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Immune TTP (iTTP) survivors have increased risk of cardiovascular disease including stroke, and report persistent cognitive difficulties during remission. We conducted this prospective study of iTTP survivors in clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neuro-deficits, during clinical remission. We also tested the hypothesis that SCI is associated with cognitive impairment assessed using the NIH ToolBox cognition battery. We used fully corrected T scores adjusted for age, sex, race, and education. Based on DSM-5 criteria, we defined mild and major cognitive impairment as T-scores that are 1-2 SD and > 2 SD below the mean on at least one test, respectively. Forty-two patients have been enrolled, with 36 completing MRI.SCI was present in 50% (18) , of which 8 (44.4%) had prior overt stroke including during acute iTTP. Patients with SCI had higher rates of cognitive impairment (66.7% vs. 27.7%, P=0.026) including major cognitive impairment (50% vs. 5.6%, P=0.010). In separate logistic regression models, SCI was associated with any (mild or major) cognitive impairment [OR 10.5 (95% CI 1.45 - 76.63); P = 0.020] and major cognitive impairment [OR 7.98 (95% CI 1.11 - 57.27); P = 0.039] after adjusting for history of stroke and Beck depression inventory scores. In summary, MRI evidence of brain infarction is common in iTTP survivors; the strong association of SCI with impaired cognition suggests that these 'silent' infarcts are neither silent nor innocuous.

BACKGROUND: Microvascular and arterial thromboses are well described in patients with thrombotic microangiopathy (TMA) including complement mediated TMA (CM-TMA)/atypical hemolytic uremic syndrome. Hemolytic disorders are associated with increased risk of venous thromboembolism (VTE), and patients with CM-TMA may have additional risk factors of hospitalization and central lines and may not consistently receive thromboprophylaxis due to thrombocytopenia. However, little is known about the prevalence and clinical correlates of VTE in CM-TMA. METHODS: We performed this single center retrospective cohort study of consecutive patients with CM-TMA enrolled in the Johns Hopkins Complement Associated Disease Registry between January 2014 and December 2020. Data regarding clinical presentation, laboratory studies including clinical complement gene sequencing, terminal complement inhibition and anticoagulation therapy, VTE events including characteristics and risk factors for VTE were collected. A diagnosis of CM-TMA was based on: (1) platelet count 10%, (4) Shiga toxin negative, and (5) serum creatinine >2.25 mg/dL at presentation, which was considered supportive but not required for diagnosis. We only included VTE events post-CM-TMA diagnosis. VTE characteristics, treatment and outcomes were summarized using descriptive statistics. The Chi-squared test and Mann Whitney test were used to compare categorical and continuous variables across groups with and without VTE, respectively. RESULTS: Of 44 patients diagnosed with CM-TMA and followed for a median of 3.1 years (IQR 0.8-5.5), 8 (18.2%) experienced at total of 10 VTE events (5.6 VTE events/100 patient-years). There was no significant difference between patients with and without VTE in age at diagnosis, sex, race, BMI, need for dialysis, treatment with eculizumab, and presence of mutations in complement genes (Table 1). VTE events included 5 deep vein thromboses, 4 pulmonary emboli and 1 splenic infarct (Table 2). The majority (70%) of VTE events were provoked with 5 (50%) associated with a catheter or vascular access for dialysis and 2 (20%) events following major surgeries. The median time from CM-TMA diagnosis to the first VTE event was 4.9 months (IQR 0.76-26) with 3 events occurring during the index hospitalization for CM-TMA. Of 10 VTE events, 5 occurred while on complement inhibition and 2 on anticoagulation (1 on therapeutic and 1 on prophylactic anticoagulation). Of note, only 1 of 3 patients diagnosed with VTE during their index CM-TMA hospitalization received thromboprophylaxis. At the time of VTE diagnosis, the median platelet count was 182.5 x 10 9/L (IQR 143.75-332.75); 80% had a platelet count >150 x 10 9/L , and 10% each had a platelet count VTE was treated with therapeutic anticoagulation with enoxaparin, warfarin or a direct oral anticoagulant in 7 of 8 patients for a median duration of 7 months (IQR 4-14). One patient experienced recurrent PEs; the first PE occurred 2 months following the index CM-TMA hospitalization and the second event was 4 years later while off of anticoagulation and complement inhibition. A second patient experienced a splenic infarct 7 months after initial CM-TMA diagnosis while non-compliant with ravulizumab, followed by a catheter-associated upper extremity DVT 2 months later while on therapeutic anticoagulation and ravulizumab. No VTEs were fatal. CONCLUSION: VTE is common in patients with CM-TMA (18.2%), with a prevalence comparable to thrombotic thrombocytopenic purpura (18%, Tse et al. 2020) but greater than that reported in dialysis patients (Moinar et al. 2017). In CM-TMA patients, VTE is commonly provoked by hospitalization or dialysis catheters and tends to occur after platelet count recovery and in the absence of thromboprophylaxis. Factors such as renal impairment, prolonged hospitalization, complement dysregulation, and free hemoglobin release may also increase VTE risk. Our results highlight the high prevalence of VTE in CM-TMA and the importance of thromboprophylaxis once the platelet count is greater than 50 x 10 9/L. Figure 1 Figure 1. Disclosures Dane: Alexion: Honoraria; Sanofi Genzyme: Honoraria; Janssen: Honoraria. Chaturvedi: Sanofi Genzyme: Other: Advisory board member; Alexion: Other: Advisory board member; Dova: Other: Advisory board member; Argenx: Other: Advisory board member; UCB: Other: Advisory board participation.

BACKGROUND: Individuals with immune mediated thrombotic thrombocytopenic purpura (iTTP) frequently exhibit cognitive impairment and are at higher risk of stroke than matched controls. However, the etiology of cognitive impairment in these individuals has not been established. We conducted this prospective study to examine the patterns of cognitive impairment and to test the hypothesis that cognitive impairment in iTTP survivors is associated with silent cerebral infarction (SCI, ischemic lesions on brain MRI without corresponding overt neurodeficits), which are also a risk factor for future stroke. METHODS: We prospectively enrolled adult (age ≥ 18 years) patients with iTTP and age- and sex-matched controls without prior iTTP or stroke. iTTP was diagnosed based on ADAMTS13 activity 150x10 9/L for at least 30 days after stopping plasma exchange and/or caplacizumab). Participants undergo annual study visits including the following study measures: 1) NIH stroke scale to rule out acute stroke, 2) NIH ToolBox Cognition battery, a comprehensive iPad based neurobehavioral tool that has been validated across multiple populations and for which normative control data are available. The NIH ToolBox Cognition Battery tests multiple cognitive domains (Figure 1) including executive function (dimensional change card sort test, flanker inhibitory control and attention test), processing speed (pattern comparison test), episodic memory (picture sequence memory test), working memory (list sort working memory test), language (oral reading recognition, picture vocabulary test). We used T scores adjusted for age, sex, race and educational attainment where the normative mean T score is 50 with standard deviation (SD) of 10. Mild and major cognitive impairment are defined as a T scores that are 1-2 SD below mean and > 2SD below mean for any domain, respectively; 2) Brain MRI: SCI is defined as a infarct-like lesion (punctate T2 and FLAIR hyperintensity) without corresponding neurodeficits. The Chi-squared test and Mann Whitney test were used to compare categorical and continuous variables across groups, respectively. RESULTS: Between September 2020 and June 2021, we enrolled 34 participants including 28 iTTP patients and 6 controls. Demographics and clinical characteristics of patients and controls are summarized in Table 1. NIH Stroke Scale score was 0 in all controls and all but one iTTP patient (score = 1). Among iTTP patients, 28.6% (8/28) had prior stroke (including during acute episodes). (i) iTTP survivors demonstrate cognitive deficits affecting executive function and processing speed: Among iTTP patients, 46.4% had cognitive impairment in at least one domain including 25% (7/28) with major cognitive impairment and 21.4% (6/28) with mild cognitive impairment (> 1 SD below mean T score). Among controls, 0% had major cognitive impairment and 16.6% (1/6) had mild cognitive impairment. Figure 1 shows detailed cognitive testing results for iTTP patients and controls. iTTP patients most commonly had deficits (T score < 40) in executive function (flanker inhibition test, dimensional change card sort test) and processing speed (pattern comparison test) (Table 1). (ii) Silent cerebral infarction is associated with major cognitive impairment: MRI was completed in 24 iTTP patients and all controls. SCI was present in 50% (12/24) of iTTP patients (representative image, figure 2A) and 16.6% (1/6) controls. Another 29.1% (7/24) had evidence of prior stroke. Rate of SCI was 35.7% in patients without cognitive deficits, 50% in those with minor cognitive deficits and 83.3% in those with major cognitive deficits. SCI was present in 83.3% (5/6) with major cognitive impairment versus 38.9% (7/18) without major cognitive impairment (P = 0.05) (Figure 2B). CONCLUSIONS: Cognitive deficits in iTTP survivors primarily affect executive function and processing speed and are associated with SCI suggesting ischemic etiology. Whether SCI occur during acute episodes or during remission (with remission ADAMTS13 as a risk factor) is being studied prospectively with serial MRI and cognitive assessment. iTTP patients may benefit from neurocognitive testing and referral to neuropsychological therapy, where appropriate, and aggressive measures to address risk factors for cerebrovascular disease. Figure 1 Figure 1. Disclosures Naik: Rigel: Research Funding. Lanzkron: GBT: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company; Novartis: Research Funding; Novo Nordisk: Consultancy; Imara: Research Funding; CSL Behring: Research Funding; Shire: Research Funding; Bluebird Bio: Consultancy. Chaturvedi: Sanofi Genzyme: Other: Advisory board member; Argenx: Other: Advisory board member; UCB: Other: Advisory board participation; Dova: Other: Advisory board member; Alexion: Other: Advisory board member.