Preventable deaths during initial episodes of acquired Thrombotic Thrombocytopenic Purpura: Past and future
Authors: Cynthia K. Saliba, James N. George
Journal: American Journal of Hematology (2019)

Eleven (12%) of the 90 consecutive, unselected patients enrolled in the Oklahoma Thrombotic Thrombocytopenic Purpura (TTP) Registry,1 1995 to 2018, died during their initial episode. The median time from presentation, defined by the intention to begin plasma exchange (PEX), to death, was 12 days (range, 1-64). This is consistent with the experience of the United Kingdom TTP Registry that reported 30 (10%) deaths in 292 patients during their initial episode, from 2009 to 2016; the median time from presentation to death was 4 days (range, 1-39).2 We believe that some deaths among our patients could have been prevented with earlier recognition of TTP and/or more effective treatment. Treatment for all registry patients began with PEX; most patients were also treated with corticosteroids.1 Rituximab was first used for refractory or relapse episodes in 2003; rituximab was not used as initial treatment for initial episodes until 2017. Patients who received rituximab required significantly fewer PEX treatments to achieve remission, but the frequency of deaths with the initial episode was not different.1 Future addition of caplacizumab to initial treatment has the potential to prevent deaths that occur within the first few days of treatment, because it promptly blocks platelet binding to the ultra-large multimers of von Willebrand factor (VWF) that characterize TTP.3 In our experience with caplacizumab treatment without PEX in a Jehovah's Witness patient, the platelet count increased by 60 000/μL on the day following the initial dose, and continued to increase by an average of 58 000/μL/day for the next 4 days. She had frequent neurologic symptoms before caplacizumab but none after caplacizumab treatment was begun.4 The resolution of her neurologic symptoms suggests that platelet adhesion to the ultra-large VWF multimers is important for microvascular thrombosis. To determine if any of the 11 deaths could have been prevented with current or future management, we reviewed each patient's clinical course. The clinical diagnosis of TTP was supported by ADAMTS13 activity <10% in 10 patients. The ADAMTS13 activity was not measured in patient 2; the diagnosis of TTP was supported by documentation of systemic microvascular thrombosis at autopsy. To model anticipated future clinical practice, we assumed that caplacizumab would be initiated shortly before the first PEX.3 One of the authors (JNG) was familiar with the clinical courses and maintained complete data for each of these patients; the other author (CKS) independently reviewed all data. Only patient 3 required extensive discussions to reach agreement. Our rationale for judging that death could have been prevented is in the Table 1; greater details for each patient's course, and a detailed rationale for our judgment regarding preventable death, are in Table S1. We believe that even with the addition of caplacizumab to optimal current treatment with PEX, corticosteroids, and rituximab, the deaths of six patients were not preventable. Patients 2 and 7 died before a central venous catheter (CVC) could be inserted and PEX begun. For both patients the diagnosis of TTP was prompt, and hospital care was consistent with current practice. These two deaths illustrate that patients with suspected TTP require urgent care, similar to patients with myocardial infarction and stroke. Emergency department protocols for patients with suspected TTP may be feasible, but we judged that these two deaths would not be preventable in the foreseeable future. Among the other four patients (numbers 3, 4, 5, and 11), TTP responded to treatment in three patients (numbers 3, 5, 11) but death in all four patients was related to their multiple additional major morbidities. We believe that deaths were preventable in five patients. For patient 1, the time required for diagnosis of TTP and initiation of treatment was appropriate. His mental status improved on days two and three, until he suddenly deteriorated and died later on day three. The interval of 34.5 h between beginning PEX and his sudden deterioration, could have been sufficient for platelet count recovery in response to caplacizumab. Patient 6 had a delayed diagnosis of TTP and then a prompt response to PEX, but TTP exacerbated when PEX was stopped. We believe that caplacizumab could have maintained her platelet count response when PEX was stopped and allowed the CVC to be removed. This decreased her risk for sepsis and the need for inserting a new CVC, which caused her death. Additionally, we assumed that immunosuppression with corticosteroids and rituximab could have established remission. Patient 8 could have survived if TTP had been recognized sooner. We assume that if PEX had begun on day two, or even on days three or four, a response could have occurred. This would certainly have occurred with addition of caplacizumab, preventing her sudden death at the beginning of PEX on day five. Patients 9 and 10 had very complex previous histories and clinical courses. Patient 9 could have benefited from caplacizumab for sustaining her initial platelet count response and allowing the CVC to be removed, possibly preventing her sepsis. However, the critical and avoidable issue that contributed to her death was failure to recognize that her persistent thrombocytopenia was caused by sepsis, not refractory TTP. In Patient 10, TTP was unresponsive to multiple treatments, in addition to PEX, corticosteroids, and rituximab. Plus, ADAMTS13 activity was not measured during her course, but we assume that her inhibitory anti-ADAMTS13 antibody titer remained high, and her ADAMTS13 activity remained undetectable. We believe that caplacizumab could have maintained a normal platelet count until prolonged immunosuppression, such as with maintenance rituximab,5 could establish a remission. The frequency of unpreventable deaths among the 90 patients enrolled in the Oklahoma Registry, from 1995 to 2018, was 7%. During the past 10 years, from 2009 to 2018, there has been only one death (3%) among 31 patients (Figure S1), which we believe was not preventable (patient 11). This suggests that current management and more prompt recognition of TTP have prevented deaths. Even with current management, caplacizumab may prevent additional deaths by providing prompt, durable platelet count responses. Beyond these advances, urgent care protocols for patients with suspected TTP will be required to achieve the maximum possible survival. The authors have no conflict with this topic or these data. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.