Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage due to endothelial injury and thrombosis. It includes a variety of disorders with similar laboratory and histological features but different clinical presentations and causes. Notable examples are hereditary or immune thrombotic thrombocytopenic purpura (TTP), complement-mediated TMA, Shiga toxin-mediated hemolytic uremic syndrome (HUS), drug-induced TMA, and secondary TMAs related to pregnancy, severe hypertension, infections, malignancies, autoimmune disorders, and organ transplants 1. Plasma exchange, with or without other immunosuppressive therapies, has greatly improved the short-term survival of TTP, and advancements in understanding complement-mediated TMAs have led to new treatment options 1. With more patients surviving an initial TMA episode, understanding the long-term effects of the disease and its treatment is needed. Although TTP survivors who achieved remission after plasma exchange were once thought to be fully recovered, about 40% relapse within the first decade 2, 3. Moreover, 5-year mortality rates are nearly double those expected in similar age, sex, and race populations 4. TTP survivors are at higher risk of developing hypertension, chronic kidney disease, cerebrovascular disease, and cardiovascular disease 5-8. However, the magnitude of long-term TMA-attributable risks remains unclear due to prior studies having few patients, short follow-up, and no non-TMA comparison groups. Using linked administrative healthcare data and manual chart review, we conducted a matched cohort study to determine whether adults in remission from TMA after plasma exchange have a higher long-term risk of major coronary artery disease events than adults without TMA selected from the general population to have similar baseline health indicators to those with TMA before onset. This population-based matched cohort study was conducted in the province of Ontario, Canada, at ICES (ices.on.ca), an independent, nonprofit research institute. Data-sharing agreements were established between ICES and 14 plasma exchange networks (Table S1). A prespecified protocol was approved by the Research Ethics Boards at each network for medical chart reviews. Data on the TMA event, diagnosis, and whether remission was achieved after plasma exchange were obtained from a manual review of hospital charts of adults experiencing their first TMA episode. Datasets were linked using unique encoded identifiers and analyzed at ICES. Details on the study databases and codes are provided in Tables S2–S4. The cohort included all adults hospitalized with TMA who received plasma exchange and achieved remission in Ontario, Canada, between 1996 and 2013. Remission was defined as survival without plasma exchange for at least 30 days. We excluded those with a history of TMA or coronary artery disease before TMA onset, those who received more than 180 days of plasma exchange to achieve remission, and those with no matched adult without TMA (details below). The TMA event was characterized using records from 30 days before to 30 days after the first plasma exchange treatment (median plasma exchange duration was 23 days). The remission date (30 days after the last plasma exchange treatment) marked the start of follow-up for long-term cardiovascular outcomes (hereafter referred to as the cohort entry date). A group of adults from the general population was selected to have baseline health indicators similar to those of the TMA patient sample (prior to the TMA event). Based on the distribution of remission dates in TMA survivors, a cohort entry date was randomly assigned to all adults in the general population, excluding those with a history of coronary artery disease, TMA, or plasma exchange treatment. The sample selection is shown in Figure S1. We matched 272 adults with TMA in a ratio of up to 1:4 to 1075 adults from the general population on age, sex, hypertension, diabetes, and a propensity score derived from 24 additional baseline characteristics (Table S5); the matching process resulted in the two groups having similar baseline characteristics (Table 1). The median age at cohort entry was 42 years (IQR 31–52), and 70% were female. Adults with and without TMA were followed from cohort entry until death, emigration from the province (the only reason for loss to follow-up from the provincial database), or the end of observation (August 31, 2023). Relapses in patients with TMA were defined as receiving plasma exchange during follow-up. The primary outcome was a major coronary artery disease event defined as hospital admission with myocardial infarction or record of coronary revascularization (angioplasty or bypass surgery). The statistical analysis is described in the Supporting Information. The characteristics of 272 patients with TMA are shown in Tables S6 and S7. Most (89.0%) had undifferentiated TMAs. During the sample accrual period (1996–2013), plasma ADAMTS13 testing was uncommon (only 16 patients were tested 5.9%, all with deficient ADAMTS13 activity, indicating TTP). In most patients (70.2%), TMA occurred in the setting of a potential secondary cause, including autoimmune disease, malignancy, pregnancy, infection, or medication use. TTP was considered idiopathic in the remaining patients (29.8%). The most common symptoms during the TMA episode were neurological (68.8%), hemorrhagic (57.7%), and gastrointestinal (54.4%). Cardiac symptoms were present in 56 (20.6%). Serum troponin was measured in 125 patients (46.0%); 57 were positive. Patients received a median of 14 plasma exchange treatments over 23 days. Most (81%) also received steroid treatment, and a few received adjunctive therapies such as cyclophosphamide or rituximab. Eculizumab was not available during the exposure time period. Over a median follow-up of 15.8 years (IQR 10.8–21.3; maximum 27.6 Table S8), the rate of major coronary artery disease events was twofold higher among adults with TMA versus without TMA (4.2 vs. 2.2 events/1000 person-years; subdistribution hazard ratio 1.8, 95% CI 1.0–3.3, p = 0.05) (Table 2). The cumulative incidence over 5-year intervals is shown in Figure 1 and Table S9. TMA was also associated with a significantly higher risk for all-cause mortality and hospitalization with myocardial infarction, heart failure, and ischemic stroke (Table 2). Cumulative incidence curves are shown in Figure S2. Relapses with additional plasma exchange occurred in 64 (23.5%) TMA patients during follow-up. The results of prespecified subgroup analyses and an examination of potential baseline risk factors are shown in Tables S10 and S11; no baseline characteristics were associated with a higher risk of major coronary disease events in patients with TMA. It is now well established that TMAs, especially TTP, are associated with an acute increase in the risk of cardiovascular disease and mortality 9-11. In our study, with a median follow-up of 16 years, adults with TMA had a significantly higher long-term risk of major coronary artery disease events and mortality than adults without TMA. This heightened risk may arise from acute injuries to the heart, brain, kidneys, and other organs at the onset of TMA or during TMA relapses. Underlying conditions, such as autoimmune diseases that may coexist with TMA, the treatments used for the condition, or ongoing subtle blood disorders and endothelial injury, may also cause cardiovascular disease. A combination of factors is likely involved, including a patient's genotype. Autopsy reports of TMA nonsurvivors almost universally report microthrombi in the coronary circulation 12, 13. TTP survivors demonstrate asymptomatic structural changes in the heart and decreased quantitative perfusion 14. TMA patients may continue to have an ADAMTS13 deficiency even after clinical remission, predisposing them to thrombus formation. Despite conflicting evidence, most reports associate ADAMTS13 deficiency in TTP remission with worse outcomes 3, 4, 15. In the general population, lower ADAMTS13 levels are associated with a higher risk of coronary heart disease and mortality 16, 17. Our population-based study, conducted in Canada's largest province, has several strengths. We followed patients for a median of 16 years (maximum 28 years), and less than 7% were lost to follow-up. A comparison group of adults without TMA was carefully selected and matched to ensure they had similar baseline characteristics to those who developed TMA. A manual chart review was coordinated across 14 plasma exchange networks to document TMA characteristics. All individuals in the study had access to a universal healthcare system that accurately recorded cardiovascular events in large healthcare databases when they occurred, allowing for unbiased outcome ascertainment. Our study has limitations. First, TMA encompasses a diverse group of conditions with unique pathophysiological processes and treatment approaches, and its classification and diagnosis have evolved substantially since this cohort of patients presented with TMA. Although all patients received plasma exchange, suggesting a clinical diagnosis of TTP, ADAMTS13 deficiency could not be confirmed because testing was not widely available at major Canadian centers until 2015. Second, we could not distinguish the pathways contributing to cardiovascular risk, including acute injury, residual injury, treatment effects, or concurrent conditions. Finally, some relevant data were missing, such as outpatient medication use, which is only universally covered and recorded in Ontario healthcare databases for patients 65 years and older. In conclusion, our study suggests that adults with TMA have a significantly higher long-term risk of major coronary artery disease events and mortality. Our results highlight the need for close follow-up of TMA survivors and careful management of cardiovascular risk factors. Further research is needed to clarify the pathophysiology and determine the most effective strategies to mitigate cardiovascular risk in these patients. H.K.J., S.E.B., A.X.G., W.F.C., and A.M.E. conceived and designed the study. Y.K. and E.M. did the statistical analysis, and all authors contributed to the analysis and/or interpretation of the data. H.K.J., A.M.E., and J.M.S. drafted the manuscript. All authors critically reviewed the manuscript for important intellectual content. A.X.G., W.F.C., and A.M.E. obtained funding. A.M.E. and A.X.G. supervised the study. A.M.E. and Y.K. are guarantors. E.M., S.S.H., and J.M.S. (in addition to all other authors) contributed to the analysis and/or interpretation of the data and critically reviewed the manuscript for important intellectual content. We thank Kerri Gallo, Megan Buchholz, Susan Sinclair, Martha Mitchell, and Janet Mader, who abstracted data from medical charts at participating plasma exchange centers, and Drs. Joseph Kim (University Health Network), Nadian Shehata (Mount Sinai Hospital), Katerina Pavenski (St. Michael's Hospital), Ronan Foley (Hamilton Health Sciences), Manish Sood (The Ottawa Hospital), and Michelle Hladunewich (Sunnybrook Health Sciences Center), who supported local ethics applications at participating centers. We also thank Bashiar Thejeel (University of Calgary), Azim Gangji (McMaster University), Ronan Foley (Hamilton Health Sciences), Katerina Pavenski (St. Michael's Hospital), and James George (University of Oklahoma) for their contributions to the grant applications. This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from Canada Post Corporation and Statistics Canada. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information and Ontario Ministry of Health and Long-Term Care. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. We thank IQVIA Solutions Canada Inc. for use of their Drug Information File. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). The research was conducted by members of the provincial ICES Kidney, Dialysis, and Transplantation Program at the ICES Western facility. ICES Western receives support from the Schulich School of Medicine and Dentistry and its member Departments, Research Western, the London Health Sciences Research Inc., the Lawson Research Institute, and the Academic Medical Organization of Southwestern Ontario. This study received grant funding from the Kidney Foundation of Canada and the Answering T.T.P. Foundation. H.K.J. was supported by the Alberta Innovates Summer Research Studentship Program. A.X.G. was supported by the Kay Family Chair in Transformational Kidney Care. The authors declare no conflicts of interest. The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at https://www.ices.on.ca/DAS/ (email: email protected). The full dataset creation plan and underlying analytic code are available from the authors upon request by December 31, 2026, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification. Data S1: ajh70278-sup-0001-Supinfo.docx. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Jamison et al. (Mon,) studied this question.