1 CASE PRESENTATION

A 26-year-old female with a history of chronic urticaria (treated with omalizumab in the past) and recently treated chlamydia trachomatis infection presented to an outside emergency department after a syncopal episode. She endorsed a three-day history of nausea, vomiting, fatigue, and ecchymoses. Initial laboratory analysis revealed macrocytic anemia (hemoglobin 4.6 g/dL) with a mean corpuscular volume (MCV) of 100.7 fL, thrombocytopenia (2000 plts/μL), indirect hyperbilirubinemia (indirect bilirubin 3.7 mg/dL), lactate dehydrogenase (LDH) 1245 units/L, absolute reticulocyte count of 0.237 million/μL, haptoglobin 1 mg/dL, international normalized ratio (INR) 1.2 and creatinine 0.75 mg/dL. Peripheral blood smear identified numerous spherocytes and microspherocytes, true thrombocytopenia, and increased reticulocytes without evidence of erythrocyte fragmentation (Figure 1). Direct antiglobulin testing (DAT) was positive for IgG (2+) and C3 (2+) at 37°C, although quantitative analysis was not performed. She received one unit of packed red blood cells and one unit of platelets and was transferred to our institution for further evaluation.

This patient presented with profound thrombocytopenia and hemolytic anemia as evidenced by elevated LDH, elevated reticulocyte count, decreased haptoglobin, and indirect hyperbilirubinemia. The lack of schistocytes or evidence of erythrocyte fragmentation on peripheral smear as well as positive DAT was consistent with Evans syndrome—warm autoimmune hemolytic anemia (AIHA) with concomitant immune thrombocytopenia (ITP). Evans syndrome can arise spontaneously (primary) or secondary to diseases that generate autoantibodies. Etiologies may include infections, autoimmune disorders, lymphoproliferative disorders, or pregnancy.

On physical exam, the patient was well-appearing. She was afebrile with the remainder of her vital signs within normal limits. Physical examination was only notable for mild gingival bleeding. No rashes, petechiae, purpura, or ecchymoses were identified. She conversed appropriately and was oriented to person, location, and time. She had not received a blood product transfusion prior to this admission. She did not have a history of pregnancy. Family history was pertinent for Hashimoto's thyroiditis in her mother.

Overall, the patient appeared clinically well. She reported mild and nonspecific infectious symptoms including malaise, nausea, and emesis after recent domestic travel with her family. No other family members reported similar symptoms. Additionally, she lacked red flag signs and symptoms for malignancy or autoimmune disease including weight loss, night sweats, lymphadenopathy, myalgias, arthralgias, and rash. Nevertheless, broad workup for underlying infectious etiology, autoimmune disease and malignancy was pursued.

Infectious workup included negative bacterial blood cultures, EBV, CMV, HIV, HSV-1, HSV-2, HHV-6, hepatitis A, B, and C serologies and gastrointestinal pathogen panel. Autoimmune labs were negative for antinuclear antibodies (ANA) as well as antibodies against double-stranded DNA, Sjögren's-syndrome-related antigen A (SSA), Sjögren's-syndrome-related antigen B (SSB), and Smith. Thyroid function tests were within normal limits. Peripheral blood flow cytometry was sent given concern for atypical lymphocytes on further review of peripheral smear as well as hepatomegaly (22 cm in craniocaudal dimension) as noted on computed tomography (CT) abdominal imaging. Flow cytometry and positron emission tomography were both negative for a malignant process.

The above workup for secondary precipitants of Evans syndrome was unrevealing. Thus, idiopathic AIHA with concomitant ITP was most likely. As such, the patient was started on intravenous immunoglobulin (IVIG, 1 mg/kg) and high dose prednisone (1 mg/kg).

Her hemoglobin responded appropriately to transfusions, but her platelet count remained low despite high-dose steroids and IVIG. On day three of hospital admission, the patient endorsed acute onset headaches and new right arm weakness. On hospital day four, she was found to be obtunded. Urgent neurologic imaging was obtained with head CT negative for acute hemorrhage. Brain magnetic resonance imaging (MRI) demonstrated cortical hypoxia raising concern for encephalitis or seizures. She was transferred to the medical intensive care unit (MICU) for neurologic monitoring.

This acute change in clinical status now raised high suspicion for a life-threatening, alternate diagnosis. With new onset neurologic manifestations, thrombotic microangiopathies (TMAs)—most notably, thrombotic thrombocytopenic purpura (TTP)—ascended on the differential as a diagnosis that must be considered. Thus, the medical team reconsidered critical data that argued against MAHA—the positive DAT results and lack of erythrocyte fragmentation on peripheral smear.

On presentation, the patient lacked hallmark manifestations of TTP including fever and encephalopathy. However, the classic pentad of fever, anemia, thrombocytopenia, renal, and neurologic symptoms is rarely observed.¹ Patients often present with few of these symptoms or nonspecific symptoms that mimic other etiologies. Furthermore, neurologic manifestations of TTP range from mild confusion to acute ischemic stroke in greater than 60% of patients.^{2, 3} Prompt diagnosis and treatment are tantamount, as without therapy, mortality rates approach 90%.⁴ Even with timely plasma exchange (PLEX) and corticosteroids, mortality remains 10%–15%.⁴

The PLASMIC score is a validated, clinical diagnostic tool that aids clinicians in assessing the likelihood of severe a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency.⁵ Notably, the PLASMIC score is only validated in those with TMAs. Thus, although the patient had a PLASMIC score of 6 on admission—placing her in the high-risk category for TTP (with a 72% risk of severe ADAMTS13 deficiency)—her peripheral smear lacked clear evidence of intravascular hemolysis indicative of a MAHA.⁶ Thus, empiric PLEX was deferred. Nevertheless, ADAMTS13 activity level was sent stat on admission; results were pending.

Additional examination of her peripheral smear on day four of hospitalization demonstrated many nucleated erythrocytes, acanthocytes, and atypical lymphocytes (Figure 2). Still, no schistocytes were noted. ADAMTS13 activity level returned undetectable and identified an ADAMTS13 inhibitor (anti-ADAMTS13 antibodies) at a titer of 2.5. Urgent PLEX was initiated, and high-dose corticosteroids continued. A peripheral blood smear from the subsequent day revealed increased numbers of schistocytes (Figure 3). After two sessions of PLEX, her hemoglobin, platelets, LDH, and total bilirubin all improved. With further PLEX sessions, her hemoglobin reached 10.3 g/dL, platelets reached 248 000 plts/μL, LDH 337 units/L, indirect bilirubin 0.2 mg/dL. Her mental status gradually returned to baseline. Her ADAMTS13 level improved from undetectable to 63% after four sessions of PLEX. Her DAT continued to remain positive for IgG and C3, though titers decreased from 2+ to only weakly positive.

This case underscores the need for clinicians to consider alternative diagnoses in the face of new data and a rapidly changing clinical course. Persistent anemia and thrombocytopenia despite IVIG and prednisone with the development of new acute encephalopathy demanded an alternate diagnosis. Despite initial data supporting Evans syndrome, TMA—most particularly TTP—became much more likely. When ADAMTS13 activity returned undetectable, TTP was confirmed. PLEX treatment was swiftly initiated.

Despite continued PLEX, platelets precipitously dropped from 218 000 to 25 000 plts/μL within 3 days. LDH also increased from 365 units/L to 659 units/L. Rituximab 375 mg/m² weekly was added. Daily PLEX sessions continued. Interval ADAMTS13 testing again returned undetectable and identified an increase in ADAMTS13 inhibitor with a titer of 11.1. Thrombocytopenia continued to worsen, reaching a nadir of 14 000 plts/μL at which time caplacizumab was initiated for recalcitrant TTP. After 1 week of caplacizumab, her ADAMTS13 activity increased to 25% with undetectable ADAMTS13 inhibitor and normal hemoglobin and platelet count. A peripheral blood smear showed decreased number of schistocytes (Figure 4). Following 1 month of caplacizumab, ADAMTS13 activity fluctuated to 17%, but counts remained stable. Caplacizumab therapy was extended to 6 weeks and after also completing four weekly doses of rituximab, her ADAMTS13 improved to 21%.

中文翻译：

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伪装成 Evans 综合征的血栓性血小板减少性紫癜

 1 案例介绍

一名 26 岁女性，有慢性荨麻疹病史（既往接受过奥马珠单抗治疗）和最近接受过沙眼衣原体感染治疗，在晕厥发作后到室外急诊科就诊。她认可了 3 天的恶心、呕吐、疲劳和瘀斑病史。初步实验室分析显示大细胞性贫血 （血红蛋白 4.6 g/dL），平均红细胞体积 （MCV） 为 100.7 fL，血小板减少症 （2000 plts/μL），间接高胆红素血症 （间接胆红素 3.7 mg/dL），乳酸脱氢酶 （LDH） 1245 单位/L，网织红细胞绝对计数为 0.237 万/μL，结合珠蛋白 1 mg/dL，国际标准化比值 （INR） 1.2 和肌酐 0.75 mg/dL。外周血涂片发现许多球形红细胞和微球形红细胞，真正的血小板减少症和网织红细胞增加，没有红细胞碎裂的证据（图 1）。在 37°C 时，直接抗球蛋白检测 （DAT） 对 IgG （2+） 和 C3 （2+） 呈阳性，但未进行定量分析。她接受了 1 个单位的浓缩红细胞和 1 个单位的血小板，并被转移到我们机构进行进一步评估。

该患者表现为严重的血小板减少症和溶血性贫血，表现为 LDH 升高、网织红细胞计数升高、结合珠蛋白降低和间接高胆红素血症。外周血涂片上缺乏裂红细胞或红细胞碎裂的证据以及 DAT 阳性与 Evans 综合征一致——温热的自身免疫性溶血性贫血 （AIHA） 伴有免疫性血小板减少症 （ITP）。埃文斯综合征可自发（原发性）或继发于产生自身抗体的疾病。病因可能包括感染、自身免疫性疾病、淋巴组织增生性疾病或妊娠。

体格检查显示，患者一般状况良好。她不发热，其余生命体征在正常范围内。体格检查仅对轻度牙龈出血感兴趣。未发现皮疹、瘀点、紫癜或瘀斑。她交谈得体，并以人、地点和时间为导向。在入院前，她没有接受过血液制品输注。她没有怀孕史。家族史与她母亲的桥本氏甲状腺炎有关。

总体而言，患者临床表现良好。她报告了轻度和非特异性感染症状，包括近期与家人进行国内旅行后出现不适、恶心和呕吐。没有其他家庭成员报告类似的症状。此外，她没有恶性肿瘤或自身免疫性疾病的危险信号体征和症状，包括体重减轻、盗汗、淋巴结肿大、肌痛、关节痛和皮疹。尽管如此，还对潜在的感染性病因、自身免疫性疾病和恶性肿瘤进行了广泛的检查。

感染性检查包括细菌血培养阴性、EBV、CMV、HIV、HSV-1、HSV-2、HHV-6、甲型、乙型和丙型肝炎血清学和胃肠道病原体检查。自身免疫实验室的抗核抗体 （ANA） 以及针对双链 DNA、干燥综合征相关抗原 A （SSA）、干燥综合征相关抗原 B （SSB） 和 Smith 的抗体呈阴性。甲状腺功能检查在正常范围内。鉴于在进一步回顾外周血涂片时关注非典型淋巴细胞以及计算机断层扫描 （CT） 腹部成像所记录的肝肿大 （颅尾尺寸 22 cm），因此发送了外周血流式细胞术。流式细胞术和正电子发射断层扫描均对恶性过程呈阴性。

上述对 Evans 综合征继发性诱因的检查未见发现。因此，特发性 AIHA 伴有 ITP 最有可能。因此，患者开始静脉注射免疫球蛋白 （IVIG， 1 mg/kg） 和高剂量泼尼松 （1 mg/kg）。

她的血红蛋白对输血有适当的反应，但尽管使用了大剂量类固醇和 IVIG，她的血小板计数仍然很低。入院第 3 天，患者认可急性发作的头痛和新的右臂无力。在住院的第四天，她被发现反应迟钝。紧急神经系统影像学检查显示，头部 CT 急性出血阴性。脑磁共振成像 （MRI） 显示皮质缺氧，引起了对脑炎或癫痫发作的关注。她被转移到内科重症监护病房 （MICU） 进行神经系统监测。

这种临床状态的急剧变化现在引起了对危及生命的替代诊断的高度怀疑。随着新发神经系统表现，血栓性微血管病 （TMA） — 最明显的是血栓性血小板减少性紫癜 （TTP） — 作为必须考虑的诊断在鉴别诊断中上升。因此，医疗团队重新考虑了反对 MAHA 的关键数据——阳性 DAT 结果和外周血涂片上没有红细胞碎裂。

就诊时，患者缺乏 TTP 的标志性表现，包括发热和脑病。然而，很少观察到发热、贫血、血小板减少、肾脏和神经系统症状的典型五联征。¹ 患者通常很少出现这些症状或与其他病因相似的非特异性症状。此外，超过 60% 的患者的 TTP 神经系统表现范围从轻度意识模糊到急性缺血性卒中。^2、3及时诊断和治疗是等同的，因为如果不治疗，死亡率接近 90%。⁴ 即使及时进行血浆置换 （PLEX） 和皮质类固醇，死亡率仍为 10%-15%。⁴

PLASMIC 评分是一种经过验证的临床诊断工具，可帮助临床医生评估伴有血小板反应蛋白 1 型基序成员 13 （ADAMTS13） 缺乏症的严重 A 型解整合素和金属蛋白酶的可能性。⁵ 值得注意的是，PLASMIC 评分仅在 TMA 患者中得到验证。因此，尽管患者入院时的 PLASMIC 评分为 6 分——使她属于 TTP 的高危类别（严重ADAMTS13缺陷的风险为 72%）——但她的外周血涂片缺乏表明 MAHA 的血管内溶血的明确证据。⁶ 因此，经验 PLEX 被推迟了。尽管如此，ADAMTS13活动水平还是在入院时发送了统计数据;结果待定。

在住院第 4 天对她的外周涂片的额外检查显示许多有核红细胞、棘红细胞和非典型淋巴细胞（图 2）。尽管如此，仍未发现裂红细胞。ADAMTS13活性水平返回检测不到，并鉴定出滴度为 2.5 的 ADAMTS13 抑制剂 （抗 ADAMTS13 抗体）。开始紧急 PLEX，并继续大剂量皮质类固醇治疗。第二天的外周血涂片显示裂红细胞数量增加（图 3）。两次 PLEX 治疗后，她的血红蛋白、血小板、LDH 和总胆红素均有所改善。通过进一步的 PLEX 治疗，她的血红蛋白达到 10.3 g/dL，血小板达到 248 000 plts/μL，LDH 337 单位/L，间接胆红素 0.2 mg/dL。她的精神状态逐渐恢复到基线水平。经过四次 PLEX 治疗后，她的 ADAMTS13 水平从检测不到提高到 63%。她的 DAT 的 IgG 和 C3 继续保持阳性，尽管滴度从 2+ 下降到仅微阳性。

该病例强调，面对新数据和快速变化的临床过程，临床医生需要考虑替代诊断。尽管接受了 IVIG 和泼尼松龙治疗，但持续性贫血和血小板减少症伴随着新的急性脑病的发展，需要替代诊断。尽管初步数据支持埃文斯综合征，但 TMA（尤其是 TTP）的可能性要大得多。当ADAMTS13活动返回无法检测到时，确认了 TTP。PLEX 治疗迅速开始。

尽管持续进行 PLEX，但血小板在 3 天内从 218 000 plts/μL 急剧下降到 25 000 plts/μL。LDH 也从 365 单位/L 增加到 659 单位/L。增加了利妥昔单抗 375 mg/m² 周。每日 PLEX 会议仍在继续。间隔ADAMTS13检测再次检测不到，并发现 ADAMTS13 抑制剂增加，滴度为 11.1。血小板减少症继续恶化，达到 14 000 plts/μL 的最低点，此时 caplacizumab 开始治疗顽固性 TTP。卡普利珠单抗治疗 1 周后，她的ADAMTS13活性增加到 25%，ADAMTS13 抑制剂检测不到，血红蛋白和血小板计数正常。外周血涂片显示裂红细胞数量减少（图 4）。caplacizumab 治疗 1 个月后，ADAMTS13活性波动至 17%，但计数保持稳定。Caplacizumab 治疗延长至 6 周，在完成每周四次的利妥昔单抗治疗后，她的ADAMTS13改善至 21%。