临床资料
患者,男性,48岁。以“肺结核治疗2个月,黑便7d”于2021年12月24日入住柳州市人民医院。患者2个月前因咳嗽咳痰就诊于外院,完善相关检查后诊断为继发性肺结核,于2021年10月23日开始2H-R-E-Z/4H-R方案抗结核治疗(H:异烟肼;R:利福平;E:乙胺丁醇;Z:吡嗪酰胺),期间定期门诊复诊血常规、肝肾功能,末次复诊时间为2021年12月1日,均未见异常,且血小板计数为231×109/L[正常值(100~300)×109/L]。7d前出现解黑色糊状便,每次量约100~200g,每日3~5次,伴倦怠乏力,病情逐渐加重。1d前出现发热,体温38.4℃,伴畏寒寒颤,无明显咳嗽咳痰,再次于外院就诊,血常规显示血红蛋白为39g/L(正常值130~175g/L),血小板计数为1.0×109/L,因病情严重遂转至我院。患者既往体健,无特殊病史。
患者入院时体温37.8℃,脉搏130次/min,呼吸频率 20次/min,血压72/36mm Hg(1mm Hg=0.133kPa),呈休克昏迷状态,面色苍白,肢端冰冷,皮肤黏膜未见出血点。双肺呼吸音粗,双下肺可闻及少许湿性啰音,未闻及心脏杂音,腹软,肝脾肋下未触及,移动性浊音阴性,双下肢无水肿。入院后血常规示:白细胞计数为18.81×109/L[正常值(3.5~9.5)×109/L]、血红蛋白为27g/L、血小板计数为1×109/L、C-反应蛋白为50.7mg/L(正常值0~6mg/L);胸部CT扫描示:双肺感染,考虑继发性肺结核可能,纵隔及肺门淋巴结钙化,双侧胸膜增厚粘连。入院后患者反复发热、解黑色糊状便,考虑消化道出血合并肺部及腹腔感染可能,予美罗培南抗感染、艾司奥美拉唑加强抑酸护胃、生长抑素抑制消化液分泌等治疗,同时输注红细胞(入院当日输注7U,次日输注5U)及血小板(1个治疗量,1次/d)治疗。考虑患者在H-R-E-Z方案抗结核治疗后出现血小板降低和白细胞升高,可能为继发感染或利福平致免疫性血小板减少,故在加强抗感染的同时予以静脉滴注人免疫球蛋白20g(1次/d)冲击治疗,但因患者反复解黑色糊状便,考虑急性上消化道出血,暂未使用糖皮质激素治疗。
12月25日,患者仍为嗜睡状态,血压稍有好转,为84/52mm Hg;血常规示:白细胞计数为34.43×109/L、血红蛋白为30g/L、血小板计数为1×109/L,遂转入感染科重症监护病房。转入后行急诊胃镜可见胃体大弯3处明显糜烂,胃体下部糜烂伴出血。予7枚钛夹夹闭出血灶,退镜时未再发现渗血。骨髓细胞形态学结果报告:涂片以成熟中性粒细胞为主,有核细胞少,血小板减少,建议观察。12月26日,患者神志恢复清醒,生命体征转好,体温36.8℃、脉搏102次/min、呼吸频率20次/min、血压88/54mm Hg,复查血红蛋白为51g/L,患者大便次数较前减少,考虑患者已行胃镜下止血,遂加用甲泼尼龙琥珀酸钠40mg(1次/d)治疗。继续输注红细胞(入院第3天输注5U,第5天输注1.5U)及血小板(1个治疗量,1次/d)。12月31日,复查血红蛋白为80g/L,血小板计数为2×109/L。
2022年1月1日,患者病情进一步平稳,体温36.5℃,脉搏80次/min,呼吸频率20次/min,血压124/84mm Hg,转入普通病房。考虑患者已进入抗结核治疗巩固期,遂调整治疗方案为异烟肼+乙胺丁醇+阿米卡星,剂量同前,因人免疫球蛋白已使用1周而血小板无任何上升趋势遂停用,继续甲泼尼龙琥珀酸钠40mg(1次/d)。患者体温恢复正常,复查血常规示:白细胞计数由最高值34.43×109/L降至6.08×109/L,C-反应蛋白由50.7mg/L降至22.45mg/L,遂以头孢曲松替换美罗培南抗感染。1月4日复查血小板计数为1×109/L,显示患者血小板无上升反而较前下降,经科内讨论后仍考虑为利福平致免疫性血小板减少,可能是前期治疗中未能完全清除患者血浆中的利福平依赖性抗体,故重新静脉滴注人免疫球蛋白10g(1次/d)治疗。1月6日,复查血红蛋白为81g/L,血小板计数上升为17×109/L,考虑治疗有效,继续静脉滴注人免疫球蛋白,剂量调整为15g(1次/d)。1月9日,复查血红蛋白为87g/L,血小板计数上升为64×109/L,停用人免疫球蛋白治疗。患者血红蛋白、血小板计数稳步上升,1月12日复查血红蛋白为97g/L,血小板计数为87×109/L,甲泼尼龙琥珀酸钠减量为20mg(1次/d)静脉滴注维持治疗。1月15日复查血红蛋白为98g/L,血小板计数为167×109/L,患者病情稳定,予异烟肼、阿米卡星、乙胺丁醇、醋酸泼尼松(20mg,1次/d)带药出院。
1月24日,复诊血红蛋白为125g/L、血小板计数为266×109/L,停用醋酸泼尼松片,继续抗结核药物治疗,方案同前。2月23日,复诊血红蛋白为131g/L、血小板计数为262×109/L,继续抗结核治疗,血小板稳定。治疗过程中血小板计数变化趋势见图1。
图1
讨论
免疫性血小板减少是一种获得性自身免疫性出血性疾病,以孤立性外周血血小板计数减少为特点,临床表现可为无症状性血小板减少、皮肤黏膜出血、致命性内脏出血。国外报道的成人免疫性血小板减少的年发病率为(2~10)/万,60岁以上老年人是高发群体[1]。药物诱导的免疫性血小板减少症通常发生在初始药物暴露后5~10d内,血小板计数通常低于20×109/L。药物诱导的免疫性血小板减少症的诊断要点基本包含以下5点[3]:(1)暴露于该药前血小板计数正常;(2)停止使用该药后血小板计数能持续恢复在正常状态;(3)该药是发生血小板减少前唯一使用的影响血小板的药物,或停用该药后重新使用其他药物,血小板计数能持续维持在正常水平;(4)排除其他原因引起的血小板减少;(5)再次暴露于该药时血小板计数再次减少。
既往研究显示,利福平是药物诱导的免疫性血小板减少最常见的药物之一,利福平作为利福霉素类半合成的广谱抗菌药物,对多种病原菌有抗菌活性[4,5],其作用机制为利福平作为半抗原,结合蛋白质或附着在细胞膜上刺激机体产生抗体,利福平在体内与抗体结合形成抗原抗体复合物,并与血小板表面表达的MHC Ⅰ类抗原结合,在补体参与下导致血小板损伤破坏[6]。利福平还可以结合血小板膜上GPⅡb/Ⅲa的钙依赖性抗原决定簇,使血小板功能降低,进而导致出血[7]。本例患者在使用H-R-E-Z方案抗结核治疗近2个月时突然发现血小板严重减少,同时伴有消化道出血,考虑抗结核药物中异烟肼或利福平可能引起血小板减少[8],且以利福平引起免疫介导的血小板减少最为常见,因此该例患者最先考虑血小板减少为利福平导致,考虑患者已进入抗结核治疗巩固期,又及吡嗪酰胺常见高尿酸血症、胃肠道反应、肝功能损伤等不良反应,遂停用利福平和吡嗪酰胺,在患者病情稳定后调整抗结核治疗方案为异烟肼、乙胺丁醇及阿米卡星,患者未再出现血小板减少。综合患者治疗过程,该例患者血小板严重降低可归因于利福平诱导的免疫性血小板减少。提示在抗结核治疗过程中应积极监测血常规,一旦发现血小板减少,应高度怀疑利福平相关,积极停用利福平,观察病情发展。
既往研究表明,药物诱导的免疫性血小板严重减少且伴出血,在无禁忌证的情况下,高剂量的免疫球蛋白和糖皮质激素的使用是治疗的关键,必要时配合输血治疗,但对于具体剂量及疗程尚未有统一共识[9]。Thaler等[10]报道了1例药物诱发的免疫性血小板减少伴皮下出血的成功治疗,早期使用大剂量的人免疫球蛋白(1g/kg)及泼尼松龙(0.75mg/kg)治疗,患者皮下出血逐渐停止,在住院4d后血小板计数恢复接近正常水平,之后人免疫球蛋白及泼尼松龙逐渐减量,患者血小板计数仍保持正常,未再出现出血现象。这可能与早期大剂量静脉滴注人免疫球蛋白有效阻止了血小板抗体的激活有关[11]。Chen和He[12]报道了1例使用H-R-E-Z方案抗结核治疗1周后出现鼻出血、血便及血尿的病例,血常规检查显示血小板低至0.4×109/L,在连续静脉滴注4d新鲜冰冻血浆及血小板治疗无效后,于第5天时予大剂量静脉滴注人免疫球蛋白治疗,在使用5d后患者出血停止,8d后血小板逐渐回升。另有研究表明,间歇不规律用药更容易触发利福平作为抗原附着在血小板表面形成抗原抗体免疫复合物,继而激活补体造成血小板内皮损伤这一超敏反应[13]。Hamad等[14]报道了1例使用利福平抗结核治疗3周后出现严重血小板减少,予甲泼尼龙琥珀酸钠1000mg 静脉滴注冲击治疗1次,之后以80mg 1次/d口服序贯治疗,血小板计数在第4天时缓慢回升。在既往的报道中多数病例在停药及治疗后1周内血小板计数即可恢复[3, 10, 12],然而,也有少数利福平诱导免疫性血小板减少的报道,发现即使经过高剂量的免疫球蛋白和糖皮质激素、输血等治疗,患者病情仍旧会进展出现脑出血而死亡[4, 6]。故本例患者在使用人免疫球蛋白静脉滴注1周时停用,再次复查时患者血小板无任何上升反而下降,经科内讨论后继续予以人免疫球蛋白治疗5d,患者血小板得以回升,避免了颅内出血风险。
消化内镜检查通常要求血小板计数在50×109/L以上才是相对安全的,即使患者血小板计数未达到50×109/L,至少也必须在20×109/L以上且在输注血小板后才可进行内镜检查,这样才可避免内镜操作过程中的出血风险[15]。但是本例患者由于入院前已反复解黑便1周,出血时间较长,出血量较大,入院时血常规提示极重度贫血,存在失血严重致失血性休克、危及生命的危险,在药物治疗无效、病情危急、患者家属同意的情况下冒险行胃镜下止血治疗,手术顺利,止血成功。患者经反复输血、加强抗感染、其他止血治疗,以及使用人免疫球蛋白和糖皮质激素治疗2周后血小板计数缓慢上升,病情稳定,好转出院。
综上,利福平诱导的免疫性血小板减少症发生率不高,但发病时病情重、进展快、死亡率高,抗结核药物治疗过程中应定期监测血常规,做到早发现、早治疗;在无禁忌证的情况下早日使用免疫球蛋白及糖皮质激素治疗,并配合输血治疗以提高救治成功率。
(本文编辑:孟莉)
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作者贡献
莫炳东:文章撰写和修改,资料整理; 莫胜林和张鹏:资料收集和整理;蒋忠胜:知识性把关
参考文献
成人原发免疫性血小板减少症诊断与治疗中国指南(2020年版)
Pathophysiology and Diagnosis of Drug-Induced Immune Thrombocytopenia
Drug-associated thrombocytopenia
Many drugs have been implicated in drug-induced immune thrombocytopenia (DITP). Patients with DITP develop a drop in platelet count 5 to 10 days after drug administration with an increased risk of hemorrhage. The diagnosis of DITP is often challenging, because most hospitalized patients are taking multiple medications and have comorbidities that can also cause thrombocytopenia. Specialized laboratory diagnostic tests have been developed and are helpful to confirm the diagnosis. Treatment of DITP involves discontinuation of the offending drug. The platelet count usually starts to recover after 4 or 5 half-lives of the responsible drug or drug metabolite. High doses of intravenous immunoglobulin can be given to patients with severe thrombocytopenia and bleeding. Although in most cases, DITP is associated with bleeding, life-threatening thromboembolic complications are common in patients with heparin-induced thrombocytopenia (HIT). Binding of antiplatelet factor 4/heparin antibodies to Fc receptors on platelets and monocytes causes intravascular cellular activation, leading to an intensely prothrombotic state in HIT. The clinical symptoms include a decrease in platelet counts by >50% and/or new thromboembolic complications. Two approaches can help to confirm or rule out HIT: assessment of the clinical presentation using scoring systems and in vitro demonstration of antiplatelet factor 4/heparin antibodies. The cornerstone of HIT management is immediate discontinuation of heparin when the disease is suspected and anticoagulation using nonheparin anticoagulant. In this review, we will provide an update on the pathophysiology, diagnosis, and management of both DITP and HIT.© 2018 by The American Society of Hematology. All rights reserved.
1例利福平致严重血小板减少并脑出血死亡的分析
Severe rifampicin-induced thrombocytopenia in a patient with miliary tuberculosis
药源性血小板减少症导致1例死亡病例分析
RITP患者血浆中利福平依赖性抗血小板抗体的特性及其作用机制
The dilemma in a case of immune thrombocytopenia in a patient with human immunodeficiency virus on antituberculosis treatment for miliary pulmonary tuberculosis
Case of Vancomycin-Induced Immune Thrombocytopenia
Successful treatment of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)
Immune Thrombocytopenia
Rifampicin-induced disseminated intravascular coagulation in pulmonary tuberculosis treatment: A case report and literature review
Recurrent disseminated intravascular coagulation caused by intermittent dosing of rifampin
Rifampin Induced Thrombotic Thrombocytopenic Purpura
Safety of endoscopy in cancer patients with thrombocytopenia and neutropenia
Cancer patients are prone to thrombocytopenia and neutropenia, which increase the risk of bleeding and infection. We assessed the safety of endoscopic procedures in cancer patients with thrombocytopenia and/or neutropenia.We studied consecutive cancer patients with thrombocytopenia and/or neutropenia who underwent endoscopic procedures from 2010 through 2015. Neutropenia was defined as an absolute neutrophil count (ANC) <1000 cells/μL, and thrombocytopenia as a platelet count <100 × 10/μL. Univariate and multivariate generalized estimating equation models were used to assess factors associated with risk of adverse events (AEs) or death.We identified 588 patients who underwent 783 procedures; 608 procedures were performed in the setting of thrombocytopenia and 675 procedures in the setting of neutropenia. Concurrent neutropenia and thrombocytopenia were recorded in 500 endoscopies. Twenty-four patients (4.1%) experienced infectious AEs, whereas 29 (4.9%) experienced bleeding AEs within 1 week of the procedure. On multivariate analysis, platelet count ≤50 × 10/μL was associated with risk of bleeding AEs. In contrast, poor performance status was associated with increased risk of infection AEs (P <.01). No association was observed between low ANC and infectious AEs. Poor performance status (P <.01) and platelet count ≤100 × 10/μL (P <.05) were associated with increased risk of 30-day mortality. A persistent platelet count <20 × 10/μL after the procedure, with a baseline platelet count of ≤20 × 10/μL before the procedure, was associated with significant risk of bleeding AEs compared with a platelet count >20 × 10/μL after the procedure (P <.01); furthermore, if the platelet count increased to >50 × 10/μL after the procedure, the bleeding risk after the procedure was greatly reduced (P <.01).Endoscopic procedures are relatively safe in cancer patients with platelet count >50 × 10/μL. Nevertheless, a platelet count of ≥20 × 10/μL could be an appropriate threshold for platelet transfusion if 50 × 10/μL is difficult to achieve. The functional status of the patient, in the absence of the need for urgent or necessary endoscopic interventions, should be considered when deciding whether to perform endoscopy. The risk of procedure and the ANC did not seem to affect the outcomes.Copyright © 2019 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.
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