Immediate Therapeutic Intervention for Acute Mortality in Immune-Mediated Thrombotic Thrombocytopenic Purpura with Positive Chest Findings at Initial Presentation

Introduction

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a fatal disease characterized by severe deficiency of the von Willebrand factor-cleaving protease ADAMTS13. We reported that the cause of sudden death in patients with iTTP in the early period after starting treatment was mainly fatal arrhythmia, pathologically representing diffuse microthrombi and ischemic changes in the heart tissue. However, few reports have evaluated the details of the chest symptoms at onset in patients with iTTP. Recent reports have shown that neutrophil extracellular traps (NETs) are associated with thrombogenesis during iTTP. Currently, positive chest findings have been considered as indicators in patients with iTTP. This study aimed to describe the relationship between positive chest findings at presentation and acute TTP-related mortality rates and evaluate the correlation between TTP-related death and NET-associated markers in the Japanese iTTP registry.

Methods

Questionnaire surveys were administered in the treating physicians.

Patients diagnosed with iTTP in hospitals across Japan between 2010 and 2023 were enrolled. We collected chest symptoms and electrocardiogram (ECG) based on the Minnesota Code Classification System and transthoracic echocardiogram (TTE) findings based on Recommendations for a Standardized Report for Adult Transthoracic Echocardiography at onset using questionnaire surveys. We measured troponin I, myeloperoxidase (MPO), and histone DNA complexes by enzyme-linked immunosorbent assay using frozen plasma at onset preserved at our institution. The overall survival (OS) rate was estimated using the Kaplan–Meier method. To compare the mortality rates, continuous variables were divided into two groups based on the median or cutoff value for clinical use. We used the Log-rank and Gray’s tests to compare the mortality rates and cumulative incidence function, respectively. Statistical significance was defined as p < 0.05.

Results

This study enrolled 125 patients with iTTP. The median follow-up period was 1026 days. ECG was performed in 100 patients, of which 40 had abnormal findings. TTE was performed in 32 patients at disease onset, of which 19 had abnormal findings. Troponin T and I levels were measured in 56 patients at each institution; the positive values were 40. The 5-year OS rate was 83.6%. Eighty samples were evaluated for troponin I, MPO, and histone DNA complex levels. Median troponin I, MPO, and histone DNA complex levels were 9.342 pg/mL (IQR; <4.4–76.56), 252.5 ng/mL (IQR; 148.6–608.3), and 2.128 mU (IQR; 0.802–6.231), respectively. During the study period, 15 patients died, of which five were TTP-related deaths; sudden cardiac death (N=4) and alveolar hemorrhage (N=1). In the cases of non-TTP-related death, the main cause of death was pneumonia (N=3), followed by cancer (N=2). Three patients with TTP-related death had ECG findings; atrial fibrillation (N=1), left bundle branch block (N=1), and sinus tachycardia (N=1). However, none of these patients presented with chest symptoms. The median survival days between TTP-related and non-TTP-related deaths were significantly different (six and 65 days, respectively, p<0.005). Between cases of survivors, TTP-related deaths, and non-TTP-related deaths, there were no significant differences in troponin I (p=0.173), MPO (p=0.116), and histone DNA complex levels (p=0.06), respectively. Based on the presence or absence of physiological findings, there were no statistically significant differences in the ECG (p=0.174) or TTE (p=0.336) findings in the mortality rate of TTP-related deaths. Based on median levels, there were no statistically significant differences in troponin I (p=0.14) and MPO levels (p=0.30), but there was a statistically significant difference in histone DNA complex levels (p=0.04) in the mortality rate of TTP-related death.

Conclusions

These results suggest that chest symptoms and physiological and biochemical findings at disease onset do not contribute to acute mortality. Paradoxically, even patients with abnormal findings at initial presentation can be treated by appropriate therapeutic interventions. Higher MPO and histone DNA complex levels may contribute to TTP-related death. However, further studies are required to confirm these findings.