Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening hematologic disease, with an incidence of 1 to 6 per million individuals (1, 2). Characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and multiorgan dysfunction linked to ischemia caused by disseminated microvascular platelet-rich thrombi, TTP has a mortality rate of 10-31% (2, 3). The critical nature of TTP demands early recognition and prompt initiation of appropriate treatment, especially in the emergency setting.

The significant deficiency of ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, which is involved in preventing excessive platelet aggregation and microthrombus formation, leads to TTP (3–5). Hereditary or congenital TTP is caused by ADAMTS13 gene mutations and immune TTP (iTTP) results from anti-ADAMTS13 autoantibodies. Some clinical factors including autoimmune diseases, infections, and drugs are also related to reductions in ADAMTS13 and iTTP (2, 6). ADAMTS13 activity < 10% is the most accurate diagnostic criterion for iTTP and plasma exchange (PE), corticosteroids, rituximab (RTX), and caplacizumab are the first-line treatment options recommended by current clinical guidelines (1, 2, 7). Although ADAMTS13 is crucial for establishing a diagnosis of iTTP, it is not always available at every medical center, especially in emergency laboratories. In addition, there is always a contradiction between the insufficiency of the complex tests and the demand to initiate precise treatments promptly (8). More clinical experience is imperative to promote timely and effective diagnosis and treatment in real-world emergency cases involving iTTP.

Over the past 21 years, our center has been actively involved in the emergency management of iTTP patients. This retrospective study aims to summarize our experience, analyze the clinical characteristics, treatment modalities, and prognoses of first-episode iTTP patients presenting to our emergency department, with the hope of contributing to the existing body of knowledge and guiding future emergency treatment of iTTP.

ITTP is unquestionably an infrequent yet fatal thrombotic disorder. Timely and effective diagnosis and intervention are paramount for improving patient outcomes, particularly in comprehensive emergency departments and centers. To the best of our knowledge, this study is the first to systemically summarize the emergency experience in managing first-episode iTTP. The key findings of our study are as follows: (1) This study characterized the baseline demographics and clinical features of 96 patients with first-episode iTTP who presented to a single emergency center. (2) First-line treatments demonstrated a favorable effect on the prognosis of these patients and patients who received RTX exhibited significantly superior prognostic outcomes. (3) Multivariate analysis identified several independent predictors of mortality in first-episode iTTP patients, including the presence of the classic pentad of TTP symptoms, advanced age, elevated LDH levels, and the absence of a previous rheumatologic or autoimmune disease history. (4) Corticosteroid pulse therapy may enhance treatment responsiveness in patients with first-episode iTTP.

Our findings align with those of previous studies in many respects. For instance, we observed that the levels of LDH, serum creatinine, and D-dimer in the iTTP-related mortality group were significantly greater than those in the survival group, which is consistent with previous findings (12, 13). Elevated LDH levels are indicative of exacerbated hemolysis, while increased creatinine concentrations reflect impaired renal function. Additionally, elevated D-dimer levels signify increased fibrinolytic activity and the decreased LVEF shows a lower level of cardiac function. Collectively, these biomarker alterations and indicators underscore the severity of iTTP and its impact on multiple organ systems.

Regarding treatment response, the total rate of clinical response reported in our study is 40.625%. This lower treatment response rate does not imply poor treatment efficacy, given that all patients in the survival group included in this study were discharged after receiving treatment and exhibited significantly improved clinical manifestations. The possible reason is that some enrolled patients were discharged early from our emergency center and lacked continuous laboratory follow-up results, which led to their failure to meet some of the criteria for a clinical response (sustained platelet count ≥ 150 × 10⁹/L and LDH < 1.5 times the upper limit of normal).

We found that RTX significantly improved survival outcomes in first-episode iTTP patients, providing additional evidence to support the current clinical consensus advocating for early RTX initiation in iTTP management (1, 7, 14). Notably, the survival benefit of RTX combined with corticosteroids in our cohort (HR = 0.27, 95% CI: 0.11-0.66) exceeds the effect sizes reported in a retrospective study conducted in the United States (HR = 0.37, 95% CI: 0.18-0.73) (15). This disparity may be attributable to the emergency department-initiated RTX administration protocol in our study, which contrasts with delayed outpatient treatment strategies. Although statistical significance was not achieved, patients receiving PE and corticosteroids tended to exhibit favorable prognostic outcomes, aligning with current clinical guidelines that recommend PE and corticosteroids as first-line therapies (1, 7). The absence of significant results for PE treatment might be explained by the limited plasma availability in our emergency center, which could have led to suboptimal PE volumes and consequently compromised treatment efficacy (12). Considering that most of the patients included in this study (94 patients, 97.9%) received corticosteroid treatment, the limited number of patients not receiving corticosteroids may be the reason for the negative statistical results. Additionally, our analysis identified corticosteroid pulse therapy as a potential independent predictor of clinical response. While the role of corticosteroid pulse therapy in iTTP management remains controversial (2, 16), our findings underscore the importance of early and adequate corticosteroid administration, in line with existing therapeutic recommendations (17).

In terms of predictors of mortality, advanced age and elevated LDH levels have been previously identified as significant mortality predictors in prior studies related to the iTTP (13, 18). In elderly patients, baseline organ function is generally compromised relative to that of younger individuals, with the cardiovascular system being particularly vulnerable. This age-related decline is inherently linked to physiological degenerative changes in vascular structure and function, such as endothelial dysfunction, arterial stiffening, and reduced vascular compliance, all of which exacerbate the disease burden in iTTP (19). Beyond this, elevated LDH levels serve as a dual biomarker in iTTP: they not only indicate severe microangiopathic hemolysis but also signal widespread multiorgan involvement, encompassing critical organs such as the brain, kidneys, heart, gastrointestinal tract, and liver (20, 21). These two factors collectively reflect the potential impact of poor organ function on iTTP prognosis. Additionally, we identified TTP pentad as a mortality predictor. Although current clinical consensus acknowledges that the classic TTP pentad (thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, renal dysfunction, and fever) is rarely observed in its complete form in real-world practice (2, 22), its partial or full manifestation is indicative of an aggressive iTTP phenotype characterized by diffuse microvascular thrombosis and severe multiorgan damage. This triggers rapid clinical deterioration and confers a substantially elevated risk of adverse outcomes. This finding underscores the need for intensified multiorgan monitoring, particularly of renal function, in iTTP management. However, there were no significant predictors of relapse identified in this study, which might be attributed to the relatively low relapse rate among the enrolled patients (8 cases, 13.6% in the survival group) (23, 24). This result stems from both our optimized management of first-episode iTTP and potential biases in follow-up data. Notably, 38.5% of patients died during follow-up and were excluded from relapse analysis, so assessments were restricted to the non-death group. Moreover, prompt emergency interventions at our center improved patient outcomes and lowered relapse risk. As an emergency center, we used a mixed telephone-outpatient follow-up strategy. However, some patients might transition to outside specialized care, potentially introducing bias.

The insights derived from this study offer several clinical implications. First, we provide valuable real-world evidence characterizing the baseline demographics and clinical features of first-episode iTTP patients presenting to an emergency center. Although existing mortality risk prediction models for iTTP can identify high-risk patients to a certain degree (25, 26), they still have limitations, including limited prediction accuracy and insufficient external validation of the models (26). The identified prognostic predictors of first-episode iTTP in this study (age, LDH, and pentad symptoms) provide a risk stratification framework for emergency clinicians, enabling more precise triage, guiding targeted multiorgan function monitoring and decisions regarding intensive care unit admission or therapeutic escalation.

Our findings also highlight the critical role of early RTX initiation in acute iTTP management. The trend of improved survival over time (mortality rate decreasing from 54.5% in 2004–2010 to 30.8% in 2018-2024) further validates the clinical impact of evolving management, particularly the increased adoption of RTX, which rose from 0% to 51.9% during the study period. Moreover, the association between corticosteroid pulse therapy and clinical response (OR = 2.8, P = 0.04) supports the utility of high-dose initial corticosteroids in emergency settings. This approach may expedite platelet recovery and improve organ function, serving as a critical bridge therapy in resource-constrained centers where PE or RTX initiation is delayed.

This study has several limitations that should be acknowledged. First, the single-center design, which is based on a tertiary referral emergency center, may limit generalizability due to regional variations in disease epidemiology and healthcare access. Comprehensive data on ADAMTS13 activity/antibody detection, along with data pertaining to the efficacy and safety of caplacizumab, are unavailable in our study cohort. Additionally, both the retrospective nature of the analysis and subsequent follow-up procedures may introduce bias, potentially leading to an overestimation of treatment efficacy or underestimation of mortality. Future studies should focus on externally validating our conclusions and constructing predictive models in larger, multi-center cohorts. Incorporating novel predictors or biomarkers (e.g., ADAMTS13 activity kinetics, caplacizumab administration, and autoantibody specificity) may improve the predictive performance of risk stratification tools. Finally, developing AI-driven predictive models and decision support systems that integrate real-time laboratory data and clinical features could optimize emergency treatment algorithms and reduce delays in therapy—a critical step toward improving first-episode iTTP outcomes in the emergency management.

In conclusion, this study provides valuable insights into the treatment and independent predictors of the prognostic outcome of first-episode iTTP from the perspective of an emergency center. However, further research is needed to overcome the limitations of this study and to develop more effective and personalized treatment approaches for this life-threatening thrombotic disorder.