Hemker, H.C.

Hensen, A.

Loeliger, E.A.

Veltkamp, J.J.

English

NARCIS 

Nature of prothrombin biosynthesis: Preprothrombininæmia in vitamin K-deficiency

Maastricht University Research Portal

   Nature of prothrombin biosynthesisCitation for published version (APA):Hemker, H. C., Veltkamp, J. J., Hensen, A., & Loeliger, E. A. (1963). Nature of prothrombin biosynthesis:Preprothrombininæmia in vitamin K-deficiency. Nature, 200(4906), 589-590.https://doi.org/10.1038/200589a0Document status and date:Published: 09/11/1963DOI:10.1038/200589a0Document Version:Other versionPlease check the document version of this publication:• A submitted manuscript is the version of the article upon submission and before peer-review. There canbe important differences between the submitted version and the official published version of record.People interested in the research are advised to contact the author for the final version of the publication,or visit the DOI to the publisher's website.• The final author version and the galley proof are versions of the publication after peer review.• The final published version features the final layout of the paper including the volume, issue and pagenumbers.Link to publicationGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with theserights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain• You may freely distribute the URL identifying the publication in the public portal.If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above,please follow below link for the End User Agreement:www.umlib.nl/taverne-licenseTake down policyIf you believe that this document breaches copyright please contact us at:repository@maastrichtuniversity.nlproviding details and we will investigate your claim.Download date: 03 Jun. 2020Nerrrnr on horrmongnrl Brosnurresrs: hs-PROTIIROMBINAEIiIIA IN VITAMIN r-O",,C,"*.".H. c.. Hen*er, I. I. uettkonry, i."rZi"*Xaffiryg'. From L'd,;*[y' ;",;'iff '#y_g:1, The Neth.erlands, Nature, London 200:5g9_5go, 1963. f,L./p !vv.uu{lsing^ a nodiffecl thrombotest (Owren) theauthors found a difference in th" b"h;;;r"#"f.rlmas with lowered clotting fu"torc fr,lrf"i ftT;X derived from patients with hepatic ;#;;"1,opposed to patients with vitamir--n fficl-ei;They suggest that the data could be explained bythe presence of an inhibitor i" uitamiri i";ffi;-cy which is acrive in both th" i;;;r; ;ffT_*rrj"_::1*tation systems. This inhibiior'*r*,De a prec'rsor of prothrombin normally ";;;;,only in hepatic cells._L C.(Reprinled lrom Nature, Vol. 200, No. 4906, pp. 589-590,November 9. 1963)Nature of Prothrombin Biosynthesis :Preprothrombinamia in Vitamin K-deficiencyTrrn activities of the clotting factors II, VII, IX, and Xaro mutually lowered to a similar degree in chronichepatic damago as well as during prolongod roal or relative(coumarin-induced) vitamin Il-deficiencyr,e. fn the. exporiments described here, Owron's thrombotest (slightlymodified, Fig. I ) is used for t,he assessment, of the eitenlof depression. Each plasma sample is tested in a serios ofdilutions (D) and the coa,g'ulation time (t, mean of 4readings) measured in a coagulometers'a. All plasmasand plasma dilutions aro kept in carefully siliconized glass-waro or plastic material. When I is plotted against, D, astraight line is obtained (Fig. l).Tho slope of the line is proportional to the substrato(complex of Factors II, VII, IX and X) concentration inthe plasma testsd. Extrapolation to infinite substraroconcentration (intercept of the line obtained with theordinate) will give tho minimal coagulation timo (f-i,r).Plasmas with different, substrate concontrations all displaythe samo value for 116r. This holds for plasmas frompatients suffering from hepatic damage of different degree(Fig. I, above). In vitamin l(-deficiency, howovor, tmin isgenerally found to be markedly elevated, suggesting thepresence of an inhibitor (Fig. 1, below). A Lineweaver-Burk plot5 of values obtained from mixtures of a constantamount of plasma from a vitamin K-deficient patieni withvanious amounts of normal plasma, as compa,red withvalues obtained with nornal plasma alone, shows that acompetitivo inhibitor is present (Fig. 2).The inhibitor appoars to bo activo in both the intrinsicand extrinsic coagulation system. Addition of factors ff,VII, and X, or of Russell's viper venom to tho reactionmixture doos not abolish tho inhibition. The inhibitor isheat labile, undialysable and adsorbablo on to bariumsulphato, aluminium hydroxido, calcium phosphate andbentonite. Thoro is a simple graphical rvay to estimate thea,mount of inhibitor (Fig. I, below) : Whon a line (l) isdrawn through l*t, of normal plasma parallel to theabscissa, the line obtainod from tho values of a plasmacontaining the inhibitor (a) will intercept Z at, a certain dis-tanco (r) left of tho ordinato. The length of r is propor-tional to tho arnount of inhibitor present, indopondont oft'he,amount of substrato. One unit of inhibitor wo defineas the amount of inhibitor resultins in an r-valuo eoua,l tothe distanco from tho origin to D=1. As can be seonfrom Fig. lb, the amount of inhibitor in eldorly coumarin-t'reatod patients displaying a clotting faitor activity below50 per cent seoms to bo independont of tho intensity oft'reatment6.op  l 8 %p 4 5 %n 100 0zD -------+i1Ii15t minFis. 1. Relation between plasnla dilution and coagulation tine' Above.inaormal Dlasma (2) anii chronic liver disease (p); below. in nornalnlasma and in plaima of dicoumarol-treated patients (i). Reactionineaium: 0 25 ml. thrombol,est reagent; 0'05 ml. plasma (lt--?-: 1)'oi o'of ml. of a mixture of plmma with n times its volume of Micha€lisbutrer (at D = fr + 1). The percentages itdicate the reletiYe amountofsuosirate present in ,n"rgT;gitlt"Jl?lTa. For explanation of theTheso findings fit in tho following hypothesis: -At proteinprecursor. of prothrombin (tont?lively _called propro-ihrombin) is synthesizod in liver cells. Ifnder normal con-ditions this protoin is converted to prothrornbin in avitamin K-depondent step. The blood-level of prothrom-bin is the feed-back signal. for preprothrombin synt-hesis.Virhon tho vitamin K-dopendent conversion is inhibited'the feed-back signa,l causes an oxcoss production of pro-prothrombin which is shed into tho bloodstrea,m and acts*as a competitive inhibitor of prothrombin conversion.Consistont with tlris view, a maximum feed'back signalu .-

Nature of prothrombin biosynthesis:Preprothrombininæmia in vitamin K-deficiency

   Nature of prothrombin biosynthesisCitation for published version (APA):Hemker, H. C., Veltkamp, J. J., Hensen, A., & Loeliger, E. A. (1963). Nature of prothrombin biosynthesis:Preprothrombininæmia in vitamin K-deficiency. Nature, 200(4906), 589-590.https://doi.org/10.1038/200589a0Document status and date:Published: 09/11/1963DOI:10.1038/200589a0Document Version:Other versionPlease check the document version of this publication:• A submitted manuscript is the version of the article upon submission and before peer-review. There canbe important differences between the submitted version and the official published version of record.People interested in the research are advised to contact the author for the final version of the publication,or visit the DOI to the publisher's website.• The final author version and the galley proof are versions of the publication after peer review.• The final published version features the final layout of the paper including the volume, issue and pagenumbers.Link to publicationGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with theserights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain• You may freely distribute the URL identifying the publication in the public portal.If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above,please follow below link for the End User Agreement:www.umlib.nl/taverne-licenseTake down policyIf you believe that this document breaches copyright please contact us at:repository@maastrichtuniversity.nlproviding details and we will investigate your claim.Download date: 01 Oct. 2023Nerrrnr on horrmongnrl Brosnurresrs: hs-PROTIIROMBINAEIiIIA IN VITAMIN r-O",,C,"*.".H. c.. Hen*er, I. I. uettkonry, i."rZi"*Xaffiryg'. From L'd,;*[y' ;",;'iff '#y_g:1, The Neth.erlands, Nature, London 200:5g9_5go, 1963. f,L./p !vv.uu{lsing^ a nodiffecl thrombotest (Owren) theauthors found a difference in th" b"h;;;r"#"f.rlmas with lowered clotting fu"torc fr,lrf"i ftT;X derived from patients with hepatic ;#;;"1,opposed to patients with vitamir--n fficl-ei;They suggest that the data could be explained bythe presence of an inhibitor i" uitamiri i";ffi;-cy which is acrive in both th" i;;;r; ;ffT_*rrj"_::1*tation systems. This inhibiior'*r*,De a prec'rsor of prothrombin normally ";;;;,only in hepatic cells._L C.(Reprinled lrom Nature, Vol. 200, No. 4906, pp. 589-590,November 9. 1963)Nature of Prothrombin Biosynthesis :Preprothrombinamia in Vitamin K-deficiencyTrrn activities of the clotting factors II, VII, IX, and Xaro mutually lowered to a similar degree in chronichepatic damago as well as during prolongod roal or relative(coumarin-induced) vitamin Il-deficiencyr,e. fn the. exporiments described here, Owron's thrombotest (slightlymodified, Fig. I ) is used for t,he assessment, of the eitenlof depression. Each plasma sample is tested in a serios ofdilutions (D) and the coa,g'ulation time (t, mean of 4readings) measured in a coagulometers'a. All plasmasand plasma dilutions aro kept in carefully siliconized glass-waro or plastic material. When I is plotted against, D, astraight line is obtained (Fig. l).Tho slope of the line is proportional to the substrato(complex of Factors II, VII, IX and X) concentration inthe plasma testsd. Extrapolation to infinite substraroconcentration (intercept of the line obtained with theordinate) will give tho minimal coagulation timo (f-i,r).Plasmas with different, substrate concontrations all displaythe samo value for 116r. This holds for plasmas frompatients suffering from hepatic damage of different degree(Fig. I, above). In vitamin l(-deficiency, howovor, tmin isgenerally found to be markedly elevated, suggesting thepresence of an inhibitor (Fig. 1, below). A Lineweaver-Burk plot5 of values obtained from mixtures of a constantamount of plasma from a vitamin K-deficient patieni withvanious amounts of normal plasma, as compa,red withvalues obtained with nornal plasma alone, shows that acompetitivo inhibitor is present (Fig. 2).The inhibitor appoars to bo activo in both the intrinsicand extrinsic coagulation system. Addition of factors ff,VII, and X, or of Russell's viper venom to tho reactionmixture doos not abolish tho inhibition. The inhibitor isheat labile, undialysable and adsorbablo on to bariumsulphato, aluminium hydroxido, calcium phosphate andbentonite. Thoro is a simple graphical rvay to estimate thea,mount of inhibitor (Fig. I, below) : Whon a line (l) isdrawn through l*t, of normal plasma parallel to theabscissa, the line obtainod from tho values of a plasmacontaining the inhibitor (a) will intercept Z at, a certain dis-tanco (r) left of tho ordinato. The length of r is propor-tional to tho arnount of inhibitor present, indopondont oft'he,amount of substrato. One unit of inhibitor wo defineas the amount of inhibitor resultins in an r-valuo eoua,l tothe distanco from tho origin to D=1. As can be seonfrom Fig. lb, the amount of inhibitor in eldorly coumarin-t'reatod patients displaying a clotting faitor activity below50 per cent seoms to bo independont of tho intensity oft'reatment6.op  l 8 %p 4 5 %n 100 0zD -------+i1Ii15t minFis. 1. Relation between plasnla dilution and coagulation tine' Above.inaormal Dlasma (2) anii chronic liver disease (p); below. in nornalnlasma and in plaima of dicoumarol-treated patients (i). Reactionineaium: 0 25 ml. thrombol,est reagent; 0'05 ml. plasma (lt--?-: 1)'oi o'of ml. of a mixture of plmma with n times its volume of Micha€lisbutrer (at D = fr + 1). The percentages itdicate the reletiYe amountofsuosirate present in ,n"rgT;gitlt"Jl?lTa. For explanation of theTheso findings fit in tho following hypothesis: -At proteinprecursor. of prothrombin (tont?lively _called propro-ihrombin) is synthesizod in liver cells. Ifnder normal con-ditions this protoin is converted to prothrornbin in avitamin K-depondent step. The blood-level of prothrom-bin is the feed-back signal. for preprothrombin synt-hesis.Virhon tho vitamin K-dopendent conversion is inhibited'the feed-back signa,l causes an oxcoss production of pro-prothrombin which is shed into tho bloodstrea,m and acts*as a competitive inhibitor of prothrombin conversion.Consistont with tlris view, a maximum feed'back signalu .-

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Nature of prothrombin biosynthesis:Preprothrombininæmia in vitamin K-deficiency

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