Thrombotic Thrombocytopenic Purpura

Overview

Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal disorder in which unusually large forms of von Willebrand factor—a blood-clotting protein—cause platelets to form tiny clots in small blood vessels. This both lowers the platelet count and can damage the brain, heart, kidneys, and other organs. In immune-mediated TTP (iTTP), the more common form, the immune system makes antibodies that disable the ADAMTS13 enzyme. In congenital TTP (cTTP), also called Upshaw–Schulman syndrome, inherited mutations leave the body unable to make enough functional ADAMTS13. FDA overview of cTTP Gene-therapy review

Without prompt treatment, an acute TTP episode can be fatal; outcomes have improved substantially with urgent treatment. For iTTP, current standard care is therapeutic plasma exchange (removing antibody-containing plasma and replacing it with donor plasma), corticosteroids, usually rituximab to suppress antibody-producing B cells, and caplacizumab to prevent platelet binding to von Willebrand factor. For cTTP, the standard is lifelong ADAMTS13 replacement using plasma or, where available, recombinant ADAMTS13. 2025 ISTH management update

Scope of Recent Research (2020–present)

Research has been active but is divided between two different therapeutic goals: achieving durable immune remission in iTTP and correcting the inherited enzyme deficiency in cTTP. The field has made a major advance in replacing ADAMTS13 safely and effectively in cTTP, but this is not a permanent genetic cure. True cure-oriented work—long-lasting gene transfer or immune-system resetting—remains preclinical or very early clinical research. Targeted ADAMTS13 replacement review Gene-therapy review

Major Breakthroughs and Emerging Therapies

Recombinant enzyme replacement for congenital TTP. The largest recent advance is recombinant ADAMTS13, marketed in the United States as Adzynma. It replaces the missing enzyme without exposing patients to donor plasma. In November 2023, the FDA approved it for preventive and on-demand treatment in adults and children with cTTP. In the pivotal randomized crossover study, prophylactic recombinant ADAMTS13 produced no acute TTP events during the controlled comparison periods and reduced several measures of subclinical disease activity relative to plasma-based therapy. This is highly effective disease control, but patients still require repeated intravenous dosing, so it should not be described as a cure. FDA approval announcement Phase 3 trial

ADAMTS13 replacement for immune TTP. In iTTP, replacing ADAMTS13 is more difficult because circulating autoantibodies can inhibit or clear the infused enzyme. Nevertheless, recombinant ADAMTS13 is being tested alongside plasma exchange, caplacizumab, and immunosuppression as a way to restore enzyme activity more directly during acute illness. A Phase 2 randomized, placebo-controlled trial of Takeda’s recombinant ADAMTS13, TAK-755, has evaluated this strategy in acute iTTP. SOAR-HI Phase 2 study abstract Recombinant ADAMTS13 in iTTP

Better immune control rather than simple clot prevention. Caplacizumab rapidly blocks the interaction between von Willebrand factor and platelets, limiting ongoing microclot formation, but it does not eliminate the anti-ADAMTS13 autoimmune response. Recent real-world evidence from more than 1,000 caplacizumab-treated patients found a 98.5% three-month survival rate versus 94% in historical controls treated without caplacizumab, reinforcing the benefit of early clot-directed treatment while immune therapies take effect. Rituximab remains the principal antibody-directed treatment, and investigators are exploring deeper B-cell and plasma-cell targeting for patients whose disease remains refractory or repeatedly relapses. Capla 1000+ cohort study 2025 ISTH management update

Gene and cell-based approaches for cTTP. A genetic cure for cTTP would require sustained production of functional ADAMTS13 after one treatment. Preclinical work has tested liver-directed adeno-associated virus (AAV) vectors, nonviral Sleeping Beauty transposons, and gene-modified blood-cell approaches. In ADAMTS13-deficient mice, AAV-mediated expression of an ADAMTS13 variant prevented toxin-triggered TTP-like disease, while Sleeping Beauty-mediated liver gene transfer maintained enzyme expression and protected mice from TTP triggers for months. These are proof-of-concept studies, not human gene-therapy trials. AAV ADAMTS13 mouse study Sleeping Beauty mouse study

Targeted delivery platforms. Researchers are also developing ways to place ADAMTS13 where it is most needed. One approach packages recombinant ADAMTS13 in platelets, which naturally travel to forming clots; another proposes messenger RNA delivery so a patient’s cells temporarily produce ADAMTS13. These platforms remain experimental, with no established human efficacy for TTP. Targeted ADAMTS13 replacement review

Clinical Trials and Experimental Approaches

The completed Phase 3 TAK-755 study, sponsored by Takeda, was a randomized, open-label crossover trial of recombinant ADAMTS13 in congenital TTP. The trial enrolled children and adults and compared regular recombinant ADAMTS13 prophylaxis with plasma-based standard care; its interim peer-reviewed report supported higher ADAMTS13 activity, fewer TTP manifestations, and acceptable short-term safety. Phase 3 trial The FDA approval was based on this development program and covers both preventive and on-demand use in cTTP. FDA approval announcement

For iTTP, Takeda’s SOAR-HI study, NCT03922308, is a Phase 2 randomized, placebo-controlled trial testing recombinant ADAMTS13 in adults experiencing an acute episode. SOAR-HI Phase 2 study abstract Sanofi’s MAYARI study, NCT05468320, is testing whether caplacizumab plus immunosuppressive therapy can safely manage selected adults with iTTP without first-line plasma exchange; this is an important effort to reduce the burden and limited availability of plasma exchange, not a curative strategy. MAYARI study summary

A newly registered observational study, NCT07429942, sponsored by Takeda, plans to examine real-world outcomes among people with cTTP who received recombinant ADAMTS13 through an early-access program, including acute episodes, treatment patterns, and pregnancy outcomes. Takeda early-access study

Methodologies and Scientific Approaches

TTP research uses ADAMTS13 activity, anti-ADAMTS13 antibody levels, platelet counts, hemolysis markers such as lactate dehydrogenase, and von Willebrand factor multimer patterns to diagnose disease, track response, and identify relapse risk. In iTTP, the central scientific challenge is distinguishing rapid clinical recovery from true immunologic remission—the point at which ADAMTS13 activity has recovered and pathogenic antibodies are suppressed. ISTH diagnostic guideline Personalized ADAMTS13-guided treatment study

For cure-oriented cTTP research, investigators use ADAMTS13-knockout mice challenged with recombinant von Willebrand factor or Shiga toxin to model thrombocytopenia, red-cell fragmentation, microvascular clots, and organ injury. These systems allow testing of whether liver-targeted gene delivery, blood-cell engineering, or platelet-targeted enzyme delivery can provide sustained protection before moving toward human studies. Animal-model review AAV ADAMTS13 mouse study

Leading Institutions and Funding

Key academic contributors include KU Leuven’s Laboratory for Thrombosis Research in Belgium, which has led much of the cTTP gene-therapy and transposon work; Massachusetts General Hospital, Harvard Medical School, and collaborating U.S. centers studying immune TTP and recombinant ADAMTS13; and University College London Hospitals, a major clinical and research center for TTP. Gene-therapy review Recombinant ADAMTS13 in iTTP TTP and ADAMTS13 review

Takeda has been the principal commercial developer of recombinant ADAMTS13 and sponsored the Phase 3 cTTP program and related early-access studies. Sanofi is sponsoring the MAYARI plasma-exchange-sparing iTTP study. In the United States, the National Heart, Lung, and Blood Institute is supporting ADAMTS13-focused research through an R01 award, R01HL180838, to investigate immune TTP and other disorders associated with low ADAMTS13 activity. FDA approval announcement MAYARI study summary NIH RePORTER project R01HL180838

Strengths, Limitations, and Challenges

The strongest recent progress is mechanistically precise: recombinant ADAMTS13 directly treats the inherited deficiency in cTTP, while caplacizumab rapidly interrupts the clotting process in iTTP. Better ADAMTS13 monitoring and early combination therapy have also made iTTP increasingly manageable. However, neither plasma exchange, caplacizumab, rituximab, nor recombinant enzyme replacement has been shown to permanently cure iTTP, and recombinant ADAMTS13 does not repair the inherited gene defect in cTTP. 2025 ISTH management update Phase 3 trial

Important unresolved issues include unequal access to urgent plasma exchange, caplacizumab, ADAMTS13 testing, and costly rare-disease treatments; the limited size of TTP trials; and the challenge of safely delivering long-lasting gene therapy. Long-term safety surveillance is also essential: in February 2026, the FDA required a safety-labeling change for Adzynma after postmarketing reports of neutralizing anti-ADAMTS13 antibodies, including one reported death in cTTP patients treated with the product. That signal does not erase the treatment’s demonstrated benefits, but it makes continued pharmacovigilance especially important. FDA Adzynma safety-labeling notification

Outlook and Future Directions

As of August 8, 2026, cTTP is closest to a functional disease-control solution: recombinant ADAMTS13 can replace the missing enzyme effectively, but a one-time genetic cure remains preclinical. iTTP is further from a cure because it requires durable elimination or resetting of the autoimmune response; the milestones to watch are results from recombinant ADAMTS13 trials in iTTP, plasma-exchange-sparing studies such as MAYARI, deeper antibody-producing-cell therapies for refractory disease, and the first human trials of durable ADAMTS13 gene delivery for cTTP. Targeted ADAMTS13 replacement review Gene-therapy review

References

• FDA overview of cTTP — U.S. Food and Drug Administration, 2023.
• Gene-therapy review — Dekimpe et al., 2023.
• 2025 ISTH management update — Zheng et al., 2025.
• Targeted ADAMTS13 replacement review — Moroniti et al., 2024.
• Phase 3 trial — Scully et al., 2024.
• SOAR-HI Phase 2 study abstract — Joly et al., 2023.
• Recombinant ADAMTS13 in iTTP — Bendapudi et al., 2024.
• Capla 1000+ cohort study — Coppo et al., 2025.
• AAV ADAMTS13 mouse study — Jin et al., 2012.
• Sleeping Beauty mouse study — Verhenne et al., 2017.
• MAYARI study summary — UK Health Research Authority, 2022.
• Takeda early-access study — ClinicalTrials.gov, 2026.
• ISTH diagnostic guideline — Zheng et al., 2020.
• Personalized ADAMTS13-guided treatment study — Völker et al., 2021.
• Animal-model review — Zheng and colleagues, 2024.
• TTP and ADAMTS13 review — Scully et al., 2026.
• NIH RePORTER project R01HL180838 — National Institutes of Health, 2026.
• FDA Adzynma safety-labeling notification — U.S. Food and Drug Administration, 2026.