本文選題：免疫性血小板減少癥 + 妊娠�。� 參考：《山東大學(xué)》2016年博士論文

【摘要】：免疫性血小板減少癥(immune thrombocytopenia, ITP)是臨床上最常見(jiàn)的出血性疾病,約占出血性疾病總數(shù)的30%。臨床表現(xiàn)主要為皮膚粘膜出血,以及胃腸道、泌尿生殖道出血甚至顱內(nèi)出血,嚴(yán)重者可能危及生命。目前公認(rèn)本病是一種獲得性自身免疫性疾病,血小板自身抗體和／或細(xì)胞毒性T淋巴細(xì)胞(CTL)所介導(dǎo)的血小板破壞增多和巨核細(xì)胞成熟障礙引起的血小板生成減少都在本病的發(fā)病機(jī)制中具有重要作用。妊娠期合并血小板減少是常見(jiàn)的妊娠期合并癥,其發(fā)病率約10%,可由多種疾病引起,以妊娠期血小板減少癥(gestational thrombocytopenia, GT)最常見(jiàn)；妊娠合并ITP亦是比較常見(jiàn)的原因,約占妊娠合并血小板減少的5%。妊娠期血小板減少癥是一種妊娠期的良性疾病,對(duì)孕婦和胎兒均無(wú)不良影響,臨床上一般無(wú)需進(jìn)行治療；而妊娠合并ITP則可能嚴(yán)重影響母體和胎兒健康,使妊娠及其處理復(fù)雜化。母體的IgG型抗血小板抗體可通過(guò)胎盤到達(dá)胎兒循環(huán),導(dǎo)致胎兒血小板減少及出血,表現(xiàn)為胎兒或新生兒的消化道及顱內(nèi)出血。因此,盡早鑒別和診斷妊娠合并ITP,并準(zhǔn)確評(píng)估孕婦和新生兒的出血風(fēng)險(xiǎn)及預(yù)后情況,對(duì)于疾病的及時(shí)治療和密切監(jiān)護(hù)具有重要意義。血小板生成素(thrombopoietin, TPO)能夠與c-Mpl受體特異性結(jié)合,進(jìn)而發(fā)揮生物學(xué)效應(yīng),調(diào)節(jié)巨核細(xì)胞增殖、分化、成熟,并分裂形成有功能的血小板。TPO主要在肝臟內(nèi)產(chǎn)生,進(jìn)入血液循環(huán)后,與血小板和巨核細(xì)胞表面的c-Mpl受體結(jié)合而被清除。由于功能正常的肝臟產(chǎn)生TPO的速度基本恒定,因此外周血TPO濃度主要被血小板計(jì)數(shù)調(diào)控,血小板計(jì)數(shù)越低,TPO水平越高。然而,近年來(lái)有多項(xiàng)研究發(fā)現(xiàn),ITP患者血清TPO水平略高于甚至不高于健康對(duì)照組；由于ITP患者血小板計(jì)數(shù)顯著降低,有學(xué)者認(rèn)為內(nèi)源性TPO生成不足為ITP發(fā)病機(jī)制之一。為了研究妊娠合并ITP患者與妊娠期血小板減少癥患者TPO水平是否存在差異,進(jìn)而討論TPO水平可否作為鑒別診斷妊娠合并ITP與GT的參考指標(biāo),并進(jìn)一步探討妊娠合并ITP的發(fā)病機(jī)制,我們研究了妊娠合并ITP患者、妊娠期血小板減少癥患者、正常妊娠女性、非妊娠期育齡女性ITP患者以及正常育齡女性的外周血血清TPO水平,以及妊娠合并ITP患者和非妊娠期育齡女性ITP患者的骨髓細(xì)胞學(xué)涂片。我們發(fā)現(xiàn),妊娠合并ITP患者的血清TPO水平顯著高于GT患者,在35位妊娠合并ITP患者中,29位患者的TPO水平高于500 pg/mL,而全部31位GT患者的血清TPO水平均低于500 pg/mL。因此,我們推測(cè),血清TPO水平可以作為鑒別診斷妊娠合并ITP與GT的參考指標(biāo),TPO水平高于500 pg/mL的妊娠女性患者極有可能為妊娠合并ITP患者,需要密切監(jiān)護(hù)和積極治療。另一方面,我們還發(fā)現(xiàn)妊娠合并ITP患者的血清TPO水平顯著高于非妊娠期育齡女性ITP患者。近年來(lái)多項(xiàng)研究證實(shí),巨核細(xì)胞不足所引起的血小板減少癥患者TPO水平顯著升高,而血小板破壞增多所引起的血小板減少癥患者TPO水平較低。因此,我們進(jìn)一步對(duì)比了妊娠合并ITP患者和非妊娠期育齡女性ITP患者的骨髓細(xì)胞學(xué)涂片,對(duì)比結(jié)果顯示,非妊娠期育齡女性ITP患者骨髓中巨核細(xì)胞數(shù)目正常或增多,而半數(shù)以上的妊娠合并ITP患者骨髓中巨核細(xì)胞數(shù)目減少。以上結(jié)果提示,妊娠合并ITP的發(fā)病可能與骨髓中巨核細(xì)胞產(chǎn)生血小板減少有關(guān),其發(fā)病機(jī)制可能與非妊娠期ITP不同。第一部分：妊娠合并ITP患者血清TPO水平及其鑒別診斷價(jià)值的研究目的：檢測(cè)妊娠合并ITP患者、妊娠期血小板減少癥患者及非妊娠期育齡女性ITP患者的外周血血清TPO水平,通過(guò)比較妊娠合并ITP患者與GT患者及與非妊娠ITP患者TPO水平的差異,分析TPO作為妊娠合并ITP與GT鑒別診斷參考指標(biāo)的可行性,并進(jìn)一步探討妊娠合并ITP的發(fā)病機(jī)制。方法：1.收集35例妊娠合并ITP患者、31例GT患者、32例正常妊娠女性、32例非妊娠期育齡女性ITP患者及35例正常育齡女性的外周血,檢測(cè)外周血血小板計(jì)數(shù),并分離血清備用。2.酶聯(lián)免疫吸附試驗(yàn)(ELISA)檢測(cè)血清中TPO的濃度。3.對(duì)23例妊娠合并ITP患者和27例非妊娠期育齡女性ITP患者行髂后上嵴骨髓穿刺,并進(jìn)行骨髓細(xì)胞學(xué)涂片,Wright-Giemsa染色,計(jì)數(shù)巨核細(xì)胞。4.改良單克隆抗體俘獲血小板抗原技術(shù)(MAIPA)檢測(cè)25例妊娠合并ITP患者及32例非妊娠期育齡女性ITP患者血漿中血小板自體抗體。結(jié)果：1.妊娠合并ITP患者血清TPO水平顯著高于GT患者。妊娠合并ITP組血清TPO水平顯著高于GT組(均數(shù)±標(biāo)準(zhǔn)差,1283±646 pg/mL vs.187±64 pg/mL,P0.01)；在35位妊娠合并ITP患者中,29位患者的TPO水平高于500 pg/mL,而全部31位GT患者的血清TPO水平均低于500 pg/mL。這些結(jié)果說(shuō)明,血清TPO水平可以作為鑒別診斷妊娠合并ITP與GT的參考指標(biāo),TPO水平高于500 pg/mL的妊娠女性患者更有可能為妊娠合并ITP患者。2.妊娠合并ITP患者血清TPO水平顯著高于非妊娠期育齡女性ITP患者。妊娠合并ITP組血清TPO水平顯著高于非妊娠期育齡女性ITP組(均數(shù)±標(biāo)準(zhǔn)差,1283±646 pg/mL vs.88±41 pg/mL,P0.01).3.大多數(shù)妊娠合并ITP患者骨髓巨核細(xì)胞數(shù)量減少。將骨髓細(xì)胞學(xué)涂片中每1到3個(gè)低倍視野見(jiàn)1個(gè)巨核細(xì)胞定義為巨核細(xì)胞數(shù)量正常,每個(gè)低倍視野2個(gè)巨核細(xì)胞為巨核細(xì)胞數(shù)量增多,每5到10個(gè)低倍視野見(jiàn)1個(gè)巨核細(xì)胞為巨核細(xì)胞數(shù)量減少�；谏鲜鰳�(biāo)準(zhǔn),在23例妊娠合并ITP患者中,14例(60.9%)巨核細(xì)胞數(shù)量減少,5例(21.7%)正常,4例(17.4%)增多；而在27例非妊娠期育齡女性ITP患者中,10例(37.0%)巨核細(xì)胞數(shù)量正常,17例(63.0%)增多。以上結(jié)果說(shuō)明,大多數(shù)妊娠合并ITP患者骨髓巨核細(xì)胞數(shù)量減少,而大多數(shù)非妊娠期育齡女性ITP患者骨髓巨核細(xì)胞數(shù)量增多,妊娠與非妊娠ITP發(fā)病機(jī)制可能存在差異。4.妊娠合并ITP患者與非妊娠期育齡女性ITP患者血小板抗體無(wú)顯著差異。改良MAIPA法檢測(cè)血小板抗體,將吸光度大于正常對(duì)照組均數(shù)+3倍標(biāo)準(zhǔn)差定義為抗血小板抗體陽(yáng)性。25例妊娠合并ITP患者和32例非妊娠期育齡女性ITP患者中,血小板抗體陽(yáng)性率分別為44.0%和62.5%,差異不具有顯著性(P0.05)。結(jié)論：1.妊娠合并ITP患者血清TPO水平顯著高于GT患者,TPO水平可作為兩種疾病鑒別診斷的參考指標(biāo)。2.妊娠合并ITP患者血清TPO水平顯著高于非妊娠期育齡女性ITP患者。3.大多數(shù)妊娠合并ITP患者骨髓巨核細(xì)胞數(shù)量減少,妊娠與非妊娠期ITP發(fā)病機(jī)制可能存在差異。第二部分：rhTPO治療對(duì)ITP患者血小板去唾液酸化調(diào)控作用的研究目的：通過(guò)檢測(cè)ITP患者和正常對(duì)照血小板去唾液酸化水平,分析ITP患者血小板去唾液酸化水平是否存在異常；檢測(cè)ITP患者在接受重組人血小板生成素(recombinant human thrombopoietin, rhTPO)治療前后的血小板去唾液酸化水平,并分析其與療效的關(guān)系。從而探討rhTPO用于ITP治療時(shí)可能存在的作用機(jī)制。方法：1.入組22例一線治療失敗或復(fù)發(fā)的慢性ITP患者,治療前收取患者外周血。同時(shí)入組24例健康志愿者作為正常對(duì)照,收取外周血,離心獲取血小板。2.對(duì)入組的慢性ITP患者給予重組人血小板生成素(rhTPO)治療(300U/kg/d),治療起效后或14天仍不起效時(shí)停止rhTPO治療,再次收取外周血,離心獲取血小板。3.用PE-Cy5-CD41a單克隆抗體標(biāo)記血小板,并同時(shí)使用FITC-RCA-1單克隆抗體標(biāo)記血小板表面去唾液酸化后所暴露的β-Gal殘基,流式細(xì)胞術(shù)檢測(cè)RCA-I的平均熒光強(qiáng)度,并以此反映血小板表面去唾液酸化水平。結(jié)果：1.接受rhTPO治療的慢性ITP患者,40.9%在14天內(nèi)達(dá)到完全反應(yīng)(complete response, CR)標(biāo)準(zhǔn)并停藥,31.8%在14天后達(dá)到反應(yīng)(response, R)標(biāo)準(zhǔn),27.3%在治療14天后仍無(wú)反應(yīng)(no response, NR)。rhTPO治療過(guò)程中,ITP患者均未出現(xiàn)嚴(yán)重不良反應(yīng)。2.ITP患者血小板去唾液酸化水平顯著高于正常對(duì)照組(P0.01)。3.接受rhTPO治療后,ITP患者血小板去唾液酸化水平降低,治療前后存在顯著性差異(P0.01)。結(jié)論：1.血小板去唾液酸化水平升高可能與ITP的發(fā)病機(jī)制有關(guān)。2. rhTPO用于ITP患者的治療安全且有效,并可顯著降低ITP患者的血小板去唾液酸化水平,這可能是rhTPO治療ITP的作用機(jī)制之一。
[Abstract]:Immune thrombocytopenia (ITP) is the most common haemorrhagic disease in clinical. The clinical manifestations of 30%., which account for the total number of hemorrhagic diseases, are mainly caused by bleeding of the skin and mucous membrane, as well as gastrointestinal tract, urogenital tract hemorrhage and even intracranial hemorrhage. Immune diseases, platelet autoantibodies and / or cytotoxic T lymphocyte (CTL) mediated platelet destruction and thrombocytopenia caused by megakaryocyte maturation disorders are all important in the pathogenesis of this disease. Pregnancy associated thrombocytopenia is a common complication of pregnancy, with an incidence of about 10%, Gestational thrombocytopenia (GT) is the most common cause of pregnancy induced thrombocytopenia (GT). Pregnancy combined with ITP is also a common cause of thrombocytopenia in pregnancy with thrombocytopenia. Thrombocytopenia in pregnancy is a benign disease of pregnancy. There is no adverse effect on pregnant women and fetus, and there is no need in clinical practice. The pregnancy combined with ITP may seriously affect the maternal and fetal health and complicate the pregnancy and its treatment. The maternal IgG antiplatelet antibody can reach the fetal circulation through the placenta, resulting in fetal thrombocytopenia and bleeding, as well as the digestive tract and intracranial hemorrhage of the fetus or newborn. Therefore, the early identification and diagnosis of pregnancy induced pregnancy Pregnancy with ITP, and accurately assessing the risk of bleeding and prognosis of pregnant and newborn babies, is of great significance for timely treatment and close monitoring of the disease. Thrombopoietin (TPO) can specifically combine with the c-Mpl receptor, and then play a biological effect, regulate megakaryocyte proliferation, differentiation, maturation, and split to form. The function of platelet.TPO is produced mainly in the liver. After entering the blood circulation, it is cleared with the c-Mpl receptor on the surface of the blood platelets and megakaryocytes. The rate of TPO in the normal liver is basically constant, so the concentration of TPO in the peripheral blood is mainly regulated by the platelet count, the lower the platelet count, the higher the TPO level. However, in recent years, the higher the TPO level. A number of studies have found that the level of serum TPO in ITP patients is slightly higher or not higher than that in the healthy control group. Due to the significant decrease in the platelet count in ITP patients, some scholars believe that endogenous TPO deficiency is one of the pathogenesis of ITP. In order to study the difference in the TPO level between the patients with pregnancy combined with ITP and the pregnancy stage of small plate reduction. Whether TPO level can be used as a reference index for differential diagnosis of pregnancy combined with ITP and GT, and to further explore the pathogenesis of pregnancy combined with ITP, we studied TPO water in peripheral blood serum of pregnant women with ITP, gestational thrombocytopenia, normal pregnancy, non pregnant women of childbearing age ITP and normal women of childbearing age. We found that the serum TPO level of patients with pregnancy combined with ITP and non pregnant women of childbearing age ITP was significantly higher than that of GT patients. In the 35 pregnancy combined with ITP, the level of TPO in 29 patients was higher than that of 500 pg/mL, while the serum TPO levels of all 31 patients were lower than those of 500 pg/mL.. Therefore, we speculate that serum TPO level can be used as a reference for differential diagnosis of pregnancy combined with ITP and GT. Women with TPO levels higher than 500 pg/mL are highly likely to be pregnant with ITP patients, requiring intensive care and active treatment. On the other hand, we also found that serum TPO levels in patients with pregnancy combined with ITP are significantly higher than those in non pregnancy. ITP patients of childbearing age. In recent years, a number of studies have confirmed that the level of TPO in patients with thrombocytopenia caused by megakaryocyte deficiency is significantly higher and the level of TPO in patients with thrombocytopenia caused by increased platelet destruction is lower. Therefore, we further compare the bone marrow of patients with ITP and non pregnant women of childbearing age ITP. Cytological smears showed that the number of megakaryocytes in the bone marrow of non pregnant women of childbearing age was normal or increased, and the number of megakaryocytes in bone marrow of more than half of the pregnant women with ITP decreased. The results suggested that the incidence of ITP in pregnancy may be related to the thrombocytopenia of megakaryocytes in the bone marrow, and the pathogenesis of the disease may be associated with the pathogenesis of ITP. It may be different from non pregnancy ITP. Part 1: the study of serum TPO level and differential diagnostic value of ITP patients with pregnancy: detection of TPO levels in peripheral blood serum of patients with pregnancy combined with ITP, gestational thrombocytopenia and non pregnant women of childbearing age ITP, by comparing pregnancy with ITP patients and GT patients and The difference in the level of TPO in the non pregnant ITP patients was analyzed, and the feasibility of TPO as a reference index for the differential diagnosis of pregnancy combined with ITP and GT was analyzed, and the pathogenesis of ITP in pregnancy was further explored. Methods: 1. a total of 35 pregnant women with ITP, 31 GT patients, 32 normal pregnant women, 32 non pregnant women of childbearing age and 35 normal childbearing were collected. The peripheral blood of the aged women, the peripheral blood platelet count, and the separation of serum.2. enzyme linked immunosorbent assay (ELISA) to detect the concentration of TPO in serum.3. were performed on 23 cases of pregnant women with ITP and 27 non pregnant women of childbearing age in the posterior superior iliac crest bone marrow puncture, and the bone marrow cytology smear, Wright-Giemsa staining, and megakaryocyte were counted by Wright-Giemsa staining. Cell.4. modified monoclonal antibody captive platelet antigen technique (MAIPA) was used to detect the blood platelet autoantibodies in 25 cases of pregnancy combined with ITP and 32 non pregnant women of childbearing age ITP. Results: the serum TPO level of the 1. pregnant ITP patients was significantly higher than that of the GT patients. The serum TPO level in the group ITP of pregnancy was significantly higher than that of the GT group. The standard deviation, 1283 + 646 pg/mL vs.187 + 64 pg/mL, P0.01). In 29 patients with ITP patients with 35 pregnancy, the level of TPO was higher than that of 500 pg/mL, and the serum TPO levels of all 31 GT patients were lower than 500 pg/mL.. The female patients with pregnant women were more likely to be significantly higher in serum TPO levels in patients with.2. pregnancy combined with ITP than in non pregnant women of childbearing age ITP. The serum TPO level of group ITP pregnant with pregnancy was significantly higher than that of non pregnant women of childbearing age ITP group (1283 + 646 pg/mL vs.88 + 41 pg/mL, P0.01) The number of megakaryocyte in bone marrow of TP patients decreased. 1 megakaryocytes were defined as megakaryocyte in 1 megakaryocytes in bone marrow smears and 1 megakaryocytes were defined as megakaryocyte, 2 megakaryocytes per low field of vision were megakaryocytes, and 1 megakaryocytes were reduced by 1 megakaryocytes for every 5 to 10 low fields. Based on the above criteria, 23 Among ITP patients with ITP, the number of megakaryocytes decreased, 5 cases (21.7%) were normal and 4 (17.4%) increased, while 10 (37%) megakaryocytes were normal and 17 (63%) increased in 27 non pregnant women of childbearing age ITP. The results showed that the number of megakaryocytes in most patients with ITP was reduced, and most of the megakaryocytes were reduced in most patients with ITP. The number of megakaryocyte in bone marrow of ITP patients in non pregnant women of childbearing age increased, and the pathogenesis of pregnancy and non pregnancy ITP may exist differences between.4. pregnancy and ITP patients and non pregnant women of childbearing age ITP. The improved MAIPA method was used to detect platelet antibody, and the absorbance was greater than that of normal control group +3 times standard difference. The positive rate of platelet antibody was 44% and 62.5% in.25 patients with ITP and 32 non pregnant women of childbearing age. The difference was not significant (P0.05). Conclusion: the level of TPO in the serum of ITP patients with 1. pregnancy was significantly higher than that of the GT patients, and TPO level could be used as a reference for the differential diagnosis of two diseases. Serum TPO level in.2. pregnancy combined with ITP patients was significantly higher than that in non pregnant women of childbearing age ITP patients with.3. and ITP patients, the number of megakaryocytes decreased, and there may be differences in ITP pathogenesis between pregnancy and non pregnancy. The second part: the study of rhTPO therapy on the regulation of blood acidification in ITP patients By detecting the level of acidification of the ITP patients and the normal control platelets, the abnormality of the blood platelet acidification level in ITP patients was analyzed, and the level of blood platelet acidification before and after the treatment of recombinant human thrombopoietin (rhTPO) with recombinant human thrombopoietin (rhTPO) was detected in patients with ITP, and the effect was analyzed and the effect was analyzed. To explore the possible mechanism of action of rhTPO for ITP treatment. Methods: 1. patients with 22 patients who had failed or relapsed in group 1. were treated to receive peripheral blood before treatment. At the same time, 24 healthy volunteers were enrolled as normal controls, receiving peripheral blood, and centrifugation to obtain platelet.2. for chronic ITP patients who were enrolled in the group. Group human thrombopoietin (rhTPO) therapy (300U/kg/d), the treatment of rhTPO after the onset of effect or 14 days was still not effective, the peripheral blood was collected again, the platelet.3. was centrifuged to mark platelets with PE-Cy5-CD41a monoclonal antibody, and the FITC-RCA-1 monoclonal antibody was used to mark the exposure of the beta -Gal residue after the acidification of the platelet surface. Base, flow cytometry was used to detect the average fluorescence intensity of RCA-I and to reflect the level of acidification on the surface of the platelets. Results: 1. of chronic ITP patients treated with rhTPO, 40.9% had complete response (complete response, CR) standards and stopped drugs within 14 days, 31.8% were 14 days after the reaction (response, R), 27.3% in 14 days after treatment. During the treatment of no response (NR).RhTPO, there was no severe adverse reaction in ITP patients with.2.ITP, the level of blood platelet acidification was significantly higher than that of the normal control group (P0.01).3. accepted rhTPO treatment, the level of platelet acidification decreased in ITP patients, and there was a significant difference before and after treatment (P0.01). Conclusion: 1. platelets are gone. The increase of salivary acidification level may be related to the pathogenesis of ITP..2. rhTPO is safe and effective for the treatment of ITP patients, and can significantly reduce the level of platelet sialic acidification in ITP patients, which may be one of the mechanisms of rhTPO for the treatment of ITP.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R714.25

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