Anti-ADAMTS13 Inhibitor Boosting During Plasma Exchange Therapy Often Causes an Intractable Acquired Idiopathic TTP

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder, characterized by classic “pentad”. Since 1998, it has been characterized by severe deficiency of ADAMTS13 activity (ADAMTS13:AC), due to genetic abnormalities or acquired autoantibodies (ADAMTS13:INH) to this enzyme. A drug-induced form of TTP, ticlopidine-associated (tc)- TTP, is also associated with severe deficiency of ADAMTS13:AC and ADAMTS13:INH, although unlike acquired idiopathic (ai)-TTP, spontaneous relapses do not occur. A first-line treatment of ai-and tc-TTP is plasma exchange (PE) that remarkably reduced the mortality. However, a certain population of the ai-TTP patients experiences a new drop in platelet count during the treatment. In 2011, we have reported that these ai-TTP patients were frequently associated with a tremendous increase of ADAMTS13:INH titers with PE, and termed “inhibitor boosting” (Isonishi et al. ISTH 2011). However, no systematic studies on this topic have been done. In this study, we analyzed ADAMTS13:INH boosting in Japan-Nara TMA registry.

Between Jan 2004 and Dec 2011, 215 patients were diagnosed with ai-TTP (100 males/115 females) and 14 tc-TTP (7m/7f) in our registry. For analyzing of ADAMTS13:INH boosting, we evaluated patients in whom both ADAMTS13:AC and ADAMTS13:INH were analyzed more than 3 times within 14 hospital days after PE initiation (selected patients). The number of selected patients with ai-TTP was 56 (24m/32f) and tc-TTP was 5 (3m/2f). Assays for ADAMTS13:AC and ADAMTS13:INH were performed by chromogenic act-ELISA, and the ADMTS13:INH titers were expressed by the Bethesda units (BU). ADAMTS13:INH boosting was defined by fulfilling the followings: 1) patients must have ADAMTS13:INH titer of more than 1 BU/ml before PE; 2) ADAMTS13:INH levels increased more than those before PE, during PE or within 14 days after PE initiation. Autoantibody titers for anti-ADAMTS13 IgG, IgM, and IgA isotypes and IgG1-4 subclasses were determined as previously described (Ferrari et al, JTH 2009).

(1) Frequency of the boosting: In ai-TTP, 174 out of 215 (81%) patients showed severely decreased ADAMTS13:AC under 0.5% of the normal. All 56 selected ai-TTP patients had severe deficiency of ADAMTS13:AC, of which ADAMTS13:INH boosting was identified in 23 patients (23/56, 41%). The frequency of inhibitor boosting versus the inhibitor titers before PE was the followings: 4/17 (24%) with ADAMTS13:INH titers of 1-<2 BU/ml, 11/20 (55%) with ADAMTS13:INH titers of 2-<5 BU/ml, 4/10 (40%) with ADAMTS13:INH titers of 5-<10 BU/ml, and 4/7 (57%) with ADAMTS13:INH titers of · 10 BU/ml. In contrast, no patients had the boosting in the selected 5 tc-TTP patients.

We analyzed the anti-ADAMTS13 immunoglobulin isotypes and IgG subtypes in 8 selected patients with ai-TTP (6 with the boosting, and 2 without) and 2 patients with tc-TTP. All 6 ai-TTP patients with boosting exhibited IgG antibodies, and 3 had additional IgA antibodies; none had IgM antibodies. As for the IgG subclasses, the following combinations were found: G1 alone (one patient), G1+G2 (one patient), G1+G2+G4 (three patients), and G1+G4 (one patient). On the other hand, among 2 ai-TTP patients without boosting, both had IgG antibodies, one had the additional IgA antibodies, and none had IgM antibodies. As for the IgG subclasses, the following combinations were found: G1 alone (one patient), and G1+G2+G4 (one patient). Thus, we did not identify any specific difference between patients with versus without the ADAMTS13:INH boosting. Further, in 2 tc-TTP patients, both had IgG+IgA antibodies. As for the IgG subclasses, one patient had G1+G2+G4, and the other had G1+G2+G3.

Five ai-TTP patients with the boosting were treated with rituximab (375 mg/m²weekly 3–5 times), which remarkably suppressed high levels of ADAMTS13:INH and achieved clinical remission.

In this study, we identified that ai-TTP patients with severe deficiency of ADAMTS13:AC with ADAMTS13:INH titers more than 2 BU/ml before PE are prone to develop the inhibitor boosting during PE, and that rituximab therapy is potentially very useful in this setting, due to suppression of IgG autoantibodies. Interestingly, the inhibitor boosting was not seen in tc-TTP patients with severe deficiency of ADAMTS13:AC with its autoantibodies.

Matsumoto:Alexion Pharma: Membership on an entity's Board of Directors or advisory committees. Plaimauer:Baxter BioScience: Employment. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.