Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD)

Seventeen patients who developed hepatic veno-occlusive disease (VOD) following hematopoietic stem cell transplantation were treated with recombinant tissue plasminogen activator (rtPA) with or without heparin. rtPA was started a median of 13 days post transplant (range 4-35). All patients received rtPA at a dose of 10 mg/day as a starting dose, and 12 patients also received heparin (1500 U bolus; then 100 U/kg/day as a continuous i.v. infusion). The median number of days of rtPA therapy was 2.5 (1-12). The median total serum bilirubin level was 116 mmol/l (range 63-194) at the beginning of treatment. Six patients showed a response to rtPA treatment (29%). It was observed that by day 2 of rtPA therapy, bilirubin levels in responders showed a downwards trend as compared to those in nonresponders. In all except one patient this response was observed after two doses of rtPA. Seven out of the 11 non-responders had a past history of liver dysfunction, compared with none of the responders. There were no differences between the two groups in terms of day of onset of liver dysfunction, manifestations of disease, maximum bilirubin and creatinine levels, and day of commencing treatment. No patient experienced severe hemorrhagic complications during therapy. Four responders survived for more than 100 days compared to none of the non-responders. Probability of survival was 33% at day 100. It is difficult to unequivocally establish the role of rtPA in the treatment of VOD. The importance of bilirubin levels on days 2 or 3 of therapy in predicting outcome should be established, as should the optimum dose of rtPA and optimum duration of therapy.     

含吡咯烷生物碱的中草药与肝小静脉闭塞病

目的 总结分析含吡咯烷生物碱(PAs)的中草药导致肝小静脉闭塞病(HVOD)的临床特点,提高对HVOD的病因及诊治认识.方法 对1980年至2006年国内报道的中草药导致HVOD病例10例,以及北京协和医院诊断的中草药导致HVOD 3例进行综合分析,并进行国内外相关文献复习.结果 国内报道的中草药致HVOD病例以土三七为主,占84.6%(11/13).土三七用量150 g～1 800 g(平均约582 g),用药持续时间10余天至4个月(平均42.5天);千里光致病者1例,嗜食茶叶致病者1例.HVOD临床症状主要为腹部胀痛、腹水、肝大、黄疸,可有不同程度的肝功能受损,多有GGT及ALP升高;超声下可见门脉血流减慢以及CT下不均匀脂肪肝样表现为其影像学特点;通过组织学诊断(9/13)和临床诊断(4/13).保守治疗好转者2例,肝移植2例,死亡5例.结论 含有吡咯烷生物碱的中草药是导致HVOD的一个重要原因,临床上应慎用此类药物.影像学检查有一定的特点,早期临床诊断对改善预后非常重要.     

Effect of low-molecular-weight heparin on recombinant tissue plasminogen activator-induced thrombolysis in canine pulmonary embolism.

We employed a canine model of pulmonary embolism induced by radioactive blood clots to determine if low-molecular-weight heparin augments recombinant tissue plasminogen activator (rtPA)-induced thrombolysis. Following embolization, dogs were randomized: group 1 dogs received heparin; group 2 dogs received low-molecular-weight heparin; group 3 dogs received 1.5 mg/kg of rtPA over 45 minutes; group 4 dogs received rtPA 3 mg/kg over 45 minutes; and group 5 dogs received 1.5 mg/kg of rtPA plus low-molecular-weight heparin. Over three hours, little thrombolysis occurred in groups 1 and 2. In contrast, significant thrombolysis occurred in groups 3 to 5, 46 percent, 49 percent, and 46 percent, respectively (all p less than 0.01 compared with groups 1 and 2). We conclude that there is an upper limit to the dose-thrombolytic rate relationship with rtPA, and that low-molecular-weight heparin does not augment rtPA-induced thrombolysis.     

肝小静脉闭塞病的临床现状及研究进展

肝小静脉闭塞病(hepatic veno-occlusive disease,HVOD)是造血干细胞移植(hematopoietic stemcell transplantation,HSCT)的主要并发症之一.其发病机制主要是局部高凝状态,主要病理改变是终末肝小静脉的闭塞及肝细胞的坏死.HVOD的确诊依靠肝组织活检.明确并避免危险因素是降低HVOD的发病率及死亡率的主要措施,药物预防效果尚不确切并且多有不良反应.HVOD的治疗以去纤苷的效果最为肯定,其他药物的疗效仍需验证.本文就HVOD的临床现状及研究进展作一综述.     

17例肝小静脉闭塞病患者的诊断和治疗

目的 总结肝小静脉闭塞病(HVOD)的诊断和治疗方法.方法 回顾性分析17例肝小静脉闭塞病的临床和病理资料. 结果根据影像学检查结果和临床及病理学资料,将肝小静脉闭塞病分为急性进展型和慢性型.其中急性进展型11例,经内科保守治疗,5例临床治愈,2例好转,2例死亡,手术治疗2例死亡,慢性型6例,经内科保守治疗1例,手术治疗5例,均达到临床治愈.结论 病理活组织检查是确诊肝小静脉闭塞病的有效方法.急性进展型的肝小静脉闭塞病宜内科保守治疗,慢性型在内科治疗无效的情况下可行手术治疗.     

Risk factors for hepatic veno-occlusive disease after high-dose busulfan-containing regimens followed by autologous bone marrow transplantation: a study in 136 children.

Risk factors for hepatic veno-occlusive disease (HVOD) were analysed in a population of 136 autografted children who received high-dose busulfan (BU) as part of a conditioning regimen. HVOD was diagnosed according to McDonald's clinical criteria. The incidence of HVOD was particularly high in this series (22%) compared with series with other conditioning regimens but the outcome was favorable in 26 patients (87%). Four deaths occurred (13%), one of which was HVOD related. The clinical presentation of HVOD was similar to that described in previous reports. Although statistical analysis failed to demonstrate any factors predictive of outcome, it did identify risk factors for the occurrence of HVOD: these were (1) a total dose of BU exceeding the standard 16 mg/kg dose; (2) the use of three as opposed to two alkylating agents; (3) the sequence of BU administration when given in the conditioning regimen containing three alkylating agents; and (4) concomitant ketoconazole therapy.     

超声联合剪切波弹性成像在经颈静脉肝内门体分流术治疗肝小静脉闭塞病的初步研究

目的分析超声联合实时剪切波弹性成像技术(shear wave elastography,SWE)在经颈静脉肝内门体分流术(transjugular intrahepatic portosystemic shunt,TIPS)治疗肝小静脉闭塞病(hepatic venoocclusive disease,HVOD)中的应用价值。 方法回顾性分析南京大学医学院附属南京鼓楼医院2014年9月至2017年4月,经TIPS手术治疗的32例HVOD患者的临床资料,采用彩色多普勒超声检测HVOD患者术前及术后门静脉内径及流速、脾静脉内径及流速;SWE检测患者术前及术后的肝脏及脾脏的SWV值。 结果TIPS治疗前患者门静脉和脾静脉内径正常、流速减低;肝、脾脏SWV值较高。治疗后,门静脉和脾静脉内径无明显变化,流速显著提高,差异均有统计学意义(P均<0.05);治疗后肝脏SWV值显著下降,差异有统计学意义(P<0.05);治疗后脾脏SWV值下降明显,差异有统计学意义(P<0.05)。 结论超声联合SWE检查能较好的评价TIPS治疗HVOD的疗效。     

Successful treatment with danhong injection for hepatic veno-occlusive disease

Hepatic veno-occlusive disease (HVOD) is a clinical syndrome characterized as hepatomegaly, ascites, jaundice and elevation of hepatic enzymes as an outcome from fibrous obliteration of small centrilobular hepatic venules. It is recognized as a rare but life-threatening complication of organ transplantation, tumor eradication chemotherapy and is associated with haematopoietic stem cell transplantation (SCT). Recent researches report that ingestion of plants which contain pyrrolizidine alkaloids (PAs) is associated with the onset of HVOD with unclear pathogenesis. Nowadays, there is no effective therapeutic strategy for HVOD besides supportive care using diuretics or albumin. In our case, a 42-year-old woman administered a concoction of Chinese traditional medicine supposed to contain PAs, was found to develop HVOD confirmed by liver biopsy. A therapeutic strategy was developed using Danhong injection, accompanied with supportive care, and obtained a favorable response manifesting as regression of symptoms and decline of hepatic enzymes. Danhong injection, a Chinese medical product exerting a milder anticoagulation and antithrombotic effect, is beneficial to HVOD probably by promoting microcirculation, ameliorating liver function and inhibiting hepatic fibrosis.     

A case report of hepatic veno-occlusive disease after ingesting dainties

INTRODUCTION Hepatic veno-occlusive disease (HVOD) is a rarely encountered ailment in the literature[1,2]. The establishment of the diagnosis of this condition can be very difficult because there is no specificity in the clinical manifestations and some c…     

异基因外周血干细胞移植治疗白血病的临床观察

目的:观察同胞供者异基因外周血干细胞移植(allo-PBSCT)治疗白血病的疗效及并发症.方法:分析11例白血病患者行同胞供者HLA相合allo-PBSCT治疗的临床资料.供者干细胞动员用粒细胞集落刺激因子(G-CSF),用CS-3000血细胞分离机采集外周血干细胞.患者用改良马利兰加环磷酰胺(Bu/CY)为预处理方案,用环孢菌素A(CSA)+短程甲氨蝶呤(MTX)+霉酚酸酯(MMF)方案预防移植物抗宿主病(GVHD),用前列腺素E1(凯时)+低分子肝素预防肝静脉闭塞病(HVOD),用美司钠预防出血性膀胱炎(HC).结果:获得单个核细胞数(MNC)的中位数为8.3(4.5～13.0)×108/kg;CD34+细胞计数的中位数为6.2(2.4～12.4)×106/kg.10例患者获得造血重建,白细胞和血小板植活的中位数时间均为15(13 ～ 18)d;1例患者干细胞未植入.并发症:发生感染11例,GVHD 8例,HVOD 3例,HC 1例.中位随访15.5(1 ～39)个月,生存率为63.6％(7例),无病存活率为54.5％(6例);4例死亡.结论:同胞供者allo-PBSCT是治疗白血病一种有效手段,移植相关并发症主要为感染、GVHD、HVOD.     

中草药致肝小静脉闭塞病11例临床分析

目的评估各种常规临床检测方法对中草药所致肝小静脉闭塞病（HVOD）的诊断价值,并探寻评价疾病转归及预后的方法。方法采用回顾性研究方法,分析我院近3年间服用中草药所致11例HVOD的临床表现、生化指标和影像学特点。结果所有患者均有明确用药史,7例患者服用土三七,2例患者服用雷公藤,2例患者服用不明中草药,CT对HVOD的诊断有重要意义,死亡4例患者均为重型患者。结论我国肝小静脉闭塞病的诊断应重视患者用药史,HVOD患者的疾病分型对病情评估有重要意义。     

Association of hepatic veno-occlusive disease with interstitial pneumonitis in bone marrow transplant recipients

Hepatic veno-occlusive disease (HVOD) and interstitial pneumonitis (IP) are both widely regarded as toxicities of intensive cytoreductive therapy, but their association has not been previously examined. Risk factors for IP were evaluated in 154 patients given intensive cytoreductive therapy followed by allogeneic bone marrow transplantation during a 2 1/2 year period. IP occurred in 68 patients; HVOD occurred in 39. The actuarial incidence of IP in patients with VOD was 71% and 45% in those without VOD (p = 0.0002). In multivariate analysis, the diagnosis of hematologic malignancy (p less than 0.001), the occurrence of HVOD (p less than 0.01), and pretransplant CMV seropositivity (p less than 0.02) were significantly associated with IP. The individual relative risks for IP of presence to absence of these factors was 4.5 for the diagnosis of hematologic malignancy, 2.1 for HVOD, and 1.9 for CMV seropositivity. Pulmonary veno-occlusive disease (PVOD), a previously rare observation, was noted at autopsy in 1/5 (20%) patients with HVOD alone, 6/20 (30%) patients with IP alone, and 10/14 (71%) of patients with both HVOD and IP. The association of HVOD and IP is supportive of the concept that toxic effects of cytotoxic therapy have a major role in pathogenesis of HVOD and IP.     

Early thrombolytic treatment reduces analgesic requirement in patients with myocardial infarction

The duration and amount of analgesics required were investigated in 67 patients with myocardial infarction treated with intravenous recombinant tissue-type plasminogen activator (rtPA) or placebo in a randomized double-blind trial. Infusion of rtPA (100 mg)/placebo was started within 5 h after the onset of symptoms, and the requirement for analgesics during the following 48 h was recorded. Sixty-seven per cent of the 30 rtPA-treated patients required analgesic treatment for less than 6 h, compared to 38% of the 37 patients in the placebo group (P = 0.04). During the study period, patients in the rtPA group used the equivalent of 5.3 mg (median value) intravenous morphine, which was significantly less than the 11.2 mg used in the placebo group (P = 0.04). In conclusion, the present study suggests that early thrombolysis with intravenous rtPA reduces the amount and duration of analgesic treatment required by patients with myocardial infarction.     

依达拉奉联合重组组织型纤溶酶原激活剂治疗急性缺血性卒中的汇总分析

目的 评价依达拉奉联合重组组织型纤溶酶原激活剂(recombinant tissue plasminogen activator,rtPA)治疗急性缺血性卒中的有效性和安全性.方法 计算机检索Cochrane注册试验数据库(Central Register of Controlled Trials,CENTRAL)、EMbase、Pubmed、中国生物医学文献数据库(China Biology Medicine disc,CBM disc)、中国期刊全文数据库(Chinese Journal Full-text Database,CJFD)、万方数据库(Wanfang Data)和维普信息资源系统(VIP),选择有关依达拉奉联合rtPA静脉溶栓治疗急性缺血性卒中的随机对照试验(randomized controlled trial,RCT)和队列研究(截止2015年12月).由2名评价员按照纳入和排除标准独立筛选文献、提取资料和评价纳入研究的方法学质量.应用改良Jadad量表评价RCT,4～7分为高质量;应用纽卡斯尔-渥太华量表评价队列研究,5～9颗星为高质量.应用ReVman 5.2软件对高质量研究进行汇总分析.结果 共纳入1项RCT和2项队列研究,共881例患者,其中rtPA联合依达拉奉367例(试验组),单用rtPA 474例(对照组).汇总分析显示,试验组临床转归显著优于对照组(相对危险度1.28,95％可信区间1.03 ～1.60;P=0.02),且未显著增高颅内出血发生率(相对危险度1.49,95％可信区间0.71 ～3.14;P=0.08).结论 依达拉奉联合rtPA静脉溶栓治疗能显著改善急性缺血性卒中患者的临床转归,且不良反应少.     

肝小静脉闭塞病研究进展

肝小静脉闭塞病(HVOD)缺乏特异治疗,重症患者常因多脏器功能衰竭而死亡,通过危险因素的分析有效避免其发生或在发病早期及时识别以早期干预至关重要。近年来对HVOD的诊断和防治取得了一定进展,此文对此作一综述。     

土三七所致肝小静脉闭塞病102例临床分析

目的总结分析土三七所致肝小静脉闭塞病（HVOD）的临床特点,提高对本病的认识。方法对1980年1月至2009年12月国内报道的土三七所致HVOD病例102例进行综合分析,并对国内外相关文献进行复习。结果患者土三七使用量150～5000 g（中位数500 g）,服药时间4 d～1年（中位时间30 d）,临床主要表现为腹胀（99.0%）、腹痛（69.6%）、肝大（93.5%）、腹水（97.7%）、黄疸（63.5%）,有不同程度的肝功能受损。B超检查见肝静脉显示不清,肝段下腔静脉外形变细,但无明显栓塞物,彩色多普勒提示门脉血流减慢或逆向,增强CT示肝脏呈＂地图状＂强化不均匀。病理学表现为肝窦淤血、扩张,流出道受阻,肝细胞不同程度变性、坏死,小叶中央静脉内皮水肿或纤维增生。经内科治疗好转69.7%（62/89）,未愈或死亡30.3%（27/89）,另13例转归不详。使用抗凝或活血化瘀者有效率为81.0%,较未用者（47.8%）,疗效差异有统计学意义（P=0.002）。结论土三七是导致HVOD的一个重要原因,影像和病理检查具有特征性,早期诊断及使用抗凝、活血治疗对改善预后有一定作用。     

Heparin-induced thrombocytopenia in pediatrics.

As in adult patients, heparin is used for prophylaxis and treatment of thromboembolism in newborns, children, and adolescents. Patients receiving heparin are potentially at risk to develop heparin-induced thrombocytopenia (HIT). HIT type II has been extensively described in the adult population; only a few reports address HIT type II in pediatric patients (total of 15 neonates, 4 young children, 12 older children and adolescents). The available data are discussed, and the case of a patient with recurrent thrombosis and HIT type II without thrombocytopenia is presented. The review of the literature reveals that HIT type II occurs especially in neonates and adolescents, corresponding to the two age peaks of thrombosis in pediatric patients. Risk factors for thrombosis include hereditary factors, immobilization, and surgery. HIT complications are severe and partly lead to life-threatening thromboembolism. In three patients, an increasing heparin demand was found. In five cases, thrombocytopenia was absent. Heparin was replaced mostly by danaparoid sodium; in three patients hirudin was used as an alternative anticoagulant. HIT type II represents a potentially dangerous complication of heparin therapy in pediatric patients and should be taken into consideration whenever heparin is given for prophylactic or therapeutic use in newborns, children, or adolescents.     

Subcutaneous unfractionated heparin for the treatment of venous thromboembolism

PURPOSE OF REVIEW: When unfractionated heparin is used to treat acute venous thromboembolism, it is usually given by intravenous infusion with dose adjustment in response to activated partial thromboplastin time measurements. These two requirements are a barrier to treatment of venous thromboembolism with unfractionated heparin, and it is uncertain if they are necessary. RECENT FINDINGS: Two recent studies compared subcutaneous unfractionated heparin and subcutaneous low-molecular-weight heparin, each given twice-daily, for the acute treatment of venous thromboembolism. The Galilei study used an initial dose of unfractionated heparin that was partially weight-adjusted, with subsequent dosing based on activated partial thromboplastin time results. The FIDO study treated patients with a first dose of unfractionated heparin of 333 IU/kg, followed by 250 IU/kg twice-daily without dose adjustment in response to the activated partial thromboplastin time or other coagulation tests. There was no difference in either study between the unfractionated heparin and low-molecular-weight heparin groups at the end of 3 months, for recurrent venous thromboembolism (Galilei: 4.2 vs. 3.9%; relative risk (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.2. FIDO: 3.8 vs. 3.4%; RR 1.1, 95% CI 0.5 to 2.3) or major bleeding (Galilei: 1.4 vs. 1.9%; RR 0.7, 95% CI 0.2 to 2.2. FIDO: 1.7 vs. 3.4%; RR 0.5, 95% CI 0.2 to 1.3). SUMMARY: Recent studies suggest that twice-daily subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for the acute treatment of venous thromboembolism, and that adjustment of unfractionated heparin dose in response to activated partial thromboplastin time measurements is not necessary with a weight-adjusted dose of unfractionated heparin.     

Risk factors for hepatic veno-occlusive disease: a retrospective unicentric study in 116 children autografted after a high-dose BU-thiotepa regimen

At our Institute, during the last decade, the incidence of hepatic veno-occlusive disease (HVOD) appears to be on the increase among pediatric patients treated with BU-thiotepa (BU-TTP)-conditioning regimen. We thus performed a retrospective analysis to identify the risk factors for HVOD, which could explain such a change. In total, 116 patients treated at Institut Gustave Roussy, between May 1998 and December 2005 were eligible for this study having received BU-TTP as their first high-dose chemotherapy regimen, followed by autologous hematopoietic SCT (AHSCT). According to McDonald's clinical criteria, HVOD was diagnosed in 31% of these children. Demographic, clinical, biological and therapeutic parameters were evaluated in uni- and multivariate analyses that showed a significant correlation between previous carboplatin therapy and risk of developing post transplant HVOD (P=0.028). Comparable results were found for etoposide (P=0.048). In addition, a correlation between HVOD and risk of post transplant death was linked to its association with other types of organ failure (P=0.029). This study demonstrates that previous VPCARBO administration in conventional chemotherapy significantly increases the risk of HVOD among brain tumor patients later consolidated with BU-TTP followed by AHSCT.     

土三七致肝小静脉闭塞病诊断及治疗体会

目的 探讨肝小静脉闭塞病(hepatic veno-occlusive disesse,HVOD)的诊断及治疗效果.方法 回顾性分析我院3例土三七致HVOD患者的临床和病理特征.结果 所有患者以腹胀、腹水和肝肿大为主要表现.2例患者的组织病理学表现为肝窦扩张、瘀血、肝索挤压、萎缩、肝细胞变性坏死.结论 土三七所致肝小静脉闭塞病临床表现无特殊性,肝穿是重要的诊断方法.