CN101374956A - 弥漫性血管内凝血综合征的病态鉴定方法 - Google Patents
弥漫性血管内凝血综合征的病态鉴定方法 Download PDFInfo
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Abstract
公开了弥漫性血管内凝血综合征(DIC)的病态的鉴定方法，该方法是分析DIC患者中的血管性血友病因子(vWF)剪切酶(ADAMTS13)的量和/或酶活性(还优选vWF量)；以及用于鉴定DIC病态的试剂盒，该试剂盒中含有与ADAMTS13进行特异性结合的抗体或其片段。根据本发明，能够从仅凭临床所见或仅凭现有标记无法进行区别的DIC患者中进行血栓形成性血小板减少性紫癜(TTP)患者的鉴别诊断。
Description
技术领域
本发明涉及弥漫性血管内凝血综合征(Disseminated IntravascularCoagulation；以下称作DIC)的病态鉴定(determination)方法。
背景技术
在弥漫性血管内凝血综合征(DIC)中，在重度基础疾病的存在下全身的微血管内形成微血栓。因此，微循环出现障碍，可见脏器功能不全或出血倾向。在DIC中发生以下三种障碍或反应。
(1)发生微血栓形成所引起的微循环障碍，多个脏器因缺血而陷入功能不全。
(2)微血栓形成所引起的消耗性凝血障碍，即组织因子在细胞表面大量表达，促进外源系凝血。另外，凝血因子或血小板被消耗，出现出血倾向。
(3)过剩纤溶，即随着凝血的促进纤溶系统也被活化，生成分解纤维蛋白的纤溶酶。当抑制纤溶酶的α2纤溶酶抑制剂(α2PI)被消耗而减少至不足正常的60％时，纤维蛋白被纤溶酶过剩分解，出现出血倾向。
DIC的本质在于凝血系统的病理性且持续性活化所引起的微血栓的形成，但纤溶系统也随之被活化。然而，两者的平衡在基础疾病或每个病例中存在差异，可见凝固活化显著而纤溶系统被抑制的情形或凝固·纤溶两者活化显著的情况等。前者分为凝固优先型，后者分为纤溶优先型。凝固优先型DIC往往并发感染症、特别是败血症，临床症状易见脏器症状。而在纤溶优先型DIC中纤溶的标记—FDP(纤维蛋白降解产物)或PIC(纤溶酶/纤溶酶抑制剂复合物)显著增加，易见出血症状。基础疾病为急性前骨髓性白血病。
DIC若治疗延误则导致死亡，因此是希望早期诊断和早期治疗的紧急性高的病态。目前DIC按照厚生省的DIC诊断基准进行诊断。在该诊断基准中，对1)是否存在脏器障碍、2)血小板数、3)FDP、4)纤维蛋白原、5)PT比(凝血酶原时间比)的值进行打分，来判定DIC。该诊断基准在DIC的确诊方面优异，但在DIC的早期诊断中存在难点，临床上按照该诊断基准进行治疗时DIC的病态往往已过度发展，为时已晚。另外，在临床上往往特别难以鉴别血小板数下降是否是DIC所致。具体例子有:伴有骨髓抑制的病态(药物、病毒感染症、各种导致造血障碍的血液疾病等)、肝硬化、肝功能不全、血栓性血小板减少性紫癜(thrombotic thrombocytopenic purpura；TTP)/溶血性尿毒症综合征(hemolytic uremic syndrome；HUS)、大量胸水·腹水等。在上述病态中不仅伴有血小板数的下降，有时还伴有FDP或D二聚物的上升，因此更难以鉴别DIC。
DIC的治疗方法是给予低分子肝素或抗凝血酶III制剂，以抑制血管内的血栓多发，同时阻止消耗性凝固障碍的发展。治疗纤溶优先型DIC时，给予具有抗凝血酶作用和抗纤溶作用的甲磺酸加贝酯。对于并发血小板数产生减少的血液疾病的DIC，用浓稠血小板来补充血小板是不可缺少的。对血中纤维蛋白原下降的DIC施行新鲜冷冻血浆(FFP)输注。
另一方面，TTP和DIC或HUS等一样，显示被称作微血管病变性溶血性贫血(microangiopathic hemolytic anemia；MAHA)的病态。因任何原因而在血管内形成大量的病理性微血栓时，微血管内产生大量变窄的部位，强行通过该变窄部位的红细胞因机械破碎而引起溶血。认为这是MAHA的发病机理。减小血管内径的微血栓的主要成分包含纤维蛋白时是DIC，而包含血小板时是TTP或HUS。
TTP是一种全身性重度疾病，1924年由美国的Moschcowitz首次报道，患病时血小板的凝集块(血小板血栓)堵塞在微动脉内，可见以下五种症状:1)血小板减少症(皮肤出现紫斑)；2)溶血性贫血(由红细胞破裂引起)；3)肾功能障碍；4)发热；5)动摇性精神神经症状。
鉴定止血因子—血浆中vWF的特异性剪切酶(VWF-cleavingprotease；VWF-CP)、别名ADAMTS13为TTP的病因。众所周知，与健康人相比TTP中的ADAMTS13量显著下降(例如非专利文献1、非专利文献2或专利文献1)。若ADAMTS13缺乏或下降，则自血管内皮细胞释放的UL-vWFM(异常大的vWF多聚体)没有被分解，利用微血管等中产生的高应力引起过剩的血小板凝集，由于血栓堵塞血管。
例如，专利文献2中公开了血栓形成倾向的程度或血栓症的检测方法，该方法的特征在于对ADAMTS13进行定量。上述血栓症的例子有:急性或慢性骨髓性白血病、急性前骨髓球性白血病、全身性红斑狼疮、肺栓塞、脑梗塞、肝中心静脉阻塞症、急性淋巴性白血病、血栓性微血管障碍、血栓性血小板减少性紫癜、溶血性尿毒症综合征或深部静脉血栓症。另外，专利文献3中公开了DIC或全身性炎症反应综合征(systemic inflammatory response syndrome；SIRS)患者中的血小板血栓症或脏器障碍的检测方法，在该方法中分析ADAMTS13和/或其分解因子(例如弹性蛋白酶、纤溶酶或凝血酶)。
另外，还存在ADAMTS13活性轻度下降或正常的非定型TTP。该情况下的病因也多种多样，有先天性和后天性要因，关于前者有人报道了由具有补体调节作用的血浆因子—因子H(Factor H)或血管内皮细胞膜贯穿型蛋白质CD46等的基因异常引起的TTP。
TTP是极罕见的疾病，通常是后天产生的，但如下所述，偶尔也有先天性因素引起的TTP。
TTP的临床症状包括:缺血性肠炎所引起的腹泻、腹痛、血便；痉挛或视力障碍等神经症状；以及肾障碍等。检查时可以发现:血栓形成所引起的末梢血的破碎红细胞、贫血、血小板减少；血清LDH(乳酸脱氢酶)、间接胆红素升高；触珠蛋白下降等溶血所伴有的变化。由于肾障碍，还可见血清肌酸酐升高。
目前，先天性TTP的治疗方法往往是每2～3周输注新鲜冷冻血浆(FFP)来补充ADAMTS13，并维持血小板数，进行发病预防治疗。禁忌血小板输血。作为后天性TTP的治疗方法，总体的约1/3的病例中ADAMTS13活性锐减，这些病例几乎全部是抗ADAMTS13的自身抗体为阳性。因此，单独给予FFP是不够的，在后天性·特发性TTP的治疗中血浆交换(plasma exchang；PE)疗法是第一选择。此时往往结合使用类固醇或类固醇脉冲疗法。当然，在实施PE前禁忌进行血小板输血。PE的效果总括了以下四点:1)补充ADAMTS13；2)除去同抑制剂；3)除去UL-vWFM；4)补充止血所必需的正常vWF。对于难治·反复的病例还应该考虑使用长春新碱或环磷酰胺等免疫抑制剂、脾摘等。在引入PE或FFP输注疗法以前TTP的死亡率高达80％以上，预后非常不好。但通过引入上述疗法或结合使用抗血小板疗法，预后改善显著，现在存活率基本达到90％以上。但是，已知治疗抵抗例或复发例多，认为这是今后应该解决的问题。当TTP的病态发展时治疗困难，其预后也极其不好，因此必需早期诊断和早期治疗。
非专利文献1:Zheng X等，J Biol Chem，(美国)2001年，第276卷，41059-41063
非专利文献2:Furlan M等，Boold，(美国)1997年，第89卷，3097-3103
专利文献1:国际公开第00/50904号小册子
专利文献2:国际公开第2005/062054号小册子
专利文献3:国际公开第2006/049300号小册子
发明内容
发明所要解决的课题
如上所述，目前在根据使用现有标记测定值的诊断基准和临床所见诊断为DIC的患者中报道了许多对DIC实施治疗却很难见到改善的病例。其中，特别是在确认血小板减少的患者中，本来诊断为TTP而实施血浆交换等适当的治疗时，认为预后改善的可能性高。在DIC中选择血小板输注作为治疗方法，但为TTP时，虽然血小板锐减，但如上所述通过血小板输注病态进一步恶化，因此禁忌血小板输注。因此，虽然血小板减少是共有的症状，但通过明确区分两疾病组的不同，作出适当的诊断，并施行适当的治疗方法，这在医疗临床中非常渴望。
本发明人反复进行深入研究，结果发现:在DIC患者中，在利用ADAMTS13量(浓度)和ADAMTS13酶活性中的一方或它们的组合进行的DIC患者组的分类以及通过使用ADAMTS13量(浓度)和/或ADAMTS13酶活性和vWF量(浓度)的组合诊断为DIC的患者组中，发现可能是后天性TTP患者的检体组。发现这是鉴别仅凭临床所见或现有标记无法区别的“应该诊断为TTP的DIC”和“与TTP无关的DIC”、对各种疾病施行特异性疗法、改善预后的方法，从而完成了本发明。
即，本发明的课题在于提供:能够从仅凭临床所见或现有标记无法区别的DIC患者中进行TTP患者的鉴别诊断的方法和试剂盒。
解决课题的方法
上述课题可以通过本发明的弥漫性血管内凝血综合征的病态鉴定方法来解决，该方法的特征在于:分析弥漫性血管内凝血综合征(DIC)患者的血管性血友病因子(von willebrand’s factor)剪切酶(ADAMTS13)的量(浓度)和/或酶活性。
根据本发明的病态鉴定方法的优选方案，进一步分析血管性血友病因子(vWF)的量(浓度)。
根据本发明的病态鉴定方法的另一优选方案，利用免疫学方法分析血管性血友病因子剪切酶。
本发明还涉及用于鉴定弥漫性血管内凝血综合征的病态的试剂盒，该试剂盒中含有与血管性血友病因子剪切酶进行特异性结合的抗体或其片段。
本说明书中的用语“分析”包括“检测”和“测定”，“检测”是指判定是否存在分析对象物质(例如ADAMTS13或vWF)，“测定”是指定量或半定量地决定分析对象物质的量(浓度)或活性。
发明效果
DIC和TTP由于病态相似，故难以明确诊断。另外，无论是哪一种疾病，若没有通过早期诊断来早期实施适当的治疗，则会导致死亡，因此鉴别“应该诊断为TTP的DIC”和“与TTP无关的DIC”非常重要。根据本发明，可以在按照现有诊断基准诊断为DIC的患者中鉴别“应该诊断为TTP的DIC”和“与TTP无关的DIC”，通过实施适当的治疗可以提高存活率或降低致死率。
附图简述
图1是显示有关ADAMTS13抗原量(Aag)的结果的图。
图2是显示有关DAMTS13酶活性(Aact)的结果的图。
图3是显示有关vWF抗原量(Vag)的结果的图。
图4是显示有关Vag/Aag的结果的图。
图5是显示有关Vag/Aact的结果的图。
实施发明的最佳方式
[1]本发明的鉴定方法
在本发明方法中，通过分析DIC患者的ADAMTS13的量(浓度)和/或酶活性中的至少一方(优选两方)或者通过使用ADAMTS13的量(浓度)和/或酶活性中的至少一方(优选两方)和vWF的量(浓度)的组合，可以鉴定DIC的病态。
本说明书中的“DIC的病态鉴定”包含作为对确定适当的治疗方针或治疗方法有用的信息的DIC患者的各种病态的鉴定，例如从诊断为DIC的患者中区分本来诊断为TTP而应该改变治疗方法的患者，即鉴别“应该诊断为TTP的DIC”和“与TTP无关的DIC”。另外，“DIC的病态鉴定”还包含根据上述病态鉴定进行各种判断和预测，例如确定适当的治疗方针或治疗方法、预测预后、检测等。
在本发明方法中，例如以DIC患者的ADAMTS13量(浓度)和/或酶活性的差异为指标，可以鉴别诊断“疑似TTP的DIC”和“与TTP无关的DIC”。并且，即使在DIC患者组中，对于苦思焦虑地进行诊断的患者以ADAMTS13量(浓度)和/或酶活性和vWF量(浓度)的组合、例如vWF量相对于ADAMTS13量(浓度)和/或其活性的比例的不同为指标，例如可以将DIC患者组进一步分为三组，鉴别为“应该诊断为TTP的DIC”和“与TTP无关的DIC”，提出患者特异性治疗方法。可以设定ADAMTS13量(浓度)和ADAMTS13活性的阈值作为分类指标。
在本说明书中，“血管性血友病因子剪切酶(vWF剪切酶)”是指特异性切断存在于血管性血友病因子(vWF)的A2结构域的酪氨酸(842)和甲硫氨酸(843)的金属蛋白酶，也被称作ADAMTS13。
众所周知，与健康人相比，TTP中的ADAMTS13量显著下降[例如Zheng X等，J Biol Chem，(美国)2001年，第276卷，41059-41063；FurlanM等，Boold，(美国)1997年，第89卷，3097-3103；WO00/50904]。另外，小野等[小野(T.ono)等，血栓止血学会，2004年(10/1抄录发行)]还报道了:虽然基础疾病多种多样，但与健康人相比，在参照DIC分数进行诊断的DIC患者组中ADAMTS13量显著下降；以及在诊断为TTP患者组的组的ADAMTS13量为5～45％，而DIC患者组的ADAMTS13量为10～95％的宽范围。
近年来，有人报道了多种疾病中的有关ADAMTS13的研究结果，如上所述，以前人们认为TTP患者中ADAMTS13活性锐减，但有报道称实际上在60％的TTP患者中ADAMTS13活性并没有锐减(松本雅则，血管医学，2005年，第6卷，65-72)。
但是，还没有报道称:在诊断为DIC的患者中可以单独利用ADAMTS13来鉴别“应该诊断为TTP的DIC”和“与TTP无关的DIC”。
可以应用本发明方法的对象(受试者)为DIC患者。受检试样例如优选血浆或血清形态的血液。此外，例如还可以使用细胞组织液、淋巴液、胸腺水、腹水、羊水、胃液、尿、胰液、骨髓液或唾液等各种体液。上述血浆优选为枸橼酸血浆或肝素血浆。
本发明方法可如下进行:从DIC和TTP患者中分别采取检样，测定各自的ADAMTS13浓度、ADAMTS13活性和/或vWF浓度，之后通过比较测定值来鉴定DIC的病态以及确定其适当的治疗方法。为了区别疑为TTP的DIC患者，优选使用自TTP患者中采取的检样，预先确定各种判定用阈值，例如ADAMTS13浓度和ADAMTS13活性的判定用阈值以及ADAMTS13浓度或其活性与vWF的比例的判定用阈值。
如后述实施例所示，例如可以进行以下分类:
1)ADAMTS13量(以下称作Aag)例如为30％以下；
2)ADAMTS13活性(以下称作Aact)例如为15％以下；
3)ADAMTS13量相对于ADAMTS13活性的比例(Aact/Aag)例如为2.0以上；
首先，将符合上述三项中的两项或三项的患者组分为“疑似TTP的DIC患者组”(A组)，将除此以外的患者组分为“非疑似TTP的DIC患者组”(B组)。对于上述患者组(A组和B组)，根据vWF量(以下称作Vag)相对于ADAMTS13量(Aag)的比例(Vag/Aag)和vWF量相对于ADAMTS13活性(Aact)的比例(Vag/Aact)可以进一步分为:
第1组:Vag/Aag例如为8以上且Vag/Aact例如为16以上、
第2组:Vag/Aag例如为8以下且Vag/Aact例如为16以上、
第3组:不符合第1组和第2组的组(即，Vag/Aact例如不足16)。
如后述实施例所示，两名诊断为TTP的患者被分入第1组。另外，如后述实施例所示，在第1组～第3组中，第1组和第2组为“应该诊断为TTP的DIC患者组”，第3组为“与TTP无关的DIC患者组”。
需要说明的是，上述Aag、Aact、Vag分别为相对于正常值的相对值，上述各比(Aact/Aag、Vag/Aag、Vag/Aact)为基于上述相对值的比。
事先确定判定用阈值时，对于作为预测对象的受试者通过分析Aag和/或Aact或者分析Aag和/或Aact以及Vag(例如分析Vag/Aag和/或Vag/Aact)，可以进行上述受试者的上述判定和/或预测。设想判定用阈值根据各种条件例如基础疾病、性别、年龄等而变化，但该领域技术人员适当选择对应于受试者的适当母集团，对由该集团得到的数据进行统计学处理，可以确定正常值范围或判定用阈值。
在本发明方法中，对分析ADAMTS13浓度的方法没有特别限定，只要可以定量或半定量地确定ADAMTS13量或者能够判定是否存在ADAMTS13即可，其例子包括:使用抗ADAMTS13抗体或其片段的免疫学方法(例如酶免疫测定法、胶乳凝聚免疫测定法、化学发光免疫测定法、荧光抗体法、放射免疫测定法、免疫沉淀法、免疫组织染色或免疫印迹法等)、生化学方法(例如酶学测定法)或测定mRNA量的分子生物学方法等。
使用免疫学方法作为ADAMTS13的分析方法时，可以按照公知方法例如国际公开第2004/029242号小册子中记载的方法制备抗ADAMTS13抗体，上述免疫学测定例如也可以按照国际公开第2004/029242号小册子中记载的方法来实施。
作为测定ADAMTS13浓度的方法，从灵敏度和简便性的角度考虑优选免疫学方法。这里的免疫学方法是指使用抗ADAMTS13抗体，例如采用ELISA法、胶乳法或免疫色谱法分析ADAMTS13。免疫学方法包括各种方法，例如标记ADAMTS13的竞争法、标记抗体的层合法、观察包被抗体的珠粒的聚集的胶乳珠粒法或使用结合在金胶体等着色微粒上的抗体的方法等。当为使用抗ADAMTS13抗体的方法时，包含在本发明的优选方案中。抗体可以是单克隆抗体也可以是多克隆抗体。另外，还可以使用抗体片段，例如Fab、Fab’、F(ab’)2或Fv。
ADAMTS13的酶活性例如可以利用以下方法进行测定:使用SDS-琼脂糖电泳法的方法[M.Furlan等，Boold，(美国)1997年，第89卷，第3097-3103页]、使用作为vWF基质的vWF的A2结构域的重组抗原的ELISA法[Whitelock JL等，“ジャ-ナルオブトロンボ—シスアンドヘモステ-シス”，(英国)，2004年，第2卷，485-491]或者使用在作为vWF剪切酶基质的vWF的A2结构域中的相当于Asp1596-Arg1668的73残基的合成肽中导入荧光基团[2-(N-甲氨基)苯甲酰基，Nma]和消光基团(2，4-二硝基苯基，Dnp)的消光性荧光基质FRETS-VWF73的方法[Kokame K等，“ブリテイツシユジャ-ナルオブヘマトロジ—”，(英国)，2005年，第129卷，93-100]。还可以利用日本特愿2005-148793号说明书中记载的分析方法进行测定，该方法具体包括以下步骤:(1)使可能含有ADAMTS13的受检试样与在不溶性载体上结合有vWF或其片段的固定化基质在溶液中接触的步骤；(2)分离上述溶液和不溶性载体的步骤；以及(3)分析残留在不溶性载体上的vWF或其片段和/或自不溶性载体上游离的溶液中的vWF片段的步骤。
vWF浓度的测定方法例如有:利用人血小板和利托菌素辅因子的凝集活性进行的活性测定方法[Allain JP等，“J Lab Clin Med.”(美国)，1975年，第85卷，第318-328页]或者使用抗vWF抗体的免疫测定法[Brown JE等，“Thromb Res.”(美国)，1986年，第43卷，第303-311页]等，从灵敏度和简便性的角度考虑优选免疫学方法。
[2]本发明的鉴定用试剂盒
本发明的试剂盒至少含有抗ADAMTS13抗体或其片段，优选含有两种以上不同的抗ADAMTS13抗体。上述抗ADAMTS13抗体可以是单克隆抗体也可以是多克隆抗体。当含有两种以上不同的抗ADAMTS13抗体时，还可以将其中任一种(第2抗体)制成标记抗体，或者还可以进一步在试剂盒中追加标记抗体，上述标记抗体是在抗第2抗体的抗体上结合有标记以代替标记化。
实施例
以下，通过实施例来具体说明本发明，但这些实施例并不限定本发明的范围。
《实施例1:DIC患者和TTP患者的凝固纤溶标记值的测定》
从23名DIC患者和2名TTP患者身上采取添加了3.8％枸橼酸的血浆。使用市售试剂盒(LPIA系列；三菱化学ヤトロン)，利用LPIA-NV7(三菱化学ヤトロン)测定除去血小板数的各测定标记。采取添加了3.2％枸橼酸的血浆，使用KX-21(シスメツクス社)测定血小板数。
各测定结果见表1。在表1中，PAI-1表示纤溶酶原活化因子抑制因子-1，D-D表示D二聚物，Fbg表示纤维蛋白原，FDP-P表示血浆FDP，PLT表示血小板，TAT表示凝血酶/抗凝血酶III复合物。在诊断为DIC的患者中可见血小板数锐减的患者，但仅凭以往的凝固纤溶标记值无法与TTP患者进行区分。
[表1]
| 诊断名 | PIC | PAI-1 | D-D | Fbg | FDP-P | PLT | TAT | |
| μg/mL | ng/mL | μg/mL | mg/dL | ng/mL | ×104/μL | ng/mL | ||
| 患者1患者2 | TTPTTP | 1.14.2 | 39.710.7 | 3.66.7 | 204- | 2.5- | 2.00.9 | -- |
| 患者3 | DIC | 4.9 | 924.5 | >2000 | 197 | 261.5 | 1.2 | 48.1 |
| 患者4 | DIC | 2.0 | 55.7 | 1000-2000 | 445 | 64.1 | - | 5.6 |
| 患者5 | DIC | 2.4 | 220.7 | >2000 | 838 | 49.2 | 0.5 | 12.9 |
| 患者6 | DIC | 1.3 | 70.4 | 500-1000 | 433 | 27.5 | - | 3.4 |
| 患者7 | DIC | 3.0 | 25.2 | 1000-2000 | 413 | 17.9 | - | - |
| 患者8 | DIC | 4.4 | 228.3 | 33.7 | 26 | 189.0 | - | 57.4 |
| 患者9 | DIC | 0.6 | 40.1 | <200 | 703 | 4.5 | - | 1.2 |
| 患者10 | DIC | 1.0 | 28.1 | 12.1 | 165 | 24.8 | - | 7.6 |
| 患者11 | DIC | 0.5 | 69.4 | <200 | 360 | 2.7 | - | 1.4 |
| 患者12 | DIC | - | 25.6 | 1.1 | 388 | 3.4 | - | - |
| 患者13 | DIC | 0.7 | - | 1.5 | 194 | 1.7 | - | 1.9 |
| 患者14 | DIC | 4.6 | 105.6 | >2000 | 423 | 24.1 | 10.4 | 32.5 |
| 患者15 | DIC | 1.1 | 29.1 | 500-1000 | 401 | 6.7 | 1 | |
| 患者16 | DIC | 4.1 | 178.0 | >2000 | 176 | - | 13.4 | 7.6 |
| 患者17 | DIC | 1.3 | 16.2 | 2.1 | 680 | 9.8 | - | 2 |
| 患者18 | DIC | 6.7 | 31.6 | >2000 | 342 | 59.9 | 3.5 | 4.4 |
| 患者19 | DIC | 0.7 | 23.8 | <200 | 416 | 2.0 | - | 1.4 |
| 患者20 | DIC | - | 1091.2 | 15.0 | 432 | 13.7 | 0.2 | - |
| 患者21 | DIC | 3.4 | 53.5 | 1000-2000 | 260 | 15.7 | 1.8 | 9.6 |
| 患者22 | DIC | - | 162.2 | 200-500 | 307 | 5.7 | 22.9 | - |
| 患者23 | DIC | - | - | >2000 | 632 | 51.0 | 25.4 | - |
| 患者24 | DIC | 31.6 | 17.9 | 22.1 | 126 | 55.9 | 1.1 | - |
| 患者25 | DIC | 7.6 | 22.4 | 33.8 | 340 | 28.9 | 5.2 | - |
《实施例2:DIC患者和TTP患者的ADAMTS13抗原量及其酶活性以及vWF抗原量的分析》
从12名健康人、23名DIC患者、2名TTP患者身上采取添加了3.8％枸橼酸的血浆。需要说明的是，DIC表示按照上述DIC诊断基准诊断为DIC的患者，TTP表示根据临床所见诊断为TTP的患者。使用市售试剂盒(ADAMTS-13ELISA试剂盒；三菱化学ヤトロン)测定ADAMTS13抗原量(Aag)。ADAMTS13酶活性(Aact)利用SDS-琼脂糖电泳法[M.Furlan等，Boold，(美国)，1997年，第89卷，第3097-3103页]进行测定。vWF抗原量(Vag)使用市售试剂盒(STA LIAtest:ロツシユダイアグノステイツクス)进行测定。测定结果见表2。需要说明的是，Aag或Aact以12名健康人的平均值为100％时的百分率表示，Vag以相对于试剂盒中所含的STD(正常人)的百分率表示。
[表2]
根据TTP患者的测定值，按照下述指标对DIC患者的测定值进行分类。
1)ADAMTS13抗原量(Aag)为30％以下
2)ADAMTS13酶活性(Aact)为15％以下
3)ADAMTS13量相对于ADAMTS13活性的比例(Aact/Aag)为2.0以上
首先，将符合上述三项中的两项或三项的患者组分为“疑似TTP的DIC患者组”(A组)，将除此以外的患者组分为“非疑似TTP的DIC患者组”(B组)。将上述患者组(A组和B组)进一步分为以下3组:
第1组:Vag/Aag为8以上且Vag/Aact为16以上；
第2组:Vag/Aag为8以下且Vag/Aact为16以上；
第3组:不符合第1组和第2组的组(即“Vag/Aact不足16”)。
比较各组和健康人时得到了图1～图3的结果。由ADAMTS13抗原量(Aag)、ADAMTS13酶活性(Aact)、vWF抗原量(Vag)的结果确认:在任一种标记中TTP和健康人群明显确认到差别。另外，在ADAMTS13抗原量和ADAMTS13酶活性方面确认到TTP与第3组的差别，可以判别两组。并且，在第2组中在ADAMTS13抗原量方面确认到与TTP的差别，在ADAMTS13酶活性方面没有确认到与TTP的差别。而在vWF抗原量方面没有确认到TTP与DIC组(第1组～第3组)的差别。
因此，根据Vag/Aag或Vag/Aact来比较TTP和分成3组的DIC组时，得到了图4～图5的结果。
使用vWF抗原量与ADAMTS13抗原量之比(Vag/Aag)和vWF抗原量与ADAMTS13活性之比(Vag/Aact)时，第1组和第2组的各值的中央值与TTP的该值相比显示2倍以内的值，而第3组的中央值与TTP的该值相比显示2倍以上的差，表示第3组是明显不同于TTP的病态。
产业实用性
本发明可以用于DIC的适当的治疗用途。
以上，按特定方案说明了本发明，但该领域技术人员自明的变形或改良也包含在本发明范围内。
Claims (4)
1.弥漫性血管内凝血综合征的病态的鉴定方法，其特征在于：分析弥漫性血管内凝血综合征患者的血管性血友病因子剪切酶的量和/或酶活性。
2.权利要求1的方法，该方法进一步分析血管性血友病因子的量。
3.权利要求1或2的方法，该方法通过免疫学方法实施血管性血友病因子剪切酶的分析。
4.用于鉴定弥漫性血管内凝血综合征的病态的试剂盒，该试剂盒中含有与血管性血友病因子剪切酶进行特异性结合的抗体或其片段。
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| RU2651708C2 (ru) * | 2011-09-30 | 2018-04-23 | Сомалоджик, Инк. | Прогнозирование риска сердечно-сосудистого события и его применение |
| JP6640494B2 (ja) * | 2015-08-28 | 2020-02-05 | シスメックス株式会社 | 血液検体分析方法、血液検体分析装置、及びコンピュータプログラム |
| EP3988938B1 (en) | 2016-01-08 | 2024-06-12 | Kyoto University | Medicine comprising adamts13 as main ingredient |
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| CN104285148A (zh) * | 2012-05-07 | 2015-01-14 | 美迪恩斯生命科技株式会社 | 检测弥散性血管内凝血或感染性弥散性血管内凝血的方法 |
| CN104285148B (zh) * | 2012-05-07 | 2016-10-12 | 美迪恩斯生命科技株式会社 | 检测弥散性血管内凝血或感染性弥散性血管内凝血的方法 |
| US9910052B2 (en) | 2012-05-07 | 2018-03-06 | Lsi Medience Corporation | Method of diagnosing and treating infectious disseminated intravascular coagulation |
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