Study links immune cell webs to acute iTTP episodes, relapses
Small study highlights role of neutrophil-driven inflammation, researchers say
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Neutrophil extracellular traps — web-like structures released by immune cells that can promote clotting — are increased during acute episodes and clinical relapses of immune-mediated thrombotic thrombocytopenic purpura (iTTP), a small study showed.
Patients treated with Cablivi (caplacizumab-yhdp) showed a more pronounced recovery in platelet counts and avoided a second rise in NET markers during treatment, the researchers found.
“These insights underscore the need to further elucidate the role of neutrophil driven inflammation in iTTP pathogenesis [disease development and progression] and recovery, and to explore adjunctive strategies targeting NETs to further optimize therapeutic outcomes,” the researchers wrote.
The study, “NETs contribute to acute episodes but not ADAMTS13 relapses in immune-mediated thrombotic thrombocytopenic purpura,” was published in Blood Vessels, Thrombosis & Hemostasis.
TTP is caused when small blood clots form due to a deficiency of the ADAMTS13 enzyme. iTTP is driven by anti-ADAMTS13 antibodies that prevent the enzyme from working properly.
Neutrophils and iTTP
Neutrophil extracellular traps (NETs) are known to contribute to acute iTTP episodes. However, “their role across different clinical stages and treatment modalities remains unclear,” the researchers wrote. These structures are released by activated neutrophils as part of the immune response. They have been implicated in various diseases, including conditions marked by the formation of clots inside small blood vessels.
To learn more about the role of NETs in iTTP and the impact of Sanofi‘s Cablivi, the researchers conducted a retrospective analysis of eight iTTP patients followed at Bern University Hospital in Switzerland for a median of 7.4 years. Participants’ ages at diagnosis ranged from 19 to 72, and six were women.
Overall, the group experienced eight first acute episodes, 14 ADAMTS13 relapses — when ADAMTS13 activity drops to 20% or lower after a remission — and six clinical relapses, when TTP symptoms (severe ADAMTS13 deficiency and low platelet counts) reappear after clinical remission.
During acute events, patients had elevated levels of circulating DNA relative to healthy controls and patients in remission, as well as other NET markers: myeloperoxidase (MPO), neutrophil elastase, and citrullinated histone H3.
Treatment for iTTP acute episodes consisted of therapeutic plasma exchange, a medical procedure that involves replacing a patient’s plasma (the liquid part of blood) with plasma from a healthy donor, immunosuppressant medications, and Cablivi when possible. There were issues with the drug’s availability in Switzerland through the end of 2024, the team noted.
Therapeutic plasma exchange reduced NET markers when circulating DNA was at its peak, but not in a statistically significant manner and not when looking at same-day samples. “These findings suggest that TPE … does not consistently remove circulating NET components nor fully suppress ongoing NET formation,” the researchers wrote.
Patients who also took Cablivi showed a trend towards more pronounced platelet count recovery from admission to three days after treatment initiation than those not on the therapy. There were no significant differences in the rate of reduction of NET markers, which was more pronounced in the first days of treatment.
However, after the first week, patients who were not treated with Cablivi experienced a secondary increase in NET markers and a decrease in platelet count below the normal range.
“Importantly, we observed neither a secondary drop in platelets nor an increase in circulating NET markers in all five acute events treated with [Cablivi],” the scientists noted.
Similar effects were seen for lactate dehydrogenase, a marker of red blood cell destruction and tissue damage, which was more consistently reduced in patients treated with Cablivi.
During ADAMTS13 relapses, NET markers remained unchanged compared with levels during disease remission.
“Our findings indicate NET involvement in acute iTTP pathophysiology [disease processes] but suggest that NET formation requires a secondary trigger beyond ADAMTS13 deficiency,” the researchers wrote.
Considering that Cablivi targets von Willebrand factor (VWF), a protein involved in blood clotting, blocking platelet aggregation, the researchers hypothesized that the second wave of NET formation and platelet decline may be driven by VWF-platelet interactions.
“Our data support the benefit of preemptive immunosuppressive treatment for ADAMTS13 relapses,” they wrote.
