Ask the Hematologists: Treating Acquired TTP With Multiple Relapses

A 40-year-old woman presents for evaluation of relapsing acquired thrombotic thrombocytopenic purpura (TTP) that has been present since age 30 years. Her initial diagnosis of TTP occurred with a presentation of microangiopathic hemolytic anemia, thrombocytopenia, and neurologic symptoms. At the time of her initial episode, ADAMTS13 levels were undetectable, and an ADAMTS13 antibody was documented. She received plasma exchange and glucocorticoid therapy. This initial course was prolonged owing to relapse upon cessation of plasma exchange therapy. She was administered one dose of vincristine and achieved remission with complete recovery of platelet count and normalization of ADAMTS13 level. Steroid therapy was weaned.

Three years later, the patient experienced a relapse and rapidly responded to plasma exchange and glucocorticoid therapy. She would ultimately have a total of eight relapses. Rituximab has been variably administered in conjunction with plasma exchange for her relapses. Her most recent relapse occurred one month before this encounter; at that time, her ADAMTS13 levels were undetectable, and the ADAMTS13 antibody was present. She was treated with plasma exchange therapy plus four weekly doses of rituximab. She was not treated with glucocorticoid therapy owing to a previous diagnosis of avascular necrosis of the hip, and limited steroid exposure was preferred.

What is your approach to acquired TTP with multiple relapses?

Acquired TTP is a rare thrombotic microangiopathy that occurs primarily in adults. The condition is characterized by hemolytic anemia and thrombocytopenia resulting from the inhibition of von Willebrand factor–cleaving protease ADAMTS13 by autoantibodies.¹  ADAMTS13 cleaves the large von Willebrand factor multimers that are synthesized and secreted by endothelial cells. When ADAMTS13 is inhibited, the resulting abnormally large von Willebrand factor multimers in plasma have a greater ability to bind to platelets, leading to microvascular platelet thrombi.² 

The standard-of-care treatment of TTP is plasma exchange to replenish functional ADAMTS13 and to remove abnormal von Willebrand factor multimers and ADAMTS13 autoantibodies.³  Immunosuppressive therapy, typically glucocorticoids, are administered in association with plasma exchange to suppress ADAMTS13 autoantibodies.⁴  The addition of rituximab is typically considered for patients who do not demonstrate a rapid response to plasma exchange. Caplacizumab was recently approved for use in acute TTP management. Caplacizumab is a novel humanized, bivalent, immunoglobulin fragment that targets the A1 domain of von Willebrand factor preventing interaction with the platelet glycoprotein Ib-IX-V receptor and the ensuing microvascular thrombosis.⁵  Used in combination with plasma exchange and glucocorticoid therapy in patients with acute TTP, patients receiving caplacizumab demonstrated more rapid normalization of platelet counts, reduced TTP-related mortality, and a lower rate of relapsed TTP during the clinical trial than those on the placebo arm.⁶ 

After remission is achieved for an acute presentation of TTP, a risk of lifetime recurrences persists. Relapses most often occur within the first year of the initial diagnosis but can occur up to 20 years later.⁷  Following an initial episode of TTP, a significant percentage of patients will, over time, demonstrate a recurrence of the ADAMTS13 antibody and falling ADAMTS13 levels. For patients with ADAMTS13 levels that drop below 10 percent, the likelihood of relapse over the course of years approaches 75 percent.⁸ 

In patients who have had one or more relapses, the goal of therapy is to prevent additional relapses. Following serial ADAMTS13 and ADAMTS13 antibody titers in such a patient is helpful in assessing the risk of a clinical relapse.

A variety of immunosuppressive therapies, including rituximab, cyclophosphamide, cyclosporine, bortezomib, mycophenolate mofetil, and N-acetylcysteine, have been used to prevent recurrences. The best studied of these is rituximab; recent data from a prospective registry showed that “pre-emptive” administration of rituximab when ADAMTS13 levels dropped below 10 percent was associated with a significant decrease in the clinical relapse rate.⁸ 

Case reports and small case series also detail the utility of splenectomy in the setting of multiple relapses.⁹  Long-term remissions have been reported in patients undergoing splenectomy, though adverse events including postoperative TTP relapse have been reported, necessitating very close monitoring of patients throughout the postoperative period.

After a discussion of options, the patient will be monitored monthly with a complete blood count and ADAMTS13 level testing. If ADAMTS13 levels decline to 10 percent, rituximab will be administered to prevent a clinical relapse. Should rituximab ultimately prove ineffective or have a short-lived benefit, the strategy can be altered with consideration of other immunosuppressive agents. Additionally, elective splenectomy was discussed and will be reserved for the future should immunosuppression prove ineffective at preventing relapses.

Should a clinical relapse occur, plasma exchange will continue as the mainstay of urgent therapy, with the consideration of adding caplacizumab. Given the complication of avascular necrosis, glucocorticoid therapy will continue to be deferred.