Long-Term Follow-Up of 21 Patients with Thrombotic Thrombocytopenic Purpura (TTP) and Severe ADAMTS13 Deficiency: Demonstration of Persistent ADAMTS13 Deficiency and Neurocognitive Abnormalities.

Many patients who have recovered from TTP report cognitive abnormalities, often described as difficulty with attention, comprehension, and memory. These abnormalities have never been objectively documented. Also there have been reports of patients with continued abnormal ADAMTS13 activity following complete hematologic recovery; the frequency, duration, and clinical importance of persistent ADAMTS13 deficiency has not been described in a cohort of consecutive patients with long-term follow-up. To evaluate these unresolved issues, we measured neurocognitive function, ADAMTS13 activity, platelet count, and hematocrit (hct) in patients from the Oklahoma TTP-HUS Registry. The Registry has measured ADAMTS13 activity on 172/193 (89%) consecutive patients treated with plasma exchange for their initial episode of clinically diagnosed TTP-HUS from 11/13/1995 to 4/30/2003. 4/30/2003 was selected to assess patients with at least 1 year of follow-up after their initial episode. 29/172 (17%) patients with apparently acquired TTP had ADAMTS13 activity <10% at the onset of their initial episode; 22 patients survived. Although severe ADAMTS13 deficiency characteristic of TTP is usually defined as <5%, our 6 surviving patients with initial ADAMTS13 activity of 5–9% all had ADAMTS13 inhibitors; 2 have relapsed and had ADAMTS13 activity of <5% at the time of their 2nd episode. 21/22 patients, who have had follow-up of 0.25–8.25 years from their most recent episode, were evaluated. 9/21 (43%) patients have had between 1–4 relapses. None of the patients had symptoms or signs of TTP at the time of this assessment. The Rey Auditory-Verbal Learning Test (RAVLT) assesses new learning and recent memory. For new learning 11 (52%) patients and for recent memory 7 (33%) patients were below the 16^th percentile for age/gender specific norms (p<0.01 and p=0.03 respectively). The Digit Span (DS) score, which assesses attention and concentration, was below the 25^th percentile in 8 (38%) patients (p=0.17). 11/20 (55%) had moderate-severe depression symptoms documented by the Beck Depression Inventory-Second Edition (BDI–II) (8 patients) or by prescribed medication for depression (3 patients). ADAMTS13 activity was abnormal (<50%) in 11/21 patients (52%); 2 patients, who were 4.0 and 8.25 years from their most recent episode, had activity <3% with inhibitors; in the other 9 abnormal patients ADAMTS13 activity was 14–50% (median 35%). 19 patients were not thrombocytopenic (platelet counts 174–659, median 286). 1 patient (ADAMTS13 > 100%) with a platelet count of 105 had developed systemic lupus erythematosus after his initial TTP episode; 1 patient (ADAMTS13=50%) with a platelet count of 134 has had intermittent, mild thrombocytopenia since her initial episode 7 years ago. Five patients had mild anemia (hct 32–40%). Relapses, cognitive function, symptoms of depression, platelet count, and hct were not significantly different between patients with normal or abnormal ADAMTS13 activity. The neurocognitive abnormalities documented here may be related to the initial diffuse thrombotic disease. Depression may contribute to these abnormalities. Persistent abnormal ADAMTS13 activity many years after apparent recovery is common but of uncertain clinical importance since ADAMTS13 levels were not associated with clinical outcomes.