Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N-acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.
Highlights
Case reports detailing the successful treatment of congenital thrombocytopenic purpura (TTP) patients with infusions of plasma led to the conclusion that a deficiency of an unknown plasma factor contributed to the disease [5,6]
In 1982, Moake et al first identified “unusually large” von Willebrand factor (VWF) multimers in the plasma of four chronic relapsing TTP patients—similar to the large multimers synthesized and secreted by human endothelial cells in culture. They hypothesized that these hyperadhesive ultralarge VWF (ULVWF) multimers were due to a suspected deficiency of a VWF depolymerase present in normal plasma [7]
In an effort to explain the variance of clinical phenotype, residual ADAMTS13 activity of different genotypes was measured and the results showed that residual ADAMTS13 activity 1 [42,74]
Summary
In 1924, Dr Eli Moschcowitz described a previously healthy 16-year-old girl who became acutely ill with fever, weakness, focal neurological symptoms, and severe thrombocytopenia. Amorosi and Ultmann introduced the classic diagnostic pentad of TTP consisting of fever, thrombocytopenia, hemolytic anemia, renal injury, and neurological manifestations Their case series and review of the literature highlighted the >90% mortality rate of this devastating condition [4]. In 1982, Moake et al first identified “unusually large” von Willebrand factor (VWF) multimers in the plasma of four chronic relapsing TTP patients—similar to the large multimers synthesized and secreted by human endothelial cells in culture. They hypothesized that these hyperadhesive ultralarge VWF (ULVWF) multimers were due to a suspected deficiency of a VWF depolymerase present in normal plasma [7]. As of 2020, the improved molecular understanding of TTP along with study of survivors have allowed for marked advancements in diagnosis [18], treatment [19,20,21,22], and the long-term management [23,24,25] of these patients
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