Abstract
Background
Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy driven by severe ADAMTS13 deficiency. While survival has improved significantly due to plasma exchange, high-dose corticosteroids, rituximab, and ADAMTS13 testing, contemporary nationwide data on TTP-related mortality trends remain limited. This study characterizes temporal, demographic, and geographic patterns of TTP-related mortality across the United States over a 22-year period.
Methods
A retrospective analysis was performed using the CDC WONDER Multiple Cause of Death database from 1999 to 2020. TTP-related deaths were identified using ICD-10 code M31.1, and age-adjusted mortality rates (AAMRs) were calculated per 100,000 population. Data were stratified by year, age group, sex, race, urbanization, geographic region, and place of death. Temporal trends in AAMR were evaluated using Joinpoint Regression (version 5.4.0, National Cancer Institute), with model selection based on the Weighted Bayesian Information Criterion (WBIC). A log-linear regression model with three joinpoints at 2001, 2012, and 2015 was selected as optimal, and annual percent changes (APCs) were computed for each segment. Model fit was assessed using the coefficient of determination (R²).
Results
A total of 7,820 TTP-related deaths occurred in the United States between 1999 and 2020. The national AAMR declined from 0.20 to 0.07 per 100,000 population during this period, corresponding to an approximate 65% relative reduction. The log-transformed Joinpoint regression model demonstrated a strong fit (R² = 0.87) and identified four temporal segments. From 1999 to 2001, the AAMR declined sharply with an APC of –13.7% (95% CI: –25.3 to –0.4; p = 0.045). This was followed by a slower but statistically significant decrease from 2001 to 2012 (APC: –3.1%; 95% CI: –4.4 to –1.9; p < 0.001). Between 2012 and 2015, a more pronounced but non-significant decline was observed (APC: –11.2%; 95% CI: –26.8 to 7.0; p = 0.19). From 2015 to 2020, mortality trends plateaued with a negligible APC of –0.24% (95% CI: –4.8 to 4.5; p = 0.91). Disparities were noted by sex, age, race, and geography. Females accounted for 64% of all deaths, with a higher AAMR than males (0.117 vs. 0.077). The majority of TTP-related deaths occurred in adults aged 45 to 84 years, who collectively accounted for over 70% of all deaths. Black individuals experienced the highest AAMR (0.285), nearly triple the overall population average (0.105), with minimal narrowing of this disparity over time. White individuals had an AAMR of 0.091, followed by Hispanic individuals at 0.070. Asian or Pacific Islander and American Indian or Alaska Native populations had AAMRs of 0.048 and 0.051, respectively. Urban-rural and state-level disparities persisted. Large central metro areas had the highest AAMR (0.123), potentially reflecting increased diagnostic capture and access to referral centers. In contrast, rural non-core regions also had a high AAMR (0.118), suggesting challenges related to healthcare access and delayed diagnosis. Mississippi (0.193) and the District of Columbia (0.200) had the highest state-specific AAMRs. The majority of deaths occurred in inpatient hospital settings (84.4%).
Conclusion
TTP-related mortality in the United States has declined significantly since 1999, particularly during the early and mid-2000s, likely reflecting improvements in diagnosis and expanded access to plasma exchange and immunosuppressive therapy. However, the rate of decline slowed after 2012, despite the introduction of newer therapeutics. Persistent disparities by sex, race, age, and geography highlight the need for targeted public health interventions. Ongoing national surveillance and equity-focused efforts, including expanded access to advanced therapeutics, are critical to reduce preventable TTP-related deaths, especially as novel therapies (e.g., caplacizumab) become more widely adopted.
