The Quest for Effective and Well-Tolerated Treatment for Congenital TTP: Half a Century of Experience in the United Kingdom
Authors: Gounder Praveen , Keogh Louisa , Lester William , Clark Amanda , Vanveen Joost , Dutt Tina , Desborough Michael , Hermans Joannes , Taylor Alice , Scully Marie 
Published: December 2024

Introduction
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare autosomal recessive genetic disorder resulting from inherited severe deficiency of the plasma metalloprotease ADAMTS13. Affected individuals are at risk of life threatening micro- and macrovascular thrombosis. The UK TTP registry, comprising a large, ethnically diverse national cohort, captures information on treatment pathways over the last 50 years. With increasing recognition of subacute symptoms (lethargy, chronic headaches, fatigue) and of the enhanced risk of stroke in patients not receiving ADAMTS13 replacement, treatment programs have evolved from episodic, on-demand regimens to regular, high-potency prophylaxis.
Methods
All registry participants or their legal guardian provided written informed consent before enrolment. Enrolment data from patients with confirmed cTTP were included. Congenital TTP was defined as those cases with a severe reduction in ADAMTS13, pathogenic variant in the ADAMTS13 gene, and either a clinical syndrome compatible with acute TTP or biallelic pathogenic variants in the ADAMTS13 gene (for patients identified via family screening). Patients were followed from their study index date until loss to follow up, death or end of the study period. Acute relapses were recorded prospectively.
Results
A total of 104 patients with cTTP were identified. 69 (66%) were female. Median (IQR) age at diagnosis was 23 (5.0-31). 41 (39%) children (aged below 18) were diagnosed with a median age of 3.0 years (0.83 - 8.0). 64 (61%) adults were diagnosed with a median age of 30 years (24 - 36). 9 patients had died, primarily due to TTP (8), and especially TTP-related stroke (4).
Excluding patients who are non-UK residents (5) or not enrolled (8), there were 91 patients with 1132 collective patient-years of treatment included in treatment analysis. Ethnicity was recorded as White (63), South Asian (21), Black (6), Mixed White/Black (1). Initial treatment varied according to year of diagnosis. Among patients not found via family screening, 44% of children and 10% of adults diagnosed pre 2010 commenced regular prophylaxis within 6 months of diagnosis. This compares with 79% and 59%, respectively, diagnosed after 2010.
By end of study period, 10/91 were lost to follow up or died. Among remaining patients, the number in each current treatment group was: 14 (15%) Prophylactic Fresh Frozen Plasma (FFP), 3 (3.7%) On-Demand FFP or BPL 8Y (a FVIII product containing ADAMTS13), 17 (21%) Prophylactic BPL 8Y, 40 (44%) Prophylactic recombinant ADAMTS13 (rADAMTS13) and 7 (8%) not on treatment.
Prophylactic FFP use was characterised by frequent alterations. Among 42 patients, a change in dose or frequency was required in 24 (57%) of patients, with 4 (10%) patients requiring 7 or more changes. Barriers to FFP use in 39 patients who ceased include transfusion reactions (18%), poor symptom control or end-organ complications (59%), difficulty with hospital visits (21%) and anxiety about plasma (5.2%). Qualitative review found recurring mention of headaches, fatigue and affective symptoms. BPL 8Y prophylaxis was home delivered, with few transfusion reactions (4.5%). Inadequate symptom control or end-organ complications were reported in 64% of patients. For On Demand patients, inadequate symptom control (61%) and transfusion reactions (11%) were substantial. Of concern, acute TTP was described in 29% of these patients.
In total, 47 acute relapses were recorded. 13 occurred in patients not receiving prophylaxis. 33 occurred in patients on prophylaxis, of which 91% were on FFP or BPL 8Y prophylaxis.
Conclusion
Data from this large, ethnically diverse cohort of cTTP patients shows that, although only a minority of patients historically began prophylaxis within 6 months of diagnosis, 88% of patients now in follow up are receiving regular prophylaxis. Despite the clear need for prophylaxis, the conventional therapies of FFP and BPL 8Y in this cohort were frequently associated with transfusion reactions and poor disease control. Patients were exposed to multiple lines of therapy, often with repeated dose and frequency changes. These data highlight the need for a therapy with good tolerability and high efficacy, and which does not require hospital administration. We must review real-world data on rADAMTS13 and assess its ability to address this need.