大江 发表于 2020-6-13 00:01:03

抗凝物

抗凝剂,通常称为血液稀释剂,是可防止或减少血液凝结,延长凝血时间的化学物质。其中一些天然存在于食血动物中,例如水蛭和蚊子,它们有助于使被咬区域保持足够长的凝结时间,以使动物获得一些血液。作为一类药物,抗凝剂用于血栓形成疾病的治疗。口服抗凝剂(OAC)以药片或片剂的形式被许多人服用,医院中使用了各种静脉抗凝剂。一些抗凝剂用于医疗设备,例如样品管,输血袋,心肺机和透析设备。第一种抗凝药华法林最初被批准用作杀鼠剂。

通过操纵各种凝血途径,抗凝剂与抗血小板药和溶栓药密切相关。具体而言,抗血小板药物抑制血小板凝集(聚集),而抗凝剂抑制凝血级联反应的特定途径,该途径在初始血小板凝集后发生,并最终导致血纤蛋白和稳定的聚集血小板产物形成。

常见的抗凝剂包括华法林和肝素。


内容
1 医疗用途
2 不良影响
3 互动
4 类型
4.1 香豆素(维生素K拮抗剂)
4.2 肝素及其衍生物
4.3 Xa因子的合成五糖抑制剂
4.4 直接作用的口服抗凝药
4.5 抗凝血酶蛋白疗法
4.6 其他类型的抗凝剂
5 逆转代理
6 凝血抑制剂的测定
7 实验室用途
8 长期服用抗凝剂的人的牙科注意事项
9 参考

医疗用途
抗凝剂的使用是根据抗凝剂的风险和益处做出的决定。抗凝治疗的最大风险是出血风险增加。在其他情况下健康的人中,出血的增加风险很小,但是最近进行过手术,脑动脉瘤和其他情况的人可能会有太大的出血风险。通常,抗凝的益处是预防或减少血栓栓塞性疾病的进展。已知可从治疗中受益的一些抗凝治疗适应症包括:

心房颤动-通常形成心房附件血块
冠状动脉疾病
深静脉血栓形成-可能导致肺栓塞
缺血性中风
高凝状态(例如,因子V Leiden)-可能导致深静脉血栓形成
机械心脏瓣膜
心肌梗塞
肺栓塞
支架再狭窄
体外循环(或其他任何需要暂时性主动脉阻塞的手术)
心脏衰竭
在这些情况下,抗凝疗法可以防止危险血凝块的形成或防止血凝块的生长。

开始治疗性抗凝的决定通常涉及使用多种出血风险可预测结果工具作为无创预测试分层,因为在血液稀释剂上可能会流血。这些工具包括HAS-BLED,ATRIA,HEMORR2HAGES和CHA2DS2-VASc。然后必须权衡使用上述风险评估工具的出血风险与血栓形成风险,以便正式确定患者在开始抗凝治疗中的总体获益。

不利影响
与抗凝剂相关的最严重和最常见的不良副作用是出血风险增加,包括非主要和主要出血事件。出血的风险取决于所用抗凝剂的种类,患者的年龄以及以前存在的健康状况。华法林估计每年的出血发生率为15-20%,威胁生命的出血率为每年1-3%。与华法林相比,新型的非维生素K拮抗剂口服抗凝药似乎减少了威胁生命的出血事件。此外,年龄在80岁以上的患者可能特别容易发生出血并发症,每100人年13处出血。由于所有NOAC在一定程度上都被肾脏排泄,因此在肾功能不全和NOAC治疗的患者中考虑出血风险尤为重要。因此,肾功能不全的患者出血风险更高。

在癌症患者中,一项系统的审查发现华法林对死亡率或血栓风险没有影响。但是,这确实增加了每1000人口中107人的重大出血风险和1000人口中167人的轻微出血风险。阿哌沙班对死亡率,血管血栓复发或大出血或小出血没有影响,但是这一发现仅来自一项研究。

非出血性不良事件比出血性不良事件少见,但仍应密切监测。华法林的非出血性不良事件包括皮肤坏死,肢体坏疽和紫趾综合症。在治疗的第三至第八天最常观察到皮肤坏死和肢体坏疽。皮肤坏死和肢体坏疽的确切发病机理尚不完全清楚,但被认为与华法林抑制蛋白C和蛋白S产生的作用有关。紫脚趾综合征通常在华法林治疗开始后三到八周发展。华法林的其他不良作用还与维生素K的消耗有关,维生素K的消耗可能导致G1a蛋白和生长停滞特异性基因6的抑制,这可能导致动脉钙化和心脏瓣膜的风险增加,尤其是如果存在过多的维生素D时。华法令对G1a蛋白的干扰也与怀孕期间接受华法令治疗的母亲的胎儿骨骼发育异常有关。长期服用华法林和肝素也与骨质疏松症有关。

与肝素使用相关的另一种潜在的严重并发症称为肝素诱导的血小板减少症(HIT)。 HIT有两种不同类型:1)免疫介导的和2)非免疫介导的。免疫介导的HIT最常见于接触肝素后五到十天。免疫介导的HIT的发病机理被认为是由与血小板上的血小板因子4 /肝素复合物结合的肝素依赖性免疫球蛋白抗体引起的,导致广泛的血小板活化。

互动
具有血液稀释作用的食品和食品补充剂包括纳豆激酶,激酶,啤酒,越桔,芹菜,小红莓,鱼油,大蒜,姜,银杏,人参,绿茶,栗子,甘草,烟酸,洋葱,木瓜,石榴,石榴,红三叶草,大豆,圣约翰草,姜黄,小麦草和柳树皮。许多草药补品具有淡化血液的特性,例如丹参和小白菊。抗凝剂的患者可以使用不与凝血相互作用的多种维生素。

但是,某些食物和补品会促进凝血。其中包括苜蓿,鳄梨,猫爪,辅酶Q10和菠菜等深色绿叶蔬菜。服用抗凝剂时应避免过量摄入上述食物,或者,如果监测凝结性,则应保持其摄入量大致恒定,以使抗凝剂的剂量保持足够高的水平,以抵消这种影响而不会引起凝结性的波动。

葡萄柚会干扰某些抗凝药,增加它们从体内代谢所需的时间,因此在服用抗凝药时应谨慎食用。

抗凝剂通常用于治疗急性深静脉血栓形成。使用抗凝剂治疗这种情况的人应避免使用卧床休息作为补充治疗,因为以这种方式使用抗凝剂继续行走并保持活动可带来临床益处。在没有医学上必要的情况下,使用抗凝剂卧床休息可能会伤害患者。

种类
有多种抗凝剂。传统药物(华法林,其他香豆素和肝素)被广泛使用。自2000年代以来,已经引入了许多药物,这些药物统称为直接作用口服抗凝剂(DOAC),新型口服抗凝剂(NOAC)或非维生素K拮抗剂口服抗凝剂。这些药物包括直接凝血酶抑制剂(达比加群)和凝血因子Xa抑制剂(利伐沙班,阿哌沙班,贝曲沙班和依多沙班),并且已被证明与香豆素同等或更好,副作用较小。新型抗凝剂(NOAC / DOAC)比传统抗凝剂更昂贵,应在患有肾脏问题的患者中谨慎使用。

香豆素(维生素K拮抗剂)
更多信息:维生素K拮抗剂
这些口服抗凝剂源自香豆素,在许多植物中都存在。该类别中最重要的成员是华法林(Coumadin),被发现是大型多专业实践中规定的主要抗凝剂。至少需要48到72个小时才能产生抗凝作用。如果需要立即起效,则必须同时给予肝素。这些抗凝剂用于治疗深静脉血栓形成(DVT),肺栓塞(PE)并预防房颤(AF)和机械人工瓣膜患者的栓子。其他实例是乙酰香豆酚,苯普鲁蒙,阿罗门汀和苯并二酮。

香豆素溴地那非和地非那克被用作灭鼠剂,但并未在医学上使用。

肝素及其衍生物
肝素是全世界使用最广泛的静脉临床抗凝剂。肝素是天然存在的糖胺聚糖。肝素主要分为三类:普通肝素(UFH),低分子量肝素(LMWH)和超低分子量肝素(ULMWH)。普通肝素通常来源于猪的肠和牛肺。 UFH与酶抑制剂抗凝血酶III(AT)结合,引起构象变化,从而导致其活化。然后,激活的AT使Xa因子,凝血酶和其他凝血因子失活。肝素可以在体内(通过注射)使用,也可以在体外使用,以防止血液或血浆凝结在医疗设备中或医疗设备上。在静脉穿刺时,装有肝素的Vacutainer品牌采血管通常有一个绿色的帽子。

低分子量肝素(LMWH)
低分子量肝素(LMWH)是通过普通肝素的受控解聚反应制得的。 LMWH表现出更高的抗Xa /抗IIa活性比,并且由于不需要监测APTT凝血参数且副作用较小而很有用。

Xa因子的合成五糖抑制剂
Fondaparinux是一种合成糖,由肝素中的五种糖(五糖)与抗凝血酶结合而成。它比低分子量肝素的分子小。
伊德拉帕林
伊达拉巴他星
直接作用的口服抗凝药
直接作用口服抗凝剂(DOAC)于2008年及之后推出。目前市场上有五种DOAC:达比加群,利伐沙班,阿哌沙班,依多沙班和贝曲沙班。它们以前也被称为“新型/新型”和“非维生素K拮抗剂”口服抗凝剂(NOAC)。

与华法林相比,DOAC起效快,半衰期相对较短。因此,它们可以更快,更有效地发挥作用,并允许药物迅速降低其抗凝作用。与华法林相比,DOAC的常规监测和剂量调整没有那么重要,因为它们具有更好的可预测的抗凝活性。

DOAC和华法林均等效,但与华法林相比,DOAC的药物相互作用较小,没有已知的饮食相互作用,治疗指数更广,并且常规剂量无需持续监测即可调整剂量。但是,与华法林不同,目前大多数DOAC尚无对策。尽管如此,DOAC的半衰期短将导致其影响迅速消退。达比加群的逆转剂依达珠单抗目前可以使用,并已获FDA批准使用。在开具这些药物的患者中,对DOAC的依从率仅略高于对华法林的依从性,因此尽管希望DOAC会导致更高的依从率,但对抗凝的依从性普遍较差。

考虑到与华法令相关的频繁血液检查的成本后,DOAC比华法令要昂贵得多。

直接因子Xa抑制剂
主要文章:直接Xa抑制剂
利伐沙班,阿哌沙班和依多沙班等药物可通过直接抑制Xa因子来发挥作用(与肝素和磺达肝癸钠不同,后者可通过抗凝血酶激活而起作用)。同样来自Portola Pharmaceuticals的贝曲西班,来自Astellas的darexaban(YM150),以及最近来自武田的来曲沙班(TAK-442)和来自辉瑞的eribaxaban(PD0348292)。贝曲西班具有重要意义,因为它是FDA批准用于急性病患者的唯一口服Xa因子抑制剂。 darexaban的研发于2011年9月终止:在双重抗血小板治疗(DAPT)之上预防心肌梗死复发的试验中,该药物未显示出疗效,出血风险增加了约300%。 II期研究结果阴性后,于2011年5月终止了letaxaban的开发,用于急性冠脉综合征。

直接凝血酶抑制剂
主条目:直接凝血酶抑制剂
另一类抗凝剂是直接凝血酶抑制剂。目前这类药物包括二价药物水rud素,瘦素和比伐卢定。单价药物argatroban和dabigatran。口服直接凝血酶抑制剂ximelagatran(Exanta)于2004年9月被美国食品和药物管理局(FDA)拒绝批准,并在有严重肝损伤和心脏病发作的报道后于2006年2月完全退出市场。 2010年11月,达比加群酯被FDA批准用于治疗房颤。

DOAC与牙科治疗的相关性
与任何侵入性手术一样,接受抗凝治疗的患者出血风险增加,因此应谨慎使用局部止血方法,以最大程度地减少手术期间和术后出血的风险。但是,对于DOAC和侵入性牙科治疗,还没有足够的临床证据和经验来证明这两者之间存在任何可靠的不良作用,相关性或相互作用。需要对DOAC进行进一步的临床前瞻性研究,以调查与牙科手术相关的出血风险和止血效果。

建议在牙科治疗之前修改DOAC的用法/剂量,这是基于每种操作的严重程度以及个体的出血风险和肾功能的平衡而提出的。由于牙科手术的出血风险较低,建议患者仍应照常服用DOAC药物,以免增加血栓栓塞事件的风险。对于具有较高出血并发症风险的牙科手术(即复杂的拔牙,相邻的拔牙导致大伤口或三个以上的拔牙),建议的做法是患者在此类手术之前错过或延迟剂量的DOAC,以最大程度地减少对出血风险的影响。

抗凝血酶蛋白疗法
抗凝血酶蛋白本身可用作蛋白质治疗剂,可以从人血浆中纯化或重组生产(例如,Atryn,它是在转基因山羊的牛奶中生产的)。

FDA批准抗凝血酶作为抗凝剂,用于预防遗传性抗凝血酶缺乏症患者在手术或分娩之前,期间或之后的血凝块。

其他类型的抗凝剂
存在许多其他抗凝剂,可用于研发,诊断或用作候选药物。

巴曲酶是蛇毒中的一种毒素,可凝结富含血小板的血浆而不影响血小板功能(溶解纤维蛋白原)。
Hementin是来自巨型亚马逊水ech Haementeria ghilianii唾液腺的抗凝蛋白酶。
维生素E
逆转代理
随着接受口服抗凝治疗的患者数量的增加,由于主要的出血事件以及对紧急抗凝治疗的需求,对逆转药物的研究越来越引起人们的兴趣。由于华法林的使用历史较长,并且能够通过测量INR(国际标准化比率)来更准确地测量患者的抗凝作用,因此,华法林的逆转剂得到了更广泛的研究,并且存在建立逆转的指导原则。通常,最常使用维生素K来逆转华法林在非紧急情况下的作用。但是,在紧急情况下,或在具有极高INR(INR> 20)的情况下,止血逆转剂(例如新鲜的冷冻血浆(FFP),重组因子VVIa和凝血酶原复合物浓缩物(PCC))已被证明具有疗效。特别是对于华法林,与FPP相比,四因子PCC(4F-PCC)在降低INR方面具有更好的安全性和死亡率优势。

尽管尚未对DOACs的特定解毒剂和逆转剂进行广泛研究,但依达西珠单抗(达比加群)和andexanet alfa(用于Xa因子抑制剂)已在临床环境中以不同的功效使用。伊达珠单抗是一种单克隆抗体,已于2015年获得美国FDA批准,可通过与游离和凝血酶结合的达比加群结合而逆转达比加群的作用。 Andexanet alfa是一种重组修饰的人类Xa因子诱饵,可通过在Xa因子抑制剂的活性位点结合并使其催化失活来逆转Xa因子抑制剂的作用。 Andexanet alfa于2018年获得了美国FDA的批准。另一种名为ciraparantag的药物,可能是直接Xa抑制剂的潜在逆转剂,目前仍在研究中。另外,止血逆转剂也已经以不同的效力用于逆转DOAC的作用。

凝血抑制剂测定
贝塞斯达单位(BU)是衡量凝血抑制剂活性的指标。在孵化期中使一半凝血剂失活的抑制剂的量。它是在美国使用的标准度量,之所以如此命名,是因为它是在马里兰州贝塞斯达的一次会议上被采用为标准的。

实验室用途
如果允许血液凝结,则实验室仪器,输血袋以及医疗和外科手术设备将被堵塞并无法使用。此外,用于实验室血液测试的试管中将添加化学药品以阻止血液凝结。除肝素外,大多数化学物质都通过结合钙离子起作用,从而阻止凝血蛋白使用它们。

乙二胺四乙酸(EDTA)牢固且不可逆地螯合(结合)钙离子,从而防止血液凝结。
柠檬酸盐在试管中呈液体形式,用于凝血试验以及输血袋中。它与钙结合,但不如EDTA强。抗凝剂在血液中的正确比例是至关重要的,因为稀释后可以通过添加钙来逆转。它可以是柠檬酸钠或柠檬酸-葡萄糖的形式。
草酸盐的机制与柠檬酸盐类似。它是草酸氟试管中使用的抗凝剂,用于确定葡萄糖和乳酸水平。
长期服用抗凝剂的人的牙科注意事项
由于患者没有任何症状,牙科医生在通过口服表现早期发现抗凝药过量中起着重要作用。就侵入性牙科手术后出血并发症的潜在风险而言,对接受抗凝剂或抗血小板药物治疗的患者进行牙科治疗会增加安全性。因此,需要针对服用这些药物的患者进行牙齿护理的某些指南。

检测过量的抗凝剂

抗凝剂过量通常发生在有心脏问题且需要长期服用抗凝剂的人中,以降低其因高血压而患中风的风险。

建议使用国际标准化比率(INR)测试,以确认药物过量,以便可以将剂量调整到可接受的标准。 INR测试测量相对于标准品,血样在血样中形成所需的时间。

INR值为1表示凝血水平与未服用华法令的普通患者相同,而INR值大于1则表示凝血时间更长,因此出血时间也更长。

评估出血风险

评估出血风险有两个主要部分:

评估与所需牙科手术有关的可能出血风险
评估患者的个人出血风险
处理牙齿出血风险的一般建议

使用抗凝剂或抗血小板药物的患者可能会接受不太可能引起出血的牙科治疗,例如局部麻醉注射,基本牙龈检查,牙菌斑上方牙菌斑和牙垢的清除,牙龈上方的牙结石和污渍,牙龈上方的直接或间接填充物,根管治疗,为假牙或冠冠做印模以及正畸矫治器的安装或调整。对于所有这些程序,建议牙医按照正常的标准程序对患者进行治疗,并注意避免任何出血。

对于需要进行牙科治疗的患者,该患者更容易引起出血,例如拔牙简单(1-3颗牙齿,伤口小),引流口腔内的肿胀,牙周膜,根部刨平,直接或间接填充,延伸到牙龈下方,复杂的充盈,皮瓣抬高程序,牙龈重塑和活检,牙医除了标准程序外还需要采取额外的预防措施。建议如下:

如果患者患有其他疾病或正在服用其他可能增加出血风险的药物,请咨询患者的全科医生或专科医生
如果患者正在接受短期抗凝或抗血小板治疗,则应延迟非紧急的侵入性治疗,直到停药
如果可能的话,在一天和一周的早些时候计划治疗,以便有时间处理长时间的出血或再出血(如果发生)
尽可能无创伤地进行手术,使用适当的局部措施,并在确认止血后才出院
如果需要紧急护理的时间,应在初次治疗时特别强调采取避免并发症的措施
建议患者服用扑热息痛(除非有禁忌),以缓解疼痛,而不是使用非甾体抗炎药(例如阿司匹林,布洛芬,双氯芬酸或萘普生)
向患者提供书面的治疗后建议和紧急联系方式
遵循针对服用不同抗凝药或抗血小板药的患者的治疗的具体建议和意见
普遍同意,在大多数情况下,在进行牙科手术之前,不得更改使用较旧的抗凝剂(例如华法林)和抗血小板药物(例如氯吡格雷,噻氯匹定,普拉格雷,替格瑞洛和/或阿司匹林)的治疗方案。停止或减少这些药物治疗的风险(即血栓栓塞,中风,心肌梗塞)远远超过了长期出血的后果,可以通过局部措施加以控制。在患有其他现有医学状况,可能增加牙科治疗后长时间出血风险的患者或正在接受其他可能增加出血风险的疗法的患者中,牙科医生可能希望咨询患者的医生,以确定是否可以安全地在初级保健机构进行护理护理室。在进行牙科手术之前,任何建议的用药方案修改都应在患者医生的咨询和建议下进行。

根据有限的证据,普遍的共识似乎是,大多数正在接受较新的直接作用口服抗凝药(例如达比加群,利伐沙班,阿哌沙班或依多沙班)并接受牙科治疗(结合常规的局部治疗)的患者。 控制出血),无需更改抗凝方案。 对于被认为有较高出血风险的患者(例如,患有其他医疗状况或正在接受与较高出血风险相关的更广泛操作的患者),可以在征询患者医生的意见和建议后,考虑推迟治疗时间 手术后每天的抗凝剂剂量; 在最后一次抗凝剂使用后尽早进行牙科干预; 或暂时中断药物治疗24至48小时。

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