Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by severe congenital or immune‐mediated deficiency in ADAMTS13, the enzyme that cleaves von Willebrand factor multimers. This rare condition leads invariably and rapidly to a fatal outcome in the absence of treatment, and therefore raises multiple diagnostic and therapeutic challenges. The novel concepts and mechanisms identified in the laboratory for this disease have been rapidly and successfully translated into the clinic for the benefit of patients, making TTP an archetypal disease that has benefited from targeted therapies. After decades of empirical treatment with plasma exchange, identification of ADAMTS13 as the key enzyme involved in TTP pathophysiology provided an explanation for the remarkable efficacy of plasma administration, in which the missing enzyme is replenished, and paved the way for development of a recombinant form of the enzyme. Similarly, the demonstration of a major role of anti‐ADAMTS13 antibodies through models of passive transfer of autoimmunity spurred development of immunomodulatory strategies based on B‐cell depletion. More recently, an inhibitor of the platelet‐von Willebrand factor interaction demonstrated efficacy in large clinical trials through prevention of formation of further microthrombi and protection of organs from ischemia. These translational breakthroughs in TTP are described in our review.

Deaths and complications associated with the management of acute immune thrombotic thrombocytopenic purpura

“…The vast majority of patients were treated during the index event (defined as the event that led to their enrollment in our study) with TPE (120/124; 97%) and daily oral steroids (113/124; 91%). The median (IQR) number of TPE procedures provided was 15 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Forty-eight percent of patients also received rituximab during their treatment course, while a small number were treated with second-line immunosuppressive drugs.…”

“…Understanding the complications associated with TPE in iTTP patients is important, as the treatment paradigms for iTTP continue to shift. Newly available approaches as well as those currently in clinical development include up‐front rituximab in addition to glucocorticoids and therapies such as recombinant ADAMTS13 and caplacizumab …”

“…Newly available approaches as well as those currently in clinical development include up-front rituximab in addition to glucocorticoids [10][11][12] and therapies such as recombinant ADAMTS13 and caplacizumab. 13,14 Efforts to effectively implement these new treatments have highlighted our limited understanding of residual mortality in iTTP. There are few published data analyzing causes of mortality and the extent of treatment-related morbidity that occur with our current standard of care.…”

Emerging roles of adjunct therapies in acquired thrombotic thrombocytopenia purpura

“…This results in end organ ischemic damage, typically to the kidneys, brain, heart, and GI tract. The assays for measuring ADAMTS13 activity are not always readily available, and therefore therapy is urgently initiated with high clinical suspicion such as a PLASMIC score of 6‐7 …”

“…Rituximab was initially administered as adjunct therapy in refractory aTTP patients who had failed TPE and steroids. These refractory patients had shorter time to remission and reduction in relapse rates when compared to historical cohorts receiving TPE with adjunct steroids or other drugs . Its use as an upfront therapy has also been investigated.…”