Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics

Abstract

Summary Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. In general, severe deficiency of plasma ADAMTS13 activity (<10 IU/dL) with or without detectable inhibitory autoantibodies against ADAMTS13 supports the diagnosis of TTP if a patient presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS13 activity (>20 IU/dL) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. While plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide, and splenectomy, etc. should be considered to eliminate autoantibodies for sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis, diagnosis, and current and potential novel therapies for hereditary and acquired TTP.

A modified PLASMIC score including the lactate dehydrogenase/the upper limit of normal ratio more accurately identifies Chinese thrombotic thrombocytopenic purpura patients than the original PLASMIC score

“…Thus, it might have little role to take MCV as the element in the score model in evaluation of suspected TTP . Meanwhile, although the classic pentad includes renal dysfunction, many studies mentioned that TTP patients often have normal or mildly impaired renal function . And as most non‐TTP patients in our cohort also had normal renal function, creatinine did not show significant difference between two groups and did not add obvious value in predicting ADAMTS13 deficiency.…”

“…TTP is a severe disease with a high mortality that requires urgent diagnosis and initiation of effective treatment, especially the plasma exchange . The hall marker of TTP is a severe ADAMTS13 deficiency . However, the ADAMTS13 activity assay is unavailable in many hospitals and needs lengthy turnaround period.…”

“…The diagnosis still mainly begins with the recognition of clinical manifestations, the classic pentad: fever, thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal dysfunction, and neurological impairment, which do not facilitate efficient diagnosis, because one or more findings may be absent in TTP patients, and these clinical findings may be present in patients with other disorders . A key test to distinguish TTP from other diseases is the plasma ADAMTS13 activity . However, the prolonged turnaround times needed for ADAMTS13 activity test can render this assay less suitable to make real‐time clinical decision.…”

Predictive Value of Schistocytes in Recurrence of Acquired Thrombotic Thrombocytopenic Purpura With Severe ADAMTS13 Deficiency at Discontinuation of Daily Therapeutic Plasma Exchange

“…The lack of biomarkers to reliably predict disease recurrence is a critical deficit in the care and management of TTP patients. In the future, different strategies, such as serial assessments of ADAMTS13 activity and incorporation of anti‐von Willebrand factor therapies with immunosuppression, may provide more meaningful avenues regarding disease treatment, monitoring, and recurrence . In conclusion, after the initial diagnosis of TTP is made, there is no demonstrable advantage to continue documenting the presence or absence of schistocytes.…”

Understanding thrombotic microangiopathies in children

“…This is also an ultra-rare disease (less than 10% of all TTP cases) [11, 12]. TTP is primarily caused by a severe deficiency of plasma ADAMTS13 activity (< 10 IU/dL).…”