ASPIRIN PROPHYLAXIS FOR HEREDITARY AND ACQUIRED THROMBOTIC THROMBOCYTOPENIC PURPURA?

To the Editor:

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 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).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.

Figure.

The Figure illustrates the sequence of reactions required for thrombosis in patients with thrombotic thrombocytopenic purpura (TTP). [1] VWF circulates in a coiled conformation. The platelet binding site on the von Willebrand factor (VWF) A1 domain is not exposed. [2] Circulatory turbulence causes uncoiling of VWF, exposing the A1 domain. [3] Platelet surface GPIbα binds to the A1 domain of VWF. Binding to the A1 domain initiates intracellular signaling to activate the platelet surface fibrinogen receptor, αIIbβ3. The intracellular signaling requires both GPIbα and its associated platelet surface protein, CLEC-2. [4] Plasma fibrinogen, because of its dimeric structure, binds to αIIbβ3 on adjacent platelets initiating aggregation and creating the platelet-VWF thrombosis. Although this sequence can happen in people without TTP (e.g., in the turbulent placental circulation of women with severe preeclampsia), the unusually large multimers of VWF in patients with TTP are much more thrombogenic.

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 intermittantly. 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 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.

Conclusion.

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.