529–539. doi: 10.1042/bj1330529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bouma B. N., Griffin J. H. Human blood coagulation factor XI. Purification, properties, and mechanism of activation by activated factor XII. J Biol Chem. 1977 Sep 25;252(18):6432–6437. [PubMed] [Google Scholar]
- Carp H., Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. 1978 Sep;118(3):617–621. doi: 10.1164/arrd.1978.118.3.617. [DOI] [PubMed] [Google Scholar]
- Colman R. W., Bagdasarian A., Talamo R. C., Scott C. F., Seavey M., Guimaraes J. A., Pierce J. V., Kaplan A. P. Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways. J Clin Invest. 1975 Dec;56(6):1650–1662. doi: 10.1172/JCI108247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Colman R. W., Edelman R., Scott C. F., Gilman R. H. Plasma kallikrein activation and inhibition during typhoid fever. J Clin Invest. 1978 Feb;61(2):287–296. doi: 10.1172/JCI108938. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Damus P. S., Hicks M., Rosenberg R. D. Anticoagulant action of heparin. Nature. 1973 Dec 7;246(5432):355–357. doi: 10.1038/246355a0. [DOI] [PubMed] [Google Scholar]
- Forbes C. D., Pensky J., Ratnoff O. D. Inhibition of activated Hageman factor and activated plasma thromboplastin antecedent by purified serum C1 inactivator. J Lab Clin Med. 1970 Nov;76(5):809–815. [PubMed] [Google Scholar]
- Habal F. M., Movat H. Z., Burrowes C. E. Isolation of two functionally different kininogens from human plasma--separation from proteinase inhibitors and interaction with plasma kallikrein. Biochem Pharmacol. 1974 Aug 15;23(16):2291–2303. doi: 10.1016/0006-2952(74)90558-9. [DOI] [PubMed] [Google Scholar]
- Harpel P. C. Separation of plasma thromboplastin antecedent from kallikrein by the plasma 2 -macroglobulin, kallikrein inhibitor. J Clin Invest. 1971 Oct;50(10):2084–2090. doi: 10.1172/JCI106702. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heck L. W., Kaplan A. P. Substrates of Hageman factor. I. Isolation and characterization of human factor XI (PTA) and inhibition of the activated enzyme by alpha 1-antitrypsin. J Exp Med. 1974 Dec 1;140(6):1615–1630. doi: 10.1084/jem.140.6.1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Janoff A., Carp H. Possible mechanisms of emphysema in smokers: cigarette smoke condensate suppresses protease inhibition in vitro. Am Rev Respir Dis. 1977 Jul;116(1):65–72. doi: 10.1164/arrd.1977.116.1.65. [DOI] [PubMed] [Google Scholar]
- KITZ R., WILSON I. B. Esters of methanesulfonic acid as irreversible inhibitors of acetylcholinesterase. J Biol Chem. 1962 Oct;237:3245–3249. [PubMed] [Google Scholar]
- Kerbiriou D. M., Bouma B. N., Griffin J. H. Immunochemical studies of human high molecular weight kininogen and of its complexes with plasma prekallikrein or kallikrein. J Biol Chem. 1980 May 10;255(9):3952–3958. [PubMed] [Google Scholar]
- Kerbiriou D. M., Griffin J. H. Human high molecular weight kininogen. Studies of structure-function relationships and of proteolysis of the molecule occurring during contact activation of plasma. J Biol Chem. 1979 Dec 10;254(23):12020–12027. [PubMed] [Google Scholar]
- Kurachi K., Davie E. W. Activation of human factor XI (plasma thromboplastin antecedent) by factor XIIa (activated Hageman factor). Biochemistry. 1977 Dec 27;16(26):5831–5839. doi: 10.1021/bi00645a030. [DOI] [PubMed] [Google Scholar]
- LEVY L. R., LEPOW I. H. Assay and properties of serum inhibitor of C'l-esterase. Proc Soc Exp Biol Med. 1959 Aug-Sep;101:608–611. doi: 10.3181/00379727-101-25034. [DOI] [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Lo T. N., Cohen A. B., James H. L. The interaction of alpha-1-antitrypsin with soluble and sepharose-bound elastase. Biochim Biophys Acta. 1976 Dec 22;453(2):345–356. [PubMed] [Google Scholar]
- Mandle R. J., Colman R. W., Kaplan A. P. Identification of prekallikrein and high-molecular-weight kininogen as a complex in human plasma. Proc Natl Acad Sci U S A. 1976 Nov;73(11):4179–4183. doi: 10.1073/pnas.73.11.4179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mannhalter C., Schiffman S., Jacobs A. Trypsin activation of human factor XI. J Biol Chem. 1980 Apr 10;255(7):2667–2669. [PubMed] [Google Scholar]
- PROCTOR R. R., RAPAPORT S. I. The partial thromboplastin time with kaolin. A simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Pathol. 1961 Sep;36:212–219. doi: 10.1093/ajcp/36.3.212. [DOI] [PubMed] [Google Scholar]
- Saito H., Goldsmith G. H., Moroi M., Aoki N. Inhibitory spectrum of alpha 2-plasmin inhibitor. Proc Natl Acad Sci U S A. 1979 Apr;76(4):2013–2017. doi: 10.1073/pnas.76.4.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schapira M., Scott C. F., Colman R. W. Protection of human plasma kallikrein from inactivation by C1 inhibitor and other protease inhibitors. The role of high molecular weight kininogen. Biochemistry. 1981 May 12;20(10):2738–2743. doi: 10.1021/bi00513a006. [DOI] [PubMed] [Google Scholar]
- Schiffman S., Pecci R., Lee P. Contact activation of factor XI: evidence that the primary role of contact activation cofactor (CAC) is to facilitate the activation of factor XII. Thromb Res. 1977 Feb;10(2):319–323. doi: 10.1016/0049-3848(77)90014-7. [DOI] [PubMed] [Google Scholar]
- Scott C. F., Colman R. W. Function and immunochemistry of prekallikrein-high molecular weight kininogen complex in plasma. J Clin Invest. 1980 Feb;65(2):413–421. doi: 10.1172/JCI109684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott C. F., Kirby E. P., Schick P. K., Colman R. W. Effect of surfaces on fluid-phase prekallikrein activation. Blood. 1981 Mar;57(3):553–560. [PubMed] [Google Scholar]
- Scott C. F., Liu C. Y., Colman R. W. Human plasma prekallikrein: a rapid high-yield method for purification. Eur J Biochem. 1979 Oct;100(1):77–83. doi: 10.1111/j.1432-1033.1979.tb02035.x. [DOI] [PubMed] [Google Scholar]
- Thaler E., Schmer G. A simple two-step isolation procedure for human and bovine antithrombin II/III (heparin cofactor): a comparison of two methods. Br J Haematol. 1975 Oct;31(2):233–243. doi: 10.1111/j.1365-2141.1975.tb00853.x. [DOI] [PubMed] [Google Scholar]
- Thompson R. E., Mandle R., Jr, Kaplan A. P. Association of factor XI and high molecular weight kininogen in human plasma. J Clin Invest. 1977 Dec;60(6):1376–1380. doi: 10.1172/JCI108898. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson R. E., Mandle R., Jr, Kaplan A. P. Characterization of human high molecular weight kininogen. Procoagulant activity associated with the light chain of kinin-free high molecular weight kininogen. J Exp Med. 1978 Feb 1;147(2):488–499. doi: 10.1084/jem.147.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson R. E., Mandle R., Jr, Kaplan A. P. Studies of binding of prekallikrein and Factor XI to high molecular weight kininogen and its light chain. Proc Natl Acad Sci U S A. 1979 Oct;76(10):4862–4866. doi: 10.1073/pnas.76.10.4862. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weber K., Osborn M. The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide gel electrophoresis. J Biol Chem. 1969 Aug 25;244(16):4406–4412. [PubMed] [Google Scholar]