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通讯作者:

刘俊岭(1971-),男,河南人,博士生导师,主要从事血栓和出血性疾病病理机制及干预研究。E-mail:liujl@shsmu.edu.cn

中图分类号:R55,R363.2+1,R-1

文献标识码:A

文章编号:2096-8965(2021)02-0046-04

DOI:10.12287/j.issn.2096-8965.20210207

参考文献 1
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参考文献 16
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参考文献 17
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目录contents

    摘要

    血小板是体内调控止血功能的重要血细胞。血小板增多症和减少症是常见的血小板相关血液疾病,危害严重。 血小板生成和血小板清除异常是这些疾病发生的主要原因。 目前治疗血小板增多症或减少症的药物多是靶向血小板生成素及其受体介导的胞内信号通路,治疗药物包括重组蛋白、小分子激动剂和抑制剂,以及多肽类药物等等。并且近年来围绕血小板清除机制研制的药物也取得了较佳的临床疗效。本文就目前治疗血小板增多症和减少症各种药物的作用机制以及临床效果等研究进展进行综述。

    Abstract

    Platelets are essential blood cells for maintaining hemostasis. Thrombocytopenia and thrombocy‐ themia are common platelet-related blood diseases with serious symptom, such as bleeding and thrombosis. Thrombocytopenic arrest and the abnormal clearance of platelets are the main causes of these diseases. The drugs for the treatment of thrombocytopenia or thrombocythemia are targeting intracellular signaling pathways mediated by thrombopoietin and its receptors. Moreover, the drugs targeting the platelet clearance have also achieved clini‐ cal effects. In this paper, the research progress in the mechanism and clinical effects of various drugs for the treat‐ ment of thrombocytopenia and thrombocythemia were reviewed.

  • 血小板是巨核细胞脱落的无核血细胞,对维护机体凝止血功能起到重要调控作用[1]。由于血小板是由巨核细胞通过增殖、成熟和终末分化等过程形成,因此巨核细胞的分化发育状态对于血小板的产生十分关键[2]。巨核细胞发育成熟过度活跃常见于原发性血小板增多症患者体内,导致造血系统紊乱,引发血小板增多症。血小板增多症患者有较高的出血、动静脉血栓形成或者骨髓增生性及纤维化疾病的风险[3]。血小板减少症患者体内的血小板数目一般低于20×109/L,常伴有血管、粘膜和内脏出血倾向[4]。血小板减少症主要的致病因素是由巨核细胞产生的血小板受损,如再生障碍性贫血,或者血小板过度破坏,如免疫性血小板减少性紫癜[4]。目前针对血小板减少症和血小板增多症等血液系统相关疾病的治疗药物种类繁多,在疗效方面各有利弊。本文将结合巨核细胞发育及血小板产生机制,详细阐述各类相关临床药物的应用情况。

  • 1 血小板的产生

  • 1.1 巨核细胞分化发育与血小板产生

  • 巨核细胞主要是由骨髓造血干细胞分化而来。巨核细胞分化是保持体内血小板数目和功能平衡的关键因素[1]。血小板生成素(Thrombopoietin, TPO) 是巨核细胞分化成熟的重要生长因子。它通过与其受体c-Mpl结合激活胞内JAK2/STAT3信号通路来诱导特定的基因转录驱动巨核祖细胞的增殖和成熟[3, 5]。在TPO的作用下,巨核细胞形成多倍体形态,胞质内吞作用下形成内凹膜系统(Elaborate Invaginated Membrane System,IMS) 并合成血小板功能相关的颗粒体[6]。巨核细胞进一步分化产生前体血小板(Proplatelets)。每个巨核细胞平均能生产10~20个前体血小板,它们进入骨髓窦状血管进而被释放到血液系统中,分化为成熟的血小板[7]

  • 1.2 血小板增多症的发病机理

  • 血小板增多症常见于骨髓增生性疾病(Myeloproliferative Neoplasms,MPN)[8]。MPN一般是由于造血细胞过度分化增殖而导致的血液肿瘤性疾病。 MPN的病理表现除原发性血小板增多症(Essential Thrombocythemia, ET) 外,还有真性红细胞增多症(Polycythemia Vera, PV) 和原发性骨髓纤维化(Primary Myelofibrosis, PMF)[9]。临床上MPN患者常有JAK2、MPL以及CALR基因天然突变[10]。其中,约有70%MPN患者存在JAK2V617F突变[10]。TPO/Mpl/JAK2/STAT3信号轴在巨核细胞发育和血小板形成中发挥重要的调控作用[11]。TPO主要在肝脏和肾脏中产生,被巨核细胞表面的血小板生成素Mpl受体识别后,Mpl受体形成二聚体,JAK2发生磷酸化。同时,活化的JAK2又进一步将Mpl磷酸化,招募含有Src同源的SH2结构域的转录激活子STAT家族。STAT发生磷酸化后进入细胞核,发挥其转录因子的功能,导致巨核细胞发育相关基因的表达。JAK2中的JAK同源2(JH2) 结构域是一个抑制JAK同源1(JH1) 结构域激酶活性的自抑制结构域,JH2结构域JAK2V617F突变是MPN患者中最常见的突变,苯丙氨酸(F) 替换为缬氨酸(V) 会导致JH2结构域抑制作用的消失,导致巨核细胞/血小板的JAK2/STAT3信号的持续激活[11, 12]

  • 1.3 血小板减少症的发病机理

  • 人外周血中正常血小板计数约为(100~300) ×109/L。当人外周血中血小板计数低于100× 109/L时,常被认为是血小板减少症,会引起内脏和粘膜出血,严重的会导致病患死亡[13]。目前,血小板过度清除和血小板生成抑制被认为是导致血小板减少症的主要致病原因[4]。免疫性血小板减少症(Idiopathic Thrombocytopenic Purpura,ITP) 是临床上最为常见的一类血小板减少症。ITP患者由于免疫系统紊乱而产生可识别并结合血小板的自身抗体,如 αIIbβ3和GP1b抗体,导致免疫系统持续激活,不断地清除自身的血小板[13]。此外,血小板过度清除还常见于弥散性血管内凝血、肝素诱导的血小板减少症、其他药物引起的血小板减少症、系统性红斑狼疮、血栓性血小板紫癜、输血后紫癜、化疗或放疗后骨髓移植导致的血小板减少症等[14, 15]。骨髓巨核细胞增殖或发育受损导致的血小板减少症,一般包括低巨核细胞性血小板减少症、Paris– Trousseau血小板减少症、家族性血小板紊乱伴髓系白血病、GATA1突变型血小板减少症、地中海贫血这些类型的血小板减少症、巨血小板综合症、灰色血小板综合症、蒙特利尔血小板综合症等疾病[14]

  • 2 治疗血小板增多症的药物应用策略

  • 2.1 JAK2抑制剂药物的应用

  • 由于TPO/Mpl/JAK2/STAT3信号轴是调控巨核细胞发育生成血小板的重要途经,目前临床治疗血小板减少症或者血小板增多症药物大多是围绕着该信号通路设计的靶分子药物[16]。芦可替尼(Ruxoli⁃ tinib) 是首个FDA批准的治疗MPN的JAK2抑制剂[17]。芦可替尼能够有效抑制JAK2过度活化造成的血小板增多,并且可改善脾脏肿大造成的血小板数目异常。但由于JAK2是全身多组织器官表达的基因,部分患者服用芦可替尼后出现不同程度的副作用。芦可替尼治疗MPN的临床治疗数据显示,部分患者在使用芦可替尼后出现贫血和血小板持续性降低的情况,增加了MPN患者因感染所致的死亡率[18]。另外服用芦可替尼也会增加患者患其他肿瘤的风险,有证据显示患者服用芦可替尼后,发生非黑色素瘤皮肤癌的几率增加,同时也有研究表明芦可替尼会增加患者发生B细胞淋巴瘤的风险。研究发现,16%的MPF患者具有休眠型侵袭性淋巴瘤,在这部分患者中约有6%的患者接收JAK2抑制剂治疗后会刺激淋巴瘤的发作[1, 18]。为了满足对MPF患者的治疗需求,一批新型JAK2抑制剂类药物已获批研发。

  • 非拉替尼(Fedratinib) 是2019年由美国FDA批准上市的二代JAK2抑制剂。非拉替尼通过选择性抑制JAK2,进而降低STAT3和STAT5发生磷酸化入核,抑制细胞过度增殖和分化。非拉替尼主要用于真性红细胞增多症以及原发性血小板增多症后的骨髓纤维化治疗。在临床试验中,非拉替尼具有良好的减轻脾脏病症的疗效[19]。研究显示患者在服用非拉替尼半年和一年时,分别有39%和47%的患者疾病症状减轻。其中,JAK2V617F突变的患者服用非拉替尼后,约有45%的患者症状好转。由于非拉替尼在临床I和Ⅱ期研究显示对骨髓纤维化患者,特别是JAK2V617F突变的患者具有较佳的治疗效果,Ⅲ期临床试验已开始[19]。与此同时, Pacritinib、Momelotinib等其他的JAK2抑制剂也已经进入临床试验阶段[20]

  • 2.2 阿那格雷(Anagrelide)

  • 阿那格雷是一类环磷腺苷(cAMP) 磷酸二酯酶抑制剂[21]。阿那格雷能够阻滞巨核细胞细胞周期后期的过程,即抑制巨核细胞分化成熟和血小板的产生。此外,阿那格雷也能通过抑制血小板cAMP磷酸二酯酶活性,使血小板cAMP水平提高,从而抑制血小板活性水平,发挥显著的抗血小板血栓的药效。阿那格雷的副作用常见头痛和心动过速,因此不适用于老年MPN患者[21, 22]

  • 3 治疗血小板减少症的药物应用策略

  • 3.1 TPO的重组蛋白

  • 重组人血小板生成素(recombinant human Thrombopoietin, rhTPO) 和聚乙二醇化-重组人巨核细胞生长发育因子(Pegylated, recombinant, human Megakaryocyte Growth and Development Factor, PEG-rhMGDF) 是最早进入临床药物研究的重组血小板生成素[23]。临床试验结构提示rhTPO和PEGrhMGDF均能提升体内血小板水平,并有效改善化疗或放疗后骨髓抑制所造成患者血小板减少水平。然而,部分患者在接受PEG-rhMGDF治疗后,体内出现了人内源性TPO抗体,导致其PEG-rhMGDF治疗无效,甚至出现与PEG-rhMGDF相关的血小板过度降低。由于患者体内产生中和性抗体,重组血小板生成素类药物的研发工作至此终止,再无后续研究[24]

  • 3.2 TPO受体激动剂(TPO Receptor Agonists, TPORAs)

  • 鉴于前期重组血小板生成素具有较佳的提高血小板水平的疗效,科学家们针对TPO受体设计并研发了一系列新型激动剂。这些激动剂能够有效刺激巨核细胞分化发育和血小板生成。目前,全球批准的TPORAs有艾曲泊帕(Eltrombopag)、芦曲泊帕(Lusutrombopag)、罗米司亭(Romiplostim) 和阿伐曲泊帕(Avatrombopag)。它们激活TPO受体的机制各有异同。例如,艾曲泊帕(Eltrombopag) 是通过高通量筛选TPO受体小分子激动剂而发现的非肽类小分子口服药。艾曲泊帕可结合于骨髓巨核细胞TPO受体的跨膜区,继而激活Mpl/JAK2/STAT3信号轴,诱导巨核细胞分化发育及血小板生成[25]

  • 罗米司亭的结构包括Fc恒定区和四肽结构域。其发挥药效功能的核心在于其四肽结构域序列[24]。 1997年,Cwirla等人利用肽库筛选到与TPO受体胞外区域特异性结合的肽段,并对这些肽段进行修饰改造,以增强其与TPO的结合能力[26]。其中,他们发现了一段14个氨基酸的肽(IEGPTLRQWLAARA) 与TPO受体有高结合力。当该肽段形成二聚肽后,其生物活性大大提高,具备了与rhTPO相当水平的激活TPO受体的能力。罗米司亭与人体内源性TPO竞争性结合巨核细胞TPO受体,介导JAK2/STAT5信号传导,进而调控巨核细胞分化发育和血小板产生。由于罗米司亭Fc区能与内皮细胞上的FcRn受体结合,使得罗米司亭避免被降解,延长其半衰期(平均120-140h)[24]

  • 3.3 TPO的激动型抗体

  • VB22B sc(FV)2和MA01G4G344是近年来开发的激活TPO受体的单克隆抗体药,用以治疗血小板减少症。此类药物能够更具特异性的靶向巨核细胞受体,与TPO受体具有高度亲和力,半衰期长,效价强。目前,VB22B sc(Fv)2和MA01G4G344已被证实能够有效促进巨核细胞分化、发育和成熟,进而促进血小板生成,并且不会诱导实验动物体内生成中和性抗体[27]。尽管VB22B sc(FV)2和MA01G4G 344尚未进入临床试验,其临床疗效和未来临床治疗应用较受关注。因为该类单克隆抗体药物的临床治疗能够为血小板相关血液疾病新的治疗策略提供重要的思路和依据。

  • 3.4 SYK抑制剂

  • 脾脏酪氨酸激酶(Spleen Tyrosine Kinase,SYK) 是BCR-ITAM介导的细胞吞噬过程的重要调控分子,因此成为治疗自身免疫性疾病的重要靶点[28]。福坦替尼(Fostamatinib) 是抑制SYK激酶活性的小分子口服药物。目前,福坦替尼已被批准用于ITP的临床试验。在ITP患者体内,其体内产生的 αIIbβ3和GP1b自身抗体能够特异性结合血小板,自身抗体的Fc片段会通过结合Fc受体而激活细胞吞噬功能,进而清除体内血小板。福坦替尼通过有效抑制SYK激酶活性所调控的细胞吞噬功能,从而减低ITP患者体内血小板的清除效率,达到治疗效果。福坦替尼有望成为治疗自身免疫性疾病诱导的血小板减少症的新型小分子药物[28]

  • 3.5 FcRn阻断剂

  • 新生儿Fc受体(FcRn) 阻断剂是一类人源化的单克隆抗体。FcRn阻断剂常用于自身免疫性疾病的治疗。它的作用机理比较明确,主要是通过靶向FcRn进而减低自身免疫性致病抗体的水平,从而缓解自身免疫病患者的临床症状。近年来,越来越多的FcRn阻断类药物用于ITP的临床试验和治疗中。如Efgartigimod,HBM9161和Rozanolixizumab等均已进入临床ITP治疗的试验阶段[29]

  • 3.6 JAK2-JH2多肽

  • 酰基甘油激酶(Acylglycerol Kinase,AGK) 对于巨核细胞分化发育和血小板生成十分关键。AGK能够通过激活JAK2/STAT3信号途径调控巨核细胞发育和血小板的生成。有研究发现JAK2的V617F突变后,JAK2与AGK的结合能力增强,进一步促进了TPO/JAK2/STAT3信号活化水平。由此,研究者设计了一段JAK2-JH2多肽YGVCF617CGDENI。体外和动物实验结果显示JAK2-JH2多肽YGVCF61 7CGDENI也能增强JAK2与AGK的结合能力,并且显著促进巨核细胞的分化发育[30]。虽然目前对于JAK2-JH2多肽仅处于基础实验研究阶段,但JAK2-JH2多肽为血小板减少症的治疗提供了有效的理论基础。

  • 4 结语

  • 尽管治疗血小板增多症和减少症的药物研制仍处于探索和验证阶段,但目前已有的部分靶向药物所取得的较佳临床治疗效果为后期新药设计提供了有效的实践基础。特别是新一代激活TPO受体的单克隆抗体药的研发,提高了此类药物特异性、亲和力和稳定性。新药的不断开发也为临床治疗血小板增多症和减少症提供了新思路和方案。

  • 参考文献

    • [1] PATEL S R,HARTWIG J H AND ITALIANO J E,et al.The biogenesis of platelets from megakaryocyte proplatelets[J].J Clin Invest,2005,115(12):3348-3354.

    • [2] KAHR W H,LO R W,LING L,et al.Abnormal megakaryocyte development and platelet function in Nbeal2(-/-)mice[J].Blood,2013,122(19):3349-3358.

    • [3] LEVINE R L,PARDANANI A,TEFFERI A,et al.Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders[J].Nat Rev Cancer,2007,7(9):673-683.

    • [4] ETO K,KUNISHIMA S.Linkage between the mechanisms of thrombocytopenia and thrombopoiesis[J].Blood,2016,127(10):1234-1241.

    • [5] KILPIVAARA O,LEVINE R L.JAK2 and MPL mutations in myeloproliferative neoplasms:discovery and science [J].Leukemia,2008,22(10):1813-1817.

    • [6] BIANCHI E,NORFO R,PENNUCCI V,et al.Genomic landscape of megakaryopoiesis and platelet function defects[J].Blood,2016,127(10):1249-1259.

    • [7] MACHLUS K R,ITALIANO J E.The incredible journey:from megakaryocyte development to platelet formation[J].J Cell Biol,2013,201(6):785-796.

    • [8] MULLALLY A,LANE S W,BRUMME K,et al.Myeloproliferative neoplasm animal models[J].Hematol Oncol Clin North Am,2012,26(5):1065-1081.

    • [9] WERNIG G,MERCHER T,OKABE R,et al.Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model[J].Blood,2006,107(11):4274-4281.

    • [10] MORGAN K J,GILLILAND D G.A role for JAK2 mutations in myeloproliferative diseases[J].Annu Rev Med,2008,59:213-222.

    • [11] PLO I,BELLANNE-CHANTELOT C,MOSCA M,et al.Genetic alterations of the thrombopoietin/MPL/JAK2 axis impacting megakaryopoiesis[J].Front Endocrinol(Lausanne),2017,8:234.

    • [12] QUENTMEIER H,MACLEOD R A,ZABORSKI M,et al.JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders[J].Leukemia,2006,20(12):471-476.

    • [13] JOHNSON B,FLETCHER S J,MORGAN N V.Inherited thrombocytopenia:novel insights into megakaryocyte maturation,proplatelet formation and platelet lifespan[J].Platelets,2016,27(12):519-525.

    • [14] MILTIADOUS O,HOU M,BUSSEL J B.Identifying and treating refractory ITP:difficulty in diagnosis and role of combination treatment[J].Blood,2020,135(12):472-490.

    • [15] PODDA G,SCAVONE M,FEMIA E A,et al.Aggregometry in the settings of thrombocytopenia,thrombocytosis and antiplatelet therapy[J].Platelets,2018,29(12):644-649.

    • [16] GROZOVSKY R,BEGONjA A J,LIU K,et al.The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling[J].Nat Med,2015,21(12):47-54.

    • [17] BOSE P,VERSTOVSEK S.JAK2 inhibitors for myeloproliferative neoplasms:what is next?[J].Blood,2017,130(12):115-125.

    • [18] GRINFELD J,GODFREY A L.After 10years of JAK2V617F:disease biology and current management strategies in polycythaemia vera[J].Blood Rev,2017,31(12):101-118.

    • [19] BLAIR H A.Fedratinib:First Approval[J].Drugs,2019,79(12):1719-1725.

    • [20] PALMER J,MESAR.The role of fedratinib for the treatment of patients with primary or secondary myelofibrosis[J].Ther Adv Hematol,2020,11(12):1-7.

    • [21] BIRGEGARD G.The use of anagrelide in myeloproliferative neoplasms,with focus on essential thrombocythemia[J].Curr Hematol Malig Rep,2016,11(12):348-355.

    • [22] SAMUELSON B,CHAI-ADISAKSOPHA C,GARCIA D.Anagrelide compared with hydroxyurea in essential thrombocythemia:a meta-analysis[J].J Thromb Thrombolysis,2015,40(12):474-479.

    • [23] KAPUR R,ASLAM R,SPECK E R,et al.Thrombopoietin receptor agonist(TPO-RA)treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia(ITP)[J].Platelets,2020,31(12):399-402.

    • [24] KUTER D J.The biology of thrombopoietin and thrombopoietin receptor agonists[J].Int J Hematol,2013,98(12):10-23.

    • [25] WINER E S,SAFRAN H,KARASZEWSKA B,et al.Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy:a randomized,placebo-controlled phase 2 study[J].Int J Hematol,2017,106(12):765-776.

    • [26] CWIRLA S E,BALASUBRAMANIAN P,DUFFIN D J,et al.Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine[J].Science,1997,276(5319):1696-1699.

    • [27] KUTER D J.New thrombopoietic growth factors[J].Blood,2007,109(12):4607-4616.

    • [28] LIU D,MAMORSKA-DYGA A.Syk inhibitors in clinical development for hematological malignancies[J].J Hematol Oncol,2017,10(12):145.

    • [29] NEWLAND A C,SANCHEZ-GONZALEZ B,REJTO L,et al.Phase 2 study of efgartigimod,a novel FcRn antagonist,in adult patients with primary immune thrombocytopenia[J].Am J Hematol,2020,95(12):178-187.

    • [30] JIANG H,YU Z,DING N,et al.The role of AGK in thrombocytopoiesis and possible therapeutic strategies[J].Blood,2020,136(12):119-129.

  • 参考文献

    • [1] PATEL S R,HARTWIG J H AND ITALIANO J E,et al.The biogenesis of platelets from megakaryocyte proplatelets[J].J Clin Invest,2005,115(12):3348-3354.

    • [2] KAHR W H,LO R W,LING L,et al.Abnormal megakaryocyte development and platelet function in Nbeal2(-/-)mice[J].Blood,2013,122(19):3349-3358.

    • [3] LEVINE R L,PARDANANI A,TEFFERI A,et al.Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders[J].Nat Rev Cancer,2007,7(9):673-683.

    • [4] ETO K,KUNISHIMA S.Linkage between the mechanisms of thrombocytopenia and thrombopoiesis[J].Blood,2016,127(10):1234-1241.

    • [5] KILPIVAARA O,LEVINE R L.JAK2 and MPL mutations in myeloproliferative neoplasms:discovery and science [J].Leukemia,2008,22(10):1813-1817.

    • [6] BIANCHI E,NORFO R,PENNUCCI V,et al.Genomic landscape of megakaryopoiesis and platelet function defects[J].Blood,2016,127(10):1249-1259.

    • [7] MACHLUS K R,ITALIANO J E.The incredible journey:from megakaryocyte development to platelet formation[J].J Cell Biol,2013,201(6):785-796.

    • [8] MULLALLY A,LANE S W,BRUMME K,et al.Myeloproliferative neoplasm animal models[J].Hematol Oncol Clin North Am,2012,26(5):1065-1081.

    • [9] WERNIG G,MERCHER T,OKABE R,et al.Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model[J].Blood,2006,107(11):4274-4281.

    • [10] MORGAN K J,GILLILAND D G.A role for JAK2 mutations in myeloproliferative diseases[J].Annu Rev Med,2008,59:213-222.

    • [11] PLO I,BELLANNE-CHANTELOT C,MOSCA M,et al.Genetic alterations of the thrombopoietin/MPL/JAK2 axis impacting megakaryopoiesis[J].Front Endocrinol(Lausanne),2017,8:234.

    • [12] QUENTMEIER H,MACLEOD R A,ZABORSKI M,et al.JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders[J].Leukemia,2006,20(12):471-476.

    • [13] JOHNSON B,FLETCHER S J,MORGAN N V.Inherited thrombocytopenia:novel insights into megakaryocyte maturation,proplatelet formation and platelet lifespan[J].Platelets,2016,27(12):519-525.

    • [14] MILTIADOUS O,HOU M,BUSSEL J B.Identifying and treating refractory ITP:difficulty in diagnosis and role of combination treatment[J].Blood,2020,135(12):472-490.

    • [15] PODDA G,SCAVONE M,FEMIA E A,et al.Aggregometry in the settings of thrombocytopenia,thrombocytosis and antiplatelet therapy[J].Platelets,2018,29(12):644-649.

    • [16] GROZOVSKY R,BEGONjA A J,LIU K,et al.The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling[J].Nat Med,2015,21(12):47-54.

    • [17] BOSE P,VERSTOVSEK S.JAK2 inhibitors for myeloproliferative neoplasms:what is next?[J].Blood,2017,130(12):115-125.

    • [18] GRINFELD J,GODFREY A L.After 10years of JAK2V617F:disease biology and current management strategies in polycythaemia vera[J].Blood Rev,2017,31(12):101-118.

    • [19] BLAIR H A.Fedratinib:First Approval[J].Drugs,2019,79(12):1719-1725.

    • [20] PALMER J,MESAR.The role of fedratinib for the treatment of patients with primary or secondary myelofibrosis[J].Ther Adv Hematol,2020,11(12):1-7.

    • [21] BIRGEGARD G.The use of anagrelide in myeloproliferative neoplasms,with focus on essential thrombocythemia[J].Curr Hematol Malig Rep,2016,11(12):348-355.

    • [22] SAMUELSON B,CHAI-ADISAKSOPHA C,GARCIA D.Anagrelide compared with hydroxyurea in essential thrombocythemia:a meta-analysis[J].J Thromb Thrombolysis,2015,40(12):474-479.

    • [23] KAPUR R,ASLAM R,SPECK E R,et al.Thrombopoietin receptor agonist(TPO-RA)treatment raises platelet counts and reduces anti-platelet antibody levels in mice with immune thrombocytopenia(ITP)[J].Platelets,2020,31(12):399-402.

    • [24] KUTER D J.The biology of thrombopoietin and thrombopoietin receptor agonists[J].Int J Hematol,2013,98(12):10-23.

    • [25] WINER E S,SAFRAN H,KARASZEWSKA B,et al.Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy:a randomized,placebo-controlled phase 2 study[J].Int J Hematol,2017,106(12):765-776.

    • [26] CWIRLA S E,BALASUBRAMANIAN P,DUFFIN D J,et al.Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine[J].Science,1997,276(5319):1696-1699.

    • [27] KUTER D J.New thrombopoietic growth factors[J].Blood,2007,109(12):4607-4616.

    • [28] LIU D,MAMORSKA-DYGA A.Syk inhibitors in clinical development for hematological malignancies[J].J Hematol Oncol,2017,10(12):145.

    • [29] NEWLAND A C,SANCHEZ-GONZALEZ B,REJTO L,et al.Phase 2 study of efgartigimod,a novel FcRn antagonist,in adult patients with primary immune thrombocytopenia[J].Am J Hematol,2020,95(12):178-187.

    • [30] JIANG H,YU Z,DING N,et al.The role of AGK in thrombocytopoiesis and possible therapeutic strategies[J].Blood,2020,136(12):119-129.

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