Insight into the Natural History of Hereditary Thrombotic Thrombocytopenic Purpura: Short- and Long-Term Outcomes in a Longitudinally Followed Large Patient Cohort of the International Hereditary TTP Registry
Authors: Schraner Marissa , Tarasco Erika , Stalder Odile , Friedman Kenneth D. , George James N. , Hrachovinova Ingrid , Knöbl Paul N. , Matsumoto Masanori , Schneppenheim Reinhard , Von Krogh Anne-Sophie , Cermakova Zuzana , Górska-Kosicka Magdalena , Sakai Kazuya , Sinkovits György , El Chazli Yasmine , Largiadèr Carlo R. , Pikovsky Oleg , Windyga Jerzy , Lämmle Bernhard , Kremer Hovinga Johanna A. 
Published: December 2023

Background:
Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is an ultra-rare, thrombotic microangiopathy resulting from bi-allelic ADAMTS13 mutations and severe congenital ADAMTS13 deficiency. Clinical presentation includes thrombocytopenia, hemolytic anemia and symptoms of organ ischemia (primarily of brain, heart, gastrointestinal tract and kidneys) during acute episodes and pregnancy complications, but less explicit symptoms (abdominal discomfort, headaches, neurocognitive problems or fatigue) responding to plasma therapy are also common. Standard of care consists of replenishing ADAMTS13 using plasma/plasma-derived blood products to treat acute episodes as well as prophylactically to prevent morbidity and mortality. Improvement of hTTP disease management requires better understanding of the treatment burden and possible shortcomings as well as short- and long-term clinical outcomes.
Aims:
Description of the natural history of hTTP in a prospectively followed large patient cohort with a focus on demographic and clinical characteristics, as well as on the occurrence of acute TTP episodes, comorbidities and mortality.
Methods:
Eligible for the current study were patients with a confirmed hTTP diagnosis (lasting ADAMTS13 activity &lt;10%, bi-allelic ADAMTS13 mutations, and exclusion of acquired, autoimmune TTP) enrolled before December 31, 2021. In an ambidirectional approach, the registry assesses the patients' detailed medical history at enrollment (retrospective data) and then prospective clinical, molecular and observational data through questionnaires completed by treating physicians during annual visits or at occurrence of acute TTP episodes. Patients were followed by the International hTTP Registry until December 31, 2022 (end of current analysis), death, or loss to follow-up, whichever occurred first and results were reported using descriptive statistics.
Results:
At the end of December 2021, the International hTTP Registry had enrolled 182 confirmed hTTP patients from 49 sites in 20 countries, who were followed for a median of 3.6 (range, 0-18.5) years. The cohort included more female (n=98, 53.8%) than male (n= 84, 46.2%) patients, a gender disparity observed in adult patients because of increased diagnosis in women related to pregnancy complications. The patients were mostly White/Caucasian (n=111, 61.0%), followed by Asian (n=50, 27.5%), Black (n=2, 1.1%) and other ethnicities (n=19, 10.4%). Although 46.2% of the patients reported first symptoms of hTTP in the perinatal period (0-3 months), the median ages (ranges) at diagnosis and registry enrollment were 19.1 (0-69.9), and 30.4 (0.1-75) years, respectively. Prior to enrollment, 85.7% of patients had experienced at least one acute TTP episode with a mean (SD) of 4.3 (4.5) reported events per patient. The medical history was notable for transient ischemic attacks or strokes in 31% of hTTP patients, followed by arterial hypertension in 20%, chronic kidney disease in 12%, migraines/severe headaches in 8.2%, and seizures in 7.7%, respectively. During prospective follow-up 82 of 182 patients (45.1%) experienced 265 acute TTP episodes resulting in an overall event rate of 296.7 (95% confidence interval [CI]: 262.0-334.6) per 1000 person-years. Eight hTTP patients died during follow-up, five of them were on regular plasma prophylaxis. The causes of death were acute TTP episodes associated with cerebral (n=3; patient ages 33, 44 and 52 years) or cardiac (n=3; 39, 49, and 56 years) events, and unknown in two patients (75 and 79 years).
Conclusions:
The clinical burden due to recurrent acute TTP episodes and resulting neurological, cardiovascular and renal sequelae and other comorbidities is significant. Delayed diagnosis and insufficient treatment likely contributed to the observed morbidity and early mortality. Awareness, timely diagnosis and sufficient ADAMTS13 replacement therapy (for acute episodes and prophylactically) are crucial for improving short- and long-term clinical outcomes and disease burden in hTTP.