NO164443B - REAGENT FOR DETERMINATION OF THE ACTIVATED PARTIAL TROMBOPLASTIN TIME. - Google Patents
REAGENT FOR DETERMINATION OF THE ACTIVATED PARTIAL TROMBOPLASTIN TIME. Download PDFInfo
- Publication number
- NO164443B NO164443B NO841231A NO841231A NO164443B NO 164443 B NO164443 B NO 164443B NO 841231 A NO841231 A NO 841231A NO 841231 A NO841231 A NO 841231A NO 164443 B NO164443 B NO 164443B
- Authority
- NO
- Norway
- Prior art keywords
- reagent
- determination
- time
- activated partial
- aptt
- Prior art date
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- 239000003153 chemical reaction reagent Substances 0.000 title claims description 21
- 239000003593 chromogenic compound Substances 0.000 claims abstract description 13
- 108090000190 Thrombin Proteins 0.000 claims description 11
- 229960004072 thrombin Drugs 0.000 claims description 11
- 150000003904 phospholipids Chemical class 0.000 claims description 8
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 6
- 230000037361 pathway Effects 0.000 claims description 6
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 claims description 5
- 239000007995 HEPES buffer Substances 0.000 claims description 5
- 108010000499 Thromboplastin Proteins 0.000 claims description 5
- 102000002262 Thromboplastin Human genes 0.000 claims description 5
- 230000002950 deficient Effects 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 102000007562 Serum Albumin Human genes 0.000 claims description 2
- 108010071390 Serum Albumin Proteins 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 210000002381 plasma Anatomy 0.000 description 11
- 239000012190 activator Substances 0.000 description 8
- 230000015271 coagulation Effects 0.000 description 8
- 238000005345 coagulation Methods 0.000 description 8
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 6
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 239000003114 blood coagulation factor Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- AFSDNFLWKVMVRB-UHFFFAOYSA-N Ellagic acid Chemical compound OC1=C(O)C(OC2=O)=C3C4=C2C=C(O)C(O)=C4OC(=O)C3=C1 AFSDNFLWKVMVRB-UHFFFAOYSA-N 0.000 description 5
- ATJXMQHAMYVHRX-CPCISQLKSA-N Ellagic acid Natural products OC1=C(O)[C@H]2OC(=O)c3cc(O)c(O)c4OC(=O)C(=C1)[C@H]2c34 ATJXMQHAMYVHRX-CPCISQLKSA-N 0.000 description 5
- 229920002079 Ellagic acid Polymers 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000001110 calcium chloride Substances 0.000 description 5
- 229910001628 calcium chloride Inorganic materials 0.000 description 5
- 235000011148 calcium chloride Nutrition 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229960002852 ellagic acid Drugs 0.000 description 5
- 235000004132 ellagic acid Nutrition 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- FAARLWTXUUQFSN-UHFFFAOYSA-N methylellagic acid Natural products O1C(=O)C2=CC(O)=C(O)C3=C2C2=C1C(OC)=C(O)C=C2C(=O)O3 FAARLWTXUUQFSN-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
- 238000011533 pre-incubation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- KZZWQCKYLNIOBT-UHFFFAOYSA-N 5-amino-2-nitrobenzoic acid Chemical compound NC1=CC=C([N+]([O-])=O)C(C(O)=O)=C1 KZZWQCKYLNIOBT-UHFFFAOYSA-N 0.000 description 2
- 102000004411 Antithrombin III Human genes 0.000 description 2
- 108090000935 Antithrombin III Proteins 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Chemical compound OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108090000113 Plasma Kallikrein Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 229960005348 antithrombin iii Drugs 0.000 description 2
- 230000008033 biological extinction Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VYLJFJGMPYBPMN-VXKWHMMOSA-N (2s)-n-[(2s)-5-(diaminomethylideneamino)-1-(4-nitroanilino)-1-oxopentan-2-yl]-1-[2-[(4-methylphenyl)sulfonylamino]acetyl]pyrrolidine-2-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NCC(=O)N1[C@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NC=2C=CC(=CC=2)[N+]([O-])=O)CCC1 VYLJFJGMPYBPMN-VXKWHMMOSA-N 0.000 description 1
- MLONYBFKXHEPCD-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO.OCC(N)(CO)CO MLONYBFKXHEPCD-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010074864 Factor XI Proteins 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 0.000 description 1
- 108010058861 Fibrin Fibrinogen Degradation Products Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010008488 Glycylglycine Proteins 0.000 description 1
- 108010077861 Kininogens Proteins 0.000 description 1
- 102000010631 Kininogens Human genes 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 108010018472 chromozym TH Proteins 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 150000001893 coumarin derivatives Chemical class 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 229940043257 glycylglycine Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000001026 thromboplastic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2337/00—N-linked chromogens for determinations of peptidases and proteinases
- C12Q2337/10—Anilides
- C12Q2337/12—Para-Nitroanilides p-NA
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Peptides Or Proteins (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
- Cephalosporin Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Oppfinnelsen vedrører et reagens til fotometrisk bestemmelse av den aktiverte partielle tromboplastintid (APTT), samt anvendelse derav. The invention relates to a reagent for photometric determination of the activated partial thromboplastin time (APTT), as well as its use.
Bestemmelsen av den aktiverte partielle tromboplastintid (APTT) er ved siden av tromboplastintiden (protrombintid, kvikk-verdi) den hyppigst gjennomførte koagulasjonsprøve. APTT beskriver forholdet til den endogene måten av koagula-sjonen. En ytterligere viktig anvendelse av denne prøve ligger i kontrollen av heparinterapi. APTT omfatter høymole-kylære kininogen, prekallikrein og faktorene XII, X, VIII, V og I, dertil også inhibitorene av koagulering, spesielt antitrombin III ved heparinterapien og f ibrinogenspaltpro-duktene (antitrombin VI), som alle forlenger APTT. The determination of the activated partial thromboplastin time (APTT) is next to the thromboplastin time (prothrombin time, quick value) the most frequently performed coagulation test. APTT describes the relationship to the endogenous mode of coagulation. A further important application of this test lies in the control of heparin therapy. APTT includes high-molecular kininogen, prekallikrein and factors XII, X, VIII, V and I, in addition also the inhibitors of coagulation, especially antithrombin III during heparin therapy and the fibrinogen cleavage products (antithrombin VI), all of which prolong APTT.
Reagenset for bestemmelse av APTT inneholder i det vesentlige fosfolipider og en egnet aktivator av "kontaktfasen". Ved kontaktaktiveringen aktiveres faktor XII, som deretter aktiverer faktor XI og prekallikrein. I reagenser innehold-ende lipider og kalsiumioner kommer det da til en aktivering av den samlede endogene vei, som ender i en f ibrinkoagula-sjonsdanning. En til dette tidspunkt nødvendig måleparameter er tid. The reagent for determining APTT essentially contains phospholipids and a suitable activator of the "contact phase". Upon contact activation, factor XII is activated, which then activates factor XI and prekallikrein. In reagents containing lipids and calcium ions, there is then an activation of the overall endogenous pathway, which ends in a fibrin coagulation formation. A measurement parameter required at this point is time.
Som aktivatorer av kontaktfasen anvendes uorganiske materialer, fortrinnsvis celitt og kaolin. Dessuten finner også ellagsyre (US-patent 3.486.981 og DE-OS 29 15 310) anvendelse. Ellagsyre byr som optisk klart reagens på fordeler ved anvendelse av optiske målefremgangsmåter til påvisning av koagulatdannelse. Ifølge Bock et al., Biochemistry 20, 7258-7266 (1982) skal riktignok den virksomme art være et vannuoppløselig kompleks av metallioner og ellagsyre. En ytterligere aktivator er dekstransulfat. Inorganic materials are used as activators of the contact phase, preferably celite and kaolin. In addition, ellagic acid (US patent 3,486,981 and DE-OS 29 15 310) is also used. As an optically clear reagent, ellagic acid offers advantages when using optical measurement methods for the detection of coagulum formation. According to Bock et al., Biochemistry 20, 7258-7266 (1982), the active species must indeed be a water-insoluble complex of metal ions and ellagic acid. A further activator is dextran sulphate.
Disse aktivatorer av kontaktfåsene er imidlertid ufysio-logiske og også vanskelige å standardisere. Eksempelvis avhenger koaguleringstiden av en kaolinaktivert APTT ganske av aktivatorens partikkelstørrelse. Noen koaguleringsfaktorer absorberes så fast på slike overflateaktive materialer at man benytter disse som absorbenser til preprarering av kon-taktfaktorene. Dessuten er imidlertid også sammensetningen av fosfolipider som inneholder et slikt reagens vesentlig for resultatet. Også lengden av forinkubasjonstiden, etter hvilke den egentlige reaksjon som fører til koagulatdannelse blir startet ved "rekalsifisering", spiller en viktig rolle, da aktiverte koaguleringsfaktorer hemmes ved de plasmatiske inhibitorer, spesielt antitrombin III. However, these activators of the contact points are non-physiological and also difficult to standardize. For example, the coagulation time of a kaolin-activated APTT is quite dependent on the activator's particle size. Some coagulation factors are so firmly absorbed on such surface-active materials that they are used as absorbents for the preparation of the contact factors. In addition, however, the composition of phospholipids containing such a reagent is also essential for the result. Also the length of the pre-incubation time, after which the actual reaction leading to clot formation is started by "recalcification", plays an important role, as activated coagulation factors are inhibited by the plasmatic inhibitors, especially antithrombin III.
Fysiologiske aktivatorer av koagulering omfatter sulfatider (Fujikawa et al., Biochem. 19 (1980), 1322-1330 og Tans und Griffin, Blood, 59 (1982) 69-75). Sulfatider hører til forbindelsesklasser av glykosfingolipider og Inneholder ved galaktoseringen en sulfatgruppe. Til denne forbindelsesgruppe hører forskjellige typer, med forskjellige typer fettsyre-kjeder. De er påvisbare i alle vev i membranene, i spesielt rikelige mengder i hjernen, hvorav man også kan utvinne det i meget ren form. Sulfatider er mere virksomme enn kaolin ved kontaktaktivering av plasmaet. Physiological activators of coagulation include sulfatides (Fujikawa et al., Biochem. 19 (1980), 1322-1330 and Tans und Griffin, Blood, 59 (1982) 69-75). Sulfatides belong to compound classes of glycosphingolipids and contain a sulfate group in the galactose ring. Different types with different types of fatty acid chains belong to this group of compounds. They are detectable in all tissues in the membranes, in particularly abundant amounts in the brain, from which it can also be extracted in very pure form. Sulfatides are more effective than kaolin in contact activation of the plasma.
Konvensjonelle APTT-bestemmelser omfatter målingen av et fibrinkoagulat. Dannelsen av et slikt koagulat er måleteknisk bare vanskelig å følge. Det ble utviklet en rekke apparater til å benytte i forskjellige mekaniske, elektriske eller optiske fremgangsmåter. Conventional APTT determinations include the measurement of a fibrin clot. The formation of such a coagulate is simply difficult to follow from a measuring point of view. A number of devices were developed for use in various mechanical, electrical or optical methods.
Etter innføring av kromogene substrater for koaguleringsfaktorer ble det også forsøkt å anvende disse for å bestemme koagulerIngsenzymer. Fordelen med kromogene substrater ligger i den enkle standardiserbarhet av de lavmolekylære substrater i motsetning til de komplekse høymolekylære naturlige substrater. Det bortfaller med problemet å måle dannelsen av et koagulat. After the introduction of chromogenic substrates for coagulation factors, it was also attempted to use these to determine coagulation enzymes. The advantage of chromogenic substrates lies in the easy standardization of the low-molecular substrates in contrast to the complex high-molecular natural substrates. The problem of measuring the formation of a coagulum is eliminated.
Også for gjennomføring av "globalprøven" ble det allerede anvendt kromogene substrater. Således omtaler Yamada og Megura, Thrombos. Res. 15 (1979), 351-358, en metode for gjennomføring av APTT. Denne beror på aktiveringen av den endogene vei med ellagsyre i nærvær av fosfolipid, kalsium og det kromogene trombinsubstrat H-D-Fe-Pip-Arg-pNA (S 2238). Ulempene ved denne fremgangsmåte er anvendelsen av en ufysiologisk aktivator, manglende spesifistet av det kromogene substrat og de ekstremt lange måletider (normal-verdi rundt 7,4 minutter). Over enkeltfaktor-følsomheten ble det bare pulbisert ufullstendige data. Chromogenic substrates were also already used for carrying out the "global test". Thus mention Yamada and Megura, Thrombos. Res. 15 (1979), 351-358, a method for carrying out APTT. This is due to the activation of the endogenous pathway by ellagic acid in the presence of phospholipid, calcium and the chromogenic thrombin substrate H-D-Fe-Pip-Arg-pNA (S 2238). The disadvantages of this method are the use of an unphysiological activator, the lack of specificity of the chromogenic substrate and the extremely long measurement times (normal value around 7.4 minutes). Above the single-factor sensitivity, only incomplete data were pooled.
En ytterligere metode omtalt hos P. Aiyappa, Ann. New York Acad. Sei. (1981), S 812-821. I dette målesystem aktiveres plasma ved ellagsyre i nærvær av fosfolipid og kalsiumioner i fem minutter, og det inntil da dannede trombinmåles med et kromogent substrat. Denne metode kan føre til dannelse av fibrin, som inneslutter aktivt trombin. Trombinet kan også bli deaktivert ved hemming. Det er ikke mulig å aktivere patologiske plasmaer fullstendig innen den valgte inkuba-sjonstid, selv om de egentlig er i stand til det. Den av Aiyppa omtalte fremgangsmåte muliggjør Ikke i mangelplasma å måle koagulasjon. A further method discussed in P. Aiyappa, Ann. New York Acad. Pollock. (1981), pp. 812-821. In this measurement system, plasma is activated by ellagic acid in the presence of phospholipid and calcium ions for five minutes, and the thrombin formed until then is measured with a chromogenic substrate. This method can lead to the formation of fibrin, which contains active thrombin. Thrombin can also be deactivated by inhibition. It is not possible to activate pathological plasmas completely within the selected incubation time, although they are actually capable of doing so. The procedure mentioned by Aiyppa makes it possible not to measure coagulation in deficient plasma.
Overraskende ble det nå funnet at vesentlige ulemper ved de omtalte APTT-metoder med kromogene substrater kan fjernes ved anvendelse av et sulfatid som fysiologisk aktivator i forbindelse med et høyspesifikt trombinsubstrat. Surprisingly, it was now found that significant disadvantages of the mentioned APTT methods with chromogenic substrates can be removed by using a sulfatide as a physiological activator in connection with a highly specific thrombin substrate.
Oppfinnelsens gjenstand er derfor et reagens for ett-trinns-bestemmelse av den aktiverte partielle tromboplastintid, kjennetegnet ved at den består av en buffer, fortrinnsvis HEPES, pH 7,2-8,5, et sulfatid eller en sulfatidblanding, et fosfolipid, et oppløselig kalsiumsalt og et kromogent substrat for trombin. The object of the invention is therefore a reagent for one-step determination of the activated partial thromboplastin time, characterized in that it consists of a buffer, preferably HEPES, pH 7.2-8.5, a sulfatide or a sulfatide mixture, a phospholipid, a soluble calcium salt and a chromogenic substrate for thrombin.
Oppfinnelsens gjenstand er videre anvendelse av et reagens i kombinasjon med et mangelplasma av en faktor av den endogene vei, for bestemmelse av denne faktor. The object of the invention is further the use of a reagent in combination with a plasma deficient in a factor of the endogenous pathway, for the determination of this factor.
Brukbare sulfatider er kommersielt tilgjengelige, eksempelvis fra firmaene Serva, Sigma eller Supelco. Fortrinnsvis anvendes slike sulfatider til tynnsjiktskromatografi på kiselgel og på en blanding av kloroform/metanol/vann 65:25:4 som elueringsmiddel har en RF-verdi på 0,2-0,3, fortrinnsvis 0,25, og med kloroform/metanol 40:15 en RF-verdi på 0,25-0,35, fortrinnsvis 0,31. Slike sulfatider kan imidlertid også fremstilles ifølge Hara og Radin, Anal. Biochem. 100 364-370 Usable sulfatides are commercially available, for example from the companies Serva, Sigma or Supelco. Preferably, such sulfatides are used for thin-layer chromatography on silica gel and on a mixture of chloroform/methanol/water 65:25:4 as eluent has an RF value of 0.2-0.3, preferably 0.25, and with chloroform/methanol 40 :15 an RF value of 0.25-0.35, preferably 0.31. However, such sulfatides can also be prepared according to Hara and Radin, Anal. Biochem. 100 364-370
(1979) eller av hjerneacetontørkepulver. Hensiktsmessige prøvekonsentrasjoner ligger mellom 0,1 og 50 pg/ml. Sulfatider kan i første rekke suspenderes ved konsentrasjon ved 0,01 g pr. 1. i 50 Mmol pr. liter HEPES-buf fer, pH 7,6, og anvendes for tilberedning av reagenset. (1979) or of brain acetone drying powder. Appropriate sample concentrations are between 0.1 and 50 pg/ml. Sulfatides can primarily be suspended at a concentration of 0.01 g per 1. in 50 Mmol per liter of HEPES buffer, pH 7.6, and used for preparation of the reagent.
Som fosfolipid kan da anvendes de vanlige reagenser ved anvendte dyr- og plantelipider. Spesielt fordelaktig er anvendelsen av lipider fra menneskelige trombocytter eller et ekstrakt av menneskelig placenta. Viktig er at disse lipider Ikke viser tromboplastisk aktivitet for Ikke også å aktivere den heksogene vei. As a phospholipid, the usual reagents for used animal and plant lipids can then be used. Particularly advantageous is the use of lipids from human platelets or an extract of human placenta. Importantly, these lipids do not show thromboplastic activity in order to not also activate the hexogenic pathway.
Det kromogene substrat for trombin må være spesifikt for å kunne anvendes i denne prøve, da trombin skal måles selektivt ved siden av de andre likeledes aktiverte koaguleringsfaktorer. "Kromozym" TH (Tos-gly-pro-arg-pNA) og S 2160 (bz-fe-val-arg-pNA) er relativt uspesifikke og viser også andre koaguleringsfaktorer, som kalekrein eller faktorene Xa og Xlla. Bedre egnet er S 2238 (HD-fe-pip-arg-pNA), enskjønt spesifiteten heller ikke her er meget høy overfor kontaktfak-torene. Foruten para-nitroanilider finnes det også andre peptidkromoforer, eksempelvis kumarinderivater, idet hydrolysen følges ved måling av fluorescensen. The chromogenic substrate for thrombin must be specific in order to be used in this test, as thrombin must be measured selectively next to the other similarly activated coagulation factors. "Chromozyme" TH (Tos-gly-pro-arg-pNA) and S 2160 (bz-fe-val-arg-pNA) are relatively non-specific and also display other coagulation factors, such as calekrein or factors Xa and Xlla. Better suited is S 2238 (HD-fe-pip-arg-pNA), although the specificity here too is not very high with respect to the contact factors. In addition to para-nitroanilides, there are also other peptide chromophores, for example coumarin derivatives, the hydrolysis being followed by measuring the fluorescence.
De for en globalprøve som APTT best egnede kromogene peptider er trombinsubstrater, slike som er omtalt i den tyske søknad P 32 44 030.8. De inneholder som kromoforderivater 5-amino-2-nitrobenzosyre. The most suitable chromogenic peptides for a global test such as APTT are thrombin substrates, such as are mentioned in the German application P 32 44 030.8. They contain 5-amino-2-nitrobenzoic acid as chromophore derivatives.
Fortrinnsvis anvendes en forbindelse med den generelle formel Preferably, a compound with the general formula is used
I IN
med R-C^-alkyl eller -CH [CH( CH3 )2] C00CH3 og X = H-D-FE, BOC-Gly- eller Tosyl-Gly. with R-C1-alkyl or -CH [CH( CH3 )2] CO0CH3 and X = H-D-FE, BOC-Gly- or Tosyl-Gly.
Substratet anvendes fortrinnsvis i meget liten konsentrasjon. De beste resultater oppnår man med 50 jjMol pr. 1. ved anvendelse av H-D-Fe-Pro-Arg-ANBS-isopropylamid. Kalsiumkon-sentrasjonen bør utgjøre mellom 1 og 10 mMol pr. liter, fortrinnsvis 5 mMol pr. liter. The substrate is preferably used in a very small concentration. The best results are achieved with 50 jjMol per 1. using H-D-Fe-Pro-Arg-ANBS-isopropylamide. The calcium concentration should be between 1 and 10 mmol per liter, preferably 5 mmol per litres.
Sulfatid, fosforlipid, kromogent substrat og kalsiumsaltet, fortrinnsvis kalsiumklorid, oppløses i en buffer som HEPES eller TRIS pH 7,2-8,5 eller suspenderes deri. Også imidazol-, glycylglycin- eller trietanol-amin-buffere er brukbare. Sulfatide, phospholipid, chromogenic substrate and the calcium salt, preferably calcium chloride, are dissolved in a buffer such as HEPES or TRIS pH 7.2-8.5 or suspended therein. Also imidazole, glycylglycine or triethanolamine buffers are usable.
Fremgangsmåten ifølge oppfinnelsen utføres hensiktsmessig ved 25-37°C, idet en plasmaprøve henger sammen med det tempererte reagens i en termostatert kuvette. I et fotometer følges reaksjonen ved 405-410 nm. The method according to the invention is suitably carried out at 25-37°C, with a plasma sample hanging together with the tempered reagent in a thermostated cuvette. In a photometer, the reaction is followed at 405-410 nm.
For et typisk normalplasma forblir ekstinksjonen konstant noen tid for deretter sterkt å stige i løpet av få sekunder. Måleparameteren er tiden som er nødvendig for å oppnå en bestemt ekstinksjonsdifferans, eksempelvis 0,1. Prinsipielt er det også mulig med en kinetisk vurdering av den eks-ponensielle kurve. Omsetningen av en bestemt substratmengde er analog til den av en konvensjonell APTT, hvor det aktiverte trombin omsetter en bestemt mengde fibrinogen og dermed utløser koagulatet. Eksempel 1 viser at fremgangsmåten i den foretrukne form, viser endringer av aktiviteten, av hver enkelt faktor i den endogene vei. For a typical normal plasma, the extinction remains constant for some time and then rises sharply within a few seconds. The measurement parameter is the time required to achieve a certain extinction difference, for example 0.1. In principle, a kinetic assessment of the exponential curve is also possible. The conversion of a specific amount of substrate is analogous to that of a conventional APTT, where the activated thrombin converts a specific amount of fibrinogen and thus triggers the clot. Example 1 shows that the method in the preferred form shows changes in the activity of each individual factor in the endogenous pathway.
I motsetning til konvensjonell APTT, hvoretter en bestemt fast aktiveringstid den egentlige til koagulat førende reaksjon startes ved hjelp av CaC^-tii.-ie ening, kan CaCl2 tilsettes fra begynnelsen. Dette fører i;i 1 ett pipetterIngs-trinn mindre (Monoreagens). Det kromogene peptid tilsettes sammen med CaCl2 først etter en bestemt forinkubasjonstid. Det viser seg da gunstig også under forinkubasjonstidfasen til sulfatidreagenset å sette noe CaClg (ca.l mMol pr. liter) og å starte den egentlige reaksjon ved tilsetning av mere CaCl2-oppløsning. Som sluttkonsentrasjon er også her 5 mMol pr. liter CaCl2 optimalt. In contrast to conventional APTT, after a certain fixed activation time the actual reaction leading to coagulum is started by means of the CaC^-tii.-ie unit, CaCl2 can be added from the beginning. This leads to one less pipetting step (Monoreagent). The chromogenic peptide is added together with CaCl2 only after a specific pre-incubation time. It then turns out to be beneficial also during the pre-incubation time phase to add some CaClg (approx. 1 mmol per liter) to the sulfatide reagent and to start the actual reaction by adding more CaCl2 solution. The final concentration is also here 5 mmol per liter of CaCl2 optimally.
Anvendelsen av sulfatider til kontaktaktivering av plasma i kombinasjon med kromogene substrater var hittil ikke kjent. Reagensfremstillere anbefaler lagring av sulfatidene under 0°C. Lyofilisering av sulfatidene sammen med de nødvendige andre bestanddeler av reagenser førte ikke til noe stabilt produkt. APTT forlenger seg stadig drastisk. The use of sulfatides for contact activation of plasma in combination with chromogenic substrates was not known until now. Reagent manufacturers recommend storing the sulfatides below 0°C. Lyophilization of the sulfatides together with the necessary other components of reagents did not lead to any stable product. APTT continues to lengthen drastically.
Overraskende oppnår man ved tilsetning av serumalbumingelatiner eller et avbygget og kryssbundet kollagen til et stabilt virksomt reagens. En konsentrasjon på bare ca. 0,1-1% muliggjør fremstillingen av et lyofilisat med god aktivitet. Surprisingly, by adding serum albumin gelatins or a degraded and cross-linked collagen, a stable active reagent is obtained. A concentration of only approx. 0.1-1% enables the preparation of a lyophilisate with good activity.
Som ved vanlige reagenser er forbindelsen med mangelplasma bestemmelsen av enkeltfaktorer av den endogene vel mulig. Hertil blir plasmaprøven fortynnet for å utkoble innvirknln-gen av andre koaguleringsfaktorer eller den anvendes i underskudd til det anvendte mangelplasma. As with ordinary reagents, the connection with deficient plasma, the determination of individual factors of the endogenous well is possible. To this end, the plasma sample is diluted to switch off the influence of other coagulation factors or it is used in deficit to the deficient plasma used.
En tilsetning av aminosyrer, for eksempel glutamin, asparagin eller glutaminsyre, øker reagensets heparin-følsomhet. An addition of amino acids, for example glutamine, asparagine or glutamic acid, increases the heparin sensitivity of the reagent.
Forkortelser: Abbreviations:
ANBS 5-amino-2-nitrobenzosyre ANBS 5-amino-2-nitrobenzoic acid
Arg Aginin Angry Aginin
Gly Glysin Gly Glycine
HEPES N-2-hydroksyetylpiperazin-N'-2-etansulfonsyre Fe Fenylalanin HEPES N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid Fe Phenylalanine
Pip Pipekolinsyre Pip Pipecholic acid
Pro Prolin Pro Proline
Tos Toluensulfonyl Two Toluenesulfonyl
TRIS Tris(hydroksymetyl)aminometan TRIS Tris(hydroxymethyl)aminomethane
Oppfinnelsen skal forklares nærmere ved hjelp av følgende eksempler. The invention shall be explained in more detail by means of the following examples.
Eksempel 1 Example 1
Det nve reagensets faktorfølsomhet. The factor sensitivity of the nve reagent.
Claims (4)
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|---|---|---|---|
| DE19833311287 DE3311287A1 (en) | 1983-03-28 | 1983-03-28 | METHOD FOR PHOTOMETRICALLY DETERMINING THE ACTIVATED PARTIAL THROMBOPLASTIN TIME AND REAGENT TO IT |
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| GB8426004D0 (en) * | 1984-10-15 | 1984-11-21 | Ortho Diagnostic Systems Inc | Coagulation monitoring |
| DE3504405A1 (en) * | 1985-02-08 | 1986-08-14 | Boehringer Mannheim Gmbh, 6800 Mannheim | DETERMINATION OF PROKALLIKREIN |
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| US4865984A (en) * | 1988-02-08 | 1989-09-12 | Mount Sinai School Of Medicine Of The City University Of New York | Dynamic continuous flow enzyme reactor |
| DE4006634A1 (en) * | 1990-03-03 | 1991-09-05 | Behringwerke Ag | FUNCTIONAL TEST TO DETERMINE PROTEIN S ACTIVITY |
| JP3180824B2 (en) * | 1991-08-30 | 2001-06-25 | シスメックス株式会社 | Blood coagulation reagent |
| DE59309374D1 (en) * | 1992-05-15 | 1999-03-25 | Immuno Ag | Reagent for determining the activated partial thromboplastin time (aPTT) |
| AT402074B (en) * | 1993-04-30 | 1997-01-27 | Immuno Ag | Reagent for determination of the aptt |
| AT398983B (en) * | 1992-05-15 | 1995-02-27 | Immuno Ag | Determn. of activated partial thromboplastin time - using mixt. of sulphatide(s) and kaolin as coagulation initiator |
| ES2131543T3 (en) * | 1993-06-30 | 1999-08-01 | Stiftung Fur Diagnostische For | MEASURING THE TIME OF ACTIVATED PARTIAL THROMBOPLASTINE (APTT) IN A SINGLE-STAGE REACTION. |
| US5780255A (en) * | 1995-06-09 | 1998-07-14 | Instrumentation Laboratory, S.P.A. | Protein C pathway screening test |
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| US6448024B1 (en) | 2000-10-03 | 2002-09-10 | Roche Diagnostics Corporation | Method, reagent, cartridge, and device for determining fibrinogen |
| CN100392406C (en) | 2001-05-09 | 2008-06-04 | 阿克西斯-希尔德公司 | Assay system |
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| CA1161432A (en) * | 1980-02-12 | 1984-01-31 | Lars G. Svendsen | Tripeptide derivatives and their application in assaying enzymes |
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| IL71370A (en) | 1989-06-30 |
| NZ207626A (en) | 1987-05-29 |
| DE3485067D1 (en) | 1991-10-24 |
| AU582534B2 (en) | 1989-04-06 |
| ZA842240B (en) | 1984-10-31 |
| ES530983A0 (en) | 1985-05-01 |
| JPH0365958B2 (en) | 1991-10-15 |
| DE3311287A1 (en) | 1984-10-04 |
| DK109084A (en) | 1984-09-29 |
| GR81852B (en) | 1984-12-12 |
| ATE67520T1 (en) | 1991-10-15 |
| NO164443C (en) | 1990-10-03 |
| AU2621184A (en) | 1984-10-04 |
| EP0123883A2 (en) | 1984-11-07 |
| DK109084D0 (en) | 1984-02-27 |
| IE840743L (en) | 1984-09-28 |
| DK162179B (en) | 1991-09-23 |
| DK162179C (en) | 1992-03-02 |
| IL71370A0 (en) | 1984-06-29 |
| IE58463B1 (en) | 1993-09-22 |
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