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.
iTTP survivors experience high rates of adverse health sequelae and increased mortality over long-term follow up. We conducted this multi-center cohort study to evaluate long-term mortality and causes of death in iTTP survivors. Between 2003 and 2020, 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries and followed for a median of 4.5 (interquartile range [IQR],75 0.4-11.5) years. Nine patients died during their first iTTP episode and 29 patients died during follow-up. Mortality rate was 1.8 times higher than expected from an age, sex and race adjusted reference population. Cardiovascular disease was a leading primary cause of death (27.6%) tied with relapsed iTTP (27.6%), followed by malignancy (20.7%), infection (13.8%), and other causes (10.3%). Male sex [HR 3.74 (95% CI 1.65-8.48, P=0.002), increasing age [HR 1.04 (95% CI 1.01-1.07), P=0.011] and number of iTTP episodes [HR 1.10 (95% CI 1.01-1.20), P=0.022] were associated with mortality in a model adjusted for African American race [HR 0.70 (95% CI 0.30-1.65), P=0.702], hypertension [HR 0.47 (95% CI 0.20-1.08), P=0.076], CKD [HR 1.46 (95% CI 0.65-3.30, P=0.358] and site [HR 1.46 (95% CI 0.64-3.30), P=0.358]. There was a trend towards shorter survival in patients with lower ADAMTS13 activity during remission (P=0.078). In conclusion, iTTP survivors are at higher risk of death compared with a reference population and cardiovascular disease is a leading cause of death. Our study highlights the need for survivorship care, and investigation focused on cardiovascular disease and early mortality in TTP survivors.
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