JPWO2007094394A1 - 意識障害患者における病態の検出方法及び検出用キット - Google Patents
意識障害患者における病態の検出方法及び検出用キット Download PDFInfo
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Abstract
Description
脳卒中は、脳の血管が破裂して起こる出血性病変によるものと、脳の血管が閉塞して起こる虚血性病変によるものに大別される。出血性病変には、くも膜下出血と脳出血があり、一方の虚血性病変は、脳梗塞と一過性脳虚血発作に分類される。
thrombocytopenic purpura;以下、「TTP」と称する)の発症に関与することが示唆され、血漿からvWF切断酵素が精製され(非特許文献1)、cDNAクローニングによりその遺伝子が決定された。実際、ADAMTS13の遺伝子変異がvWF分解活性を著しく低下させることが明らかにされている(非特許文献2)。近年、ADAMTS13に対するモノクローナル抗体又はポリクローナル抗体を応用した酵素免疫測定法が開発され(特許文献1)、血小板凝集が関与した血栓症の原因および血栓症の血栓形成傾向の検出法が確立された。これを使用し、各種血栓症患者の血漿中におけるADAMTS13の濃度が健常人と比べて顕著に低下していることが見いだされている。
inflammatory response syndrome;SIRS)患者における血小板血栓症又は臓器障害の検出方法が開示されている。
本発明の検出方法の好ましい態様によれば、前記の病態の検出が、脳血管障害の検出、動脈硬化性血管障害の検出、あるいは、重篤度の検出又は重篤度の予測である。
本発明の検出方法の別の好ましい態様によれば、フォンヴィルブランド因子切断酵素量の分析を、フォンヴィルブランド因子切断酵素に特異的に結合する抗体又はその断片を使用する免疫学的手法により行う。
本発明の検出方法の更に別の好ましい態様によれば、フォンヴィルブランド因子切断酵素活性の分析を、フォンヴィルブランド因子又はその断片を使用することにより行う。
また、本発明は、フォンヴィルブランド因子切断酵素に特異的に結合する抗体若しくはその断片、又はフォンヴィルブランド因子若しくはその断片を含む、意識障害患者における病態の検出用キットに関する。
本発明の検出用キットの好ましい態様によれば、前記の病態の検出が、脳血管障害の検出、動脈硬化性血管障害の検出、あるいは、重篤度の検出又は重篤度の予測である。
例えば、本発明は、意識障害患者(例えば、脳血管障害患者)において、意識障害及び/又は多臓器不全の発症を伴う重篤な症状に陥る可能性のある患者をいち早く察知することを可能としたものであり、その臨床的価値は非常に高いものと考える。本発明によれば、簡便性、迅速性、及び特異性に優れた意識障害、及び/又は多臓器不全の検出が可能となる。また、後述する実施例より、意識障害、あるいは多臓器不全発症のあらたな成因として“ADAMTS13の著減”が示唆でき、従来は当該患者に対して処方されることのなかったADAMTS13を増やす、あるいは減らさないような治療方法[新鮮凍結血漿(FFP)の輸注、血漿交換、など]を行えば病状の悪化を食い止められることが考えられる。このことはADAMTS13のモニタリングが直接的に脳梗塞患者に対する前述のような治療効果の良否判定に使えることを示すものである。
本発明方法では、ADAMTS13の量(濃度)又はその酵素活性の少なくとも一方を分析(好ましくは測定又は定量)し、健常人のADAMTS13の量(濃度)又はその酵素活性と比較することにより、あるいは、量(濃度)及び活性を経時的に測定又は定量することにより、意識障害患者における病態の検出を行うことができる。本発明方法は、
(1)被検試料中のADAMTS13の量(濃度)又は酵素活性を分析する工程、及び
(2)前記分析値を健常人の値と比較する工程
を含むことができる。あるいは、本発明方法は、
(1)被検試料中のADAMTS13の量(濃度)又は酵素活性を経時的に分析する工程、及び
(2)前記分析値の経時的傾向を解析する工程
を含むことができる。
例えば、後述の実施例に示す母集団においては、ADAMTS13濃度に関して、異常とみなせる値は50%以下であり、ADAMTS13の酵素活性に関して、異常とみなせる値は40%以下であった。
本発明の検出用キットは、本発明方法を実施するのに用いることができる。本発明の検出用キットには、その分析対象に応じて、ADAMTS13濃度を分析することにより前記障害を検出することができる検出用キット(以下、濃度分析型キットと称する)と、ADAMTS13の酵素活性を分析することにより前記障害を検出することができる検出用キット(以下、酵素活性分析型キットと称する)とが含まれる。
ADAMTS13を含む正常ヒトプール血漿及びその希釈系列を、トリス緩衝液(pH7.4;1.5mol/L尿素及び0.1mol/L塩化バリウム含有)と等量混合し、更に終濃度2.4mmol/Lとなるように4−[2−アミノエチル]−ベンゼンスルホニルフルオリド塩酸塩(4-[2-Aminoethyl]-benzenesulfonyl fluoride, hydrochloride;Pefabloc;Roche社)を添加した。このように処理したサンプル溶液を、vWF(非特許文献3に記載の方法により、ヒト血漿から精製したもの)3μg/mLを含むトリス緩衝液(pH7.4、1.5mol/L尿素)と1:5の容量比で混合し、37℃で一晩インキュベーションし、組み換えvWFをサンプル溶液中のADAMTS13で分解した。分解反応は、終濃度40mmol/LとなるようにEDTAを添加することにより停止させた。このように調製したサンプルを非還元下のSDS−アガロースゲル電気泳動(1.4%アガロースゲル)にて分離後、ウエスタンブロット法にて、PVDF(polyvinylidene
difluoride)膜にトランスファーした。市販のブロッキング剤(ブロックエース;大日本製薬)で室温にてブロッキングした後、トリス緩衝液(pH7.4)で洗浄した。トリス緩衝液(pH7.4)/10%ブロックエースで1/1000希釈したHRP(horseradish
peroxidase)標識抗vWF抗体(DAKO社)にて1時間室温で反応させた後、トリス緩衝液(pH7.4)で3回洗浄後、市販の発色キット(イムノステインHRP−1000;コニカ社)にて発色した。
vWFバンドの長さ(単位=mm)を縦軸、プール血漿の含有割合を横軸にとり、図2に示す標準曲線を作成した。
アテローム血栓性脳梗塞症例及びラクナ型脳梗塞症例の患者由来の血漿を被検試料として、ADAMTS13抗原量を測定した。ADAMTS13抗原量は、市販キット(vWF切断酵素 ELISA kit;三菱化学ヤトロン)を使用して測定した。
また、ラクナ型脳梗塞症例(図4)においては、MRI画像上で解析を行って単発梗塞群と多発梗塞群とに選別し、それぞれにおいてADAMTS13抗原量を比較した。単発梗塞群に比べ、多発梗塞群ではADAMTS13抗原量が有意に低下していた。
図3及び図4に示す結果は、脳血管障害患者においてADAMTS13の血液中の濃度が低ければ、より動脈硬化性の血管障害が進行していることを示唆するものであり、このことはADAMTS13の脳血管障害の程度を反映するマーカーとしての意義を示すものである。例えば、アテローム血栓性脳梗塞は、内頸動脈起始部や中大脳動脈水平部のアテローム形成による動脈狭窄・閉塞に起因する。また、陳旧性心筋梗塞、閉塞性動脈硬化症も動脈硬化性血管障害とみなされる。更に、ラクナ型脳梗塞は、穿通動脈の細動脈硬化を主因とし、この梗塞が多発している場合、脳動脈以外にも動脈硬化部位を認めることが多く、単発と多発を比べると、より動脈硬化性の血管障害が進行していると考えられる。
亜急性期〜慢性期の脳血管障害133症例(アテロ−ム血栓性脳梗塞50例、心原性脳塞栓症22例、ラクナ型脳梗塞34例、脳出血19例、くも膜下出血8例)において、実施例1に示すSDS−アガロースゲル電気泳動によりADAMTS13酵素活性を測定し、また、実施例2に示す市販キット(vWF切断酵素 ELISA kit;三菱化学ヤトロン)によりADAMTS13抗原量を測定した。これらの中で、ADAMTS13酵素活性が30%未満の症例は6例であり、この6例は全て脳梗塞[心原性脳塞栓症(CEBI)3例、ラクナ型脳梗塞(LBI)3例]であり、重度の肝障害(胆管癌1例、アルコール性肝炎1例、慢性C型肝炎4例)及び意識障害を伴っていた。前記6例の臨床像とADAMTS13値を表1に示す。
以上、本発明を特定の態様に沿って説明したが、当業者に自明の変形や改良は本発明の範囲に含まれる。
Claims (10)
- 意識障害患者において、フォンヴィルブランド因子切断酵素の量及び/又は活性を分析することを特徴とする、前記意識障害患者における病態の検出方法。
- 病態の検出が、脳血管障害の検出である、請求項1に記載の方法。
- 病態の検出が、動脈硬化性血管障害の検出である、請求項1に記載の方法。
- 病態の検出が、重篤度の検出又は重篤度の予測である、請求項1に記載の方法。
- フォンヴィルブランド因子切断酵素量の分析を、フォンヴィルブランド因子切断酵素に特異的に結合する抗体又はその断片を使用する免疫学的手法により行う、請求項1〜4のいずれか一項に記載の方法。
- フォンヴィルブランド因子切断酵素活性の分析を、フォンヴィルブランド因子又はその断片を使用することにより行う、請求項1〜4のいずれか一項に記載の方法。
- フォンヴィルブランド因子切断酵素に特異的に結合する抗体若しくはその断片、又はフォンヴィルブランド因子若しくはその断片を含む、意識障害患者における病態の検出用キット。
- 病態の検出が、脳血管障害の検出である、請求項7に記載のキット。
- 病態の検出が、動脈硬化性血管障害の検出である、請求項7に記載のキット。
- 病態の検出が、重篤度の検出又は重篤度の予測である、請求項7に記載のキット。
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CN101056989A (zh) * | 2004-11-08 | 2007-10-17 | 株式会社三菱化学药得论 | 血小板血栓或脏器损伤的检测方法 |
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US8945895B2 (en) | 2009-07-31 | 2015-02-03 | Baxter International Inc. | Methods of purifying recombinant ADAMTS13 and other proteins and compositions thereof |
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JPWO2012067152A1 (ja) * | 2010-11-16 | 2014-05-12 | 三菱化学株式会社 | EndothelialProteinCReceptor蛋白質による脳梗塞の検査方法 |
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WO2007094394A1 (ja) | 2007-08-23 |
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