Rewriting the natural history of cTTP Free

In this issue of Blood, Stubbs et al¹ provide detailed longitudinal follow-up of nearly 100 patients with congenital thrombotic thrombocytopenic purpura (cTTP) from the inception of the UK TTP Registry in 2009. They report 16 novel, previously unreported ADAMTS13 variants and also, the responses to prophylactic therapy over time.

cTTP is the hereditary form of TTP, which comprises ∼5% to 10% of all TTP cases and is characterized by biallelic mutations in ADAMTS13 resulting in severe ADAMTS13 deficiency. Over 200 variants have been described in the literature to date, but the reports are principally from individuals of European ancestry with little information on other racial/ethnic groups. In this updated report from the UK TTP Registry, >40% of patients were of non-European or indigenous descent and 16 novel previously undescribed ADAMTS13 variants are reported.

The majority of patients (∼80%) were also receiving prophylactic therapy with regular plasma infusions or intermediate purity factor VIII concentrates on a weekly or biweekly basis. Notably, and in contrast to some prior cTTP registry reports, prophylaxis was effective with only 31.5% experiencing a subsequent acute TTP episode compared with 89.5% among those not on prophylaxis (0.06 acute episodes/patient-year vs 0.68 acute episodes/patient-year). Long-term complications were also improved as evidenced by decreasing rates of stroke, cardiovascular disease, hypertension, and degree of renal impairment. Not only were these complications reduced when compared with patients not on prophylactic therapy, but they were also largely mitigated when comparing pre- and postprophylaxis incidence within the prophylaxis cohort. Importantly, the incidence of stroke and cardiovascular disease reduced from 19.5% and 13.8% to 1.5% and 1.5%, respectively, after initiating prophylaxis. Given the younger age at which these events occur in this population and their potential for life-long morbidity, this represents a substantial improvement.

Although prophylaxis in this cohort may prevent acute episodes and improve long-term outcomes, a significant proportion of patients continue to experience nonovert symptoms associated with cTTP, including headache, mood disorder, abdominal pain, and fatigue/lethargy. Additionally, about 27% of patients receiving plasma prophylaxis had infusion reaction/allergy or evidence of subclinical disease activity. It is therefore unsurprising that with these issues, just under 60% of those receiving prophylaxis have switched their therapy to newly available recombinant ADAMTS13 (rADAMTS13). Although long-term data are yet unavailable, patients often report resolution of nonovert cTTP symptoms, and this therapy alleviates challenges associated with prior reaction to human-derived products.² Given that rADAMTS13 achieves significantly higher peak ADAMTS13 activity and sustains it for a longer duration than plasma infusions,³ it can be inferred that the long-term extrahematologic manifestations of cTTP are, at least in part, mediated by persistent ADAMTS13 deficiency. Although further data and follow-up are needed, the improvement in outcomes noted over 15 years of longitudinal follow-up in the UK TTP Registry, suggest that all patients with cTTP should be encouraged to receive some form of prophylactic therapy, if possible.

These findings in cTTP, a pure model of inherited ADAMTS13 deficiency, offer a unique lens through which to examine the pathophysiology of immune-mediated TTP (iTTP), where similar long-term complications may arise despite disease remission.⁴ Although the mechanism of deficiency in iTTP is immunologic rather than genetic, the chronic consequences of insufficient ADAMTS13 activity appear to converge. Several studies have shown that patients in clinical remission from iTTP continue to experience cardiovascular sequelae, cognitive impairment, fatigue, headache, and reduced quality of life,⁴ suggesting that persistent subclinical ADAMTS13 deficiency may contribute to ongoing end-organ dysfunction. Understanding how durable ADAMTS13 repletion with rADAMTS13 alters these pathways in cTTP may, therefore, inform not only symptom management but also long-term therapeutic goals in iTTP.

However, unlike cTTP, where the pathology is largely attributable to enzymatic deficiency alone, iTTP likely involves additional immunologic and inflammatory factors that may exacerbate vascular injury. Prior studies examining cardiovascular complications in iTTP survivors suggest the presence of a vasculopathy⁵ and accelerated vascular phenotype with events occurring more frequently and earlier than expected.⁶ Aside from one study reported by Upreti et al,⁷ where cerebrovascular accidents in iTTP survivors in remission were associated with reduced ADAMTS13 activity, there has been no clear connection made between long-term complications in patients with iTTP and reduced ADAMTS13 activity. In one prospective study of patients with iTTP in remission, there was no association between cognitive function and ADAMTS13 activity.⁸ Rather, levels of soluble thrombomodulin (CD141), an endothelial surface transmembrane glycoprotein regulator of hemostasis, coagulation, fibrinolysis, and inflammation, was associated with neurocognitive function in patients with iTTP in remission. In further contrast to the study from Stubbs et al where patients with cTTP on weekly prophylaxis (with presumably higher ADAMTS13 activity) had decreased headache symptoms (36.6% vs 51.9%), there was no association between the ADAMTS13 activity and severity of headaches in a study of patients with iTTP in remission, where over 90% of the ADAMTS13 measurements were >20% over the 2-year follow-up period.⁸ 

Because rADAMTS13 is now under investigation in iTTP, its effects on both acute clinical outcomes and underlying vascular injury may help disentangle the relative contributions of pure ADAMTS13 deficiency vs immune-mediated inflammation. Further work is needed to define the inflammatory milieu active during iTTP in remission and to determine whether targeted modulation alongside potentially improving ADAMTS13 activity in remission can mitigate long-term morbidity of iTTP as well.

Conflict-of-interest disclosure: S.S. has received honoraria from Sanofi and Alexion. S.R.C. is a consultant to Takeda and the maker of recombinant ADAMTS13 that is discussed in the manuscript.