蘭文家(綜述)，史 策，周 晉(審校)

(哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院血液內(nèi)科，哈爾濱 150001)

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組織因子對(duì)急性早幼粒細(xì)胞白血病凝血功能紊亂發(fā)生的影響

蘭文家(綜述)，史 策，周 晉※(審校)

(哈爾濱醫(yī)科大學(xué)附屬第一醫(yī)院血液內(nèi)科，哈爾濱 150001)

出血和血栓并發(fā)癥是導(dǎo)致急性早幼粒細(xì)胞白血病(APL)患者死亡的主要因素。在出血及凝血功能紊亂發(fā)生、發(fā)展中，組織因子(TF)的高表達(dá)可以造成患者血液高凝，進(jìn)一步促進(jìn)凝血紊亂的發(fā)生。TF的高表達(dá)與早幼粒細(xì)胞白血病/維甲酸受體、細(xì)胞因子和細(xì)胞膜表面磷脂酰絲氨酸暴露密切相關(guān)。作為凝血活化的交匯點(diǎn)，選擇性抑制TF對(duì)改善APL出凝血紊亂和彌散性血管內(nèi)凝血發(fā)生極為重要。

急性早幼粒細(xì)胞白血?。唤M織因子；凝血功能紊亂；彌散性血管內(nèi)凝血

全反式維甲酸(all tran-retinoic acid，ATRA)和亞砷酸使急性早幼粒細(xì)胞白血病(acute promyelocytic leukemia，APL)的治療取得了巨大突破，但是嚴(yán)重的凝血功能紊亂和出血并發(fā)癥的發(fā)生依然是導(dǎo)致患者早期死亡和治療失敗的主要因素。在APL出凝血紊亂的發(fā)生、發(fā)展過(guò)程中，組織因子(tissue factor，TF)扮演了關(guān)鍵的角色。由于APL細(xì)胞及內(nèi)皮細(xì)胞膜表面TF的過(guò)度活化及外周血中富含TF微粒(tissue factor microparticle，TF-MP)的存在，導(dǎo)致凝血系統(tǒng)的激活、血液高凝，并對(duì)隨后出現(xiàn)的彌散性血管內(nèi)凝血(disseminated intravascular coagulation，DIC)埋下了隱患。因此，研究TF活化的發(fā)生機(jī)制可對(duì)APL凝血功能紊亂的發(fā)生、發(fā)展有更深入的了解，同時(shí)有效抑制TF活化有望成為糾正APL凝血功能紊亂的新靶點(diǎn)。現(xiàn)就TF對(duì)APL凝血功能紊亂發(fā)生的影響予以綜述。

1 APL概述

APL是一種以第15號(hào)和第17號(hào)染色體長(zhǎng)臂移位[t(15;17) (q22;q21)]，融合基因早幼粒細(xì)胞白血病-維甲酸受體α(promyelocytic leukemia-retinoic acid receptor α,PML-RARα)陽(yáng)性的急性髓細(xì)胞白血??；其特點(diǎn)還包括細(xì)胞表達(dá)CD9、CD13及CD33，髓過(guò)氧化物酶和蘇丹黑染色強(qiáng)陽(yáng)性[1]。APL患者早期出血風(fēng)險(xiǎn)高、病死率高。近年來(lái)盡管ATRA和亞砷酸使APL治愈率大有改善，但致命性出血仍為患者死亡及誘導(dǎo)緩解治療失敗的主要原因[1-2]。

APL患者出凝血紊亂的特點(diǎn)為出血與血栓并存。大量研究證實(shí)[3-10]，出血的發(fā)生與纖維蛋白原下降[3,7,10]、血小板下降[3,5,8]、凝血酶原時(shí)間和活化部分凝血活酶時(shí)間延長(zhǎng)[3-4,10]、高白細(xì)胞血癥[3,6,10]、纖維蛋白原降解產(chǎn)物和D-二聚體升高[7,9]、乳酸脫氫酶升高[7-8]、血肌酐升高[8]、C反應(yīng)蛋白升高[8]、國(guó)際血栓與止血協(xié)會(huì)DIC評(píng)分>6分[3,10]、肺炎及維甲酸綜合征[6]密切相關(guān)。血栓是APL患者另外一個(gè)常見(jiàn)并發(fā)癥，其發(fā)生部位常見(jiàn)于腦、冠狀動(dòng)脈及下肢[2,11-12]；APL患者血栓的發(fā)生往往與長(zhǎng)期臥床及制動(dòng)、血液高凝狀態(tài)及分化綜合征有關(guān)[2,11]。

臨床研究證實(shí)，因出凝血紊亂導(dǎo)致DIC的發(fā)生是APL患者發(fā)生致命性出血的主要原因[4]。在DIC發(fā)生和進(jìn)展過(guò)程中，血液高凝、凝血因子和血小板的大量消耗及纖溶系統(tǒng)亢進(jìn)同時(shí)并存，最終導(dǎo)致致命性出血發(fā)生[2,13-14]。APL患者凝血紊亂原因極為復(fù)雜：腫瘤類促凝物質(zhì)、膜聯(lián)蛋白Ⅱ(AnnexinⅡ)、蛋白水解酶、細(xì)胞因子、磷脂酰絲氨酸(phosphatidylserine，PS)及TF的高表達(dá)均與APL凝血功能紊亂密切相關(guān)，其中TF及細(xì)胞釋放的表達(dá)TF-MP可以導(dǎo)致APL凝血功能紊亂的發(fā)生，加速DIC的發(fā)生、發(fā)展[2,13]。在多種因素引起APL凝血功能紊亂中，TF是凝血系統(tǒng)活化的交匯點(diǎn)，細(xì)胞因子、PML/RARα、PS暴露等都需要通過(guò)TF的活化啟動(dòng)凝血系統(tǒng)，繼而由于凝血系統(tǒng)過(guò)度激活最終導(dǎo)致出凝血異常[2,13]。

2 TF在APL出凝血紊亂中的作用

2.1 TF凝血和DIC發(fā)生的啟動(dòng)因子 在生理性止血過(guò)程中，TF是一種膜表面糖蛋白，是體內(nèi)凝血級(jí)聯(lián)通路的啟動(dòng)物質(zhì)。TF可以與凝血酶Ⅶ因子結(jié)合，使其轉(zhuǎn)變?yōu)榛罨蘑饕蜃?Ⅶa)，誘發(fā)血小板表面凝血酶生成，進(jìn)而啟動(dòng)凝血系統(tǒng)，使血液凝固及血栓形成，促進(jìn)機(jī)體的生理性止血[15-16]。正常情況下，細(xì)胞膜表面的TF處于非活化狀態(tài)，而TF的激活往往與細(xì)胞膜磷脂活化有關(guān)，當(dāng)細(xì)胞死亡或者凋亡時(shí)，位于細(xì)胞膜內(nèi)表面的PS暴露于細(xì)胞膜外表面，促凝性TF-Ⅶa復(fù)合物生成增加，啟動(dòng)凝血級(jí)聯(lián)通路[17]。由細(xì)胞釋放的MP中同時(shí)高表達(dá)TF，具有較高的促凝活性。此外，有白血病細(xì)胞釋放的TF-MP會(huì)出現(xiàn)大量積聚，這些TF-MP可以通過(guò)P-選擇素及P-選擇素糖蛋白配體1與血小板結(jié)合，啟動(dòng)凝血級(jí)聯(lián)通路發(fā)揮促凝作用[15-16]。但有研究表明[17-18]，白血病患者體內(nèi)TF出現(xiàn)過(guò)度表達(dá)，這使白血病患者處于出血、血栓甚至DIC發(fā)生的風(fēng)險(xiǎn)中。在APL中，患者體內(nèi)的異常早幼粒細(xì)胞以及早幼粒細(xì)胞系的NB4細(xì)胞都存在TF的異常高表達(dá)，表現(xiàn)為TF-mRNA、TF促凝活性和TF抗原過(guò)度表達(dá)[18]，加之化療、白血病細(xì)胞的凋亡和白血病細(xì)胞對(duì)內(nèi)皮細(xì)胞的損傷都可以使凝血系統(tǒng)活化，TF-Ⅶa形成增加，使白血病患者處于出血、血栓及DIC發(fā)生的高風(fēng)險(xiǎn)中[17,19]。此外，脂質(zhì)的過(guò)氧化也可以促進(jìn)TF的生成，在APL患者化療過(guò)程中可產(chǎn)生大量的活性氧類，并導(dǎo)致TF的生成增加[13]。

2.2 PML/RARα促進(jìn)TF表達(dá) APL細(xì)胞TF的高表達(dá)與PML/RARα融合基因密切相關(guān)。一項(xiàng)研究認(rèn)為，PML/RARα通過(guò)促進(jìn)Fos/Jun與TF啟動(dòng)子活性區(qū)域內(nèi)的AP-1位點(diǎn)結(jié)合促進(jìn)TF的表達(dá)[20]。另一項(xiàng)研究認(rèn)為，PML/RARα可以作用于編碼TF的GAGC基序和核苷酸腹側(cè)部促進(jìn)TF的表達(dá)[21]。然而，當(dāng)RARα活化時(shí)因誘導(dǎo)APL細(xì)胞分化而降低TF表達(dá)，RARα誘導(dǎo)APL細(xì)胞分化依賴磷脂酰肌醇3-激酶信號(hào)通路，應(yīng)用磷脂酰肌醇3-激酶抑制劑可以抑制細(xì)胞分化進(jìn)而恢復(fù)TF的表達(dá)[22]。

2.3 APL細(xì)胞釋放的細(xì)胞因子可以促進(jìn)TF的表達(dá) 在APL患者中，早幼粒細(xì)胞釋放的細(xì)胞因子對(duì)凝血功能紊亂起到促進(jìn)作用，包括白細(xì)胞介素(interleukin,IL)1、腫瘤壞死因子α(tumor necrosis factor α，TNF-α)在內(nèi)的多種細(xì)胞因子可以誘導(dǎo)TF的表達(dá)，加速TF-Ⅶa復(fù)合物的形成；同時(shí)下調(diào)血栓調(diào)節(jié)素及纖溶酶原活化因子抑制劑1的表達(dá)[13,23]。細(xì)胞因子與TF作用是相互的，在TF高表達(dá)的基礎(chǔ)上，TF-Ⅶa復(fù)合物通過(guò)激活內(nèi)源性蛋白酶活化受體信號(hào)通路，促進(jìn)細(xì)胞因子IL-1、IL-8、成纖維細(xì)胞生長(zhǎng)因子β基因轉(zhuǎn)錄增加。在APL治療過(guò)程中，ATRA促進(jìn)APL細(xì)胞分泌IL-1β、IL-6、IL-8、TNF-α[24-25]，這些細(xì)胞因子(尤其是IL-1β、TNF-α)不僅可以使細(xì)胞凋亡增加，而且可以使內(nèi)皮細(xì)胞、血管平滑肌細(xì)胞的TF表達(dá)增加，最終激活凝血系統(tǒng)[13,23]。

2.4 TF-MP可導(dǎo)致凝血功能紊亂 MP是一種具有細(xì)胞膜性結(jié)構(gòu)的囊泡樣物質(zhì)，大小為0.1～1.0 μm，由血小板、內(nèi)皮細(xì)胞、單核細(xì)胞、血管平滑肌細(xì)胞和肝細(xì)胞等釋放的MP有促凝、促炎癥和調(diào)節(jié)內(nèi)皮功能的作用。而促凝活性最強(qiáng)的MP來(lái)源于高表達(dá)TF的內(nèi)皮細(xì)胞和白血病細(xì)胞[26]，在APL患者的外周血中會(huì)出現(xiàn)不同程度的TF-MP升高[27-28]。研究證明，TF-MP使APL并發(fā)靜脈血栓栓塞和DIC的風(fēng)險(xiǎn)明顯升高[27-28]。此外，APL細(xì)胞釋放的MP表面可以檢測(cè)到一些可溶性或游離狀態(tài)的TF，其也可與血漿中的Ⅶ因子結(jié)合組成TF-Ⅶ因子復(fù)合物，進(jìn)一步啟動(dòng)凝血系統(tǒng)[13,29]。同時(shí)表面富含TF-MP被內(nèi)皮細(xì)胞吞噬吸收后，MP表面的TF可以轉(zhuǎn)移至內(nèi)皮細(xì)胞表面增加內(nèi)皮細(xì)胞的促凝活性[30]。因此，檢測(cè)血清中TF-MP的水平有望成為預(yù)測(cè)深靜脈血栓和DIC發(fā)生風(fēng)險(xiǎn)的指標(biāo)，同時(shí)也有望成為糾正APL凝血功能紊亂的治療靶點(diǎn)[27-28]。

2.5 PS可以激活TF PS是一種分布于細(xì)胞膜內(nèi)表面的陰離子磷脂，當(dāng)細(xì)胞出現(xiàn)凋亡或死亡時(shí)由細(xì)胞膜內(nèi)表面轉(zhuǎn)向細(xì)胞膜外表面[31]。在化療過(guò)程中，化療藥物不僅可以損傷APL細(xì)胞、內(nèi)皮細(xì)胞、紅細(xì)胞、血小板等，同時(shí)還可以誘導(dǎo)細(xì)胞出現(xiàn)凋亡，使上述細(xì)胞膜表面出現(xiàn)PS暴露，同時(shí)富含PS的微顆粒也會(huì)釋放入血，進(jìn)而激活TF-Ⅶa復(fù)合物，導(dǎo)致凝血抗凝系統(tǒng)紊亂[32-33]。此外，APL細(xì)胞釋放細(xì)胞因子(如IL-1β、TNF-α)可以促進(jìn)內(nèi)皮細(xì)胞、平滑肌細(xì)胞和白血病細(xì)胞的PS表達(dá)。這些都可以激活TF，加速患者凝血功能紊亂的進(jìn)展[33-36]。

2.6 抑制TF的表達(dá)有望成為控制血栓發(fā)生的重要途徑 ATRA和亞砷酸是目前治療APL的一線用藥，ATRA和亞砷酸可以提高患者的完全緩解率和長(zhǎng)期生存時(shí)間[1,37-38],而且兩藥在降低APL出凝血紊亂上也有良好的臨床作用[1]。多項(xiàng)回顧性研究表明，ATRA與亞砷酸可以降低APL細(xì)胞TF的表達(dá)[1,39]。ATRA和亞砷酸分別通過(guò)作用于RARα和PML的RBCC鋅指結(jié)構(gòu)域抑制PML/RARα的表達(dá)[1]，進(jìn)而下調(diào)APL細(xì)胞TF-mRNA的轉(zhuǎn)錄水平，減少TF抗原表達(dá)，降低TF的促凝活性,從而在治療早期即可改善患者的出血癥狀。此外，TF的表達(dá)與細(xì)胞分化密切相關(guān)，在未成熟的單個(gè)核細(xì)胞系中，TF處于高表達(dá)狀態(tài)；隨著細(xì)胞分化TF表達(dá)下降，成熟單個(gè)核細(xì)胞中TF的表達(dá)則受到嚴(yán)格的調(diào)控。在ATRA誘導(dǎo)NB4細(xì)胞分化過(guò)程中，通過(guò)ATRA與RARα的結(jié)合而抑制TF-mRNA的AP-1位點(diǎn),降低TF-mRNA的轉(zhuǎn)錄活性使TF的表達(dá)受到抑制[39-40]。在APL治療過(guò)程中，ATRA可以下調(diào)含TF-MP水平，降低患者血液高凝狀態(tài)，ATRA不僅可以抑制TF的表達(dá)，同時(shí)可以對(duì)內(nèi)皮細(xì)胞起到保護(hù)作用，減少促凝物質(zhì)對(duì)內(nèi)皮細(xì)胞的損傷[25]。

同樣值得關(guān)注的是，亞砷酸通過(guò)作用于PML的RBCC結(jié)構(gòu)域下調(diào)PML/RARα表達(dá)，進(jìn)而降低TF合成，促進(jìn)TF蛋白轉(zhuǎn)換并抑制TF的促凝活性[40]。此外，亞砷酸可以降低APL細(xì)胞和內(nèi)皮細(xì)胞PS暴露，糾正凝血功能紊亂。與傳統(tǒng)化療藥物相比，應(yīng)用亞砷酸過(guò)程中APL細(xì)胞的PS暴露則明顯下降，因此患者凝血功能紊亂得到控制，DIC發(fā)生率下降[32,41]。

3 結(jié) 語(yǔ)

TF在APL的出凝血紊亂中起關(guān)鍵作用，TF活化與細(xì)胞內(nèi)TF-mRNA轉(zhuǎn)錄，PML/RARα表達(dá)，細(xì)胞因子釋放，PS暴露密切相關(guān)。目前針對(duì)APL出凝血紊亂的治療仍局限于應(yīng)用支持治療、抗凝治療、抗纖溶治療等方面。然而，針對(duì)TF的靶向治療處于初步探索階段[13]。值得關(guān)注的是，與柔紅霉素等傳統(tǒng)化療藥物相比，ATRA和亞砷酸可以明顯降低APL細(xì)胞TF的表達(dá)，改善治療過(guò)程中凝血紊亂的發(fā)生，降低患者致命性出血的發(fā)生、發(fā)展，提高患者的緩解率和生存率[32-33,36,40-41]。

一項(xiàng)研究發(fā)現(xiàn)，在敗血癥中應(yīng)用TF抗體可以輕微延長(zhǎng)凝血時(shí)間，改善凝血功能紊亂[42]；而另外一項(xiàng)研究認(rèn)為TF抗體-血栓調(diào)節(jié)素融合蛋白可以顯著地抑制凝血系統(tǒng)的活化，這種TF抗體-血栓調(diào)節(jié)素融合蛋白的抗凝活性更強(qiáng)，是TF抗體的20倍，是可溶性血栓調(diào)節(jié)素的80倍，在動(dòng)物實(shí)驗(yàn)中發(fā)現(xiàn)應(yīng)用TF抗體-血栓調(diào)節(jié)素融合蛋白可以明顯降低DIC的致死率[43]。通過(guò)應(yīng)用抗TF抗體可以有效抑制APL細(xì)胞來(lái)源的TF-MP所引起的外源性凝血，降低TF-MP的促凝活性[27]。而上述藥物尚未在APL患者治療中進(jìn)行臨床應(yīng)用，因此針對(duì)TF的特異性抗體有望成為APL治療過(guò)程中糾正患者凝血功能紊亂的新靶點(diǎn)。

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Study on the Effect of Tissue Factor in the Coagulopathy of Acute Promyelocytic Leukemia

LANWen-jia,SHICe,ZHOUJin.

(DepartmentofHematology,theFirstAffiliatedHospitalofHarbinMedicalUniversity,Harbin150001,China)

Hemorrhage and thrombotic complications are the major causes for mortality in patients with acute promyelocytic leukemia(APL).During the incidence and development of hemorrhage and coagulopathy,highly expressed tissue factor(TF) can initiate the hypercoagulability and lead to coagulopathy and fatal hemorrhage.The high expression of TF is closely related with promyelocytic leukemia/retinoic acid receptor α,cytokines and phosphatidylserine exposure in membrane surfaces.Selective inhibition of TF,the intersection of coagulation activation,plays an important role in improving APL hemostatic dysfunction and disseminated intravascular coagulation.

Acute promyelocytic leukemia; Tissue factor; Coagulopathy; Disseminated intravascular coagulation

R733.71

A

1006-2084(2015)12-2139-04

10.3969/j.issn.1006-2084.2015.12.010

2014-04-15

2014-12-04 編輯：伊姍