0 引言

傳統(tǒng)觀點(diǎn)認(rèn)為肝硬化患者處于低凝狀態(tài),出血風(fēng)險(xiǎn)高

.然而,當(dāng)前的證據(jù)提示肝硬化患者凝血系統(tǒng)處于“再平衡”狀態(tài),不僅存在出血傾向,而且常伴發(fā)多種靜脈血栓栓塞性疾病(venous thromboembolism,VTE)

.肝硬化患者中,最常發(fā)生VTE的部位是門靜脈

.肝硬化患者發(fā)生門靜脈血栓(portal vein thrombosis,PVT)的風(fēng)險(xiǎn)是普通人群的7倍

,其發(fā)病率為3%-17%,患病率為5%-26%

.PVT可增加肝硬化患者消化道出血、腹水、急性腎損傷及肝移植術(shù)后死亡的風(fēng)險(xiǎn)

.此外,肝硬化患者發(fā)生其他部位VTE的風(fēng)險(xiǎn)是普通人群的1.7倍

,主要包括深靜脈血栓(deep vein thrombosis,DVT)和肺栓塞(pulmonary embolism,PE).肝硬化患者DVT或PE發(fā)病率為0.2%-6.3%

,患病率為0.4%-4.7%

.肝硬化合并DVT患者30 d死亡率為7%,為非肝硬化患者的2.17倍;肝硬化合并PE患者30 d死亡率為35%,為非肝硬化患者的1.3倍

.

抗凝是預(yù)防及治療肝硬化VTE的重要手段之一,可顯著減少肝硬化患者血栓發(fā)生率、增加血栓再通率,甚至可以降低肝臟失代償率并提高總體生存率

.肝素類藥物是目前臨床最常用的抗凝藥物

,主要包括普通肝素、低分子肝素(依諾肝素、那曲肝素、達(dá)肝素、達(dá)那肝素等)以及合成肝素(磺達(dá)肝癸鈉等)

.2020年美國重癥醫(yī)學(xué)會指南

推薦普通肝素及低分子肝素可用于預(yù)防及治療肝硬化患者VTE,但該推薦強(qiáng)度弱、證據(jù)質(zhì)量低.更值得一提的是,肝硬化患者常合并食管胃底靜脈曲張及血小板減少癥,故在臨床實(shí)踐中需考慮肝素類藥物在肝硬化患者中應(yīng)用的安全性

.目前,肝硬化患者應(yīng)用肝素類藥物的適應(yīng)癥、藥物種類、藥物劑量及監(jiān)測等問題尚無定論.為此,本文通過回顧國內(nèi)外相關(guān)文獻(xiàn),總結(jié)肝素類藥物防治肝硬化VTE的研究進(jìn)展,為臨床合理用藥提供參考.

1 肝素類藥物的種類與特點(diǎn)

普通肝素是一種硫酸化的葡萄糖胺聚糖混合物,平均分子量為12 kDa

.其通過與抗凝血酶Ⅲ(AT-Ⅲ)特異性結(jié)合,加速滅活血漿中凝血因子Ⅱa、Ⅸa、Ⅹa、Ⅺa和Ⅻa

,進(jìn)而發(fā)揮抗凝作用.普通肝素的生物利用度約為30%,藥物半衰期為30 min-60 min

.出血是普通肝素主要的不良反應(yīng),可表現(xiàn)為各種黏膜出血、關(guān)節(jié)腔積血和傷口出血等.普通肝素也可導(dǎo)致免疫誘導(dǎo)性血小板減少癥,發(fā)生率達(dá)5%,多發(fā)生在給藥后7 d -10 d.

低分子肝素是從普通肝素中分離或由普通肝素降解后得到的短鏈制劑,一般分子量低于7 kDa

.由于分子鏈較短,不能與AT-Ⅲ和凝血因子Ⅱa同時(shí)結(jié)合形成復(fù)合物,故主要對凝血因子Ⅹa發(fā)揮作用.生物利用度約為90%.藥物半衰期為119 min-180 min,約為普通肝素的2-4倍.常見的不良反應(yīng)有出血、免疫誘導(dǎo)性血小板減少癥等.臨床常用的低分子肝素包括依諾肝素、那曲肝素、達(dá)肝素、達(dá)那肝素等.

廣東語文高職高考說明文閱讀主要考查的是考生信息的收集、概括和歸納的能力，難度其實(shí)不大，如下一些解題方法可以借鑒。

最近,我國抗凝藥物指南推薦低分子肝素可作為預(yù)防肝硬化患者DVT/PE的首選藥物

,但證據(jù)尚不充分.一項(xiàng)回顧性研究發(fā)現(xiàn)

,與未接受低分子肝素預(yù)防的患者相比,接受低分子肝素預(yù)防的患者DVT/PE發(fā)生率更低(0.63%

1.38%,

=0.530),出血發(fā)生率更高(3.18%

1.38%,

=0.380),但兩組間無顯著差異(表1).薈萃分析結(jié)果顯示

,接受與未接受肝素類藥物預(yù)防的肝硬化患者之間DVT/PE發(fā)生率也無顯著性差異(OR=1.65,95%CI:0.36-7.54,

>0.05).因此,肝素類藥物預(yù)防肝硬化DVT/PE的確切療效仍有待更為嚴(yán)格的隨機(jī)對照試驗(yàn)加以驗(yàn)證.

磺達(dá)肝癸鈉是一種以AT-Ⅲ-肝素結(jié)合位點(diǎn)結(jié)構(gòu)為基礎(chǔ)人工合成的戊多糖.僅對凝血因子Ⅹa發(fā)揮抑制作用.與普通肝素和低分子肝素相比,該藥具有更高的生物利用度(100%)及更長的藥物半衰期(17 h以上),且基本上不會導(dǎo)致出血及免疫誘導(dǎo)性血小板減少癥的不良反應(yīng)

.

2 肝素類藥物的劑量與監(jiān)測

2020年,我國《肝硬化門靜脈血栓管理專家共識》建議

,肝硬化PVT抗凝治療的主要適應(yīng)證為急性癥狀性PVT、等待肝移植、合并腸系膜靜脈血栓.主要禁忌證為近期出血史、嚴(yán)重的食管胃靜脈曲張、嚴(yán)重的血小板減少癥.近年的研究發(fā)現(xiàn),肝素類藥物治療肝硬化PVT具有重要作用,但易引起出血事件及血小板減少癥等不良反應(yīng)

(表1).肝硬化PVT患者經(jīng)達(dá)那肝素治療2 wk后

,PVT體積可平均縮小72%-77%,完全再通率為15%,部分再通率為62%,未發(fā)生大出血、血小板減少、肝損傷等不良反應(yīng).肝硬化PVT患者經(jīng)達(dá)肝素或依諾肝素抗凝治療6 mo后

,治療應(yīng)答率(包括完全再通及部分再通)為61%-78.5%,無應(yīng)答率為16.7%-30.8%,PVT進(jìn)展率為4.4%,總體出血率為4%-23.5%

,致死性出血率為2.1%

.肝硬化PVT患者經(jīng)那曲肝素治療5.5 mo后

,治療應(yīng)答率(包括完全再通及部分再通)為63%,總體出血率為8.5%.肝硬化PVT患者經(jīng)磺達(dá)肝癸鈉治療21 d后

,完全再通率為100%,未發(fā)生出血或血小板減少等不良反應(yīng),但該研究樣本量小(僅7例患者),且治療時(shí)間較短(僅21 d).最近,一項(xiàng)回顧性研究比較了低分子肝素與磺達(dá)肝癸鈉治療肝硬化PVT患者36 mo后的療效

,接受磺達(dá)肝癸鈉治療患者的治療應(yīng)答率(77%

51%,

=0.001)及出血事件發(fā)生率(27%

13%,

=0.06)均高于接受低分子肝素治療患者.薈萃分析結(jié)果顯示

,低分子肝素及磺達(dá)肝癸鈉治療肝硬化PVT后,治療應(yīng)答率分別為71.2%及71.6%,完全再通率分別為41.0%及43.0%,總體出血事件發(fā)生率分別為6.5%及15.1%.盡管磺達(dá)肝癸鈉給藥劑量固定

,且無血小板減少等不良反應(yīng)

,但該藥在肝硬化患者中似乎有著較高的出血率.因此,低分子肝素被推薦作為治療肝硬化PVT的首選肝素類藥物

,療程為6 mo或直至門靜脈再通

.

3 肝素類藥物在肝硬化VTE中的預(yù)防價(jià)值

低分子肝素可有效安全地預(yù)防肝硬化患者發(fā)生PVT(表1).一項(xiàng)隨機(jī)對照試驗(yàn)結(jié)果顯示

,48 wk及96 wk時(shí),接受依諾肝素預(yù)防的患者無一例發(fā)生PVT,未接受依諾肝素的患者PVT發(fā)生率分別為16.6%及27.7%;隨訪結(jié)束時(shí),接受依諾肝素預(yù)防的患者PVT發(fā)生率顯著低于未接受依諾肝素的患者(8.8%

27.7%,

=0.006);兩組間出血事件發(fā)生率無顯著性差異(5.8%

2.7%,

=0.521).該研究也顯示

,接受依諾肝素預(yù)防的患者肝臟失代償率(38.2%

83.0%,

<0.0001)及死亡率(23.5%

36.1%,

=0.251)均更低.基于此,2016年意大利肝病學(xué)會和意大利醫(yī)學(xué)學(xué)會有關(guān)肝硬化止血平衡的共識建議將低分子肝素用于預(yù)防肝硬化PVT

.

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4 肝素類藥物在肝硬化VTE中的治療價(jià)值

通常情況下,普通肝素預(yù)防劑量為首劑皮下注射5000 U,之后每12 h注射5000 U

,治療劑量為首劑靜脈注射5000 U,之后每1 h持續(xù)注射18 U/kg

,用藥4 h后應(yīng)監(jiān)測抗Ⅹa因子活性,參考范圍為0.35 U/mL-0.7 U/mL

;低分子肝素預(yù)防劑量為皮下注射4000 U-5000 U,每日1次

.治療劑量為皮下注射100 U/kg,每日2次

,用藥4 h后同樣應(yīng)監(jiān)測抗Ⅹa因子活性,參考范圍為0.6 U/mL-1.3 U/mL

;磺達(dá)肝癸鈉治療劑量為皮下注射2.5 mg,每日1次

.然而,目前研究不建議肝硬化患者根據(jù)抗Ⅹa因子活性調(diào)整劑量

,可使用總體止血試驗(yàn)作為補(bǔ)充監(jiān)測

.Bechmann等

發(fā)現(xiàn),接受標(biāo)準(zhǔn)劑量依諾肝素的肝硬化患者未能達(dá)到推薦的預(yù)防性及治療性抗Ⅹa因子活性.該研究納入了84例肝硬化患者,分別給予預(yù)防劑量(4000 U,每日1次)及治療劑量(100 U/kg,每日1次)依諾肝素,給藥4 h后,接受預(yù)防及治療劑量的肝硬化患者的平均抗Ⅹa因子活性分別為(0.169±0.122) U/mL及(0.432±0.173) U/mL,均低于參考范圍.此外,依諾肝素給藥后發(fā)生出血的患者比未發(fā)生出血的患者抗Ⅹa因子活性更低[(0.088±0.038) U/mL

(0.174±0.016 U/mL)].因此,肝硬化患者根據(jù)抗Ⅹa因子活性調(diào)整劑量并不可靠.相比于抗Ⅹa因子活性監(jiān)測,總體止血試驗(yàn),如凝血酶生成試驗(yàn),可能會更精確、更高效地反映肝素類藥物在肝硬化患者中的抗凝活性

.Potze等

留取了30例肝硬化患者及30例健康對照者的血漿樣本,分別添加0.3 U/mL普通肝素、0.2 U/mL依諾肝素及0.5 μg/mL磺達(dá)肝癸鈉.結(jié)果顯示,肝硬化患者凝血酶生成曲線下面積的下降幅度較健康對照者更大,這說明肝硬化患者對普通肝素及低分子肝素的反應(yīng)增加

,抗凝效果增強(qiáng),建議減量使用

;而磺達(dá)肝癸鈉在肝硬化患者血漿中的反應(yīng)降低,抗凝效果減弱,建議增加劑量

.然而,這一結(jié)論并未考慮到肝硬化患者體內(nèi)血小板對凝血過程的影響.尚不清楚調(diào)整劑量后的肝素類藥物是否能在肝硬化患者體內(nèi)最大限度地發(fā)揮藥物療效以及減少不良反應(yīng).總之,目前仍需更多的臨床研究探討凝血酶生成試驗(yàn)以及其他監(jiān)測方法對指導(dǎo)肝素類藥物劑量調(diào)整的臨床實(shí)用價(jià)值.

(3)《老甲》簡9：“竺(孰)能濁以靜者，將徐清。”《老甲》簡10：“竺(孰)能安以動(dòng)者?！?竺，端母覺部；孰，禪母覺部。)

兩項(xiàng)回顧性研究探討了普通肝素及低分子肝素治療肝硬化DVT/PE患者的安全性(表1);2008年,García-Fuster等發(fā)現(xiàn)

,接受低分子肝素治療的患者有著較高的出血率.該研究納入了1992-2007住院的17例肝硬化DVT/PE患者.其中,11例接受低分子肝素治療,6例接受低分子肝素序貫華法林治療.治療期間,16例發(fā)生出血,6例需要輸注血液制品,14例因嚴(yán)重的出血事件不得不提前中止應(yīng)用抗凝藥物,出血率達(dá)83%.然而,2020年,Summers等發(fā)現(xiàn)

,相比于普通肝素,接受低分子肝素治療的肝硬化DVT/PE及PVT患者有著較低的出血率.該研究納入了59例肝硬化DVT/PE患者及23例PVT患者,其中接受普通肝素治療52例,大出血率為19.2%,小出血率為5.8%;低分子肝素治療30例,大、小出血率均為0%.因此,普通肝素及低分子肝素在肝硬化DVT/PE患者中的安全性仍存在爭議.

5 結(jié)論

肝硬化患者使用肝素類藥物時(shí),不推薦通過監(jiān)測抗Ⅹa因子活性調(diào)整用藥劑量;相比之下,總體止血試驗(yàn)可能會更好地評估肝素類藥物的抗凝效果及安全性.肝素類藥物可有效防治肝硬化PVT,但對DVT/PE的防治效果尚有待進(jìn)一步驗(yàn)證.

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