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.

AbstractTransplant‐associated thrombotic microangiopathy (TA‐TMA) has a wide range of presentations after hematopoietic stem‐cell transplantation (HSCT). We retrospectively studied the risk factors and outcomes of patients with early (≤day 100) and late (>day 100) TA‐TMA. Among the 1451 HSCT recipients, early TA‐TMA occurred in 45 (3.1%) patients at a median of 27 (3‐91) days, and late TA‐TMA in 39 (2.7%) patients at a median of 303 (122‐2595) days. Patients with early TA‐TMA were more likely to have high blood calcineurin‐inhibitor levels (P < .001) and acute graph‐vs‐host disease (GVHD, P < .001), while late TMA patients were more likely to have chronic GVHD (P < .001). The estimated median overall survival after onset of TMA for the entire cohort was 6 months. The estimated median overall survival was not reached in patients with an improvement of TMA vs 2 months in patients with no improvement (P < .001). In the early TMA group, older age (for every 10 years, HR 1.40; 95% CI 1.00‐1.94; P = .049) and bacterial infection (HR 2.42; 95% CI 0.98‐6.00; P = .056) were positively associated with mortality. Switching to MMF treatment (HR 0.40; 95% CI 0.16‐0.99; P = .047) and improvement of TMA (HR 0.08; 95% CI 0.03‐0.25; P < .001) were negatively associated with mortality in the multivariate analysis. In the late TMA group, the improvement of TMA was the only independent predictor associated with a lower risk of death (HR 0.05; 95% CI 0.02‐0.19; P < .001). Mortality rates in both early and late TMA remain unacceptably high. Future studies are needed for early diagnosis, trigger identifications, and use of targeted treatments.

AbstractObjectivesDescribe the clinical presentation, treatment, and outcomes of postsurgical thrombotic microangiopathy (TMA).MethodsIn this retrospective study, records of individuals diagnosed with TMA developing within 30 days of a surgical procedure at Mayo Clinic from 2000 to 2016 were reviewed. Available literature regarding postsurgical TMA was comparatively reviewed.ResultsTwenty patients were diagnosed with TMA developing within 30 (median 6.5, range (1‐28)) days) following a procedure. Preceding procedures included orthopedic (n = 4), vascular (n = 4), abdominal (n = 8), thoracic (n = 2), and other (n = 2). Review of the literature identified 65 patients with postsurgical TMA and cardiovascular procedures were the most common preceding surgery. The majority of patients in the current cohort and literature were treated with therapeutic plasma exchange (TPE). Among the evaluable patients in the current cohort, 100% demonstrated response to TPE; however, 25% required the addition of other therapy including eculizumab to maintain a response 80% of patients in the literature demonstrated a response to TPE.ConclusionsAlthough rare, early recognition and treatment of postsurgical TMA can lead to good outcomes. More research is necessary to determine the underlying pathophysiology and optimal treatment for postsurgical TMA.