Abstract: Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create the world's largest database of patients with this rare disease. While there is consensus on the use of therapeutic plasma exchange (TPE) for treatment of iTTP, there are no large randomized trials on which to base use of rituximab. The drug is frequently used for refractory or relapsed iTTP, but is currently being used more frequently for de novo (first episode) iTTP. We queried the USTMA iTTP registry to determine whether relapse free survival (RFS) is superior when rituximab is added to TPE and corticosteroids for treatment of iTTP. We hypothesized that the addition of rituximab would improve RFS at 5 years in both de novo and relapsing iTTP. Methods Following IRB approval at each institution, investigators independently reviewed individual patient records to confirm diagnostic criteria and entered demographic, treatment and outcomes data into the REDCap database housed at the University of North Carolina. The diagnosis of iTTP was defined as ADAMTS13 & lt; 10% or ADAMTS13 & lt; 20% with an inhibitor or antibody detected at any point or a clinical diagnosis of iTTP based on presenting characteristics, response to treatment and/or relapsing phenotype before ADAMTS13 testing became available (N=173). Relapse was defined as a recurrence of iTTP after at least 30 days of remission (recurrence within 30 days was considered an exacerbation, or continuation of the prior episode). To explore the effect of rituximab added to TPE and corticosteroids, we first assessed the treatment effect in de novo iTTP patients and then separately in relapse. We constructed Kaplan-Meier curves to compare RFS for patients treated with rituximab plus corticosteroids versus corticosteroids alone in both groups, and compared RFS at specific time points using the Klein method. To better understand whether other patient variables had an effect on RFS in both de novo episodes and relapses, ordinary (time-to-event) and mixed-effects (recurrent time-to-event) Cox proportional hazards models were used to examine the relationships of treatment, race/ethnicity, sex, age, treatment year, and presenting signs/symptoms with the outcome. Analyses were conducted using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Results As of July, 2019, the USTMA database contains 775 unique study patients with a confirmed diagnosis of iTTP with 1397 unique iTTP episodes. The treatment of patients' de novo iTTP episode was available for analysis in 375 patients, 188 of whom were treated with corticosteroids alone, 131 with corticosteroids plus rituximab, and 56 with other therapies. RFS was significantly higher in patients treated with corticosteroids and rituximab compared to those treated with corticosteroids alone at 1 year (0.93 vs. 0.78, p=0.0002) and 3 years (0.82 vs. 0.66, p=0.004) but not 5 years (0.60 vs. 0.56, p=0.39). In addition, the risk of relapse decreased with later treatment year for de novo iTTP (hazard ratio (HR) 0.95, 95% CI 0.92-0.99, p=0.03), consistent with rituximab use increasing over time, and was increased in African Americans compared with Caucasians (HR 1.83, 1.10-3.06, p=0.02). We then explored the treatment effect in all iTTP relapses (743 relapses in 426 patients). Here, a significant (p=0.0007) interaction between treatment and race was found. Among African Americans, we found no difference in RFS when rituximab was added (HR 1.15, 0.81-1.62, p=0.43). However, among Caucasians, RFS was significantly improved when rituximab was added (HR 0.15, 0.06-0.35, p & lt;0.0001). Conclusions For de novo iTTP, adding rituximab to corticosteroids for immunosuppression likely delays but does not prevent relapse. Unlike in de novo disease, in patients with relapsed iTTP, we found a novel and significant interaction between race and treatment: while Caucasians had significantly improved RFS with the addition of rituximab, there was no effect on RFS in African Americans. Further investigation is warranted to determine the mechanisms of this difference in the response to rituximab in relapsed iTTP to improve outcomes in African Americans. Figure Disclosures Marshall: Sanofi: Membership on an entity's Board of Directors or advisory committees. Farland:Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Imara: Other: PI on Clinical trial- Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Zheng:Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding; Ablynx/Sanofi: Consultancy, Speakers Bureau; Alexion: Speakers Bureau. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Off Label Disclosure: rituximab for immunosuppression in TTP.

Abstract: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Abstract: Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ impairment. The incidence of iTTP is higher among African-Americans (AA), however, differences in presentation and outcomes have not been fully investigated. In a multi-center cohort of patients with iTTP from the United States Thrombotic Microangiopathy (USTMA) Consortium, we tested the hypothesis that AA race is an independent predictor of poor outcomes including iTTP related mortality and relapse. Methods: We queried data from the USTMA iTTP registry, which currently includes data from 785 individual patients from 15 institutions across the United States. Data from at least one iTTP episode are available for 734 patients. The cohort is 35.1% (N = 272) White, 58.7% (N = 455) African American, 0.4% (N=3) Asian, 1.8% (N=14) Hispanic, and 4.0 % (N=31) other/unknown race. We restricted our analyses to AA and White participants because of small numbers in the other groups. We compared presenting features and treatments using the chi-squared test and t-test for categorical and continuous variables, respectively. A relapse was defined as a recurrent iTTP episode occurring at least 30 days after last therapeutic plasma exchange. To evaluate relapse-free survival, we included only patients enrolled in the registry at their first TTP episode (144 White and 246 AA) since patients presenting with a relapse as their index episode are already confirmed to have relapsing iTTP. Kaplan Meier analysis was used to compare relapse-free survival in White and AA patients, and a Cox regression model was developed to evaluate the independent effect of race on relapse, adjusting for potential confounders including age, sex, and the use of rituximab. Results: Demographics and presenting features of 390 individuals (144 White and 246 AA) presenting with a first episode of iTTP are shown in Table 1. Presenting symptoms including fever, confusion, seizure, memory deficits, stupor, headache, stroke, chest pain, abdominal pain, fatigue, and dark urine were similar between Whites and AA except for petechiae, which were more frequently documented in Whites (28.8% vs 17.7%, p=0.011). Presenting laboratory studies were also comparable though AA had a higher rate of elevated serum troponin (50.6% vs 32.5%, p=0.003), lower hemoglobin level (8.27 ± 0.13 vs 8.81 ± 0.19, p=0.0176) and platelet count (20.3 ± 1.2 vs 26.2 ± 3.2, p=0.0432). In addition to therapeutic plasma exchange and corticosteroids, rituximab was administered to 23.7% of White patients and 22.7% of AA during their first iTTP episode (P=0.815). Median time to platelet count recovery (days of daily plasma exchange until normal platelet count for two consecutive days) was shorter in AA compared with White patients [5 (IQR 4, 10) vs. 8 (IQR 5, 14), log rank P = 0.004]. AA race remained a significant predictor of the shorter time to platelet count recovery [HR 1.44 (95% CI 1.12, 1.85), P=0.004] after adjusting for rituximab therapy [HR 0.60 (95% CI 0.0.46, 0.80), P 〈 0.001], female sex [HR 0.95 (95% CI 0.73, 1.22), P=0.669] , age [HR 0.99 (95% CI 0.99, 1.01), P=0.682], platelet count [HR 1.00 (95% CI 0.99, 1.04), P=0.820] and LDH at presentation [HR 1.00 (95% CI 1.00, 1.00), P=0.525]. Death during the first episode occurred in 8.9% of White patients and 5.5% of AA patients (P=0.206). Relapse-free survival after the first episode of iTTP was lower in AA than White patients (Figure 1). AA race was associated with the reduced relapse free survival [HR 1.79 (95% CI 1.08, 2.98), P=0.024] in a Cox regression model adjusted for age [HR 1.00 (95% CI 0.98, 1.01), P=0.683] , sex [HR 0.96 (95% CI 0.60, 1.54), P=0.867], and rituximab therapy [HR 0.93 (95% CI 0.55, 1.59), P=0.806] . Conclusion: African Americans with iTTP have a higher relapse rate and shorter relapse free survival after the first episode of the disease compared with Caucasian patients, which is independent of age, sex and rituximab therapy. Contrary to our hypothesis, acute outcomes of iTTP (time to platelet count recovery and mortality) were not worse in AA patients. The factors contributing to the higher relapse rate in AA with iTTP need to be further investigated. Our findings suggest that AA patients may also benefit from closer follow up. Disclosures Farland: Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Shire: Other: PI on clinical trial Sickle cell ; Imara: Other: PI on Clinical trial- Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Zheng:Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy.

Abstract: Approximately 10% of hereditary hemorrhagic telangiectasia (HHT) patients harbour brain vascular malformations (VMs). Intracranial hemorrhage (ICH) from brain VMs can lead to death or morbidity, while treatment options for brain VMs also have associated morbidity. The modified Rankin Scale (mRS) may provide an approach to identifying HHT-brain VM patients with poor outcomes, and their predictors. We aimed to measure the relationship between mRS score and brain VM, brain VM number, as well as other aspects of HHT, at enrollment and during prospective follow-up. Methods 1637 HHT patients (342 with brain VMs) were recruited from 14 HHT centres of the Brain Vascular Malformation Consortium since 2010 and followed prospectively (mean = 3.4 years). We tested whether the presence of brain VM, other HHT organ involvement, and HHT mutation genotype were associated with worse mRS scores at baseline and during follow-up, using linear mixed models, adjusting for age, sex, and year of visit. Results Presence of brain VMs was not associated with worse mRS score at baseline and there was no significant worsening of mRS with prospective follow-up in these patients; 92% had baseline mRS of 0–2. HHT-related gastrointestinal (GI) bleeding was associated with worse mRS scores at baseline (0.37, 95% CI 0.26–0.47, p   〈  0.001), as were history of anemia (0.35, 95% CI 0.27–0.43, p   〈  0.001) and liver VMs (0.19, 95% CI 0.09–0.30, p   〈  0.001). Presence of pulmonary arteriovenous malformations (AVMs) was not associated with worse mRS scores at baseline. mRS score was not associated with either HHT genotype ( Endoglin vs ACVRL1 ). Only GI bleeding was associated with a significantly worsening mRS during prospective follow-up (0.64, 95% CI 0.21–1.08, p  = 0.004). Conclusion Most HHT-brain VM patients had good functional capacity (mRS scores 0–2) at baseline that did not change significantly over 3.4 mean years of follow-up, suggesting that mRS may not be useful for predicting or measuring outcomes in these patients. However, HHT patients with GI bleeding, anemia history or liver VMs had worse mRS scores, suggesting significant impact of these manifestations on functional capacity. Our study demonstrates the insensitivity of the mRS as an outcomes measure in HHT brain VM patients and reinforces the continued need to develop outcomes measures, and their predictors, in this group.

Abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that causes vascular malformations throughout the body. The most prevalent and accessible of these lesions are found throughout the skin and mucosa, and often rupture causing bleeding and anemia. A recent increase in potential HHT treatments have created a demand for quantitative metrics that can objectively measure the efficacy of new and developing treatments. We employ optical coherence tomography (OCT)—a high resolution, non-invasive imaging modality in a novel pipeline to image and quantitatively characterize dermal HHT lesion behavior over time or throughout the course of treatment. This study is aimed at detecting detailed morphological changes of dermal HHT lesions to understand the underlying dynamic processes of the disease. We present refined metrics tailored for HHT, developed from a pilot study using 3 HHT patients and 6 lesions over the course of multiple imaging dates, totalling to 26 lesion images. Preliminary results from these lesions are presented in this paper alongside representative OCT images. This study provides a new objective method to analyse and understand HHT lesions using a minimally invasive, accessible, cost-effective, and efficient imaging modality with quantitative metrics describing morphology and blood flow.

Abstract: Venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism, is a common disorder with at least 250 000 new events occurring each year in the United States alone. Treatment of venous thromboembolism includes anticoagulation, which is achieved initially with the use of a parenterally administered agent followed by a more prolonged course of treatment with an oral vitamin K antagonist. The duration of treatment depends on the clinical assessment of the benefit-to-risk ratio of prolonged anticoagulation versus the risk of recurrent events. In this review, we discuss some of the issues that we believe are among the most critical unanswered questions in the management of venous thromboembolism in the present era.

Abstract: Abstract 224 Introduction: Heparin-induced thrombocytopenia (HIT) is a major cause of drug-induced thrombocytopenia and occurs in 1–5% of individuals exposed to heparin. Paradoxically, 30–50% of individuals with HIT develop thrombosis. The mechanism of thrombosis in HIT is poorly understood. We recently reported that HIT antibody complexes induce tissue factor (TF) expression in monocytes and result in the release of TF-positive microparticles (MPs). The mechanism by which HIT antibody complexes induce monocyte TF has not been established. The objective of this study is to characterize the receptors involved in HIT antibody complex mediated induction of TF expression in monocytes. As HIT antibody complex mediated activation of platelets is dependent on the FcgRIIA receptor, we evaluated the role of the FcgRII receptor in the induction of monocyte TF by HIT antibody complexes. We also evaluated the role of toll like receptor-4 (TLR4) and the platelet factor 4 (PF4) chemokine receptor CXCR3 in this process. Methods: The combination of heparin, PF4 and the murine monoclonal PF4/heparin-specific antibody KKO has been shown to cause activation of platelets and monocytes, and mimic HIT in vitro. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers were pre-incubated for 30 min at 37°C with an inhibitory antibody to the FcgRII receptor (IV.3); anti-CXCR2, 3, or 4 antibodies; anti-TLR4 antibody; or mouse-IgG (mIgG) control. Following pre-incubation with antibodies for 30 minutes, heparin (1U/mL), PF4 (10μg/mL), and KKO (100μg/mL) – together referred to as the HIT antibody complex – were added. Heat-aggregated mIgG and LPS were used as positive controls for the FcgRII and TLR4 receptors, respectively. Following a 6-hour incubation, PBMCs were pelleted by centrifugation and MPs were isolated from the supernatant. The procoagulant activity (PCA) of PBMCs and MPs was measured using clotting assays performed in the presence of the anti-TF antibody HTF-1 or control antibody. TF dependent PCA was calculated by reference to a standard curve generated using relipidated recombinant TF. Results: Incubation of PBMCs with heat aggregated mIgG for 6 hours resulted in significant induction of cellular TF (345 +/− 36 pg/106 cells) which was blocked by 30 min pre-incubation with the antibody IV.3 (146 +/− 17 pg/106 cells, N=3, p 〈 .003). However, pre-incubation with IV.3 had no significant effect on TF induction (140 +/− 5 pg/106 cells) associated with the HIT antibody complex when compared to control mIgG (110 +/− 18 pg/106 cells, N=3, p 〈 0.11). PBMCs incubated with HIT antibody complexes in the presence of a TLR-4 antibody showed less TF activity (52 +/− 4 pg/106 cells) compared to control mIgG (80 +/− 10 pg/106 cells N=3, p 〈 0.025). A similar, partial inhibition of TF activity was also observed in PBMCs incubated with LPS in the presence of an anti-TLR4 antibody (121 +/− 3 pg/106) compared with a control antibody (89 +/− 2 pg/106, N=3, p 〈 .0013). Experiments with a more effective inhibitor of TLR4 are in progress. PBMCs incubated with the HIT antibody complexes in the presence of an anti-CXCR3 antibody showed less TF activity (36 +/− 7 pg/mL) compared to control mIgG (118 +/− 15 pg/106 cells, N=3, p 〈 0.004). Antibodies against CXCR2 and CXCR4 did not have any significant effect on TF induction. Measurement of MP TF activity mirrored the results described above. Using flow cytometry and an anti-CXCR3 antibody labeled with FITC, we found that 5% (± 0.5%) of monocytes expressed CXCR3 (N=3), which is consistent with the reported literature. Conclusions: These data suggest that induction of TF in monocytes by HIT antibody complexes is not mediated by the FcgRII receptor. This is contrary to the mechanism of platelet activation by these antibody complexes, which is an FcgRIIa dependent process. We found that TLR4 plays a role in HIT antibody complex mediated induction of TF in monocytes and blocking TLR4 led to a 30% decrease in TF activity. On the other hand, CXCR3 appeared to play a more significant role with blockade of CXCR3 leading to a 70% decrease in TF activity. Further characterization of the role of these receptors in HIT antibody complex mediated induction of TF expression in monocytes is required. We speculate that the extent of CXCR3 and TLR4 expression in monocytes may influence the susceptibility to developing thrombotic complications in HIT. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 1419 The use of Rituximab (R), a chimeric monoclonal antibody against CD20, has been reported in the treatment of various non-neoplastic immune disorders including Acquired Hemophilia (AH). Approximately 1/3 of patients with AH are refractory to traditional immunosuppressive regimens (e.g. prednisone/cyclophosphamide) and therefore R has been advocated as an initial therapeutic option. When R is utilized in the treatment of AH it has typically been paired with corticosteroids. However, there is considerable morbidity associated with prolonged courses of corticosteroids in what is typically an elderly patient population. Published case series investigating single agent R have been limited to very small numbers of cases. Therefore, we investigated the use of single agent R as the first line immunosuppressive regimen in patients with AH. Methods: We identified all patients evaluated at the University of North Carolina for AH from 8/2005 until 8/2010. Demographic data and clinical characteristics were available for all patients. Complete remission (CR) was defined as FVIII:c 〉 70 IU/dL or Bethesda Inhibitor Unit (BIU) titer of 0. Results: Our single center experience includes data on 22 patients with an average age of 76 years (range 52–92). 55% were male and 59% self identified as Caucasian and 18% African American. 86% were diagnosed during the course of an inpatient admission to our medical center. The remaining patients were clinic referrals that completed their evaluation and treatment as outpatients. At diagnosis the average BIU titer was 193 BU/mL (range 1–1148, median 49.5, IQR 17.8–177.8) and the average FVIII:c was 3.5 IU/dL (range 0–25, median 1.0, IQR 0–5.3). The average time from onset of symptoms (hemorrhage, elevated aPTT, etc) to diagnosis was 27 days (range 1–240, median 14, IQR 7–26.3). The following associated conditions were noted: a) infection (4.2%), b) past malignancy (12.5%), c) active or suspected malignancy (25%), d) autoimmune disorder (25%), and e) idiopathic (33.3%). Notably our series includes no cases of postpartum AH. Of these 22 patients, 2 were lost to follow-up after their initial hospitalization. Six additional patients died during their initial hospitalization or were discharged to hospice (unrelated to their response to immunosuppressive treatment). Notably, there were no statistically significant differences between these groups in regards to baseline FVIII levels or BIU titers. Fourteen patients were therefore evaluable for response to an initial immunosuppressive regimen. Of these, 12 received R as a single agent, 1 received a combination of R and prednisone (initiated prior to referral), and 1 received prednisone and cyclophosphamide. Of the 12 individuals who received R alone, 7/12 achieved a CR with 1 additional patient (who is under active follow-up) achieving a PR. The remaining 4 patients required additional immunosuppressive agents to achieve a CR (most commonly cyclophosphamide, although one patient required both cyclophosphamide and another course of R). Additional immunosuppressive agents were employed when BIU titer was not felt to be responding adequately. One of these 4 relapsed after an initial CR had been achieved. Those patients who achieved a CR or PR on R alone had an average baseline BIU titer of 51 (range 1–163, median 22, IQR 5.3–112.8) vs. those who achieved CR with multiple lines of therapy who had an average initial BIU titer of 712 (range 34–1148, median 833.5, IQR 192.8–1111). This difference was statistically significant (p=0.0283). There was no significant difference in baseline FVIII levels between these two groups. Approximated time to CR was also not statistically significant between the two groups (median 127 vs. 258 days, p=0.1274). No significant adverse reactions were encountered in patients treated with R. Conclusion: R appears to be an effective single agent immunosuppressive agent in AH with little morbidity, especially in patients with baseline BIU titers 〈 150. Additional agents may be indicated for patients with higher baseline titers. This appears to be the largest single center experience with first line immunosuppression in AH with single agent R described to date. Disclosures: No relevant conflicts of interest to declare.