Prevalence of neuropsychiatric symptoms and stroke in patients with hereditary thrombotic thrombocytopenic purpura

TO THE EDITOR:

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare (0.5-2.0 patients per 10⁶ population) autosomal recessive disorder caused by a severe deficiency of ADAMTS13, a plasma metalloprotease that cleaves ultralarge von Willebrand factor (ULVWF).¹ The persisting ULVWF multimers can create von Willebrand factor–platelet microthrombi causing microvascular thrombosis and organ ischemia.¹ The clinical features of hTTP are extremely diverse. Some patients appear to have excellent health, whereas others may die soon after birth or have major morbidities.^2,3 Patients with immune-mediated TTP (iTTP) often have disorders of cognitive function, depression,^4-10 and silent cerebral infarctions during clinical remission.^11-14 Stroke is also frequent in patients who have reduced ADAMTS13 activity (median, 43%) during remission following iTTP.¹⁵ Aims of the present study were to determine the neurological long-term effects in patients with hTTP by documenting their rates of stroke, stroke-related disability, and presence of neuropsychiatric symptoms.

Patients living in the United States who had enrolled and previously consented to participate in the International hTTP Registry³ were contacted to schedule an interview. Those interested signed a new consent to participate in this study. Hereditary TTP was confirmed in all patients by identification of biallelic pathogenic ADAMTS13 mutations and ADAMTS13 activity <10%. Author A.B. interviewed the patients and/or parents of minors by telephone for 30 to 60 minutes using discussion guides specific for young children (≤6 years old), older children (7-17 years), or adults (≥18 years old). Participants were asked about neuropsychiatric symptoms (Table 1) and stroke, the age they occurred, and residual symptoms or disability. The occurrence of stroke was accepted from the patients’ descriptions of symptoms, diagnostic evaluations, diagnosis conveyed to them bytreating physicians, and clinical course. Participants were also asked about prophylaxis, when it began, and any adverse reactions. The interview questions regarding hospitalizations,prophylaxis, and stroke are detailed in supplemental Table 1, available on the Blood Web site. Neuropsychiatric symptoms were compared between patients with or without history of stroke.

As of July 2021, 45 US patients with confirmed hTTP had been enrolled into the International hTTP Registry. Twelve previously enrolled US patients had been lost to follow-up, 2 died, and 4 did not consent (supplemental Figure 1). Twenty-seven patients from 17 US states were interviewed between April 2020 and July 2021: 25 adults (ages 19-63 years, median age, 38 years) and 2 children (ages 20 months and 12 years). The participants were predominantly female (70%) and white (89%) and had a college or postgraduate education (72%) (supplemental Table 2). The patients’ sex, mutations, number of strokes, age of first symptoms, diagnosis, and follow-up are presented in supplemental Table 3. Twenty-five of 26 (96%) patients (excluding the infant) reported 2 to 14 (median, 6) of the 14 neuropsychiatric symptoms (Table 1). Symptom onset occurred across all ages. Common symptoms were recurrent headaches (88%), poor concentration (65%), and depression (62%). Headache with aura (presumed migraine) was reported by 15 (58%) patients. Only dysarthria was more common in patients with a history of stroke (Table 1). The symptoms were often described as beginning during “childhood,” during “high school,” or after a significant hTTP event, such as a hospitalization. These data suggest that patients of all ages are at risk for neuropsychiatric symptoms.

Strokes had occurred in 17 (63%; 95% confidence interval, 42%-81%) patients. The median age of the first stroke was 26 years (range, newborn to 58 years); the occurrence increased with age (Figure 1). All 6 patients whose age was ≥49 years had had a stroke. In 12 patients, stroke preceded the diagnosis of hTTP. Three of the 12 patients were diagnosed at the time of their first stroke; the other 9 patients were diagnosed with hTTP 2 months to 19 years after their first stroke. Eleven of the 17 patients had residual symptoms; 7 suffered recurrent strokes. Seven patients have received stroke-related disability benefits, beginning at a median age of 43 years (18-55 years) (supplemental Table 4).

Twenty-five (93%) patients had received plasma for treatment of symptoms or for prophylaxis; 21 patients described allergic reactions to plasma: rash/itching (14), dyspnea/chest pain (4), anaphylaxis (2), or infection (1 [hepatitis C]) (supplemental Table 5). Seventeen (63%) of the 27 patients were on prophylaxis at the time of interview: 12, plasma; 5, pdFVIII. Prophylaxis was begun at age 2 months to 63 years (median, 30 years) and continued for a duration of 1 to 53 years (median, 4.5 years). None of the 17 patients were on prophylaxis at the time of their first stroke. Of the 7 patients with recurrent strokes, none received prophylaxis at the time of their second stroke but were subsequently placed on prophylaxis. Four of those 7 had another stroke while on prophylaxis. Five patients who switched to pdFVIII from plasma reported improved convenience of self-administration.

Like patients in remission from iTTP, almost all patients with hTTP have neuropsychiatric symptoms. Our data emphasize that patients with hTTP have life-altering neuropsychiatric symptoms beginning at young ages that continue throughout their lives. The occurrence of neuropsychiatric symptoms must be confirmed in future studies using standardized assessments, such as the Repeatable Battery for the Assessment of Neuropsychological Status for cognitive decline and the Patient Health Questionnaire-9, for depression.^4-7 The impact of the neuropsychiatric symptoms on the patients’ lives must be described by qualitative evaluation.¹⁶ 

Fifty-eight percent of patients had headaches with aura, presumed migraine. Previous studies have demonstrated that migraine with aura is an independent risk factor for stroke, especially cryptogenic ischemic stroke,¹⁷ and is associated with silent brain infarcts.¹⁸ The high frequency of strokes among patients with hTTP suggests that the neuropsychiatric symptoms may be caused by silent cerebral infarction, similar to patients with iTTP.^11-14 The overall occurrence of stroke was 63%, more than twice the rate from prior reports, possibly because the median age of our patients is >10 years older than in prior reports,^2,3 because patients with stroke may be more likely to be enrolled in the Registry and to participate in this study, or because of the small size of this study. Strokes often preceded the diagnosis of hTTP. Therefore, in patients with an embolic stroke of undetermined source,^19,20 measurement of ADAMTS13 activity is important.

Our data emphasize the significance of beginning effective, lifetime prophylaxis at a young age. Current common practice is to begin plasma prophylaxis when a major complication has occurred. We recommend a baseline cerebral magnetic resonance imaging at the first occurrence of neuropsychiatric symptoms to identify silent strokes and to document the need for prophylactic therapy.^11-14 However, the inconvenience of plasma administration and the frequent allergic reactions to plasma may cause hesitancy to begin prophylaxis and insufficient frequency once prophylaxis has begun. A report of the International hTTP Registry found no statistical difference in the frequency of acute episodes of hTTP in patients with or without prophylactic plasma.²¹ These observations highlight the limitations of current prophylaxis. Until recombinant ADAMTS13²² is available, an adequate amount of plasma (≥15 mL/kg) at frequent intervals (≤2 weeks) to maintain ADAMTS13 activity is appropriate.

Our data have significant limitations. The number of patients is small because hTTP is a rare disorder.¹ In addition, there is potential for selection bias, as enrollment into the International hTTP Registry requires motivation of the patient and awareness of the Registry by the patient’s hematologist.

Despite these limitations, our data document that almost all patients have neuropsychiatric symptoms, suggesting the need for regular cognitive and depression screening of hTTP and effective prophylaxis when abnormalities are identified.