Changes in enzyme shape may help predict iTTP relapse risk
Open ADAMTS13 in remission may indicate likelihood of symptom return
Written by |
The shape of the ADAMTS13 enzyme during remission (a period when symptoms ease or disappear) may help predict which people with immune-mediated thrombotic thrombocytopenic purpura (iTTP) are more likely to experience a relapse (when symptoms return), a study suggested.
Researchers found that patients whose ADAMTS13 remained in a more open shape within six months before relapse were more likely to see their symptoms return and tended to relapse sooner than those whose enzyme stayed mostly in a closed form. The open shape may make the enzyme easier for anti-ADAMTS13 antibodies to attack, the researchers said.
“These preliminary findings suggest that ADAMTS-13 conformation may guide follow-up strategies and optimal timing of interventions,” the researchers wrote, while cautioning that additional studies are needed.
The study, “Monitoring ADAMTS13 conformation in immune-mediated thrombotic thrombocytopenic purpura: Towards personalized management,” was published in Research and Practice in Thrombosis and Haemostasis.
iTTP, also known as acquired TTP, occurs when antibodies mistakenly attack ADAMTS13, an enzyme that regulates blood clotting. Reduced ADAMTS13 activity leads to the formation of abnormal blood clots in small blood vessels, causing organ damage and TTP symptoms.
Shape shifting
Standard TTP treatment, which aims to restore ADAMTS13 activity and calm the overactive immune response, can bring patients into remission, but relapses remain common. Doctors usually monitor ADAMTS13 activity in the blood to estimate risk or relapse, although this approach doesn’t always reliably predict who will relapse or when.
ADAMTS13 can shift shapes, sometimes taking a more open form that may make the protein easier for the immune system to attack. Recent studies have suggested that this open shape can appear by the time patients experience a relapse, when ADAMTS13 activity levels drop sharply.
“An open ADAMTS-13 conformation could represent an earlier predictive marker than ADAMTS13 activity, for the risk of both ADAMTS13 relapse and iTTP clinical relapse,” wrote the researchers, who set out to examine whether changes in the protein’s shape over time are linked to risk of relapse in people with iTTP.
The team conducted a retrospective study (NCT00426686) involving 15 adults with iTTP who were followed at Saint-Antoine Hospital in Paris from January 2008 to December 2020. All underwent monitoring of ADAMTS13 activity. Eight participants were women, and seven were men.
Over a median follow-up of seven years, the researchers recorded 15 clinical relapses and 39 ADAMTS13 relapses, resulting in a median annual relapse rate of 0.5.
Based on this rate, eight participants were classified into a low-relapse group, defined by an annual relapse rate lower than 0.5, while seven participants were classified into a high-relapse group, with a rate of 0.5 or higher. Median annual relapse rates were 0.23 and 0.64, respectively.
All achieved clinical remission at least once during follow-up. Recovery of ADAMTS13 activity — referred to as ADAMTS13 remission — between relapses occurred more consistently in the low-relapse group, seen after 94.1% of relapses, compared with 70.3% in the high-relapse group. This indicated that patients with fewer relapses tended to have a more durable ADAMTS13 remission.
Analysis of 471 blood samples showed that an open ADAMTS13 form was present in nearly all samples (98.1%) with low ADAMTS13 activity and in nearly all samples (97.8%) collected at the time of clinical or ADAMTS13 relapse.
Among 39 samples collected within six months prior to relapse, during the absence of iTTP symptoms and partial or complete ADAMTS13 remission, the ADAMTS13 form was open in 30 samples (77%): eight samples (66.6%) from the low-relapse group and 22 (81.5%) from the high-relapse group.
Although not statistically significant, the higher proportion of open ADAMTS13 in the high-relapse group — where recovery of ADAMTS13 activity between episodes was less consistent — may point to a trend linking a persistent open form with higher relapse risk, the researchers said.
This association became clearer when the analysis focused on patients with complete ADAMTS13 remission. In samples collected within six months before relapse, a closed ADAMTS13 form was more common in the low-relapse group (56.3%) than in the high-relapse group (34.6%), suggesting that even with normal ADAMTS13 activity, a persistently open form may signal a higher likelihood of relapse.
Patients with complete ADAMTS13 remission in the high-relapse group relapsed much sooner after an open ADAMTS13 form was detected — a median of five months versus 21 months in the low-relapse group.
This suggests that “relapse might occur more quickly after detection of an open conformation despite normalized activity, possibly reflecting a less stable remission,” the researchers wrote.
One patient in the low-relapse group maintained a consistently closed ADAMTS13 form during remission and remained relapse-free throughout follow-up, supporting the idea that a stable closed form may be linked to more durable disease control.
“Our study suggests that ADAMTS13 conformation monitoring may provide complementary information to ADAMTS13 activity measurements in predicting relapse risk in iTTP,” the researchers concluded. “A persistent or recurrent open conformation, even when ADAMTS13 activity is normal, could potentially identify patients at higher risk of relapse.”
