JP5513828B2 - 血液凝固アッセイ - Google Patents
血液凝固アッセイ Download PDFInfo
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- JP5513828B2 JP5513828B2 JP2009229198A JP2009229198A JP5513828B2 JP 5513828 B2 JP5513828 B2 JP 5513828B2 JP 2009229198 A JP2009229198 A JP 2009229198A JP 2009229198 A JP2009229198 A JP 2009229198A JP 5513828 B2 JP5513828 B2 JP 5513828B2
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Description
血液凝固カスケードの1つ又はそれ以上の成分を分析する方法の以下の具体的な実施態様は、説明のためであり限定するために提供するものではない。
以下のペプチドは、標準的なFmoc化学を用いて合成した。N末端のFLAG配列DYKDDDDK及びヒト第XIII因子由来のトロンビン感受性配列KLVPRGF、そして以下に示すスペーサー基によってビオチンに連結したC末端のグリシン残基から成るペプチドで構成された切断可能部分。全体の配列は次の通りであった:DYKDDDDKLVPRGFG−NHCH2−CH2−NH−ビオチン。
前記のように製造したトロンビン感受性ペプチドは、水に0〜1000ng/mLの濃度で溶解した。ケミビーズ試薬は100μg/mLに、センシビーズ試薬は500μg/mLになるように、HEPES(50mM)、NaCl(300mM)、EDTA(1mM)、Triton X(登録商標) 405(0.1%)、BSA(1mg/mL)、Proclin(登録商標)300(0.15%)、硫酸ネオマイシン(0.1mg/mL)を含むpH8.0の緩衝液で希釈した。標準ヒト血漿(SHP)及び因子欠損血漿はSiemens Healthcare Diagnostics Products GmbH(Marburg, Germany)のものを使用し、製造元の指示に従って調製した。血漿サンプルは、0.9%NaClで実験する直前に手動で希釈した。組換え組織因子基準PT試薬INNOVIN(登録商標)(Siemens Healthcare Diagnostics Products GmbH)は、製造元の指示に従って水で再構成した。一部の実験では、凝固阻害ペプチド(3mg/mL)(Bachem, Bubendorf, Switzerland)をINNOVIN(登録商標)試薬に添加した。
上記のように製造したトロンビン感受性ペプチドを水に溶解し、0〜1000ng/mLとした。ケミビーズ試薬は100μg/mLに、センシビーズ試薬は500μg/mLになるように、HEPES(50mM)、NaCl(300mM)、EDTA(1mM)、Triton X(登録商標)405(0.1%)、BSA(1mg/mL)、Proclin(登録商標)300(0.15%)、硫酸ネオマイシン(0.1mg/mL)を含むpH8.0の緩衝液で希釈した。標準ヒト血漿(SHP)及び因子欠損血漿はSiemens Healthcare Diagnostics Products GmbHから入手したものを使用し、製造元の指示に従って調製した。血漿サンプルは、0.9%NaClで実験する直前に手動で希釈した。リン脂質及び二酸化ケイ素活性剤を含むaPTT試薬Pathromtin SL(登録商標)(Siemens Healthcare Diagnostics Products GmbH)は製造元の指示に従って調製し、凝固阻害ペプチド(Bachem)(3mg/mL)を補充した。
上記のように製造したトロンビン感受性ペプチドを、蒸留水に1μg/mLの濃度に溶解した。上記のケミビーズ試薬は100μg/mLに、上記のセンシビーズ試薬は500μg/mLになるように、HEPES(50mM)、NaCl(300mM)、EDTA(1mM)、Triton X(登録商標)405(0.1%)、BSA(1mg/mL)、Proclin(登録商標)300(0.15%)、硫酸ネオマイシン(0.1mg/mL)を含むpH8.0の緩衝液で希釈した。標準ヒト血漿(SHP)はSiemens Healthcare Diagnostics Products GmbHから入手したものを使用し、製造元の指示に従って調製した。血漿サンプルは、0.9%NaClで実験する直前に手動で希釈した。ヘビ毒のエカリン(Ecarin)は、Pentapharm(Basel, Switzerland)から購入し、メーカーの指示に従って調製した。直接トロンビン阻害剤のヒルジン(RefludanとしてPharmionから購入)及びメラガトラン(Astra Zenecaから購入)はメーカーの指示に従って調製した。
Claims (19)
- サンプル中の血液凝固カスケードのタンパク質分解性凝固因子の活性を測定する方法であって、
(a)反応混合物に、
(i)サンプル、及び
(ii)血液凝固カスケードのタンパク質分解性凝固因子を直接的に又は間接的に活性化するための活性剤、
(iii)活性化タンパク質分解性凝固因子によって切断される切断部位を有する切断可能部分であって、その切断可能部分は、化学発光剤及び増感剤の両者と結合しており又は結合することができるものであり、
(iv)化学発光剤、及び
(v)増感剤、
ここで、化学発光剤と増感剤は、近接している場合、増感剤の活性化が化学発光剤を励起させることに関係する、
を組み合わせて用意すること;
(b)化学発光シグナルを測定し、シグナルを血液凝固カスケードのタンパク質分解性凝固因子の活性と関連付けること;
を含む方法。 - 切断可能部分が反応混合物に加える別の試薬に含まれる、請求項1に記載の方法。
- 切断可能部分が別の試薬内の化学発光剤及び/又は増感剤に結合する、請求項2に記載の方法。
- 切断可能部分が3〜150のモノマー単位の長さのペプチドを含む、請求項2又は3に記載の方法。
- 切断可能部分が、サンプルに含まれ且つ反応混合物において化学発光剤及び増感剤に結合する、活性化タンパク質分解性凝固因子の天然基質である、請求項1に記載の方法。
- サンプルが全血又は血漿である、請求項1〜5のいずれか1項に記載の方法。
- 増感剤が、照射されると一重項酸素を発生しそして一重項酸素が化学発光剤を励起する光増感剤である、請求項1〜6のいずれか1項に記載の方法。
- 化学発光剤が化学発光化合物を結合した粒子を含む、請求項1〜7のいずれか1項に記載の方法。
- 増感剤が増感剤化合物を結合した粒子を含む、請求項1〜8のいずれか1項に記載の方法。
- 化学発光シグナルが活性化タンパク質分解性凝固因子の活性に逆比例する、請求項1〜9のいずれか1項に記載の方法。
- タンパク質分解性凝固因子が第II因子、第VII因子、第IX因子、第X因子、第XI因子、第XII因子及びプロテインCを含むグループから選択される、請求項1〜10のいずれか1項に記載の方法。
- タンパク質分解性凝固因子を直接的又は間接的に活性化するための活性剤が、トロンボプラスチン、第IIa因子、第VIIa因子、第IXa因子、第Xa因子、第XIa因子、第XIIa因子、活性化プロテインC、ヘビ毒、負に荷電したリン脂質、カルシウムイオン、組織因子、シリカ、カオリン、エラグ酸及びセライトを含むグループから選択される、請求項1〜11のいずれか1項に記載の方法。
- タンパク質分解性凝固因子の活性が、サンプル中の分析すべきタンパク質分解性凝固因子の活性に影響を及ぼす1つ又はそれ以上の成分の存在又は活性を示す、請求項1〜12のいずれか1項に記載の方法。
- 更に、測定するタンパク質分解性凝固因子の活性に影響を及ぼす単一成分が欠損した血漿又は全血が反応混合物に添加され、且つ、測定すべきタンパク質分解性凝固因子の活性がサンプル中の上記の単一成分を示す、請求項1〜13のいずれか1項に記載の方法。
- 活性化タンパク質分解性凝固因子の活性が、血液凝固カスケードの内因性経路の機能性を示す、請求項1に記載の方法。
- 活性化タンパク質分解性凝固因子の活性が、血液凝固カスケードの外因性経路の機能性を示す、請求項1に記載の方法。
- 活性化タンパク質分解性凝固因子の活性が、1つ又はそれ以上の治療的抗凝固剤の存在を示す、請求項1〜16のいずれか1項に記載の方法。
- 請求項1〜17のいずれか1項に記載の方法に使用するためのキットであって、以下の成分:
a)血液凝固カスケードのタンパク質分解性凝固因子を直接的又は間接的に活性化するための活性剤、
b)化学発光剤、
c)増感剤、及び
d)活性化タンパク質分解性凝固因子によって切断される切断部位を有する切断可能部分であって、化学発光剤を結合させる手段及び増感剤を結合させる手段を有する切断可能部分
を含むキット。 - サンプル中の血液凝固カスケードのタンパク質分解性凝固因子の活性を測定する方法であって、
(a)反応混合物に、
(i)サンプル、及び
(ii)血液凝固カスケードのタンパク質分解性凝固因子を直接的に又は間接的に活性化するための活性剤、及び
(iii)活性化タンパク質分解性凝固因子によって切断される切断部位を有する切断可能部分であって、その切断可能部分は、化学発光剤及び増感剤の両者と結合しているものであり、
ここで、化学発光剤と増感剤は、近接している場合、増感剤の活性化が化学発光剤を励起させることに関係する、
を組み合わせて用意すること;
(b)化学発光シグナルを測定し、シグナルを血液凝固カスケードのタンパク質分解性凝固因子の活性と関連付けること;
を含む方法。
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EP08017334.7 | 2008-10-02 | ||
EP08017334A EP2177624A1 (en) | 2008-10-02 | 2008-10-02 | Blood coagulation assays |
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JP5513828B2 true JP5513828B2 (ja) | 2014-06-04 |
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AT (1) | ATE540126T1 (ja) |
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WO2008070865A2 (en) * | 2006-12-07 | 2008-06-12 | University Of Florida Research Foundation Inc. | Materials and methods for efficient and accurate detection of analytes |
AU2008239586B2 (en) * | 2007-04-13 | 2013-09-26 | Catalyst Biosciences, Inc. | Modified factor VII polypetides and uses thereof |
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ATE540126T1 (de) | 2012-01-15 |
EP2177625A1 (en) | 2010-04-21 |
US20100086953A1 (en) | 2010-04-08 |
ES2378599T3 (es) | 2012-04-16 |
EP2177624A1 (en) | 2010-04-21 |
CA2681436A1 (en) | 2010-04-02 |
JP2010085411A (ja) | 2010-04-15 |
EP2177625B1 (en) | 2012-01-04 |
US8304205B2 (en) | 2012-11-06 |
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