Sridharan, Meera

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.

AbstractEculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation are limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before 1 January 2021, were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred eighty patients from 40 publications were included. Median age was 28 years, and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n = 59) and MCP/CD46 (n = 38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant whereas the remaining had variants of uncertain significance (VUS). Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. VUS (P < .001) and likely pathogenic/pathogenic variants (P < .001) were associated with increased relapse. Presence of a renal allograft (P = .009); decreasing age (P = .029); and detection of variants in CFH (P < .001), MCP/CD46 (P < .001), or C3 (P < .001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.

AbstractHospitalized patients with COVID‐19 infection frequently have coagulopathy resembling disseminated intravascular coagulation (DIC). An elevation of D‐dimer level is associated with a poor prognosis; however, the role of other fibrin degradation products, such as soluble fibrin monomers (SFMC), is not known.The objective of the study was to investigate the frequency and prognostic role of elevated SFMC in patients with COVID‐19. In this retrospective cohort study, patients hospitalized between April 1, 2020 and December 14, 2020 at Mayo Clinic with COVID‐19 infection who underwent DIC panel testing were identified. Results of laboratory tests and outcomes (thrombosis and death) within 40 days of testing were obtained via medical record review.Of 108 patients, D‐dimer was elevated in 82 (75.9%) patients. Of those with elevated D‐dimer, SFMC was elevated in 19/82 (23%) patients. There were 16 thrombotic events and 16 deaths during the 40‐day follow‐up. The incidence of overt‐DIC was 4.6%. In univariate analysis, D‐dimer ≥5 x highest upper limit normal (ULN) and elevated SFMC were each associated with higher 40‐day mortality. However, when used in combination with D‐dimer ≥5 x highest ULN, an elevated SFMC provided no further mortality predictive value.Compared to 75.9% of patients with elevated D‐dimers, of those tested, only 23% had elevated SFMC. These results support the hypothesis that elevated D‐dimer in COVID‐19 infection is a direct consequence of endothelial damage and not overt‐DIC.

Abstract Background: Immune Thrombotic thrombocytopenic purpura (iTTP) is a relapsing disorder, resulting from depletion of ADAMTS13. With the goal of preventing clinical relapse there has been considerable interest in ADAMTS13 monitoring and preemptive treatment. Indeed, preemptive treatment with rituximab has shown significant promise and is now included in the 2020 International Society on Thrombosis and Haemostasis (ISTH) treatment guidelines. Evaluation of long-term outcomes of ADAMTS13 based preemptive treatment have generally relied on limited numbers of historical controls which did not incorporate matching for known risk factors for relapse such as race, number of prior episodes, and immunosuppression. Our study aims to leverage the data in the United States Thrombotic Microangiopathy (USTMA) iTTP registry to compare the clinical relapse-free survival (RFS) intervals between iTTP patients treated preemptively based on ADAMTS13 level and those treated only for clinical relapse base on clinical and laboratory manifestations of iTTP. Methods: We carried out a retrospective study utilizing the multi-center cohort of patients with iTTP from the USTMA Consortium (spanning 1985-2019 and containing 780 participant records). We selected for patients with relapsing disease treated either preemptively based on ADAMTS13 level or for clinical relapse. Each preemptively treated episode was matched to up to five clinically relapsed episodes using covariate balancing propensity score nearest-neighbor matching by age, gender, race, prior relapse status, acute treatment, treatment center, and calendar year, with exact matching required for treatment center and prior relapse status. Time from prior episode to relapse was compared between preemptively treated episodes and matched controls using a Cox proportional hazards model weighted by the matching weights, including subclasses as a cluster, and using cluster-robust standard errors. Results: We identified 1068 episodes of iTTP. Of these. Thirteen participants accounting for a total of seventeen preemptive treatment episodes were included in the data set however, we included only the thirteen first uses of preemptive treatment to avoid selection bias. These were matched with 59 episodes treated for clinical relapse. Over 70% of the included participants in both groups were identified as black/African American. Distribution of immunosuppressive medications used in clinically relapsed cases were not significantly different than those used in preemptive treatment, and corticosteroids were the most frequently used. Demographic and treatment data before and after matching are included in Table 1. There was no significant difference in RFS between the groups, hazard ratio 0.63 (95% confidence interval 0.26-1.54), p=0.31. Conclusion: To our knowledge this is the first study to use matching controls to obtain a causal estimate of the effect of ADAMTS13 monitoring based preemptive treatment on RFS in iTTP. In contrast to previous work, we did not observe a significant increase in RFS in the preemptively treated group. It is possible that the limited number of preemptively treated episodes herein did not provide sufficient power to detect a difference. However, given the significant effect size that has been proposed, based on prior work, we suspect other factors may have also influenced this finding. Previous analysis of the USTMA iTTP registry has shown a higher incidence of relapse in African American participants. While the precise reason for this finding is not yet clear, it is worth considering that there may also be differential response to preemptive treatment. Our study highlights the importance of continued efforts to determine the generalizability and efficacy of ADAMTS13 monitoring based preemptive treatment in iTTP. Figure 1 Figure 1. Disclosures Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Masias: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; I-mAb: Consultancy; Sunovion: Consultancy; Genentech/Hoffman LaRoche: Research Funding; UniQure: Membership on an entity's Board of Directors or advisory committees; Aspa: Consultancy. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. OffLabel Disclosure: Rituximab, an anti CD20 monoclonal antibody will be discussed in relation to treatment of thrombotic thrombocytopenic purpura.

Abstract Introduction Women with inherited bleeding disorders (IBD) are at increased risk of peripartum bleeding complications. The aim of our study was to assess our institutional outcomes of management of women with IBD during pregnancy and the peripartum period. Methods Eligible patients included women with IBD followed at the Mayo Clinic, Rochester Hemophilia Treatment Center and were followed at our institution for antenatal and peripartum care. Patients were excluded if detailed delivery outcomes were unavailable in the electronic medical record (EMR). If delivery was not in our institution but all records were available to review in EMR the pregnancy was included in analysis if our group was primarily involved in providing management recommendations. The EMR was retrospectively reviewed and details regarding factor usage, delivery method and outcome, analgesia, and post-partum hemorrhage (PPH) were recorded. Thrombotic complications 6 weeks post-partum was also recorded. Results 73 pregnancies in 46 unique patients met our inclusion criteria for this study. Distribution of underlying IBD in the 73 pregnancies was as follows: 50% type 1 VWD (n=37), 15% (n=11) hemophilia A carrier, baseline (bl) fVIII 46 (21-88)%.), and 13.7% (n=10) hemophilia B carrier (bl fIX 43 (23-69)% . In the remaining pregnancies, underlying IBD included type 2 VWD (n=6), type 3 VWD (n=1), VWF multimer abnormality (n=2) , factor XI deficiency (n=2, bl fXI: 44%), factor VII deficiency (n=2, bl fVII 37%) and factor V deficiency (n=2, bl fV 11%). Surprisingly, at the time of 24 deliveries, the patient's bleeding disorder (type 1 VWD, n=15) had not yet been diagnosed. In 56 % of pregnancies (n=41), a hematology delivery plan was in place prior to admission for delivery. Of 30 delivery inductions, 11 were performed due to IBD. There were 46 vaginal deliveries, 25 C-sections, and 2 dilation and curettage (D&C). Two C-sections were recommended due to IBD (hemophilia B and type 2 VWD). In 37/46 of vaginal deliveries neuraxial anesthesia was used with no complications noted. 26 deliveries were performed under the cover of hemostatic pharmacologic agents (Table one). Due to naturally increasing levels of VWF during the peripartum period, only 8/37 (21.6 %) pregnancies in those with type 1 VWD required hemostatic treatment. 61/73 pregnancies were at least at early term (>37 weeks) and all resulted in live birth. Of the remaining pregnancies (n=12), 5 resulted in a nonviable fetus. In one pregnancy, fetal demise was due to termination of pregnancy due to type III VWD and recent lymphoma in the mother. Pharmacologic hemostatic agents were used in 19 pregnancies in the post-partum period (Table 2). 10 pregnancies (6 vaginal), met American College of Gynecology criteria for early PPH. Underlying IBD for pregnancies with PPH included (type 1 VWD: n=7,hemophilia A carrier (n=1), type II VWD (n=1), factor VII deficiency (n=1). 4 of these had received pharmacologic hemostatic treatment prior to delivery. Primary management of PPH involved uterine intervention (ie. Massage and uterotonic agents). In three pregnancies, a D&C was required (one due to stillborn birth and two due to retained placenta). One case of PPH was due to placental abruption. Additional pharmacologic hemostatic management was utilized in 4 deliveries where PPH was noted. Red blood cell transfusions were needed in 3 pregnancies due to PPH. There were no thrombotic complication up to 6 weeks post-partum. Conclusion Though rates of early PPH were >10% in our cohort, most causes of PPH were unrelated to the underlying IBD. Although the current study is limited due to lack of many patients with type II and III VWD, results demonstrate that bleeding risk during delivery due to the IBD is low when patients are evaluated and managed with the use of a multidisciplinary care team. Figure 1 Figure 1. Disclosures Pruthi: CSL Behring: Honoraria; Merck: Honoraria; HEMA Biologics: Honoraria; Bayer Healthcare AG: Honoraria; Genentech: Honoraria; Instrumentation Laboratory: Honoraria.

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy due to reduced activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, 13). This disorder can be due to a congenital deficiency state or be acquired (immune TTP (iTTP)) due to an antibody which either inhibits or causes clearance of ADAMTS13. The aim of our study was to determine whether ADAMTS13 inhibitor titer at initial presentation could serve as a predictor of refractory disease and relapse in iTTP. We also measured clinical outcomes across different gender and racial subgroups. Methods: The United States Thrombotic Microangiopathy (USTMA) iTTP registry was used to extract patient information for two academic institutions in Eastern North Carolina. Descriptive statistics were used to analyze the data. The first iTTP episode recorded in the data base was used as the index episode. All patients included in the final analysis had an ADAMTS13 activity of <10%. An inhibitor level of 5 Bethesda units was arbitrarily chosen as the cutoff between low (<5) and high (>/5) inhibitor level. Response time was defined as the number of days of plasma exchange (PEX) required to achieve a platelet count of 150,000 for two consecutive days. Relapse was defined as occurrence of a new episode of iTTP 30 days after achievement of response. Refractory disease was defined as persistence of thrombocytopenia or absence of a sustained platelet count increment or platelet counts of < 50,000 despite 4-7 days of plasma exchanges and steroid treatment. Rituximab resistance was defined as lack of platelet recovery to more than 150,000 within 11 to 14 days of administration of the first dose of Rituximab. Results: A total of 161 patients with iTTP were identified. Ten patients had ADAMTS13 activity >10% and 15 patients did not have a reported inhibitor level. These subjects were not included in the final analysis. The cohort had 28% male (n =38/136) and 72% (n=98/136) female patients. There were more African American patients 73% (n=99/136) than Caucasians 24% (n=32/136). There were also 2 Hispanic, 1 Native American and 2 patients with unidentified race. Median ADAMTS3 inhibitor titer was 1.05 (Range 0-87). Forty three patients with ADAMTS13 activity <10 % had an inhibitor level of 0 (i.e undetectable).They were included in the low inhibitor group. Overall, 88% patients (n=120/136) had low inhibitor level and only 12% (n=16/136) had a high inhibitor. Thirteen percent females (n=13/98) and 8% (n=3/38) males had a high inhibitor level (p=0.387). Fourteen percent (n=14/99) African Americans and 6 % (n=2/32) Caucasians had a high inhibitor, p=0.23. In the low inhibitor group 30% (n=36/120) patients suffered at least one episode of relapse whereas 31% (n=5/16) had relapsed in the high inhibitor group. The median time to response was 6 days (range 1-76) in the low inhibitor group and 7 days (range 4-20) in the high inhibitor group (p=0.61). While looking at the various subgroups, median time to response for males was 6 days (range 4-21), females 6 days (range 1-76) , African Americans 6 days (range 3-29) , and Caucasians 6 days (range 1-76). The frequency of refractory disease was 31 % (n=5/16) in the high inhibitor group and 29% (n=34/119) in the low inhibitor group. At the time of enrollment in the registry, Rituximab was not a part of first line therapy. Only 26 out of 136 patients had received Rituximab. In the low inhibitor group 5 patients displayed Rituximab resistance whereas there were no patients in the high inhibitor group with Rituximab resistance. Conclusion: When evaluating patients presenting with iTTP in two centers in North Carolina, no correlation was found between a high inhibitor levels of >/ 5 Bethesda units and risk of relapse or refractory disease. A larger study is needed to evaluate this further. Disclosures No relevant conflicts of interest to declare.

Abstract Background: COVID-19 vaccinations in the United States (Janssen, Moderna, and Pfizer) have been deemed generally safe and effective. Rare thrombotic events, now termed vaccine-induced thrombotic thrombocytopenia (VITT), have been reported after the Janssen and Moderna vaccinations. With millions of vaccinations being administered to adults, it is expected that some deep vein thrombosis (DVT) will occur coincidentally with vaccination. Whether COVID-19 vaccinations may contribute to DVT risk more generally (outside of VITT) has not been well studied outside of the initial clinical trials. Aims: Evaluate trends in DVT diagnosis before and after COVID-19 vaccination Methods: Vaccinated patients ≥ 18 years between 11/6/2020 through 6/1/2021 were analyzed using electronic medical records across the Mayo Clinic enterprise. Upper and lower DVT venous Duplex ultrasound (DUS) reports occurring 90 days before and after vaccination date (first dose for Pfizer and Moderna vaccines) were extracted and analyzed with a highly accurate, previously validated, Natural Language Processing (NLP) algorithm for acute DVT. Results: 382,527 patients with at least 1 COVID-19 vaccination were identified. The median age was 61 (IQR 44-72) and 55.3% were male. Pfizer was the most common vaccine administered (n=245,572, 64.2%), followed by Moderna (n=120,683, 31.6%) and Janssen (n=16,272, 4.3%). Most patients (91.5%) receiving vaccinations were from states with Mayo Clinic health services (Minnesota, n=197,834; Wisconsin, n=80,720; Florida, n=42,391; Arizona, n=28,882). The mean age at vaccination was 61.0 (SD 17.7), 56.5 (SD 19.1), and 54.7 (SD 16.3) for Moderna, Pfizer, and Janssen vaccines respectively. Women were most likely to receive the Pfizer (56.3%) compared to Moderna (54.1%) and Janssen (49.5%) vaccines. Non-white patients were most likely to receive Janssen (21%) compared to Moderna (7.7%) and Pfizer (8.2%) vaccines. Among all patients, 7,265 upper and lower venous DUS were performed in 5,960 patients. Figure 1 shows the utilization of DUS before and after COVID-19 vaccination and shows that more patients underwent DUS in the 90 days after vaccination compared to 90 days pre-vaccination. Acute DVT was identified by the NLP algorithm in 808 (714 patients) ultrasounds (11.1%); 656 out of 6136 lower extremity DUS (10.7%) and 152 out of 1129 upper extremity DUS (13.5%). The overall rate of acute DVT (upper and lower) was 1.86 per 1000 patients, consistent with the expected background epidemiologic rate. Figure 2 shows the daily probability of acute DVT by ultrasound report in the 90 days before and after vaccination with a linear regression best fit line showing no overall correlation (R 2 = 0.0). Overall acute DVT post-vaccination occurred on 10.8% of DUS compared to 11.6% pre-vaccination (p=0.28). Among ultrasound reports in Janssen vaccinated patients, 7.0% of post-vaccination compared to 18.0% of pre-vaccination were positive for acute DVT (p=0.003). Among ultrasound reports in Moderna vaccinated patients, 11.0% of post-vaccination compared to 12.7% of pre-vaccination were positive for acute DVT (p=0.15). Among ultrasound reports in Pfizer vaccinated patients, 11.0% of post-vaccination compared to 10.4% of pre-vaccination were positive for acute DVT (p=0.56). Using a Cox proportional hazard model, pre vs post-vaccination time among the same patient cohort was compared for each vaccine. The hazard ratio for DVT post-vaccination was 0.68 (95% CI 0.34-1.38) for Janssen, 1.08 (95% CI 0.86-1.35) for Moderna, and 1.20 (95% CI 0.99-1.46) for Pfizer. After adjusting for age and sex, Pfizer and Janssen's vaccines did not have different risks for DVT compared to Moderna in the 90 days post-vaccination (HR 0.80, 95% CI 0.98-1.25 and HR 0.75, 95% CI 0.42-1.32 respectively). Conclusions: In this large cohort of COVID-19 vaccinated patients, no increased risk for acute DVT post-vaccination was identified for any of the approved vaccinations in the United States. Additionally, no significant difference was seen in the risk for DVT post-vaccination when comparing each vaccine to each other. The probability of acute DVT on ultrasounds in the 90 days post-vaccination was lower than the pre-vaccination period with the Janssen vaccine possibly indicating over-testing in this group. These results provide additional reassurance of the safety of approved COVID-19 vaccines. Figure 1 Figure 1. Disclosures Padmanabhan: Veralox Therapeutics: Membership on an entity's Board of Directors or advisory committees. Pruthi: HEMA Biologics: Honoraria; CSL Behring: Honoraria; Genentech: Honoraria; Instrumentation Laboratory: Honoraria; Bayer Healthcare AG: Honoraria; Merck: Honoraria.