Introduction:
Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially lethal thrombotic microangiopathy; however, prompt therapy with plasma exchange and immunosuppression leads to survival in over 90% of patients. Though TTP survivors were previously thought to return to baseline levels of health, recent reports suggest that TTP survivors have high rates of adverse health sequelae including hypertension, stroke, cognitive impairment, and poor quality of life as well as higher mortality rates compared with an age, race, and sex matched controls population. We conducted this multi-center cohort study to evaluate long term mortality and causes of death in patients that survived their first TTP episode.
Methods:
All available patients in The Ohio State University and Johns Hopkins Hospital Thrombotic Microangiopathy (TMA) registries were reviewed. Patients with confirmed iTTP based on ADAMTS13 activity <10% during an acute episode were included for analysis. A total of 238 patients met inclusion criteria, with 38 experiencing death during follow up. We evaluated primary and secondary cause of death where applicable. We also collected data on patient demographics, details of TTP history, and comorbidities including hypertension, diabetes, obesity, heart failure, hyperlipidemia, autoimmune conditions, chronic kidney disease, smoking, etc. Mortality was compared with an age, sex and race standardized US population using indirect standardization methods. A multivariable cox regression analysis was used to evaluate risk factors for reduced survival.
Results:
A total of 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries between 2003 and 2020, of which 70.3% were female, and median age at enrollment was 42 (IQR [interquartile range] 29, 55) years. There were 38 deaths over a median follow up of 4 (IQR 0, 11) years (and a total of 1318 patient years of follow up). Characteristics of the study cohort are summarized in Table 1.
Of the 38 patients that died, 9 died during their first episode of TTP and 29 died after surviving the first TTP episode. Median age at death among those that survived the first TTP episode was 49 (IQR 39, 65) years. Among survivors of acute TTP, cardiovascular disease was the leading primary cause of death (27.6%) followed by relapsed TTP (27.6%), malignancy (20.7%), infection (13.8%), and other/unknown causes (10.3%) (Table 2). Cardiovascular disease was the primary or secondary cause of death in 31% (9 of 29) patients. Cardiovascular causes of death included myocardial infarction, arrhythmia, decompensated heart failure, stroke, and hypertensive emergency. The median age of death from any cardiovascular cause (primary or secondary) was 49 years. Among TTP survivors, male sex [HR 4.39 (95% CI 1.83-10.52, P=0.001), age [HR 1.03 (95% CI 1.01-1.06), P=0.039] and number of TTP episodes [HR 1.12 (96% CI 1.05-1.21), P=0.001] were risk factors for mortality in a Cox regression model also adjusted for hypertension [HR 0.60 (95% CI 0.26-1.37), P=0.228], CKD [HR 1.38 (95% CI 0.61-3.13, P=0.436] and SLE [HR 1.26 (95% CI 1.04-1.21), P=0.771].
The mortality rate in TTP survivors was significantly higher than the expected mortality rate from an age and sex standardized reference US population (2228.3 per 100,000 person years versus 1273.8 per 100,000 person years, P = 0.007) (Figure 1). The median age at death was also lower in TTP survivors compared with the general population (49 versus 78.7 years).
Conclusions: TTP survivors have two-fold higher mortality rate than expected rates from a reference US population, adjusted for age, sex and race. Cardiovascular disease is a leading cause of death in patients that survive their first episode of TTP. This may be due to higher rates of cardiovascular risk factors such as hypertension in TTP survivors. Reduced ADAMTS13 activity is a risk factor for all cause and cardiovascular death in the general population (Sonneveld et al.Arterioscler Thromb Vasc Biol. 2016) and may contribute to cardiovascular death in TTP survivors. Our results highlight the need to screen and aggressively manage cardiovascular risk factors in TTP survivors, and for prospective studies examining the vascular sequelae of TTP.
Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Chaturvedi:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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