Stroke is a common, critical complication and the major cause of morbidity for patients with hereditary thrombotic thrombocytopenic purpura (hTTP).^{1, 2} Patients with acquired autoimmune TTP (iTTP) also have a high risk for stroke and other thrombotic events during remission, especially when plasma ADAMTS13 activity is less than normal.^{3, 4} Current management of hTTP and of iTTP during remission is not sufficient for prevention of stroke and other thrombotic events.^1-4 The result is premature deaths among patients with hTTP¹ or iTTP.⁴

Although low-dose aspirin is effective for secondary prevention of stroke and other thrombotic events, it has been assumed that aspirin may not be effective for preventing stroke and thrombotic events in patients with TTP. Aspirin is effective because it prevents platelet aggregation by blocking the activation of the platelet fibrinogen receptor, αIIbβIII. However, it has been assumed that thrombosis in TTP may only require platelet GPIbα adhesion to von Willebrand factor (VWF), without subsequent platelet aggregation.

Our recent observations in a mouse model of TTP documented that adhesion of platelet GPIbα to VWF caused activation of the platelet fibrinogen receptor, αIIbβ3, allowing fibrinogen binding and initiation of platelet aggregation (Figure 1).⁵ Thrombus size was decreased by pre-treatment of mice with aspirin, which blocks the activation of αIIbβ3, or eptifibatide, which blocks binding of fibrinogen to αIIbβ3.⁵ Based on these experimental observations, we considered that aspirin may diminish the risk for stroke and other thrombotic events in patients with hTTP and in iTTP during remission.

Hereditary TTP (HTTP): In a review of case reports describing 226 patients with hTTP, 62 (27%) had strokes. The median age of stroke was 22 years; 13 (21%) of the 62 strokes occurred in children age ≤10 years. Fourteen patients developed end-stage kidney disease.¹ In telephone interviews with 27 United States patients enrolled in the International Hereditary TTP Registry, 17 (63%) had a history of stroke (median age, 26 years).² Eleven of these 17 patients had residual symptoms; 7 received disability support. In 4 of the 17 patients, strokes occurred while receiving plasma prophylaxis. Plasma prophylaxis commonly does not begin until a major morbidity occurs.¹ The current regimen of plasma prophylaxis is a major lifestyle burden and may not be effective for preventing symptomatic episodes and major morbidities.¹

Acquired autoimmune TTP (ITTP): Current management of acute episodes iTTP is very effective; deaths rarely occur. Once remission is achieved, the clinical course of iTTP is unpredictable and management becomes less certain. Low ADAMTS13 activity may persist during clinical remission or recur intermittently. Upreti, et al. reported that among 51 patients in remission, ADAMTS13 activity was always normal (≥70%) in 22 (43%) patients; none had stroke. Among the other 29 patients whose ADAMTS13 activity was at some time <70% (median ADAMTS13 activity among these 29 patients, 43%), 8 (28%) had strokes.³ The occurrence of stroke with lower ADAMTS13 activity is consistent with the Rotterdam Study of cardiovascular risk factors. Among 5941 participants in this study, the frequency of stroke in people in the lowest quartile of ADAMTS13 activity (≤81%) was 7.3%, twice the frequency of people in the highest quartile of ADAMTS13 activity (≥102%), 3.6%. Currently, patients whose ADAMTS13 activity is <20% during remission are treated with preemptive rituximab to prevent relapse. Patients with low ADAMTS13 activity during remission, but not <20%, currently receive no prophylactic treatment.

Data describing the efficacy and safety of low-dose aspirin prophylaxis in adults and children: Current data describing the efficacy and safety of low-dose aspirin (60–100 mg/day) prophylaxis are presented in the Supplement, which includes four tables (Tables S1–S4) and descriptive text, to this article. Table S1 shows the efficacy and bleeding risks of low-dose aspirin for the secondary prevention of stroke in older adults; Table S2 summarizes the increased risk for bleeding caused by low-dose aspirin among older adults; Table S3 shows the prevention of preeclampsia in pregnant women by low-dose aspirin (importantly, there was no excessive bleeding with low-dose aspirin); and Table S4 demonstrates the efficacy and safety of aspirin in children for secondary prevention of ischemic stroke and for the management of disorders with increased risk for thrombosis, which includes Sturge–Weber syndrome, Kawasaki disease, and antiphospholipid syndrome.

Could aspirin prophylaxis safely prevent stroke and other thrombotic events in patients with TTP?: Low-dose aspirin prophylaxis is effective for secondary prevention of stroke (Table S1) but has minimal benefit for primary prevention of cardiovascular events (Table S2). Prophylaxis in patients with TTP would be comparable to secondary prevention because the risk for stroke and other thrombotic events is great. Prophylaxis with low-dose aspirin for the prevention of cardiovascular events is associated with increased risk for major bleeding. The risk for bleeding is much greater in older patients (Table S2). Low-dose aspirin is effective for prevention of preeclampsia without increased bleeding (Table S3). The absence of increased bleeding with low-dose aspirin treatment during pregnancy may be because the age of pregnant women is much younger than the age of patients treated with low-dose aspirin for the prevention of stroke (Tables S2, S3).

The effectiveness of low-dose aspirin for secondary prevention of stroke and cardiovascular events and effective prevention of preeclampsia without increased bleeding support the efficacy and safety of aspirin prophylaxis in young patients with hTTP or iTTP in remission. Consideration of lifetime prophylactic aspirin for patients with hTTP requires understanding the potential risks for young children with TTP who have risk for stroke¹ and for whom there is less information about safety of aspirin. Table S4 provide our analysis of data supporting the effectiveness and safety of aspirin in children. These data are from reports of secondary prevention of ischemic stroke, prevention of stroke and seizures in Sturge–Weber syndrome, treatment of Kawasaki disease, and primary prevention of thrombosis in antiphospholipid syndrome.

Determining the efficacy and safety of aspirin for prevention of stroke: Although the rare occurrence hTTP (prevalence, 0.5–2.0/10⁶ population) and iTTP (incidence, 2/10⁶ population/year) would make a clinical trial difficult, a randomized trial of low-dose aspirin and placebo would be important to provide evidence supporting the efficacy and safety of aspirin for prevention of stroke in children and adults with hTTP and iTTP in remission. Stroke and other thrombotic events are common and critical complications for patients with hTTP and patients with iTTP in remission. For patients with hTTP, adequate ADAMTS13 replacement is the essential prophylaxis. The convenience and effectiveness of prophylaxis will be substantially improved with the future availability of recombinant ADAMTS13. Until recombinant ADAMTS13 is available, low-dose aspirin may effectively and safely supplement current plasma prophylaxis. For patients with iTTP, cardiovascular disease is the leading cause of premature death during remission.⁴ ADAMTS13 activity less than normal during remission not only increases risk for stroke³ but also may increase the occurrence of atherosclerois. Although aspirin was a standard treatment for acute episodes of iTTP before therapeutic plasma exchange became the standard treatment,⁶ aspirin has not been used for routine prophylaxis during remission. We believe that aspirin prophylaxis would be appropriate for patients in remission from iTTP who have decreased ADAMTS13 activity or risk factors for thrombosis such as obesity, tobacco use, diabetes, or hyperlipidemia. For patients with iTTP in remission who have low ADAMTS13 activity, aspirin prophylaxis may be simpler and safer than increasing the threshold for preventive treatment with rituximab. For all patients with hTTP or iTTP in remission, aspirin may provide effective, simple, and safe lifetime protection from stroke and other thrombotic events.

中风是遗传性血栓性血小板减少性紫癜（hTTP）患者常见的严重并发症，也是发病的主要原因。^{1, 2}患有获得性自身免疫性 TTP (iTTP) 的患者在缓解期间也有很高的中风和其他血栓事件风险，尤其是当血浆 ADAMTS13 活性低于正常水平时。^{3, 4}当前 hTTP 和缓解期间 iTTP 的管理不足以预防中风和其他血栓事件。^1-4结果是 hTTP ¹或 iTTP 患者过早死亡。⁴

尽管低剂量阿司匹林对于中风和其他血栓事件的二级预防有效，但人们认为阿司匹林可能无法有效预防 TTP 患者的中风和血栓事件。阿司匹林之所以有效，是因为它通过阻断血小板纤维蛋白原受体 αIIbβIII 的激活来防止血小板聚集。然而，人们认为 TTP 中的血栓形成可能只需要血小板 GPIbα 粘附到冯维勒布兰德因子 (VWF)，而不需要随后的血小板聚集。

我们最近在 TTP 小鼠模型中的观察表明，血小板 GPIbα 与 VWF 的粘附导致血小板纤维蛋白原受体 αIIbβ3 的激活，从而允许纤维蛋白原结合并引发血小板聚集（图 1）。⁵用阿司匹林预处理小鼠可减少血栓大小，阿司匹林可阻断 αIIbβ3 的激活，或依替巴肽可阻断纤维蛋白原与 αIIbβ3 的结合。⁵基于这些实验观察结果，我们认为阿司匹林可以降低 hTTP 患者和 iTTP 缓解期间发生中风和其他血栓事件的风险。

遗传性 TTP (HTTP)：在对描述 226 名 hTTP 患者的病例报告进行审查时，其中 62 名 (27%) 患有中风。中风的中位年龄为 22 岁；62 例中风中有 13 例（21%）发生在 10 岁以下的儿童中。十四名患者出现终末期肾病。¹在对国际遗传性 TTP 登记处登记的 27 名美国患者进行电话采访时，其中 17 名 (63%) 有中风病史（中位年龄为 26 岁）。²这17名患者中有11名有残留症状；7 人获得了残疾支持。17 名患者中有 4 名在接受血浆预防期间发生中风。血浆预防通常要等到重大发病发生后才开始。¹目前的血浆预防方案是主要的生活方式负担，并且可能无法有效预防症状发作和主要发病率。¹

获得性自身免疫性 TTP (ITTP)：目前对急性发作 iTTP 的治疗非常有效；死亡很少发生。一旦达到缓解，iTTP 的临床病程是不可预测的，治疗也变得不太确定。ADAMTS13 低活性可能在临床缓解期间持续存在或间歇性复发。乌普雷蒂等人。报道称，在 51 名缓解患者中，22 名 (43%) 患者的 ADAMTS13 活性始终正常 (≥70%)；没有人中风。在 ADAMTS13 活性在某个时间<70% 的其他 29 名患者中（这 29 名患者中 ADAMTS13 活性的中位数为 43%），其中 8 名（28%）患有中风。³ ADAMTS13 活性较低时卒中的发生与心血管危险因素鹿特丹研究一致。在这项研究的 5941 名参与者中，ADAMTS13 活性最低四分位数 (≤81%) 的人群中风频率为 7.3%，是 ADAMTS13 活性最高四分位数 (≥102%) 人群中风频率 3.6% 的两倍。目前，缓解期间 ADAMTS13 活性<20% 的患者会先行利妥昔单抗治疗以预防复发。缓解期间 ADAMTS13 活性较低但不低于 20% 的患者目前未接受预防性治疗。

描述成人和儿童低剂量阿司匹林预防的有效性和安全性的数据：补充中提供了描述低剂量阿司匹林（60-100 毫克/天）预防的有效性和安全性的当前数据，其中包括四个表（表S1–S4）和描述性文本，参见本文。表S1显示了小剂量阿司匹林对老年人脑卒中二级预防的疗效和出血风险；表 S2 总结了老年人中低剂量阿司匹林引起的出血风险增加；表S3显示低剂量阿司匹林预防孕妇先兆子痫（重要的是，低剂量阿司匹林没有出现过多出血）；表 S4 表明阿司匹林在儿童中用于缺血性中风二级预防和治疗血栓形成风险增加的疾病（包括斯特奇-韦伯综合征、川崎病和抗磷脂综合征）的有效性和安全性。

阿司匹林预防能否安全预防 TTP 患者中风和其他血栓事件？：低剂量阿司匹林预防对中风二级预防有效（表 S1），但对心血管事件一级预防益处甚微（表 S2）。TTP 患者的预防与二级预防相当，因为中风和其他血栓事件的风险很大。使用低剂量阿司匹林预防心血管事件会增加大出血的风险。老年患者出血的风险要大得多（表 S2）。低剂量阿司匹林可有效预防先兆子痫，且不会增加出血（表 S3）。怀孕期间使用小剂量阿司匹林治疗没有增加出血可能是因为孕妇的年龄比使用小剂量阿司匹林预防卒中的患者年龄小得多（表S2、S3）。

小剂量阿司匹林对中风和心血管事件二级预防的有效性以及在不增加出血的情况下有效预防先兆子痫的有效性支持阿司匹林预防治疗年轻 hTTP 或 iTTP 缓解期患者的有效性和安全性。^{考虑对 hTTP 患者终身预防性服用阿司匹林，需要了解患有 TTP 的幼儿的潜在风险，他们有1 型}中风的风险，并且有关阿司匹林安全性的信息较少。表 S4 提供了我们对支持阿司匹林对儿童的有效性和安全性的数据的分析。这些数据来自缺血性中风的二级预防、斯特奇-韦伯综合征中的中风和癫痫发作的预防、川崎病的治疗以及抗磷脂综合征中的血栓形成的一级预防的报告。

确定阿司匹林预防中风的功效和安全性：虽然罕见的 hTTP（患病率，0.5–2.0/10 ⁶人群）和 iTTP（发病率，2/10 ⁶人群/年）会使临床试验变得困难，但随机小剂量阿司匹林和安慰剂的试验对于提供证据支持阿司匹林预防 hTTP 和 iTTP 缓解期儿童和成人中风的有效性和安全性非常重要。中风和其他血栓事件是 hTTP 患者和缓解期 iTTP 患者常见且严重的并发症。对于 hTTP 患者，充足的 ADAMTS13 替代是必要的预防措施。随着重组 ADAMTS13 的未来上市，预防的便利性和有效性将得到显着提高。在重组 ADAMTS13 上市之前，低剂量阿司匹林可以有效且安全地补充当前的血浆预防疗法。对于 iTTP 患者来说，心血管疾病是缓解期间过早死亡的主要原因。⁴缓解期间 ADAMTS13 活性低于正常水平不仅会增加^{3 型}中风的风险，还可能增加动脉粥样硬化的发生。尽管在治疗性血浆置换成为标准治疗之前，阿司匹林是 iTTP 急性发作的标准治疗方法，但⁶阿司匹林尚未用于缓解期间的常规预防。我们认为，阿司匹林预防适用于 iTTP 缓解期、ADAMTS13 活性降低或血栓形成危险因素（如肥胖、吸烟、糖尿病或高脂血症）的患者。对于 ADAMTS13 活性较低的 iTTP 缓解期患者，阿司匹林预防可能比提高利妥昔单抗预防性治疗阈值更简单、更安全。对于所有 hTTP 或 iTTP 缓解期患者，阿司匹林可以提供有效、简单且安全的终生保护，预防中风和其他血栓事件。