ADAMTS-13 Clearance Major Pathogenic Mechanism in iTTP


The findings suggest recombinant ADAMTS-13 may be a useful adjunct therapy to plasma exchange among patients who have thrombotic thrombocytopenic purpura (iTTP).

Clearance of ADAMTS-13 mediated by immunoglobulin G antibodies appears to be the major pathogenic mechanism by which patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) experience ADAMTS-13 deficiency, according to a new report.

The study findings, published in Journal of Thrombosis and Haemostasis, suggests that the autoantibodies enhance ADAMTS-13 clearance 4- to 10-fold and play a role both at presentation and during plasma exchange (PEX) therapy.

The study authors explained that people with ADAMTS-13 levels below 10 IU/dL experience a lack of regulation of von Willebrand factor (VWF) multimers, which in turn can lead to the development of ultra-large VWF within the patient’s circulation. They said this can lead to microvascular occlusion and TTP, characterized by microangiopathic hemolytic anemia, schistocytes, and end organ damage. TTP comes in a congenital form or an acquired form. Most cases (around 95%) are the latter form, which is caused by anti–ADAMTS-13 autoantibodies.

Treatment for TTP typically involves PEX, along with immunosuppressive therapy. PEX helps provide ADAMTS-13, removes ultra-long VWF, and may reduce plasma levels of anti–ADAMTS-13 antibodies. Such therapies are generally effective, the study authors said; however, the significant rate of relapse means patients require long-term follow-up.

“More recently, caplacizumab, an anti-VWF A1 domain antibody that blocks VWF-platelet binding, has been demonstrated to be effective in ameliorating TTP symptoms,” the investigators wrote. “Although this alleviates the incidence of VWF-dependent microvascular thrombosis in patients with iTTP, it does not treat the cause of the disease (ie, ADAMTS-13 deficiency).”

Recombinant ADAMTS-13 has been found to effectively replace the deficient enzyme in patients with congenital TTP, but the investigators said it has not yet been studied in patients with iTTP due to concerns that it may not work in patients with anti–ADAMTS-13 autoantibodies.

They noted that patients who survive a TTP episode typically have higher ADAMTS-13 antigen levels than patients who die from such episodes.

“This suggests that the levels of anti-ADAMTS-13 antibodies that actively promote ADAMTS-13 clearance and the rate at which clearance occurs may directly influence or compromise the efficacy of the treatment,” they said.

They added that both ADAMTS-13 inhibition and clearance play important pathogenic roles, but it is not yet clear how much each mechanism contributes to the disease.

“Therefore, we analyzed both ADAMTS-13 clearance and inhibition in patients with iTTP during PEX treatment,” they said.

The investigators tracked 17 patients with iTTP during 20 acute episodes. They found that, at baseline, 14 of the 15 patients with iTTP for whom data were available had severely reduced ADAMTS-13 antigen levels and the rest had moderately reduced levels. Those data suggest ADAMTS-13 clearance played a major role in the patients’ cases.

After the first round of PEX, ADAMTS-13 antigen and activity levels increased at similar rates, the authors said, and anti–ADAMTS-13 autoantibody titer decreased in all patients, , “revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP.”

When the investigators compared ADAMTS-13 antigen levels between consecutive PEX treatments, they found that in 9 of the 14 patients, the rate of ADAMTS-13 clearance was much faster than the estimated normal rate of clearance, ranging from 4 to 10 times faster. Thus, they said, antibody-mediated clearance of ADAMTS-13 appears to be the major pathogenic mechanism leading to ADAMTS-13 deficiency in iTTP.

The authors said their findings have significant implications for treatment of people with iTTP. They said a single PEX treatment will not be enough to prevent relapse, likely because anti–ADAMTS-13 autoantibody production will continue. However, they said their data also show that it is important to start PEX therapy early.

“Not only does this provide a source of ADAMTS-13, but it also markedly reduces the anti–ADAMTS-13 titer (in combination with immunosuppression),” they wrote. “The latter feature of PEX is likely of particular importance in the response of patients with iTTP.”

They said it is probable, therefore, that recombinant ADAMTS-13 would be an effective adjunctive therapy to PEX.

“Trials to formally test the efficacy of this approach, as well as the benefit of reducing iTTP patient time on PEX, could have appreciable therapeutic advantages for both the patient and the health care system,” they said.


Underwood MI, Alwan F, Thomas MR, Scully MA, Crawley JTB. Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura. J Thromb Haemost. Published online February 20, 2023. doi:10.1016/j.jtha.2023.02.011

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